Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1)[CH2:3][NH2:4].[CH2:13]([O:15][C:16](=[O:28])[CH2:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[C:20](F)[C:19]=1[F:27])[CH3:14]>CS(C)=O>[CH2:13]([O:15][C:16](=[O:28])[CH2:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[C:20]([NH:4][CH2:3][C:2]([F:1])([F:12])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=2)[C:19]=1[F:27])[CH3:14]
Reactant: Cc1cccc(C(F)(F)CN)n1
Reactant: CCOC(=O)Cc1c(C#N)ccc(F)c1F
Solvent: CS(C)=O
Product: CCOC(=O)Cc1c(C#N)ccc(NCC(F)(F)c2cccc(C)n2)c1F
Temperature: 150 °C
Yield: 42.5 %

Procedure:
A mixture of 2,2-Difluoro-2-(6-methyl-pyridin-2-yl)-ethylamine (223.6 mg, 1.3 mmol), as prepared in the preceding step, and (6-cyano-2,3-difluoro-phenyl)-acetic acid ethyl ester (225 mg, 1.0 mmol), as prepared in Example 2f, was dissolved in DMSO (1.0 mL) and heated at 150° C. under microwave irradiation for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The combined EtOAc extracts were dried over Na2SO4 and evaporated. The crude product was purified by flash column chromatography on silica gel (EtOAc/hexanes 2/1, v/v) to afford the product as a white solid (208 mg, 42.5% yield based on the initial amine). 1H NMR (CDCl3) δ 7.71 (t, J=8.02 Hz, 1H), 7.47 (d, J=8.15 Hz, 1H), 7.30 (dd, J=8.61 and 1.28 Hz, 1H), 7.25 (m, 1H), 6.79 (t, J=8.28 Hz, 1H), 4.18 (q, J=7.16 Hz, 2H), 4.12 (t, J=13.21 Hz, 2H), 3.81 (d, J=2.0 Hz, 2H), 2.60 (s, 3H), 1.27 (t, J=7.13 Hz, 3H); LC/MS (m/z) [M+1] 378.3 (calculated for C19H19F3N3O2, 378.1).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[Cl:15][C:16]1[C:17]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[C:18]2[C:23](=[CH:24][C:25]=1[Cl:26])[N:22]=[C:21]([O:27][CH3:28])[C:20]([O:29][CH3:30])=[N:19]2.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][C:16]1[C:17]([N:31]([CH2:2][CH2:3][N:4]2[C:8](=[O:9])[C:7]3=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]3[C:5]2=[O:14])[S:32]([CH3:35])(=[O:34])=[O:33])=[C:18]2[C:23](=[CH:24][C:25]=1[Cl:26])[N:22]=[C:21]([O:27][CH3:28])[C:20]([O:29][CH3:30])=[N:19]2
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: COc1nc2cc(Cl)c(Cl)c(NS(C)(=O)=O)c2nc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1nc2cc(Cl)c(Cl)c(N(CCN3C(=O)c4ccccc4C3=O)S(C)(=O)=O)c2nc1OC
Reaction time: 48 h
Yield: 85.5 %

Procedure:
N-(2-bromoethyl)phthalimide (1.73 g, 6.81 mmol) was added to a refluxing mixture of N-(6,7-dichloro-2,3-dimethoxy-quinoxalin-5-yl)-methanesulphonamide (2.00 g, 5.68 mmol) and potassium carbonate (1.88 g, 13.63 mmol) in acetone (100 ml) under nitrogen. After 48 hours, further N-(2-bromoethyl)phthalimide (1.73 g, 6.81 mmol) was added and refluxing continued for 18 hours. After cooling the mixture was concentrated under reduced pressure and the residue dissolved in dichloromethane. The resulting solution was washed twice with 1N sodium hydroxide solution, water and brine and then dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with hexane:ethyl acetate) to afford N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-phthalimidoethyl)methanesulphonamide as a pale yellow solid (2.55 g, 85%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]([NH2:37])[CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:31]1([CH2:30][CH2:29][CH2:28][CH:27]([NH:37][C:14]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH2:26][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-2-carboxylic acid (3 g; 13.1 mmol) is dissolved in methylene chloride (100 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (4.77 g; 15.7 mmol), diisopropylethylamine (7.3 mL; 41.9 mmol), and PyBOP (8.17 g; 15.7 mmol) are added sequentially. The mixture is stirred for 17 hours at ambient temperature then concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (10%→30% ethyl acetate in hexanes) affording the desired product as an oil. ESMS: MH− 479.4
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:34])[C@H:8]([CH2:31][CH2:32][CH3:33])[NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18](C3C=CC(S(C)(=O)=O)=CC=3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH2:5][CH2:4]1)#[N:2].[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:41]=1[F:42]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[C:1]([C:3]1([NH:6][C:7](=[O:34])[C@@H:8]([NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([C:38]3[CH:39]=[CH:40][C:41]([F:42])=[C:36]([F:35])[CH:37]=3)=[CH:17][CH:16]=2)[C:11]([F:12])([F:14])[F:13])[CH2:31][CH2:32][CH3:33])[CH2:5][CH2:4]1)#[N:2]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CCC[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCC[C@H](N[C@@H](c1ccc(-c2ccc(F)c(F)c2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1

Procedure:
The title compound was prepared in similar manner to that described for N1-(1-cyanocyclopropyl)-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-norvalinamide via Suzuki cross-coupling between 3,4-difluorophenylboronic acid and N2-[(1)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-norvalinamide in the presence of 1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), dichloromethane complex.
Reaction SMILES: [F:1][C:2]([F:15])([C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8])[CH:3]=[CH2:4].[Cl:16][SiH:17]([Cl:19])[Cl:18]>C1(C)C(C)=CC=CC=1>[F:1][C:2]([F:15])([C:5]([F:13])([F:14])[C:6]([F:11])([F:12])[C:7]([F:9])([F:8])[F:10])[CH2:3][CH2:4][Si:17]([Cl:19])([Cl:18])[Cl:16]
Reactant: C=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Cl[SiH](Cl)Cl
Solvent: Cc1ccccc1C
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CC[Si](Cl)(Cl)Cl
Temperature: 140 °C
Reaction time: 0.13 h
Yield: 92 %

Procedure:
123 g (0.5 mol) of 3,3,4,4,5,5,6,6,6-nonafluorohexene and 76 g (0.5 mol) of trichlorosilane together with 0.34 g of CPC 072 (Pt(0)-divinyltetramethyldisiloxane in xylene; concentration Pt:3,3,4,4,5,5,6,6,6-nonafluorohexene=1:20,000) are charged to a 250 ml laboratory steel autoclave. The autoclave is closed and heated to 140° C. in an oil bath over 70 minutes. The exothermic reaction begins after about 8 minutes, the reaction mixture rising to 165° C. It is subsequently cooled, the reactor is emptied, and short-path distillation gives 176 g (0.46 mol) of 3,3,4,4,5,5,6,6,6-nonafluorohexyltrichlorosilane (yield: 90%, purity: >98 area % GC-TCD).
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]2[NH:6][C:7]([C@@H:9]([NH:15][C:16](=[O:40])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:24])=[C:19]([Cl:39])[CH:18]=3)[CH2:10][CH2:11][S:12]([CH3:14])=[O:13])=[N:8][C:4]=2[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:48].ClCCl.CO.ClCl>ClCCl>[Cl:1][C:2]1[CH:42]=[CH:41][C:5]2[NH:6][C:7]([C@@H:9]([NH:15][C:16](=[O:40])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:24])=[C:19]([Cl:39])[CH:18]=3)[CH2:10][CH2:11][S:12]([CH3:14])(=[O:48])=[O:13])=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)CC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: ClCl
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](CCS(C)(=O)=O)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 46 %

Procedure:
Prepared analogously to Example 85 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfinylpropyl]-3-chloro-4-[(2S)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide and 2 equivalents of 3-chloroperoxybenzoic acid in dichloromethane/glacial acetic acid. Yield: 46%; Rf value: 0.38 (silica gel; dichloromethane/methanol=9:1); C29H35Cl2N5O6S (652.60); mass spectrum: (M+H)+=652/654/656 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:27]([O:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:26][CH:25]=[CH:24][C:23]=2[F:35])[C:18]([Cl:36])=[CH:17][N:16]=1>>[Cl:36][C:18]1[C:19]([NH:21][C:22]2[C:27]([O:28][CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:26][CH:25]=[CH:24][C:23]=2[F:35])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: Fc1cccc(OC2CCOCC2)c1Nc1nc(Cl)ncc1Cl
Product: O=C1CCCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OC4CCOCC4)n3)cc2N1

Procedure:
8-{5-Chloro-4-[2-fluoro-6-(tetrahydro-pyran-4-yloxy)-phenylamino]-pyrimidin-2-ylamino}-1,3,4,5-tetrahydro-1-benzazepin-2-one was prepared from 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(tetrahydro-pyran-4-yloxy)-phenyl]-amine in an analogous manner to Example 1221d. Title compound was isolated as a white solid (80 mg, 60%). HPLC purity 99%, LCMS 498.21 (M+H), 1H-NMR (DMSO-D6, 400 MHZ) Δ 9.47 (s, 1H), 9.13 (s, 1H), 8.77 (s, 1H), 8.15 (s, 1H), 7.33-7.30 (m, 1H), 7.11 (d, J=8.2 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.93-6.89 (m, 2H), 6.82 (d, J=8.3 Hz, 1H), 4.61-4.59 (m, 1H), 3.603.56 (m, 2H), 3.37-3.33 (m, 2H), 2.55-2.52 (m, 2H), 2.07-2.03 (m, 4H), 1.78-1.74 (m, 2H), 1.48-1.45 (m, 2H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1([C:12]2[S:16][C:15]([NH2:17])=[N:14][N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(OCC)(=O)C>[CH3:5][C:6]1([C:12]2[S:16][C:15]([N:17]=[C:1]=[O:2])=[N:14][N:13]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CC1(c2nnc(N)s2)CCCCC1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CC1(c2nnc(N=C=O)s2)CCCCC1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-(1-methylcyclohexyl)-2-amino-1,3,4-thiadiazole (6 grams) in ethyl acetate (100 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is filtered to recover the desired product 5-(1-methylcyclohexyl)-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:24][CH2:25][CH2:26]Br.O>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:26][CH2:25][Br:24])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCBr
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(OCCBr)cc1
Reaction time: 4 h

Procedure:
A mixture of 8.6 g (39 mmol) of crude N-tertiary butoxycarbonyltyramine, 27.6 g (200 mmol) of potassium carbonate and 73.3 g (390 mmol) of 1,2-dibromoethane is heated at boiling for 4 hours while stirring. The reaction mixture is cooled, and then 200 ml of water and 400 ml of ethyl acetate are added and the organic phase is separated off. After concentration by evaporation under reduced pressure, a crystalline residue remains which, after recrystallisation from 2-propanol, yields N-tertiary butoxycarbonyl-2-[p-(2-bromoethoxy)-phenyl]-ethylamine, which has a melting point of 70°-72°.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[Li]CCCC.[CH2:27]([N:34]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@@H:35]1[CH2:39][CH2:38][CH:37]([CH:40]=[O:41])[CH2:36]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[Cl:1][C:2]1[C:3]([CH:40]([CH:37]2[CH2:38][CH2:39][C@@H:35]([N:34]([CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:36]2)[OH:41])=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)c(Cl)cnc21
Reactant: O=CC1CC[C@@H](N(Cc2ccccc2)Cc2ccccc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CC[C@@H](N(Cc4ccccc4)Cc4ccccc4)C3)c(Cl)cnc21
Reaction time: 0.67 h
Yield: 67.6 %

Procedure:
A solution of 5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.23 g, 2.83 mmol, Adesis) in THF (10 mL) was cooled to about −78° C. and n-BuLi (1.6 M in hexanes, 2.3 mL, 3.7 mmol) was added drop-wise while keeping the temperature below about −70° C. The mixture was stirred for about 40 min, and a solution of (3R)-3-(dibenzylamino)cyclopentanecarbaldehyde (0.83 g, 2.8 mmol, Step B) in THF (3 mL) was added drop-wise, and the resulting mixture was stirred at about −75° C. for about 2 h. The reaction mixture was quenched by a drop-wise addition of saturated aqueous NH4Cl (20 mL), and the organic solvent was removed under reduced pressure. The aqueous mixture was extracted with EtOAc (25 mL) and the organic layer was washed with brine (20 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-20% EtOAc in heptane to yield (5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)((3R)-3-(dibenzylamino)cyclopentyl)methanol (1.14 g, 67%): LC/MS (Table 2, Method a) Rt=3.31 min; MS m/z: 602 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[F:31][C:32]([F:39])([F:38])[CH2:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[F:31][C:32]([F:39])([F:38])[CH2:33][S:34]([NH:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)CC(F)(F)F)ccc3N2)c(O)c2cccnc21
Temperature: 120 °C
Yield: 17.4 %

Procedure:
To the product of Example 205 (21.5 mg, 0.05 mmol) in pyridine (1 mL) was added 2,-2,-2-trifluoroethanesulfonyl chloride (28 μl, 0.25 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with of 1:1 hexane:ethyl acetate. The crude product was chromatographed on silica gel eluting with 1:1 ethyl acetate/hexane to give the title compound (5 mg, 17%). 1H NMR (300 MHz, DMSO-d6): δ 0.97 (d, J=6.62 Hz, 6 H) 1.49 (m, 2 H) 1.64 (m, 1 H) 4.31 (t, J=7.53 Hz, 2 H) 4.58 (q, J=9.93 Hz, 2 H) 7.17 (dd, J=7.35, 4.78 Hz, 1 H) 7.43 (m, 4 H) 8.38 (dd, J=7.72, 1.84 Hz, 1 H) 8.57 (d, J=2.94 Hz, 1 H) 10.63 (s, 1 H) 15.90 (s, 1 H). MS (ESI−) m/z 572 (M−H)−.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH:5]1[CH2:10][CH2:9][C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=O)=O.[Cl:32][C:33]1[CH:34]=[C:35]([N:40]2[C:44]3([CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[C:43](=[O:50])[NH:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[F:39].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:7][CH2:6][CH:5]([N:47]3[CH2:46][CH2:45][C:44]4([N:40]([C:35]5[CH:36]=[CH:37][C:38]([F:39])=[C:33]([Cl:32])[CH:34]=5)[CH2:41][NH:42][C:43]4=[O:50])[CH2:49][CH2:48]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)cc1
Reactant: O=C1NCN(c2ccc(F)c(Cl)c2)C12CCNCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCN(c2ccc(F)c(Cl)c2)C12CCN(C1CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC1)CC2
Reaction time: 5 h

Procedure:
A mixture of 10.6 g of 4,4-bis(p-fluorophenyl)cyclohexyl tosylate, 5.7 g of 1-(3-chloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (m.p. 194.5°-196.5° C), 3.3 g of potassium carbonate, 4 g of potassium iodide and 50 ml of dimethylformamide is stirred at 75°-80° C for 5 hours. The reaction mixture is poured into water, and the precipitated crystals are collected by filtration, dried in a desiccator and dissolved in a mixture of chloroform and methanol (9:1). The solution is concentrated to some degree and cooled. The precipitated crystals are collected by filtration and purified in the same manner to give 8-[4,4-bis(p-fluorophenyl)cyclohexyl]-1-(3-chloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one as white crystals, melting at 201°-203° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:29](=[O:31])[NH2:30].[OH-].[Na+]>C(O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:29](=[O:31])[NH2:30]
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
A suspension of the {9-[(2,3-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (85 mg, 0.2 mM) and 0.22 mL (0.22 mM) of 1 N NaOH in 5 mL of ethanol was stirred for 18 hours at 25° C. A small volume of diethyl ether/hexanes was added, then cooled in the refrigerator. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH/diethyl ether/hexanes, then dried in vacuo to afford 77 mg (89%) of the {9-[(2,3-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ7.7-7.2 (m, 6H), 7.2-7.0 (m, 3H), 6.6 (d, 1H, J=8 Hz), 6.45 (t, 1H, J=8 Hz), 5.7 (s, 2H), and 4.35 (s, 2H). IR (KBr, cm−1) 3467, 3390, 1662, and 1616. MS (ES) m/e 409, 411, 433.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][CH:15]=[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:11]3=[N:10][C:9]=2/[CH:23]=[CH:24]/[C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)=[CH:4][CH:3]=1.[N:35]1[N:36]=[C:37]([SH:40])[NH:38][CH:39]=1.CC(C)([O-])C.[K+].O>CC(N(C)C)=O>[N:35]1[N:36]=[C:37]([S:40][C:2]2[N:7]=[CH:6][C:5]([C:8]3[N:12]4[N:13]=[CH:14][CH:15]=[C:16]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[C:11]4=[N:10][C:9]=3/[CH:23]=[CH:24]/[C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:4][CH:3]=2)[NH:38][CH:39]=1
Reactant: Clc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Reactant: Sc1nnc[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C(=C/c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(Sc2nnc[nH]2)nc1)\c1ccc2ccccc2n1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
A solution of compound 49a (0.50 g, 1.1 mmol) in DMA (3 mL) was treated with 4H-1,2,4-triazole-3-thiol (0.16 g, 1.6 mmol) and potassium tert-butoxide (0.24 g, 2.1 mmol). The resulting mixture was stirred at 140° C. for 3 h, allowed to cool to rt and treated with water (10 mL). The solids obtained were collected by filtration and purified by RP Prep-HPLC. The title compound 22 was obtained as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 14.65 (s, 1H), 8.86 (s, 1H), 8.74 (s, 1H), 8.31 (d, J=8.7 Hz, 1H), 8.13 (d, J=5.7 Hz, 1H), 8.08-8.05 (m, 1H), 7.99-7.92 (m, 3H), 7.81-7.70 (m, 3H), 7.58-7.52 (m, 1H), 7.36 (d, J=7.8 Hz, 1H), 6.44 (d, J=6.0 Hz, 1H), 4.15-4.05 (m, 4H), 3.85-3.75 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H23N9OS: 534.2 (M+H). Found: 534.2.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10]([CH2:15][CH:16]=[CH2:17])[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:27]([CH2:30][CH3:31])[C:28]#[N:29]>CC#N>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10]([CH2:15][CH:16]=[CH2:17])[C:9]=2[C:8](=[O:18])[N:7]([CH2:31][CH2:30][CH2:27][C:28]#[N:29])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Reactant: CCC(Br)C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C=CCn1c(Cl)nc2c1c(=O)n(CCCC#N)c(=O)n2CCCC
Temperature: 80 °C
Yield: 83.4 %

Procedure:
3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.0 g, 0.0072 mol) in dry MeCN (20 ml) was added Cs2CO3 (4.68 g, 0.0144 mol) followed by bromobutyronitrile (1.38 g, 0.0094 mol). The mixture was heated at 80° C. for 18 h and then allowed to cool. The reaction mixture was evaporated and the crude product partitioned between EtOAc and HCl (2N). The organic phase was separated and washed with brine, dried (MgSO4) and evaporated to give the crude product. This was purified by silica SPE (50 g), eluting with cyclohexane:ethylacetate (2:1 to 1:1) to afford the title compound as a clear oil (2.1 g, 85%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1B(O)O.[F-].[Cs+]>COCCOC.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>[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(Cl)cccc1[N+](=O)[O-]
Reactant: Cc1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2ccc(C)cc2C)cccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 47.5 %

Procedure:
A mixture containing 0.5 g (2.3 mmol) of methyl 2-chloro-6-nitrobenzoate, 0.76 g (3.5 mmol) of 2,4-dimethylphenyl boronic acid, 0.7 g (4.6 mmol) of cesium fluoride, and 0.27 g (0.23 mmol) of tetrakis(triphenylphosphine)palladium(0) in 10 ml of 1,2-dimethoxyethane was heated to 100° C. under a nitrogen atmosphere overnight. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 20% ethyl acetate/hexanes gave 0.312 g (47%) of product.