Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH3:12][C:13]1[C:14](B(O)O)=[CH:15][C:16]2[C:17]([CH3:26])([CH3:25])[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[C:21]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:13]1[C:14]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])=[CH:15][C:16]2[C:17]([CH3:26])([CH3:25])[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[C:21]=2[CH:22]=1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Reactant: COc1ccc(C=O)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C=O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A mixture of 3-bromo-4-methoxybenzaldehyde (19.0 g, 88.4 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) boronic acid (23.8 g, 97.2 mmol) and potassium carbonate (48.8 g, 353.6 mmol) in 1,2-dimethoxyethane (500 mL) and water (40 mL) was degassed with argon for 60 minutes. Tetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.3 mmol) was added and the mixture heated at reflux under argon for 16 hours. The solution was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed successively with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluent: ethyl acetate/hexane, 1:9) to give 26.8 g of 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-methoxy-benzaldehyde (90%). 1H NMR (500 MHz; CDCl3): δ1.26 (s, 6 H); 1.32 (s, 6 H); 1.70 (s, 4 H); 2.08 (s, 3 H); 3.89 (s, 3 H); 7.06 (d, J=8.5 Hz, 1 H); 7.09 (s, 1 H); 7.16 (s, 1 H); 7.71 (d, J=2.0 Hz, 1 H); 7.88 (dd, J1=2.0 Hz, J2=8.5 Hz 1 H), 9.91 (s, 1 H).
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH2:18][C:19]([OH:21])=O)[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(CC(O)=O)N=1)CCCCCCCCC.[F:41][C:42]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:43]=1[NH2:44].C(C1C=CC=C(C(C)C)C=1N)(C)C>>[F:41][C:42]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:43]=1[NH:44][C:19](=[O:21])[CH2:18][N:16]1[N:15]=[N:14][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:17]1
Reactant: CCCCCCCCCCCCc1nnn(CC(=O)O)n1
Reactant: Nc1ccc(F)cc1F
Agent: CC(C)c1cccc(C(C)C)c1N
Agent: CCCCCCCCCCc1nnn(CC(=O)O)n1
Product: CCCCCCCCCCCCc1nnn(CC(=O)Nc2ccc(F)cc2F)n1

Procedure:
When in the general procedure of Example 88 an appropriate amount of 5-dodecyl-2H-tetrazole-2-acetic acid was substituted for 5-decyl-2H-tetrazole-2-acetic acid and 2,4-difluoroaniline was substituted for 2,6-diisopropylaniline, the title compound was obtained, mp 103°-106° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[H-].[Na+].[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[C:18]([O:17][C:16]([N:15]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:14])[F:13])=[CH:7][N:6]2[C:2]=1[Cl:1])[S:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:33])=[O:32])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(C(F)(F)F)cn2c1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1nc2ccc(C(F)(F)F)cn2c1Cl)S(=O)(=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of compound 9-C (0.100 g, 0.300 mmol) in DMF (5 mL) at room temperature was added 60% NaH (0.012 g, 0.300 mmol) and the reaction mixture was stirred for 10 minutes. Benzenesulfonyl chloride (0.053 g, 0.300 mmol) was added and the reaction mixture was stirred at room temperature overnight. DMF was removed in vacuo and water and methylene chloride were added. The organic layer was washed with H2O (2×), brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford the crude product. The crude material was purified by flash column chromatography (SiO2) eluting with a gradient of 0-100% ethyl acetate in hexane to afford compound 9-D (0.040 g, 28%); MS m/z (M+H+) 476.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]2[N:14]=[C:15]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=3)=[C:4]2[CH:3]=1.C(=O)(O)[O-:34].[Na+].ClC1C=C(C=CC=1)C(OO)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[N:5]2[N:14]=[C:15]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([S:23]([CH3:24])=[O:34])[N:18]=3)=[C:4]2[CH:3]=1
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(SC)n2)cc1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(S(C)=O)n2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
To a solution of N-{5-chloro-2-(4-methoxyphenyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-yl}-N-cyclopentylamine (133 mg, 0.28 mmol) in chloroform (10 mL) was added sodium bicarbonate (24 mg, 0.28 mmol). The reaction mixture was cooled to 0° C. m-Chloroperoxybenzoic acid (57˜86%, 86 mg, 0.50 mmol) was added. After stirring at 0° C. for 1.5 hours, the reaction mixture was quenched by addition of aqueous sodium bicarbonate and the resulting mixture extracted with dichloromethane. The organics were combined and washed with water, then dried over magnesium sulfate. Filtration and concentration followed by chromatography (19:1 dichloromethane/methanol) gave N-{5-chloro-2-(4-methoxyphenyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-yl}-N-cyclopentylamine (121 mg, 88%) as a yellow solid. 1H NMR (CDCl3) δ 8.43 (d, 1H), 7.93 (d, 1H), 7.51 (d, 2H), 7.00 (d, 2H), 6.98 (d, 1H), 6.11 (d, 1H), 6.08 (d, 1H), 3.96 (m, 1H), 3.88 (s, 3H), 2.99 (s, 3H), 2.13 (m, 2H), 1.82–1.66 (m, 6H). MS m/z 482 (M+1).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[OH-].[Na+].[CH2:17]([NH2:19])[CH3:18].Cl>C1COCC1.C(#N)C>[CH2:17]([NH:19][S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH3:18]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Reactant: CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCNS(=O)(=O)c1ccc(F)c(C(=O)O)c1

Procedure:
To a 5 ml Biotage microwave reaction tube was added 5-(chlorosulfonyl)-2-fluorobenzoic acid (0.4 g, 1.68 mmol) and a Teflon covered magnetic stir-bar followed by 2.5 ml of THF. To the resulting mixture was added 10N aqueous NaOH (0.369 ml, 3.38 mmol) with stirring. After formation of a cloudy suspension, ethylamine (0.838 ml, 1.68 mmol) was added as a 2M solution in THF. The reaction vessel was capped and heated to 110° C. for 1.1 min in a Biotage Initiator 8 microwave set at high absorbance. Reaction mixture was then diluted with 4 ml acetonitrile and acidified with 6M aqueous HCl (0.670 ml, 4.02 mmol). Water was removed from the mixture by adding excess anhydrous Na2SO4 and subsequent filtration. The filtered was washed with acetonitrile and DMF. The combined filtrates were concentrated with rotary evaporation, yielding the crude 5-[(ethylamino)sulfonyl]-2-fluorobenzoic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]12[CH2:24][CH:12]3[CH2:13][C:14]([O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])([CH2:16][C:10](C(OCCCC)=O)([CH2:11]3)[CH2:9]1)[CH2:15]2.[CH3:32][Mg]Br.Cl.[OH-].[Na+].[CH2:38]1[CH2:42][O:41]CC1>>[CH3:32][C:42]([CH3:38])([C:10]12[CH2:16][C:14]3([O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:13][CH:12]([CH2:24][C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])([CH2:15]3)[CH2:9]1)[CH2:11]2)[OH:41]
Reactant: C[Mg]Br
Reactant: CCCCOC(=O)C12CC3CC(OCOCCOC)(CC(OCOCCOC)(C3)C1)C2
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COCCOCOC12CC3CC(OCOCCOC)(C1)CC(C(C)(C)O)(C3)C2
Reaction time: 2 h

Procedure:
A solution of 100 mmole of the above-prepared n-butyl 3,5-bis(2-methoxyethoxymethoxy)-1-adamantanecarboxylate in 150 ml of THF was added dropwise to the above-prepared methylmagnesium bromide solution in such a rate that the solvent 4 was gently refluxed. The reflux operation was continued for further 2 hours after the completion of addition. The resulting reaction mixture was added dropwise to a 10% by weight hydrochloric acid cooled on ice, while stirring, and the mixture was stirred for further 2 hours at a temperature in a range from 0° C. to room temperature. A 10% by weight aqueous sodium hydroxide solution was added to the reaction mixture to adjust the mixture to around neutrality, and the neutralized mixture was separated to an organic layer and an aqueous layer; the aqueous layer was extracted with toluene; the organic layer was concentrated; and the concentrate was subjected to column chromatography on a silica gel to yield α,α-dimethyl-3,5-bis(2-methoxyethoxymethoxy)-1-adamantanemethanol.
Reaction SMILES: C1(C)C=CC=C(C)C=1.[Cl:9]Cl.C[C:12]1[C:17]([Cl:18])=[C:16]([Cl:19])[C:15](Cl)=[C:14]([Cl:21])[C:13]=1[CH3:22].[C:23](Cl)(Cl)(Cl)[Cl:24]>[Hg]>[CH3:22][C:13]1[C:12]([Cl:9])=[C:17]([Cl:18])[C:16]([Cl:19])=[C:15]([CH2:23][Cl:24])[C:14]=1[Cl:21]
Reactant: Cc1c(C)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: ClCl
Reactant: ClC(Cl)(Cl)Cl
Agent: [Hg]
Solvent: Cc1cccc(C)c1
Product: Cc1c(Cl)c(Cl)c(Cl)c(CCl)c1Cl
Reaction time: 3 h
Yield: 77 %

Procedure:
530 g of m-xylene in 5 liters of CCl4 was chlorinated in the nucleus in the presence of 10 g of FeCl3 by passing chlorine over the reaction solution while stirring the latter, at a pressure of 0.06 atmospheres excess pressure, with the exclusion of light. The first half of the amount of chlorine calculated for dimethyltetrachlorobenzene was introduced into the gas chamber of the reaction vessel with the temperature of the liquid phase at 20° C, the remainder at 40° C. The reaction time was about 3 hours. Then, while irradiating the gas chamber in the reaction vessel with a 250-watt mercury vapor lamp at a temperature of 70° C in the liquid phase and 0.06 atmospheres excess pressure, the side chain chlorination was performed, which was completed within 4 hours 30 minutes. Total chlorine consumption: 110% of the calculated amount with respect to xylene. The reaction solution was stirred with 400 g of calcium hydroxide, rendering the solution neutral and iron-free. The calcium hydroxide containing iron and chloride was removed on a suction filter and the solution, after removal of the CCl4 by distillation, was fractionated at 12 Torr in a packed column. The principal fraction distilled at 182°-187° C. 1125 g of 1-methyl-3-chloromethyl-2,4,5,6-tetrachlorobenzene was obtained in a purity of 95.3% (yield 77%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[S:12]([O-:15])([OH:14])=[O:13].[Na+:16].C(O)C>O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([S:12]([O-:15])(=[O:14])=[O:13])=[N:3][CH:4]=1.[Na+:16]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])c1ccc(C(F)(F)F)cn1
Yield: 85.6 %

Procedure:
In a flask, 2-chloro-5-(trifluoromethyl)pyridine (54.5 g, 0.3 mol), sodium hydrogen sulfite (125 g, 1.2 mol), ethanol (600 ml) and water (600 ml) were charged and heated under reflux for 198 hours. After evaporating off the solvent, to the solid residue, conc. hydrochloric acid was added. The mixture was evaporated to dryness. The residue was extracted with methanol and filtrated. The filtrate was evaporated to dryness to obtain sodium 5-(trifluoromethyl)pyridine-2-sulfonate (64.0 g). Yield, 86%. Decomposition point, 356°-370° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17]C)[CH:15]=2)[CH2:10][CH2:9][CH2:8]1)(=[O:3])[CH3:2].B(Br)(Br)Br.O.C(OCC)(=O)C>ClCCl>[C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CCC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NCCC1CCCc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 52 %

Procedure:
To a solution of 1-[2-(acetylamino)ethyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene (3.14 g, 12.7 mmol) in dichloromethane (70 ml) was added dropwise, under ice-cooling, boron tribromide (6.4 g, 25.4 mmol). The reaction mixture was stirred for 50 minutes at room temperature, which was poured into water. The organic layer was subjected to extraction with chloroform. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (chloroform:methanol=9:1) to give the above-titled compound (1.54 g, yield 52%), m.p.153-155° C. (recrystallized from ethyl acetate).
Reaction SMILES: [F:1][C:2]1[C:10]2[N:11]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:12](=[O:14])[NH:13][C:9]=2[C:8]2[O:7][CH:6]=[CH:5][C:4]=2[C:3]=1[F:23].[CH2:24]([C:27]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28]1)[CH:25]=[CH2:26].C(OCC)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCCCCC>[CH2:24]([C:27]1([S:30]([IH:21][C:18]2[CH:19]=[CH:20][C:15]([N:11]3[C:10]4[C:2]([F:1])=[C:3]([F:23])[C:4]5[CH:5]=[CH:6][O:7][C:8]=5[C:9]=4[NH:13][C:12]3=[O:14])=[C:16]([F:22])[CH:17]=2)(=[O:32])=[O:31])[CH2:29][CH2:28]1)[CH:25]=[CH2:26]
Reactant: O=c1[nH]c2c3occc3c(F)c(F)c2n1-c1ccc(I)cc1F
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCC1(S(=O)(=O)[IH]c2ccc(-n3c(=O)[nH]c4c5occc5c(F)c(F)c43)c(F)c2)CC1
Temperature: 30 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
TEA (02611 g, 2.581 mmol) was added to a solution of 4,5-difluoro-3-(2-fluoro-4-iodophenyl)-1H-benzofuro[6,7-d]imidazol-2(3H)-one (I-32a: 0.37 g, 0.8604 mmol) in dry DCM (20 mL) at 0° C. This was followed by the addition of 1-allyl-cyclopropanesulfonyl chloride (0.229 g, 1.89 mmol) and catalytic amount of DMAP (10 mg). The reaction mass was stirred for 12 hours at 20-40° C. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mass was diluted with DCM (50 mL) and partitioned between water and DCM. The organic layer was washed with water, brine solution and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 0.228 g of the product (46% yield). 1H NMR (CDCl3, 300 MHz): δ 7.71 (dd, 3H), 7.30 (t, 1H), 7.00 (s, 1H), 5.56-5.57 (m, 1H), 4.90 (t, 2H), 2.70-2.80 (q, 2H), 1.90-2.05 (m, 2H), 1.10-1.19 (m, 2H). LCMS: 98.85%, m/z=574.4 (M+1). HPLC: 97.1%
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].C([NH:9][CH2:10][CH2:11][NH2:12])(=O)C.[CH2:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]>C(Cl)(Cl)Cl>[ClH:5].[CH3:1][S:2]([NH:9][CH2:10][CH2:11][NH2:12])(=[O:4])=[O:3].[ClH:5].[CH2:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]
Reactant: CC(=O)NCCN
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCN
Product: Cl
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Methanesulphonyl chloride (16.8 g) in dry chloroform (25 ml) was added dropwise to a stirred solution of mono-N-acetylethylene diamine (15 g) and triethylamine (15 ml) in dry chloroform (25 ml) at 0°. The solution was stirred at ambient temperature for 60 hours. The reaction mixture was then extracted with water (3×50 ml) and the combined aqueous fractions were shaken with chloroform and separated. The aqueous fraction was evaporated in vacuo and the residue in methanol (100 ml) and concentrated hydrochloric acid (50 ml) was heated under reflux for 12 hours. The solvent was then evaporated in vacuo and the residue treated with methanol at reflux. The insoluble solid was filtered off and discarded. The filtrate was evaporated in vacuo and the residue treated with chloroform at reflux. The solvent was decanted leaving N-monomethanesulphonylethylene diamine, hydrochloride as a semi-solid also containing triethylamine hydrochloride. The product was used in the preparation of the product of Example 36 without further purification.
Reaction SMILES: CC(C1NC(=O)C(CCSC)NC(=O)C(NC(C(NC(C(NC(C(NC(C(N)CC(O)=O)=O)C(O)C)=O)CCSC)=O)CCCNC(N)=N)=O)CSSCC(C(NC(C(NC(C(NC(C(O)=O)C(C)C)=O)CCC(O)=O)=O)CC2C3C(=CC=CC=3)NC=2)=O)NC(=O)C2N(CCC2)C(=O)C(CCCNC(N)=N)NC(=O)C(C[C:128]2[CH:133]=[CH:132][C:131]([OH:134])=[CH:130][CH:129]=2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC1=O)C.[BH4-].[Na+].[OH2:147].[CH2:148]1[CH2:152][O:151][CH2:150][CH2:149]1>CCOCC>[OH:134][CH:131]1[CH2:130][CH2:129][CH2:128][CH:133]([C:150]([O:151][CH2:152][C:148]2[CH:149]=[CH:130][CH:129]=[CH:128][CH:133]=2)=[O:147])[CH2:132]1
Reactant: O
Reactant: C1CCOC1
Reactant: CSCCC1NC(=O)C(NC(=O)C(CCCNC(=N)N)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(N)CC(=O)O)C(C)O)CSSCC(C(=O)NC(Cc2c[nH]c3ccccc23)C(=O)NC(CCC(=O)O)C(=O)NC(C(=O)O)C(C)C)NC(=O)C2CCCN2C(=O)C(CCCNC(=N)N)NC(=O)C(Cc2ccc(O)cc2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)CNC(=O)C(C(C)C)NC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(OCc1ccccc1)C1CCCC(O)C1
Temperature: 0 °C

Procedure:
To a 0° C. solution of benzyl 3-oxocyclohexanecarboxylate 1 (2.50 g, 10.8 mmol) in 55 mL of THF was added NaBH4 (814 mg, 21.5 mmol) portionwise. The reaction mixture was maintained at 0° C. for 20 min. Then water was slowly added to the reaction, and the reaction was diluted with Et2O. The resulting layers were separated and the aqueous layer was further extracted with Et2O. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. Purification of the resulting residue by flash chromatography (Biotage™ 40M 5-25% EtOAc/hexanes then 25-35% EtOAc/hexanes) afforded the title compound as a clear, colorless oil. LCMS: calculated for C14H18O3 234.29, observed m/e 235.0 (M+H)+ 256.9 (M+Na) (Rt 1.74/4 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]=[CH:21][N:22]([CH3:24])C)#N>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]2[C:11]3[C:12](=[CH:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=3)[N:20]=[CH:21][N:22]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 148 °C

Procedure:
A solution of 23.74 ml of 3-bromo aniline and 40.5 g N'-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine in 100 ml of glacial acetic acid was stirred and heated in an oil bath at 148° C. for 1.5 hours. On cooling, filtration of the resulting solid gives a quantitative yield of N-(3-bromophenyl)-6-nitro-4-quinazolinamine: mp=267°-270° C.; mass spectrum (m/e): 345.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:30].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:30])=[N:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(OCc3cccc(Cl)c3)n2)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nc(OCc3cccc(Cl)c3)cnc2F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6′-(3-chloro-benzyloxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (1-1b) (600 mg, 1.49 mmol) in acetonitrile (12.4 ml) at 0° C. under a nitrogen atmosphere was treated with Selectfluor™ ([1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]-octane bis(tetrafluoroborate)]) (526 mg, 1.49 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was partitioned between CH2Cl2 and water. The organic phase was washed twice with water, twice with saturated aqueous NaHCO3 solution and twice with brine, dried over MgSO4 (anhydrous), filtered and concentrated in vacuo. The residue was purified by flash chromatography (CHCl2-EtOAc 99:1 to 95:5). Three compounds were obtained in the following elution order: difluorinated material (160 mg, 25%), Intermediate I-3i (32 mg, 5%) and Intermediate I-3i′ (141 mg, 22%). The structures of the two monofluorinated products were assigned by nuclear Overhauser effect (nOe) experiments.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[C:16](=[O:18])[NH:15][C:14]2([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][F:31].[H-].[Na+]>C(OCC)(=O)C>[CH2:21]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[C:16](=[O:18])[N:15]([CH2:29][CH2:30][F:31])[C:14]2([CH3:20])[CH3:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: FCCBr
Reactant: CC1(C)NC(=O)c2c(N(Cc3ccccc3)Cc3ccccc3)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1(C)c2cccc(N(Cc3ccccc3)Cc3ccccc3)c2C(=O)N1CCF
Temperature: 25 °C
Reaction time: 4 h

Procedure:
67 mg (0.188 mmol) 7-dibenzylamino-3,3-dimethyl-2,3-dihydro-isoindol-1-one are dissolved in 1 ml (7.877 mmol) 1-bromo-2-fluoroethane and combined with 52 mg (0.376 mmol) sodium hydride. After 4 h stirring at ambient temperature the mixture is diluted with ethyl acetate and extracted three times with 1 M hydrochloric acid. The combined organic phases are dried and the solvent is eliminated in vacuo.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[C:50]([F:56])=[C:51]([CH:53]=[CH:54][CH:55]=2)[NH2:52])[CH:38]=[CH:37][N:36]=1.[N:57]1[CH:62]=[CH:61][CH:60]=[C:59]([S:63](Cl)(=[O:65])=[O:64])[CH:58]=1>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([CH:46]([CH3:48])[CH3:47])=[N:43][C:42]=2[C:49]2[C:50]([F:56])=[C:51]([NH:52][S:63]([C:59]3[CH:58]=[N:57][CH:62]=[CH:61][CH:60]=3)(=[O:65])=[O:64])[CH:53]=[CH:54][CH:55]=2)[CH:38]=[CH:37][N:36]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2F)c(-c2ccnc(Cl)n2)s1
Yield: 75.3 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-isopropylthiazol-4-yl)-2-fluoroaniline (3 g, 8.6 mmol) and pyridine-3-sulfonyl chloride (1.68 g, 9.5 mmol) the title compound of Step A was obtained (2.1 g, 75.3% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.97-9.01 (br, 1H), 8.76-8.79 (m, 1H), 8.35 (d, J=5.3 Hz, 1H), 8.08-8.12 (m, 1H), 7.68-7.74 (m, 1H), 7.40-7.44 (m, 1H), 7.22-7.34 (m, 3H), 6.69 (d, J=5.3 Hz, 1H), 3.29-3.38 (m, 1H), 1.44 (d, J=6.8 Hz, 6H). MS (ES+): 490 [M+H]+.