Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]([S:22]([CH3:25])(=[O:24])=[O:23])[C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]([S:22]([CH3:25])(=[O:24])=[O:23])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCc1ccc(-c2ccc(F)cc2)cc1)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)C(CCc1ccc(-c2ccc(F)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a solution of ethyl 4-(4′-fluorobiphenyl-4-yl)-2-(methylsulfonyl)butanoate in THF (2.2 mL) and methanol (0.6 mL) was added a solution of lithium hydroxide in water (37 mg, 1.54 mmol, 0.6 mL water) and stirred at room temperature for 30 minutes. The mixture was diluted with water (30 mL) and washed with Et2O 50 mL. The organic layer was discarded. The aqueous layer was acidified with 0.5N HCl and the white suspension was re-extracted with Et2O. The ether extract was washed with brine 50 mL, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a white solid (113 mg, 87.5%) MS (LC/MS) m/z 335.1 (M−1)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[F:34][CH:35]([F:46])[O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1.Cl.CN(C)CCCN=C=NCC>CC#N>[F:34][CH:35]([F:46])[O:36][C:37]1[CH:38]=[CH:39][C:40]([C:41]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:42])=[CH:44][CH:45]=1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)c1ccc(OC(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(OC(F)F)cc4)c3C2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.70 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 4-difluoromethoxy benzoic acid (0.45 g, 2.4 mmol) were added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL) and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min) to afford 4-difluoromethoxy-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide as a yellow solid (0.63 g, 64%): mp, 155-157° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.2 min. (97%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.50-2.65 (m, 2H), 2.85-2.92 (m, 1H), 4.95 (d, J=5.8 Hz, 2H), 5.16-5.21 (dd, J=5, 12 Hz, 1H), 7.28-7.30 (m, 2H), 7.36 (t, J=73.5 Hz, 1H), 7.72-7.86 (m, 3H), 7.98-8.02 (m, 2H), 9.18 (t, J=5.8 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.34, 48.86, 112.61, 116.03, 117.97, 119.45, 121.87, 127.13, 129.45, 130.55, 131.52, 133.05, 134.79, 139.22, 153.30, 165.60, 166.95, 167.52, 169.81, 172.74. Anal Calcd for C22H17F2N3O6: C, 57.77; H, 3.75; N, 9.19; F, 8.31. Found: C, 57.67; H, 3.59; N, 9.01; F, 8.22.
Reaction SMILES: CN(C)[CH:3]=[O:4].CO[C:8](OC)([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=1)[CH:9]([OH:11])C.S(=O)=O.ClCl.[CH:29](Cl)(Cl)Cl>>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:8]([CH3:29])[C:9]([O:4][CH3:3])=[O:11])=[CH:17][CH:16]=1)[CH:19]([CH3:20])[CH3:21]
Reactant: COC(OC)(c1ccc(CC(C)C)cc1)C(C)O
Reactant: CN(C)C=O
Reactant: ClC(Cl)Cl
Agent: ClCl
Agent: O=S=O
Product: COC(=O)C(C)c1ccc(CC(C)C)cc1
Reaction time: 2 h

Procedure:
In this example, 11 g of N,N-dimethylformamide was added to 2.52 g of α-hydroxy-p-isobutylpropiophenone dimethylacetal. Then, 18 ml of sulfur dioxide and 1.1 g of chlorine were added to the mixture at -50° C. The temperature was elevated to 10° C. over 2 hours, and 20 ml of chloroform was added thereto. Subsequent post-treatment was performed in a manner similar to Example 8 to obtain 1.1 g of methyl 2-(4-isobutylphenyl)propionate.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([I:8])=[CH:6][CH:7]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>CC(O)(C)C>[I:8][C:5]1[N:4]=[N:3][C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc(I)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(I)nn2)CC1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
3-chloro-6-iodopyridazine (510 mg, 2.1 mmol) and tert-butyl piperazine-1-carboxylate (415 mg, 2.23 mmol) were taken up in tBuOH (8 mL). iPr2NEt (480 μL, 2.8 mmol) was added and the stirred reaction mixture was heated to 100° C. After 48 h, the reaction mixture was cooled and was partitioned between EtOAc and water. The phases were separated, and the organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-25% Et2O in DCM) to afford tert-butyl 4-(6-iodopyridazin-3-yl)piperazine-1-carboxylate 7.12. LCMS-ESI+ (m/z): [M+H—CO2tBu]+ calcd for C8H121 N4: 291.0; found: 291.0.
Reaction SMILES: [Cl-].[Na+].C(CC[CH:8]([CH:14]([C:19]#[N:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])(O)=O.CS(C)=O>O.C(OC)(C)(C)C>[C:19]([CH:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:20]
Reactant: CCOC(=O)C(CCC(=O)O)C(C#N)CC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: CCOC(=O)CC(C#N)CC(C)C
Reaction time: 0.38 h
Yield: 89.4 %

Procedure:
An 800 L still was charged with sodium chloride (21 kg, 359 mol), 2-carboxyethyl-3-cyano-5-methylhexanoic acid, ethyl ester (80.0 kg, 313 mol), dimethylsulfoxide (238 kg), and water (10.8 kg, 600 mol). The mixture was heated to 137°-148° C. for 8.5 hours. The mixture was cooled to below 50° C., and treated with methyl tert-butyl ether (125 kg). The mixture was cooled to 0°-10° C., and treated with water (160 L) in portions to maintain the temperature below 40° C. After stirring for 15-30 minutes, the phases were separated. The aqueous phase was extracted with methyl tert-butyl ether (125 kg). The organic extracts were combined with a vessel rinse (25 kg methyl tert-butyl ether) and was extracted with water (110 L). The water phase was discarded. The methyl tert-butyl ether phase was concentrated by atmospheric pressure distillation to a batch temperature of about 65° C. The batch was cooled to 30°-40° C. and further concentrated by vacuum distillation until the solvent content was acceptable (<5% methyl tert-butyl ether by area %GC analysis). The product was obtained as a brown oil (51.3 kg, 85.7%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:4]=1[NH2:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>O1CCCC1>[Br:10][C:8]1[CH:7]=[CH:6][C:4]([NH:5][C:13](=[O:15])[CH3:14])=[C:3]([C:2]([F:1])([F:11])[F:12])[CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
A solution of 2-(trifluoromethyl)-4-bromoaniline (4.8 g, 20 mmol) in dry tetrahydrofuran (20 mL) was cooled to 0° C. and then treated with acetic anhydride (8.2 g, 80 mmol). The reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. The reaction mixture was stirred at 25° C. for 2 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The crude residue precipitated from diethyl ether (50 mL) and hexanes (50 mL). The solid was collected by filtration and washed with hexanes to afford N-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (5.07 g, 90%) as an amorphous white solid: EI-HRMS m/e calcd for C9H7BrF3NO (M+) 281.8352, found 281.8348.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[C@@H:23]([NH2:25])[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][NH:31]2.CCN(C(C)C)C(C)C>C(O)CCC>[N:35]1[C:27]([NH:25][C@H:23]([C:15]2[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=2)[CH3:24])=[C:28]2[C:32]([NH:31][CH:30]=[N:29]2)=[N:33][CH:34]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: C[C@H](N)c1nc2ccccc2n1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[2-((S)-1-aminoethyl)benzoimidazol-1-yl]piperidine-1-carboxylic acid tertbutyl ester from Example 6 (202 mg), 6-chloro-9H-purine (91 mg, 0.586 mmol) and DIPEA (0.2 mL, 1.17 mmol) in n-butanol (1 mL) was stirred in a sealed tube for 3 h at 120° C. After cooling to RT, the crude reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then triturated with diethyl ether affording 112 as a pale brown solid (113 mg, 38% over two steps). LCMS: RT 3.24 min [M+H]+ 463.2. 1H NMR (CDCl3, 400 MHz): δ 8.54 (1H, s), 7.98 (1H, s), 7.78 (1H, d, J=7.55 Hz), 7.49 (1H, d, J=7.36 Hz), 7.28-7.07 (3H, m), 6.13 (1H, br), 4.89-4.78 (1H, m), 4.47-4.04 (2H, m), 2.97-2.78 (1H, m), 2.60-2.26 (3H, m), 1.99-1.62 (6H, m), 1.49 (9H, s)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:12]=1.CN(C)C1C=CC=CC=1.Cl[C:30]([N:32]=[C:33]=[O:34])=[O:31].[Cl:35][CH2:36]Cl>>[Cl:35][C:36]1[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=1[C:3]1[C:30](=[O:31])[NH:32][C:33](=[O:34])[N:12]2[CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[CH2:10][S:9][C:8]=12
Reactant: ClCCl
Reactant: O=C=NC(=O)Cl
Reactant: Fc1ccccc1C1CSC(c2ccccc2Cl)=N1
Solvent: CN(C)c1ccccc1
Product: O=c1[nH]c(=O)n2c(c1-c1ccccc1Cl)SCC2c1ccccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
To 2-(2-chlorophenyl)-4-(2-fluorophenyl)-4,5-dihydrothiazole (0.303 g, 1.00 mmol) and N,N-dimethylaniline (0.135 mL, 1.05 mmol) in dichloromethane (2 mL) at 0° C. was added dropwise chlorocarbonyl isocyanate (0.080 mL, 1.0 mmol). The mixture was allowed to warm to room temperature and stirred for 24 hours. The resulting suspension was cooled to 0° C., filtered, and washed with ice-cold 1:1 dichloromethane/ether (2×1 mL) to give the title compound as a white powder (0.251 g, 67%). MS=375.1 ((M+H)+). 1H NMR (TMS/DMSO-D6, 400 MHz): 7.59-7.08 (m, 8H); 6.18 (d, J=7.6 Hz, 1H); 4.05 (dd, J=11.2, 7.6 Hz, 1H); 3.25 (d, J=11.2, 1H); 2.87 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:21])[CH2:10][N:9]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2ccccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: S=C1CN=C(c2ccccc2Cl)c2ccccc2N1

Procedure:
A mixture of 23 g. (0.085 mole) of 1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepin-2-one [Sternbach et al., J. Med. Chem. 6, 261 (1963)] and 21 g. of P2S5 in 1500 ml. of pyridine was heated rapidly to the reflux temperature and refluxed for 45 min. It was then concentrated to dryness in vacuo and the residue was treated with 150 ml. of saturated NaCl solution and extracted (thrice) with methylene chloride. The CH2Cl2 solution was washed (water), dried (MgSO4), filtered and evaporated to dryness. The residue was dissolved in 1 l. of abs EtOH treated with Darco and filtered hot. The solution was then concentrated to 200 ml. and allowed to cool giving 19 g. (78%) of yellow crystalline compound, m.p. 228-229° C. The ir and nmr support the structure.
Reaction SMILES: C(OCOCOC[C:14]1[CH:19]=[CH:18]C=CC=1)C1C=CC=CC=1.C(Cl)Cl.ClCOC[C:27]1[CH:32]=[CH:31]C=CC=1.[CH2:33]([N:35](CC)CC)[CH3:34]>>[CH:32]([N:35]([CH:19]([CH3:18])[CH3:14])[CH2:33][CH3:34])([CH3:31])[CH3:27]
Reactant: ClCOCc1ccccc1
Reactant: c1ccc(COCOCOCc2ccccc2)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCN(C(C)C)C(C)C

Procedure:
As shown in the reaction Scheme 1, aldehyde 1 (prepared as described in Goulet, M. T.; Boger, J. Tetrahedron Lett. 1990, 31, 4845) in an inert organic solvent such as toluene is treated with a disopropyl tartrate-modified allyl boronate at about -78° C. for a period of one to twelve hours to give the homoallylic alcohol 2 with a high degree of diastereoselection. Epoxidation of the olefin contained in 2 is conducted by treatment of a solution 2 in an inert organic solvent such as benzene, toluene, methylene chloride, or tetrahydrofuran with an alkyl hydroperoxide such as tertbutyl hydroperoxide and a catalytic amount of vanadyl acetylacetonate at room temperature for a period of ten to twenty-four hours to give the cis epoxy-alcohol 3 as the major product. Alcohol 3 is protected as the benzyloxymethyl ether by treatment of a methylene chloride solution with benzyl chloromethyl ether and an amine base such as diisopropylethyl amine or triethylamine at room temperature for a period of ten to twenty-four hours to give the protected analog 4. The extended alcohol 5 is prepared by subjection of a solution of epoxide 4 in an inert organic solvent such as diethyl ether or tetrahydrofuran to the cyanocuprate prepared from 4-pentenyl lithium at about -20° C. for one to three hours. Alcohol 5 is protected as the tert-butyldimethylsilyl ether by subjection of a solution in methylene chloride to tert-butyldimethylsilyl trifluoromethanesulfonate and an amine base such as 2,6-lutidine at room temperature for fifteen minutes to one hour giving the protected derivative 6. Selective hydroboration of olefin 6 to the primary alcohol 7 is accomplished by treatment of a solution of 6 in ethylene glycol dimethyl ether with 9-borabicyclo[3.3.1]nonane a 0° C. for a period of one to eight hours, followed by addition of saturated sodium bicarbonate and hydrogen peroxide. This mixture is stirred at room temperature for thirty minutes to two hours to give alcohol 7. Treatment of alcohol 7 as a mixed solution in carbon tetrachloride, acetonitrile, and water with periodic acid and a catalytic amount of ruthenium (III) chloride at room temperature for two to five hours, followed by treatment of the crude reaction product with diazomethane in ether gives methyl ester 8. The benzyloxymethyl ether protecting group is removed from 8 by treatment of an ethyl acetate solution with hydrogen and a catalytic amount of palladium hydroxide on carbon to produce the free alcohol. Treatment of this crude product with an excess of the lithium anion of methyl diethylphosphonate in tetrahydrofuran at -40° C. for a period of thirty minutes to two hours is followed by acidification with a weak acid such as aqueous ammonium chloride to give the β-keto-phosphonate 9.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.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.C(O)C>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Fc1ccc(Oc2ccc3c(Cl)nncc3c2)cc1
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: ClCCl
Product: Fc1ccc(Oc2ccc3c(-c4ccccc4Cl)nncc3c2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A 10 mL round-bottomed flask under argon was charged with 1-chloro-6-(4-fluorophenoxy)phthalazine (42.90 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium (9 mg, 0.008 mmol), 2-chlorophenylboronic acid (37 mg, 0.23 mmol), ethylene glycol dimethyl ether (1.6 mL), and ethanol (0.4 mL), followed by 2M aqueous sodium carbonate solution (0.23 mL, 0.45 mmol). The reaction was stirred at 90° C. for 3 h. The cooled reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3 and brine, then dried (MgSO4). Flash chromatography eluting with a gradient of 25:10:65, 40:10:50, 50:10:40, 60:10:30, and 70:10:20 ethyl acetate-dichloromethane-hexanes gave the title compound as a tan amorphous solid. MS (ES+): 351.1 (M+H)+.
Reaction SMILES: [N:1]1([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:9]2[CH:8]=[CH:7][N+:6]([O-])=[CH:5][C:4]=2[CH:3]=[CH:2]1.[CH3:21][C:22]([NH2:29])([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:23].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[CH3:21][C:22]([NH:29][C:5]1[C:4]2[CH:3]=[CH:2][N:1]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:9]=2[CH:8]=[CH:7][N:6]=1)([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:23]
Reactant: O=C(OCc1ccccc1)n1ccc2c[n+]([O-])ccc21
Reactant: CC(C)(C)CC(C)(C)N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)CC(C)(C)Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
A solution of benzyl 1H-pyrrolo[3,2-c]pyridine-1-carboxylate 5-oxide (500 mg, 1.9 mmol, Step b) in chloroform was treated dropwise with 2,4,4-trimethylpentan-2-amine (1.57 mL, 8.5 mmol) and stirred for about 15 minutes. The mixture was cooled to 0° C. followed by the portion wise addition of p-toluenesulphonyl chloride (745 mg, 4.2 mmol). The reaction mixture was then stirred at room temperature for 1 hour, diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum to yield viscous oil. The crude product was purified by silica gel (100-200 mesh) column chromatography using ethyl acetate in hexane (1.5%) as eluent to yield benzyl 4-[(2,4,4-trimethylpentan-2-yl)amino]-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (390 mg, 43%) as a pale yellow solid.
Reaction SMILES: C[C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1NC(C1C(N2N=CC=N2)=CC=CN=1)=O.[CH3:32][C@:33]1([NH:39][C:40]2[CH:45]=[N:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=2)[CH2:37][CH2:36][CH2:35][C@@H:34]1[NH2:38].[N:50]1[CH:55]=[CH:54][CH:53]=[N:52][C:51]=1[C:56]1[CH:64]=[CH:63][CH:62]=[CH:61][C:57]=1[C:58](O)=[O:59].C(N(CC)CC)C>>[CH3:32][C@:33]1([NH:39][C:40]2[CH:45]=[N:44][C:43]([C:46]([F:49])([F:47])[F:48])=[CH:42][N:41]=2)[CH2:37][CH2:36][CH2:35][C@@H:34]1[NH:38][C:58](=[O:59])[C:57]1[CH:61]=[CH:62][CH:63]=[CH:64][C:56]=1[C:51]1[N:50]=[CH:55][CH:54]=[CH:53][N:52]=1
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Reactant: O=C(O)c1ccccc1-c1ncccn1
Agent: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Solvent: CCN(CC)CC
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ccccc1-c1ncccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 48 mg, 0.15 mmol), 2-(pyrimidin-2-yl)benzoic acid (CAS number 400892-62-8; 41 mg, 0.20 mmol) and triethylamine (0.077 ml, 0.55 mmol) except this was purified by column chromatography (silica, 0-100% ethyl acetate/petrol)) followed by reverse phase chromatography (C18 silica, 0-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [CH:1]([O:4][P:5]([CH2:11]Br)(=[O:10])[O:6][CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2].[OH:13][CH2:14][C:15]([CH2:38][CH3:39])=[CH:16][CH2:17][C:18]1[C:26]([O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[C:25]2[C:21]([CH2:22][O:23][C:24]2=[O:34])=[C:20]([CH3:35])[C:19]=1[O:36][CH3:37].CC(C)([O-])C.[Li+].[Cl-].[Li+]>CN(C=O)C>[CH:1]([O:4][P:5]([CH2:11][O:13][CH2:14][C:15]([CH2:38][CH3:39])=[CH:16][CH2:17][C:18]1[C:26]([O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])=[C:25]2[C:21](=[C:20]([CH3:35])[C:19]=1[O:36][CH3:37])[CH2:22][O:23][C:24]2=[O:34])(=[O:10])[O:6][CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2]
Reactant: CC(C)OP(=O)(CBr)OC(C)C
Reactant: CCC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CO
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)COCP(=O)(OC(C)C)OC(C)C
Temperature: 70 °C
Yield: 34.7 %

Procedure:
To a solution of bromomethylphosphonate diisopropyl ester (680 mg, 2.62 mmol) and 6-(3-hydroxymethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (688 mg, 1.75 mmol) in DMF (3 mL) was added lithium t-butoxide (1.0M in THF; 2.6 mL). The reaction was heated at 70° C. for 2 hours. After cooling to ambient temperature, more bromomethylphosphonate diisopropyl ester (680 mg, 2.62 mmol) and lithium t-butoxide (1.0M in THF; 2.6 mL) were added. The reaction mixture was heated at 70° C. for a further hour, cooled, poured into a solution of lithium chloride (5% aqueous) and extracted with ethyl acetate. The organic extract was dried and the product was purified by chromatography on silica gel, eluting with hexane-ethyl acetate to provide 347 mg (35%) of the product as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.04 (s, 9H), 1.09 (t, 3H, J=7.5 Hz), 1.20-1.26 (m, 2H), 1.31 (t, 12H, J=6 Hz), 2.18 (s, 3H), 2.29 (q, 2H, J=7.5 Hz), 3.5 (m, 2H), 3.59 (d, 2H, J=8.7 Hz), 3.78 (s, 3H), 3.98 (s, 2H), 4.28-4.35 (m, 2H), 4.6-4.8 (m, 2H), 5.13 (s, 2H), 5.4 (t, 1H, J=7 Hz) ppm; 31P (121.4 MHz, CDCl3) δ 20.26 ppm; MS (m/z) 593.3 [M+Na]+.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([OH:36])=O)[CH2:28][CH2:27]1.CS(N)(=O)=O.[CH3:55][O:56][CH2:57][CH2:58][S:59]([NH2:62])(=[O:61])=[O:60]>>[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:42][CH2:43][C:44]([F:48])([F:47])[CH2:45][CH2:46]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([NH:62][S:59]([CH2:58][CH2:57][O:56][CH3:55])(=[O:61])=[O:60])=[O:36])[CH2:27][CH2:28]1
Reactant: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC(F)(F)CC1
Reactant: COCCS(N)(=O)=O
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2(C)CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with 2-methoxyethanesulfonamide, the title compound was obtained (0.162 g, 55%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.72-8.57 (m, 1H), 7.68-7.55 (m, 1H), 6.63-6.51 (m, 1H), 3.94-3.70 (m, 6H), 3.31 (s, 3H), 2.08-1.75 (m, 7H), 1.68-1.58 (m, 2H), 1.17 (s, 3H), 0.99-0.89 (m, 2H), 0.70-0.60 (m, 2H); MS (ES+) m/z 464.1 (M+1).