Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH:13]1(B(O)O)[CH2:15][CH2:14]1>>[CH:13]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=2)[CH2:15][CH2:14]1
Reactant: COC(=O)c1ccc(Br)cc1F
Reactant: OB(O)C1CC1
Product: COC(=O)c1ccc(C2CC2)cc1F

Procedure:
The title compound was prepared from methyl 4-bromo-2-fluorobenzoate and cyclopropylboronic acid according to the procedure for the preparation of EXAMPLE 152, part A. 1H NMR (400 MHz, CDCl3): δ 0.74-0.78 (2H, m), 1.04-1.09 (2H, m), 1.87-1.94 (1H, m), 3.90 (3H, s), 6.75-6.79 (1H, m), 6.86-6.89 (1H, m), 7.79-7.82 (1H, m).
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:7]=1F.C1COCC1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:7]=1[S:3][CH2:1][CH3:2]
Reactant: Fc1cc(SC(F)(F)F)ccc1Br
Reactant: CC[S-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCSc1cc(SC(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
0.21 g of sodium ethanethiolate (80%) was added to a mixture of 0.55 g of l-bromo-2-fluoro-4-trifluoromethylsulfanylbenzene and 4 ml of THF under ice cooling, and the mixture was stirred at room temperature for 30 minutes. 2 mL of DMF was added to the reaction mixture, and the mixture was stirred at 80° C. for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate and then dried with anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.37 g of 1-bromo-2-ethylsulfanyl-4-trifluoromethylsulfanylbenzene.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23])[CH2:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].[CH3:26][N:27]1[C:31]([C:32]2[N:36]([CH3:37])[N:35]=[CH:34][CH:33]=2)=[CH:30][C:29]([C:38](O)=[O:39])=[CH:28]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[O:14]=[C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:13])[N:4]1[CH2:3][C@@H:2]([NH:1][C:38]([C:29]1[CH:30]=[C:31]([C:32]2[N:36]([CH3:37])[N:35]=[CH:34][CH:33]=2)[N:27]([CH3:26])[CH:28]=1)=[O:39])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:23])[F:24]
Reactant: Cn1cc(C(=O)O)cc1-c1ccnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.97 mmol)[prepared according to Preparation 5], 1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxylic acid (339 mg, 0.97 mmol) and N,N-diisopropylethylamine (0.85 ml, 4.87 mmol) in dichloromethane (4.873 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (501 mg, 1.07 mmol) in one portion. The solution was stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxamide (522 mg, 0.93 mmol, 95% yield) as a white foam: LCMS (ES) m/e 536 (M+H)+.
Reaction SMILES: [CH:1]([N:3]1[C:15]2[C:14]([O:16][CH3:17])=[CH:13][CH:12]=[C:11]([S:18](Cl)(=[O:20])=[O:19])[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:2].C([N:24]([CH2:27][CH3:28])CC)C>C(Cl)(Cl)Cl>[CH:1]([N:3]1[C:15]2[C:14]([O:16][CH3:17])=[CH:13][CH:12]=[C:11]([S:18]([NH:24][C:27]3[CH:28]=[CH:4][C:9]([CH3:10])=[CH:8][CH:7]=3)(=[O:20])=[O:19])[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:2]
Reactant: CCN(CC)CC
Reactant: COc1ccc(S(=O)(=O)Cl)c2c3ccccc3n(C=O)c12
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)Nc2ccc(C)cc2)c2c3ccccc3n(C=O)c12
Yield: 75 %

Procedure:
Intermediate 63 (0.2 g, 0.62 mM) was dissolved in 50 ml of chloroform. To it was added p-toludine (0.165 g, 1.54 mM) and 0.16 g triethylamine. The reaction was refluxed for 15 hrs. Solvent was evaporated and the residue was taken up in ethyl acetate. The organic layer was washed with 10% HCl solution, brine and then dried over anh Na2SO4. It was then evaporated to obtain the crude residue which was then purified over silica gel column using ethylacetate-hexane system to obtain the desired compound as beige solid with a yield of 75% (0.18 g); mp 193-199° C.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].Cl.[NH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]1.[OH-].[Na+]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:11][CH:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: OC1CCC(Nc2nc(Cl)nc(Cl)n2)CC1
Temperature: 2.5 °C

Procedure:
To cyanuric chloride (1.2209 g, 6.6 mmol) dissolved in acetone (15 mL) stirring at 0-5° C., was added a solution of trans-4-aminocyclohexanol hydrochloride (1.0044 g, 6.6 mmol) in acetone (15 mL) followed by the addition of 2.5 N NaOH (5.3 mL, 13.2 mmol). The reaction mixture was allowed to stir at 0-5° C. for 1 hour under nitrogen. The reaction mixture was extracted 3 times with dichloromethane; the combined organic layers were washed with brine solution and dried over sodium sulfate. The filtered sample was concentrated by rotary evaporation and the resulting solid was dried overnight under vacuum. The product was used with no further purification, (155a, 1.49 g, 86%), mp 120° C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 6.1 min, 92.6% purity.
Reaction SMILES: [NH2:1][C:2](=[N:21][OH:22])[C:3]1[CH:4]=[CH:5][C:6]([F:20])=[C:7]([CH:19]=1)[CH2:8][N:9]([CH3:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH3:23][O:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[CH3:41])[C:29](O)=O>>[F:20][C:6]1[CH:5]=[CH:4][C:3]([C:2]2[N:1]=[C:29]([C:28]3[CH:32]=[CH:33][C:34]([N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]4[CH3:41])=[C:26]([CH2:25][O:24][CH3:23])[CH:27]=3)[O:22][N:21]=2)=[CH:19][C:7]=1[CH2:8][N:9]([CH3:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: COCc1cc(C(=O)O)ccc1N1CCCCC1C
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cc(C(N)=NO)ccc1F
Product: COCc1cc(-c2nc(-c3ccc(F)c(CN(C)CC(=O)OC(C)(C)C)c3)no2)ccc1N1CCCCC1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 60 (256.87 mg; 0.83 mmol) and Intermediate 58 (197.50 mg; 0.75 mmol). The reaction mixture was filtered through a SPE NH2 column (10 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.31 (d, J=2.1 Hz, 1H), 8.22 (dd, J=7.0, 2.2 Hz, 1H), 8.11-8.06 (m, 2H), 7.23-7.14 (m, 2H), 4.67-4.55 (m, 2H), 4.16-4.08 (m, 2H), 3.89 (s, 2H), 3.49 (s, 3H), 3.27 (s, 2H), 3.18-3.12 (m, 1H), 3.06-2.99 (m, 1H), 2.67-2.59 (m, 1H), 2.46 (s, 3H), 1.89-1.76 (m, 2H), 1.73-1.65 (m, 2H), 1.51 (s, 9H), 0.89 (d, J=6.3 Hz, 3H). LC/MS (Method B): 539.4 (M+H)+. HPLC (Method A) Rt 3.84 min (Purity: 99.1%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:12][CH:13]([Cl:32])[C:14]([N:16]1[C@H:20]([CH2:21][F:22])[C@@H:19]([C:23]2[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=2)[O:18][C:17]1([CH3:31])[CH3:30])=[O:15]>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.O>[Cl:12][CH:13]([Cl:32])[C:14]([N:16]1[C@H:20]([CH2:21][F:22])[C@@H:19]([C:23]2[CH:28]=[CH:27][C:26]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=3)=[CH:25][CH:24]=2)[O:18][C:17]1([CH3:31])[CH3:30])=[O:15]
Reactant: CC1(C)O[C@H](c2ccc(I)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Reactant: OCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CO)cc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Temperature: 80 °C
Yield: 67 %

Procedure:
A mixture of (4-(hydroxymethyl)phenyl)boronic acid (2.5 g, 16.8 mmol), 2,2-dichloro-1-((4S,5R)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyloxazolidin-3-yl)ethanone (5.0 g, 11.21 mmol) Cs2CO3 (7.3 g, 22.4 mmol) and Pd(PPh3)4 (1.3 g, 1.12 mmol) dioxane (100 mL) and water (30 mL) is heated at 80° C. for 4 hours under nitrogen. Reaction is cooled, washed with water (30 mL), dried over Na2SO4, and concentrated to a syrup. Crude compound adsorbed on celite and purified on silica gel column eluting from 10% to 50% EtOAC/heptane to get the title compound (3.2 g): 1H NMR (400 MHz, CDCl3) δ: (1H NMR) 1.68 (bs, 3H), 1.75 (bs, 3H), 4.50-4.75 (m, 2H), 4.78 (d, 2H, J=6.0 Hz) 4.80-4.87 (m, 0.5H) 5.0-5.13 (br, 1H), 5.14-5.3 (m, 0.5H), 6.2-6.41 (br, 1H), 7.48 (d, 1H, J−8 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.62 (d, 1H, J=8.0 Hz), 7.65 (d, 1H, J=8.0 Hz), (m/z (Cl) 368 [M-(CH3)2CO].
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[C:17]([NH:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:44]2[CH2:45][CH2:46][CH:41]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:42][CH2:43]2)=[O:14])=[CH:10][C:9]=1[C:17]([NH:19][C:20]1[CH:21]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1ccc(Cc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(=O)N2CCC(Cc3ccccc3)CC2)ccc1Cc1ccccc1
Yield: 76.7 %

Procedure:
Using 4-benzyl-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid and 4-benzylpiperidine as the raw materials, the same operation as the example 84(3) gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.[C:16](=O)(O)[O-].[Na+]>CO.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([O:13][CH3:16])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])O
Reactant: COc1cccc(C(C)(C)CC(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(C)(C)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
3-(3-Methoxyphenyl)-3-methylbutanoic acid 85.D (0.22 g, 1.1 mmol) was dissolved in MeOH (11 mL) and a catalytic amount (˜5 drops) of sulfuric acid was added. The solution was heated to reflux and stirred overnight. The reaction was cooled to room temperature and saturated sodium bicarbonate was added to neutralize the reaction. The mixture was then concentrated and the residue taken up in EtOAc and washed with water (2×30 mL), 1M lithium chloride solution (1×30 mL) and brine (1×30 mL) and dried over magnesium sulfate to give the desired product methyl 3-(3-methoxyphenyl)-3-methylbutanoate 85.E (0.227 g, 97% yield). MS ESI (pos.) m/e: 240.1 (M+H2O)+.
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[C:8]1[C:9]([N:19]2[CH2:24][C@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]2)=[C:10]([F:18])[C:11]([F:17])=[C:12]([C:14](=[O:16])[CH3:15])[CH:13]=1)(C)(C)C.Cl.O>O1CCOCC1>[CH3:25][C@H:23]1[O:22][C@@H:21]([CH3:26])[CH2:20][N:19]([C:9]2[C:8]([CH2:7][OH:6])=[CH:13][C:12]([C:14](=[O:16])[CH3:15])=[C:11]([F:17])[C:10]=2[F:18])[CH2:24]1
Reactant: CC(=O)c1cc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1cc(CO)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-4-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-2,3-difluoro-phenyl]-ethanone (Intermediate 9, 7.2 g, 28 mmol) and 4N HCl in dry dioxane (75 mL) was stirred at room temperature for 12 hours. The reaction mixture was treated with cold water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases combined were dried (Na2SO4) and concentrated. The residue was purified over a silica gel flash column using a gradient of ethyl acetate in pet. ether to give the title compound as yellow solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:32])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[C:28]([O:30]C)=[O:29])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+].C(O)(=O)C.O>CO>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:32])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[C:28]([OH:30])=[O:29])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cn(CC2CC2)c(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C(=O)O)c2c1
Reaction time: 0.5 h

Procedure:
To a solution of the product of step iv) (1.5 g) in methanol (20 mL) at reflux was added sodium hydroxide (1N, 5.23 mL) and the solution stirred at this temperature for 30 min. The reaction mixture was treated with acetic acid (0.34 mL) and water and stirred overnight at room temperature. The solid was filtered and washed with methanol:water (1:1) then water. The solid was dried under vacuum at 60° C. to yield the sub-title compound (1.25 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:19]([OH:21])=O)=[N:4][C:5]([N:12]([CH3:18])[S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl-].[CH3:23][NH:24][C:25]([C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34][NH3+:35])=[O:26].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:16]([S:13]([N:12]([CH3:18])[C:5]1[N:4]=[C:3]([C:19]([NH:35][CH2:34][C:28]2[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=2[C:25]([NH:24][CH3:23])=[O:26])=[O:21])[C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:14])=[O:15])[CH3:17]
Reactant: CCS(=O)(=O)N(C)c1nc(C(=O)O)c(O)c2ncccc12
Reactant: CNC(=O)c1cc(F)ccc1C[NH3+]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(C)c1nc(C(=O)NCc2ccc(F)cc2C(=O)NC)c(O)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Hydroxy-5-[methyl(ethylsulfonyl)amino]-1,6-naphthyridine-7-carboxylic acid was coupled with {2-[(methylamino)carbonyl]4-fluorophenyl}methanaminium chloride (prepared as described in Example 3). A solution of 8-Hydroxy-5-[methyl(ethylsulfonyl)amino]-1,6-naphthyridine-7-carboxylic acid (50 mg, 0.16 mmol) in dry DMF (15 mL) was stirred at zero degrees. To this was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol), 1-hydroxy-7-azabenzotriazole (28 mg, 0.21 mmol). The mixture was stirred for 35 minutes at which time the {4-fluoro-2-[(methylamino)carbonyl]phenyl}-methanaminium chloride (38 mg, 0.21 mmol) and diisopropylethylamine (27 mg, 0.21 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was filtered through a glass fiber filter. The filtrate was vacuum reduced and purified by preparative HPLC (Gilson semi preparative HPLC system using a Waters Nova pak column (10×40 mm I.D. cartridges, C18, 6 μM pore size) eluting with 95-5% water (0.025% TFA)/acetonitrile (0.025% TFA) at 35 mL/min). The desired fractions were freeze dried to give the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:31]4[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=4)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(-c4cccnc4)ccc3C2=O)cc1
Reaction time: 0.33 h
Yield: 59 %

Procedure:
The procedure of Example 2 was repeated except that N-(2-aminophenyl)-4-((5-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 56 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3-pyridyl boronic acid instead of phenyl boronic acid were used, and the reaction was performed for 20 mins, to obtain the title compound (59%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=CC=1.IC1C=C2C(=CC=1)C(=[O:41])NC(=O)C2=COC.NCC1C=CC(C2C=COC=2)=C(O)C=1>>[O:41]1[CH:27]=[CH:28][CH:29]=[C:24]1[C:3]1[CH:4]=[CH:5][C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])=[CH:7][C:2]=1[OH:1]
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Agent: NCc1ccc(-c2ccoc2)c(O)c1
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccco2)c(O)c1
Yield: 53 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (80 mg, 0.24 mmol) and 5-Aminomethyl-2-furan-3-yl-phenol (50 mg, 0.26 mmol) in 53% yield: MS (ESI): 485.1 (M−1)−1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C@H:8]([C:44]1[C:52]2[S:51][C:50](=[O:53])[NH:49][C:48]=2[C:47]([OH:54])=[CH:46][CH:45]=1)[CH2:9][N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:43][CH2:42][C:30]2([O:35][CH2:34][CH2:33][N:32](C(=O)C(F)(F)F)[CH2:31]2)[CH2:29][CH2:28]1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]>O.CO>[O:35]1[C:30]2([CH2:29][CH2:28][N:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:10]([CH2:9][C@H:8]([OH:7])[C:44]3[C:52]4[S:51][C:50](=[O:53])[NH:49][C:48]=4[C:47]([OH:54])=[CH:46][CH:45]=3)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:43][CH2:42]2)[CH2:31][NH:32][CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCCN1CCC2(CC1)CN(C(=O)C(F)(F)F)CCO2)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCCCCCCCN1CCC2(CC1)CNCCO2)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of potassium carbonate (165 mg) in water (24 mL) was added to a solution of (R)-tert-butyl 2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl(9-(4-(2,2,2-trifluoroacetyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)nonyl)carbamate (example 183-222, step c) (495 mg) in MeOH (24 mL). The resulting mixture was stirred at RT for 4 h. Methanol was removed by evaporation under a stream of nitrogen keeping the reaction mixture at 30° C. Water (20 mL) and brine (80 mL) were added and the mixture was extracted with EtOAc (5×60 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The brown solid residue was purified by silica gel chromatography eluting with 0-20% (2M NH3 in MeOH)/DCM to give the subtitled compound as a yellow solid. Yield 323 mg.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:29][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4C)c3O2)cc1
Product: CNCC1Cc2cc(F)cc(-c3ccccc3C)c2O1

Procedure:
The title compound was prepared (0.038 g, 34%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.36 mmol) and methylamine (0.112 g, 3.60 mmol). mp 102-104° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[CH2:9][N:8]([C:22](=[O:30])[NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:22]([NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)=[O:30])[C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Reaction time: 1 h
Yield: 99.4 %

Procedure:
The t-butyl 5-bromo-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (54.2 mg, 0.105 mmol) obtained in Example 1 was dissolved in methylene chloride (0.5 mL). Thereafter, trifluoroacetic acid (0.5 mL) was added to the above obtained solution at room temperature, and the obtained mixture was then stirred for 1 hour. The reaction solution was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and a solid was then collected by filtration, followed by drying, to obtain the captioned compound (43.2 mg, 100%) in the form of a white solid.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[S:39](Cl)(=[O:41])=[O:40]>O1CCCC1.[Cl-].[Na+].O>[C:1]1([C:7]2[N:11]([S:39]([C:35]3[S:34][CH:38]=[CH:37][CH:36]=3)(=[O:41])=[O:40])[CH:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOC(=O)c1c[nH]c(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2cccs2)c1
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution (20 mL) of ethyl 5-phenyl-1H-pyrrole-3-carboxylate (440 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 123 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (675 mg) was added dropwise and the mixture was stirred for 30 min. 2-Thiophenesulfonyl chloride (485 mg) was added, and the mixture was further stirred for 1 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3), and crystallized from diisopropyl ether.hexane to give the title compound as colorless crystals (yield 710 mg, 96%).