Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[C:9]([O:22][CH3:23])[CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[CH:27][C:28]([F:32])=[C:29](I)[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([F:32])=[C:27]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:2])[CH3:3])(=[O:5])=[O:6])=[CH:8][C:9]=2[O:22][CH3:23])[CH:26]=1
Reactant: Fc1ccc(Br)cc1I
Reactant: COc1cc(S(=O)(=O)C(C)C)ccc1B1OC(C)(C)C(C)(C)O1
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: O
Solvent: C1COCCO1
Product: COc1cc(S(=O)(=O)C(C)C)ccc1-c1cc(Br)ccc1F
Temperature: 100 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
To a solution of 2-(4-(isopropylsulfonyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 36, 374 mg, 1.10 mmol) and 5-bromo-2-fluoroiodobenzene (300 mg, 1.00 mmol) in dioxane (6 mL) and water (2.5 mL) was added sodium carbonate (317 mg, 3.00 mmol). The mixture was degassed with nitrogen for 20 minutes, tetrakis(triphenylphosphine)palladium(0) (58.0 mg, 0.05 mmol) was added and the reaction mixture was stirred at 100° C. under a nitrogen atmosphere for 12 hours. The cooled reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with EtOAc/cyclohexane 25/75 to afford the title compound as a yellow oil in 69% yield, 0.27 g.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH2:13][CH2:12]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH2:13][CH2:12]2
Reactant: O=C1CCc2cc(O)ccc21
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Oc3ncccn3)ccc21
Temperature: 100 °C

Procedure:
A mixture of 2-chloropyrimidine (220 mg, 1.9 mmol), 5-hydroxyindan-1-one (209 mg, 1.4 mmol) and potassium carbonate (250 mg, 1.8 mmol) in N,N-dimethyl formamide (5 mL) was heated to about 100° C. overnight. The reaction was cooled to room temperature and the solvent was evaporated under high vacuum. The residue was purified by flash column chromatography on silica gel using ethyl acetate/methanol (99:1) as the mobile phase to provide the desired product. 1H NMR (500 MHz, CDCl3): δ 2.75 (t, J=7 Hz, 2H), 3.18 (t, J=7 Hz, 2H), 7.09 (m, 1H), 7.25 (d, J=7 Hz, 1H), 7.32 (s, 1H), 7.82 (d, J=7 Hz, 1H), 8.62 (d, J=7 Hz, 1H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11](=[CH:13][CH2:14][CH2:15][CH:16]([CH2:18][CH2:19]O)[CH3:17])[CH3:12].S(=O)(=O)(O)O>O1CCCC1>[C:1]([O:9][CH2:19][CH2:18][CH:16]([CH3:17])[CH2:15][CH2:14][CH:13]=[C:11]([CH3:12])[CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=CCCC(C)CCO
Reactant: O=C(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)CCOC(=O)c1ccccc1
Yield: 19 %

Procedure:
A mixture of benzoic acid (14.6 g, 0.12 mol) and citronellol (15.6 g, 0.1 mol) in tetrahydrofuran (THF) was heated on a water bath for 4 hours after the addition of concentrated sulfuric acid. The reaction was monitored by thin layer chromatography (TLC), and when the reaction was over, the reaction mixture was quenched over ice/water, extracted with THF or methylene chloride, washed with 5% sodium hydrogen carbonate, and dried over magnesium sulfate. The reaction mixture was concentrated under vacuum and purified by open column chromatography to yield 4.95 g (yield: 19%) of a product having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:26]([C:28]3[O:29][C:30](=[O:44])[C:31]4[C:36]([C:37]=3[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][Si](C(C)(C)C)(C)C)[CH:12]=3)[C:3]=12>Cl.CCO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:26]([C:28]3[O:29][C:30](=[O:44])[C:31]4[C:36]([C:37]=3[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:27])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([F:17])[CH:16]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cc(F)cc(O[Si](C)(C)C(C)(C)C)c2)c2c(N)ncnc21
Agent: Cl
Solvent: CCO
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
3-(1-(4-amino-3-(3-((tert-butyldimethylsilyl)oxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one single enantiomer (intermediate Q.2, first eluted enantiomer under the conditions described above, 40 mg, 0.065 mmol) was dissolved in a solution of 1M HCl in EtOH (0.2 ml) and stirred at room temperature for 5 hrs. The volatiles were removed under reduced pressure and the residue was purified by flash chromatography on silica gel cartridge (DCM to DCM:MeOH=97:3) to afford title compound as a white solid (28 mg, 0.056 mmol, 87%). This compound proved to be the second eluted enantiomer under Chiral HPLC conditions of Method A5: Rt=12.0 min, ee=98.6%.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)=[CH:10][C:7]=1[C:8]#[N:9].[Sn](Cl)Cl>O.Cl.[OH-].[Na+]>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([F:22])[CH:19]=1)[CH2:15][O:14][C:11]1[CH:10]=[C:7]2[C:6](=[CH:13][CH:12]=1)[NH:5][N:9]=[C:8]2[NH2:1]
Reactant: O=N[O-]
Reactant: N#Cc1cc(OCc2cc(F)cc(F)c2)ccc1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1n[nH]c2ccc(OCc3cc(F)cc(F)c3)cc12
Reaction time: 2 h
Yield: 76.4 %

Procedure:
A solution of sodium nitrite (13 gr, 190 mmol) in water (15 mL) was added dropwise to a cooled (0° C.) mixture of 2-amino-5-[(3,5-difluorobenzyl)oxy]benzonitrile (42.9 g, 165 mmol) in 37% hydrochloric acid (340 mL). After 2 hours, the resulting reaction mixture was added over a period of 1 hour to a previously prepared cooled suspension of tin(II) chloride (250 gr, 1.32 mol) in 37% hydrochloric acid (286 mL) trying to keep the temperature below 10° C. After 1 hour, the resulting reaction mixture was diluted with water (400 mL) and 35% NaOH (735 mL) was added to obtain a pH value of 9-10. The reaction mixture was extracted with EtOAc (1 L) and washed with EtOAc (2×0.5 L). Collected organic phases were dried over sodium sulfate, filtered and evaporated to dryness. The crude residue was purified by chromatography on silica gel using dichloromethane/7M NH3 in MeOH 96:4 as the eluant, affording 34.7 g of the title compound (76% yield).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH2:7][CH:8]([CH3:18])[CH2:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[C:16]#[N:17]
Reactant: CC(Cc1cccc(C#N)c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)Cc1cccc(C#N)c1

Procedure:
A solution of [2-(3-Cyano-phenyl) -1-methyl-ethyl]-carbamic acid tert-butyl ester (180 mg, 0.69 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was stirred for 15 min at room temperature. Solvents removed under vacuum, and residue was partitioned between dichloromethane and 1 N sodium hydroxide. Organic dried over magnesium sulfate and reduced to an oil under vacuum. M+1=161.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:25]=[CH:24][C:11]([CH2:12][N:13]2[C:17]3[N:18]=[CH:19][CH:20]=[C:21](O)[C:16]=3[C:15]([CH3:23])=[N:14]2)=[CH:10][CH:9]=1>ClC(Cl)C>[Cl:3][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[N:13]([CH2:12][C:11]3[CH:24]=[CH:25][C:8]([O:7][CH3:6])=[CH:9][CH:10]=3)[N:14]=[C:15]([CH3:23])[C:16]=12
Reactant: COc1ccc(Cn2nc(C)c3c(O)ccnc32)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Temperature: 115 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a 500 mL round bottom flask was added phosphorous oxychloride (6.63 mL, 72.4 mmol) followed by dichloroethane (120 mL). 1-(4-Methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (6.5 g, 24.1 mmol), prepared according to the procedure of Example 5, Step B, was added directly as a solid. The reaction mixture was stirred for 1 hour at refluxing temperature (115° C.) under N2. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduce pressure. Any remaining solvent was removed by toluene azeotrope (2×50 mL). The resulting crude material was dissolved in dichloromethane (50 mL), and saturated NaHCO3 was added slowly until vigorous bubbling ceased. The biphasic mixture was diluted with additional dichloromethane and aqueous sodium bicarbonate and the organic layer washed separated, washed with brine, dried over sodium sulfate and evaporated to afford 6.6 g of off-white solid. The crude was chromatographed on Silica (Biotage 40M) loading with dichloromethane and eluting with 80/20 hexanes/ethyl acetate to obtain the product (6.0 g, 87%) as a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J=5.1 Hz, 1H), 7.24 (d, J=5.1 Hz, 1H), 7.15 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0 Hz, 2H), 5.46 (s, 2H), 3.64 (s, 3H), 2.57 (s, 3H).
Reaction SMILES: Br[Si](C)(C)C.C([O:8][P:9]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([O:11]CC)=[O:10])C>C(#N)C>[OH:10][P:9]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)([OH:11])=[O:8]
Reactant: CCOP(=O)(OCC)c1ccc(O)cc1
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: O=P(O)(O)c1ccc(O)cc1
Reaction time: 1 h

Procedure:
Bromotrimethylsilane (1 ml) was added to 24 (0.5 g) in dry acetonitrile (10 ml) and the solution was refluxed for 24 h. The volatiles were removed under reduced pressure and acetonitrile (20 ml) was added to the residue and the solution stirred for 1 hour. The volatiles were removed under reduced pressure to yield 25 in quantitative yield, which was used without further purification in the next step. 1H NMR (DMSO-d6, 25° C., 500 MHz) δ 8.6 (br s, 3H, COH/POH), 7.49 (dd, 2H, ArH, J=12.5/8.5 Hz), 6.81 (dd, 2H, ArH, J=8.5/3.0 Hz); 13C NMR (DMSO-d6, 25° C., 126 MHz) δ 159.82 (d, 4JP-C=3.3 Hz), 132.52 (d, 2JP-C=11.3 Hz), 123.47 (d, 1JP-C=189.4 Hz), 114.92 (d, 3JP-C=15.3 Hz); 31P NMR (DMSO-d6, 25° C., 243 MHz) δ 14.69. Crystal/refinement details for 25a: C10H15O4P, M=230.19, F (000)=488 e, monoclinic, P21/n (No. 14), Z=4, T=100(2) K, a=8.5520(3), b=15.5263(4), c=8.6384(2) Å, β=92.433(2)°, V=1145.98(6) Å3, Dc=1.334 gcm−3, μMo=0.232 mm−1, sin θ/λmax=0.7035, N (unique)=3340 (merged from 13120, Rint=0.0303, Rsig=0.0306), No (I>2σ(I))=2694, R=0.0350, wR2=0.0948 (A, B=0.06, 0.1), GOF=1.003, |Δρmax|=0.41(6) e Å−3.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([CH2:21][NH:22][C:6](=[O:8])[CH2:5][C:4](=[O:3])[CH3:9])=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)NCc1ccc(C(C)(C)C)cc1
Temperature: 130 °C
Yield: 55.9 %

Procedure:
2,2,6-Trimethyl-4H-1,3-dioxin-4-one (1.6 ml, 12.09 mmol) and (4-tert-butylphenyl)methanamine (2.0 ml, 11.36 mmol) were dissolved in toluene (2 ml) and heated at 130° C. for 28 hours. Reaction was cooled to room temperature and diluted with EtOAc (40 ml). The organic phase was washed with HCl (2*30 ml, 1M) and NaHCO3 (2*30 ml, sat aq), dried over MgSO4 and evaporated. The crude product was purified by precipitation from toluene/pet.ether to give 1.57 g (56%) of N-(4-tert-butylbenzyl)-3-oxobutanamide as a pale powder.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH2:12]([NH2:14])[CH3:13]>CO.O1CCCC1>[CH2:12]([NH:14][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:13]
Reactant: CCN
Reactant: ClCCCOc1cccnc1
Solvent: CO
Solvent: C1CCOC1
Product: CCNCCCOc1cccnc1
Temperature: 100 °C
Yield: 38.1 %

Procedure:
The 3-chloro-1-(3-pyridyloxy)propane (1.00 g, 5.84 mmol) was dissolved in methanol (50 mL) and added to a 2.0 M solution of ethylamine in tetrahydrofuran (5 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH of the solution was adjusted to 6, and impurities were extracted with ether (3×15 mL). The aqueous layer was basified to pH 10 with 10% NaOH solution and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 400 mg (38.1%) of an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C)[C:5]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([C:21]([OH:24])([CH3:23])[CH3:22])=[C:15]([O:25][CH3:26])[CH:14]=2)=[CH:4][N:3]=1.[OH-].[K+]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([O:25][CH3:26])[C:16]([C:21]([OH:24])([CH3:23])[CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2NC(C)=O)cc(OC)c1C(C)(C)O
Agent: [K+]
Agent: [OH-]
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1C(C)(C)O
Temperature: 10 °C

Procedure:
A suspension of 11.3 g. of N-{2-amino-5-[4-(1-hydroxy-1-methyl-ethyl)-3,5-dimethoxy-benzyl]-4-pyrimidinyl}-acetamide in 40 ml. of 10% methanolic potassium hydroxide was boiled at reflux for 1 hour and then cooled to about 10°C. The crystals were removed by filtration with suction and washed with a small amount of methanol. After crystallization from methanol, there was obtained 4-[(2,4-diamino-5-pyrimidinyl)-methyl]-2,6-dimethoxy-α,α-dimethyl-benzyl alcohol having a m.p. of 248°-250°C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>CCOC(C)=O.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.CCO>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1cc(-c2ccccc2)nc(Cl)n1
Yield: 110.1 %

Procedure:
A mixture of 2,4,6-trichloropyrimidine 8 (1 g, 5.45 mmol), phenylboronic acid (665 mg, 5.45 mmol), Pd(PPh3)4 (100 mg) and 2N aqueous Na2CO3 (4.1 mL) in 1:1 toluene:EtOH (15 mL) was heated in a microwave at 120° C. for 20 min. The reaction mixture was diluted with EtOAc and washed with H2O and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give 2,4-dichloro-6-phenylpyrimidine as a solid (1.35 g), which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]2([C:19]([F:22])([F:21])[F:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.C(N=C=NCCCN(C)C)C.[N:35]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37][CH2:36]1.Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[N:35]1([S:39]([NH:42][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([O:12][CH2:13][C:14]3([C:19]([F:21])([F:22])[F:20])[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:4][C:5]=2[F:11])(=[O:41])=[O:40])[CH2:38][CH2:37][CH2:36]1
Reactant: O=C(O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCC2)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2(C(F)(F)F)CCCC2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
To a stirred solution of 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclopentyl)-methoxy)benzoic acid (0.34 g, 1.00 mmol) in dichloromethane (20 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g, 1.50 mmol) and 4-dimethylaminopyridine (0.28 g, 2.30 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes, azetidine-1-sulfonamide (0.20 g, 1.50 mmol) was added and the stirring was continued at ambient temperature for 17 hours. 5% aqueous hydrochloric acid solution (10 mL) were added and diluted with ethyl acetate (100 mL), washed with water and brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (30% ethyl acetate in hexanes) afforded the title compound (0.22 g, 46%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.61 (br s, 1H), 8.11 (d, J=7.2 Hz, 1H), 6.69 (d, J=12.9 Hz, 1H), 4.22 (br s, 4H), 4.03 (s, 2H), 2.31-2.17 (m, 2H), 2.08-1.92 (m, 2H), 1.89-1.70 (m, 6H); MS (ES+) m/z 459.0, 461.0 (M+1); MS (ES−) m/z 457.1, 459.1 (M−1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][N:9]([CH2:13][C:14]1[S:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[C:10]([NH2:12])=[S:11])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]1)=O>CO>[C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][N:9]([C:10]1[S:11][CH:22]=[C:23]([C@H:25]2[CH2:26][CH2:27][C@H:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:29][CH2:30]2)[N:12]=1)[CH2:13][C:14]1[S:15][C:16]([CH3:19])=[CH:17][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(CN(CCC(=O)OC(C)(C)C)C(N)=S)s1
Reactant: CC(C)(C)[C@H]1CC[C@H](C(=O)CBr)CC1
Solvent: CO
Product: Cc1ccc(CN(CCC(=O)OC(C)(C)C)c2nc([C@H]3CC[C@H](C(C)(C)C)CC3)cs2)s1

Procedure:
3-[1-(5-methyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (100 mg, 0.318 mmol) in MeOH (about 4 mL) was treated with two portions of 2-Bromo-1-(trans-4-tert-butyl-cyclohexyl)-ethanone (2×83 mg, 2×0.318 mmol) (second addition spaced at an interval of 2 hours after first portion) at 60° C. following a method analogous to General Procedure C to produce 3-[[4-(trans-4-tert-Butyl-cyclohexyl)-thiazol-2-yl]-(5-methyl-thiophen-2-ylmethyl)-amino]propionic acid tert-butyl ester (158 mg). which was isolated by a workup that included evaporation of the solvent and partitioning the resulting material between EtOAc and saturated aq sodium bicarbonate solution. Extraction of the aq sodium bicarbonate layer with EtOAc (2 times), drying the combined organic portion over sodium sulfate and evaporation of the solvent gave the crude material which was purified using silica gel chromatography (eluent hexanes→19:1 ethyl acetate:hexanes→9:1 ethyl acetate:hexanes).
Reaction SMILES: [Mg].[F:2][C:3]([F:16])([F:15])[C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([CH3:28])[CH:26]=2)[N:21]=[C:20]([CH3:29])[CH:19]=1.[F:30][C:31]([F:45])([F:44])[C:32]1[CH:33]=[C:34]([Mg:42][Br:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>O.C1COCC1>[F:45][C:31]([F:30])([F:44])[C:32]1[CH:33]=[C:34]([Mg:42][Br:43])[CH:35]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:37]=1.[F:2][C:3]([F:16])([F:15])[C:4]1[CH:5]=[C:6]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH3:28])[CH:26]=3)[N:21]=[C:20]([CH3:29])[CH:19]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: Cc1ccc2nc(C)cc(Cl)c2c1
Agent: FC(F)(F)c1cc([Mg]Br)cc(C(F)(F)F)c1
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2nc(C)cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Magnesium (1.60 g) was added to THF (60 ml) in a nitrogen atmosphere and 3,5-bis (trifluoromethyl)phenylbromide (17.58 g) was dropped. The resulting mixture was stirred for 30 minutes at room temperature and a THF solution of 3,5-bis (trifluoromethyl)phenylmagnesiumbromide was prepared. In a nitrogen atmosphere, 4-chloro-2,6-dimethylquinoline (2.88 g) and Ni(dpp)Cl2 (500 mg) were added to THF (30 ml) and dispersed. The THF solution of 3,5-bis(trifluoromethyl)phenylmagnesiumbromide prepared as above was dropped to the suspension and the resulting solution was stirred for 4 days at room temperature. Water was poured into the reaction solution, impurities were filtered, and extraction was performed using AcOEt (ethyl acetate). A drying process was applied using Na2SO4 and the solvent was removed under a reduced pressure. The residue was purified through a silica gel column (hexane/ethyl acetate=3/2) to obtain 4-(3,5-bis(trifluoromethyl)phenyl)-2,6-dimethylquinoline (4.40 g) represented by the following chemical formula (49).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][C:27]2[O:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][C:27]2[O:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Sc2c(NCc3ccco3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Sc2c(NCc3ccco3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 25 °C

Procedure:
The mixture of 2.3 g of 4-(4-acetamidophenylmercapto)-3-furfurylamino-5-sulfamoylbenzoic acid and 23 ml of 2N aqueous sodium hydroxide is refluxed for 1 hour under nitrogen. After cooling to room temperature it is acidified to pH = 5 and the precipitate formed filtered off. It is dissolved in 25 ml of 50% hot aqueous ethanol, the solution cooled to room temperature and decanted from some amorphous substance. The supernatant solution is allowed to stand at room temperature for a longer period of time, the precipitate formed filtered off and this rcrystallization procedure repeated several times, to yield the 4-(4-aminophenylmercapto)-3-furfurylamino-5-sulfamoylbenzoic acid, starting to melt at about 125°.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=O)[CH:7]([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:27]1[C:31]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:40][C@H:41]([OH:51])[C@@H:42]([NH2:50])[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:34][CH:33]=2)=[CH:30][N:29]=[CH:28]1>CN(C=O)C>[S:27]1[C:31]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:40][C@H:41]([OH:51])[C@@H:42]([NH:50][C:10](=[O:12])[C@H:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:34][CH:33]=2)=[CH:30][N:29]=[CH:28]1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)OC(C)(C)C)C(C)C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, 2.66 g (15.2 mmol) of N-methoxycarbonyl-(L)-valine, 5.46 g (28.5 mmol) of EDC and 2.57 g (19 mmol) of HOBT are dissolved in 42 ml of DMF. 7.9 ml (57 mmol) of TEA are added and after 20 min a solution of 4.46 g (9.5 mmol) of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane (Example 2b) in 85 ml of DMF is added dropwise. After 1.5 hours, the reaction mixture is worked up analogously to Example 2c. Crystallisation from THF/ether yields the title compound: m.p: 114-115° C.; HPLC20-100 :tRet =15.1; FAB MS (M+H)+ =626.