Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([NH:9][C:10](=[S:42])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]1[CH2:38][C:37]2[CH:36]=[C:35]([O:39]C)[CH:34]=[CH:33][C:32]=2[C@@H:31]2[C@@H:22]1[C@H:23]1[C@@:27]([CH2:29][CH2:30]2)([CH3:28])[C@@H:26]([OH:41])[CH2:25][CH2:24]1)[CH2:6][CH2:7][CH3:8].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:5]([NH:9][C:10](=[S:42])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]1[CH2:38][C:37]2[CH:36]=[C:35]([OH:39])[CH:34]=[CH:33][C:32]=2[C@@H:31]2[C@@H:22]1[C@H:23]1[C@@:27]([CH2:29][CH2:30]2)([CH3:28])[C@@H:26]([OH:41])[CH2:25][CH2:24]1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCNC(=S)CCCCCCCCCC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCNC(=S)CCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: -20 °C
Reaction time: 4 h

Procedure:
Boron tribromide (0.5 ml.) was added to a stirred solution of the above thioamide (0.061 g.) in methylene chloride (3 ml.) which was cooled to -20° C., and the mixture was stirred at that temperature for 4 hours and then poured into saturated aqueous sodium bicarbonate solution (2 ml.). The mixture was extracted three times with methylene chloride (2 ml. each time) and the combined extracts were washed with water, dried and evaporated to dryness. The residue was purified by chromatography as described above and there was thus obtained as an oil N-n-butyl-11-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)thioundecanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:8]2[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[NH2:25][NH2:26]>CO>[CH2:12]([O:11][C:10]1[C:9](=[O:19])[N:8]2[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:7]2=[N:6][C:5]=1[C:3]([NH:25][NH2:26])=[O:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NN
Reactant: COC(=O)c1nc2ccc(C)cn2c(=O)c1OCc1ccccc1
Solvent: CO
Product: Cc1ccc2nc(C(=O)NN)c(OCc3ccccc3)c(=O)n2c1
Temperature: 45 °C
Yield: 78 %

Procedure:
To a stirred solution of the product from Example 8.1 (800 mg, 2.56 mmol) in methanol (30 mL), was added hydrazine (6.0 eq) at room temperature. The mixture was then heated at 45° C. for 4 h then partially concentrated in vacuo (not to dryness), then cooled to room temperature. The resulting solid was filtered, washed with water and dried under vacuum to afford the desired compound (650 mg, yield 78%).
Reaction SMILES: [CH3:1][C:2]1([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)[CH2:5][O:4][CH2:3]1.[OH-].[Na+].Cl>O>[CH3:1][C:2]1([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)[CH2:5][O:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(OCCCCCCOCC2(C)COC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(COCCCCCCOc2ccc(C(=O)O)cc2)COC1
Yield: 82.5 %

Procedure:
A mixture of ethyl 4-[6-(3-methyloxetane-3-ylmethoxy)hexyloxy]benzoate (83 g), sodium hydroxide (12 g), water (50 mL), and Solmix (registered trademark: 200 ml) was refluxed for 2 hours. The reaction mixture was rendered acidic with hydrochloric acid, extracted with ethyl acetate and an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 4-[6-(3-methyloxetane-3-ylmethoxy)hexyloxy)benzoic acid (OX1: 63 g). Melting point: 58.5° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16]([C:18]([O:20]C)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:22])[CH:14]=2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:22])[CH:14]=2)[C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cn(Cc2ccccc2)c(=O)c2ccc(Br)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cn(Cc2ccccc2)c(=O)c2ccc(Br)cc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of the product of Example 47 step i) (0.65 g) in methanol (10 mL) was added a 5M aqueous solution of sodium hydroxide (3.53 mL) and the mixture stirred at 70° C. for 2 hours. The reaction was concentrated to approximately half volume and acidified with acetic acid. The sub-title compound was collected by filtration (0.36 g).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(OC([NH:23][C@@H:24]([CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25](O)=[O:26])=O)(C)(C)C>>[NH2:23][C@@H:24]([CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCc1ccccc1)C(=O)O
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Product: N[C@@H](CCCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 21 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-fluorophenoxy)aniline and (S)-2-(tert-butoxycarbonylamino)-5-phenylpentanoic acid, gave (S)-2-amino-N-(4-(4-fluorophenoxy)phenyl)-5-phenylpentanamide (165 mg, 21%).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.[CH3:47][O:48][CH2:49][C:50](Cl)=[O:51].C(N(CC)CC)C>O1CCCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:50](=[O:51])[CH2:49][O:48][CH3:47])=[CH:42][CH:41]=2)=[N:17]1
Reactant: COCC(=O)Cl
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)Nc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Yield: 9 %

Procedure:
The title compound was prepared as described in Example 376, using 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.302 g, 0.50 mmol) in tetrahydrofuran (4.5 mL) was added methoxyacetyl chloride (0.07 mL, 0.75 mmol) and triethylamine (0.35 mL, 2.52 mmol). The final crude product was purified by preparative HPLC (5–100% acetonitrile to H2O, 30 min.) (0.015 g, 9% yield): 1H NMR (CD3OD) δ 8.75 (d, 1H), 8.40 (s, 1H), 8.10 (dd, 1H), 8.02 (d, 2H), 7.83 (d, 2H), 7.68 (dd, 1H), 4.09 (s, 2H), 3.52 (s, 3H); ES-MS (m/z) 349 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:11][C:10]=2[F:25])=[C:5]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:4][N:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[F:25])=[C:5]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[S:4][N:3]=1
Reactant: CC(C)(C)OC(=O)CCc1cc(F)c(OCc2c(Cl)nsc2-c2ccc(Cl)cc2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1cc(F)c(OCc2c(Cl)nsc2-c2ccc(Cl)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed tert-butyl 3-(4-[[3-chloro-5-(4-chlorophenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate (50 mg, 0.09 mmol, 1.00 equiv, 90%), CF3COOH (0.4 mL), dichloromethane (2 mL). The resulting solution was stirred overnight at 25° C. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with 2×5 mL of methanol. The solids were collected by filtration. This resulted in 3.8 mg (9%) of 3-(4-[[3-chloro-5-(4-chlorophenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoic acid as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.56 (s, 4H), 6.84 (d, J=9.3 Hz, 2H), 5.09 (s, 2H), 2.88 (t, J=7.2 Hz, 2H), 2.61 (t, J=7.5 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C19H13C12F2NO3S, 444.0 (M+H). found 444.0.
Reaction SMILES: [F:1][C:2]([F:36])([C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH2:3][CH2:4][C:5]([O:8][C:9](=[O:13])N(C)C)([CH3:7])[CH3:6].C(Cl)Cl.C(O)([C:42]([F:45])([F:44])[F:43])=O>>[F:1][C:2]([F:36])([C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH2:3][CH2:4][C:5]([O:8][C:9](=[O:13])[C:42]([F:45])([F:44])[F:43])([CH3:7])[CH3:6]
Reactant: CN(C)C(=O)OC(C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OC(=O)C(F)(F)F
Yield: 100 %

Procedure:
Dimethylamine (2-perfluorooctylethyl)isopropyl carbamate 10 (251 mg, 0.44 mmol) was stirred with 1:1 CH2Cl2/TFA at room temperature overnight. After evaporation of solvent, the residue was partitioned between dichloromethane and aqueous K2CO3. The organic phase was dried over MgSO4 and evaporated to give pure product (262 mg, 100%); 1H NMR (CDCl3)δ 2.22-2.08 (m, 4H), 1.63 (s, 6H); 19F NMR (CDCl3) δ −74.6 (3F), −79.6 (2F), −113.3 (2F), −120.8 (6F), −121.6 (2F), −122.1 (2F), −125.0 (2F). 13C NMR (CDCl3) δ 156.4 (t), 121.5-105.1 (m), 86.7, 31.5, 25.7 (t), 25.0; LRMS: m/z (relative intensity) 587 (M+−Me, 70%), 489 (M+−CF3CO2, 68%), 155 (82%); HRMS calcd. for C13H10F17: 489.0511, found: 489.0504,; IR (thin film): 2992, 1784, 1371, 1214 cm−1.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[C:6]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:5]=2)[CH2:3][CH2:2]1.[Br:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[Br:28][C:29]1[CH:34]=[C:33]([C:8]2[CH:7]=[C:6]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[CH:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:9]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(Oc1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CC2)n1)C(F)(F)F
Reactant: OB(O)c1cccc(Br)c1
Product: FC(F)(F)c1ccc(-c2cc(-c3cccc(Br)c3)nc(C3CC3)c2)cc1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.34) (1.0 g, 2.43 mmol) and commercially available 3-bromo-benzene-boronic acid (0.573 g, 2.85 mmol) according to the general procedure IVb. Obtained as a white solid (0.91 g, 89%). MS (ISP) 418.1 [(M+H)+] and 420.1 [(M+2+H)+].
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4].[Na+].[I-:18].[O-][Mn](=O)(=O)=O.[K+]>CC(C)=O>[I:18][CH2:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)CCl
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)CI
Temperature: 25 °C
Reaction time: 18 h
Yield: 116.5 %

Procedure:
To a solution of tert-butyl 2-(2-chloroacetyl)pyrrolidine-1-carboxylate (5 g, 20.24 mmol) in 200 mL of acetone was added 3 g (20.24 mmol) of NaI. The reaction was let to stir at room temperature for 18 h. The reaction was monitored by TLC (20% EtOAc/hexanes, the plate was developed by KMnO4 stain). The reaction mixture was filtered over celite, concentrated and dried to afford tert-butyl 2-(2-iodoacetyl)pyrrolidine-1-carboxylate (8 g, 99% yield). 1H NMR (CDCl3): δ 1.45 (d, 9H), 1.99 (s, 3H), 2.20 (m, 1H), 3.50 (m, 2H), 4.90 (m, 2H), 4.50 (m, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:6]=1[CH:7]=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:21]([OH:25])(=[O:24])[CH:22]=[CH2:23].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:7]([C:6]1[CH:9]=[C:10]([CH:11]=[CH:12][C:5]=1[O:4][C:1](=[O:3])[CH3:2])[CH:23]=[CH:22][C:21]([OH:25])=[O:24])=[O:8]
Reactant: CC(=O)Oc1ccc(I)cc1C=O
Reactant: C=CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Oc1ccc(C=CC(=O)O)cc1C=O
Temperature: 67.5 °C
Yield: 58.8 %

Procedure:
2-Acetyloxy-5-iodobenzaldehyde (0.2 g, 0.69 mmol) is dissolved in 25 ml of acetonitrile and oxygen is removed by bubbling nitrogen through the solution. Triethylamine (0.673 ml, 4.82 mmol) and acrylic acid (0.095 ml, 1.38 mmol) are added dropwise with stirring, followed by 0.016 g of tri-o-tolylphosphine (0.069 mmol) and 0.008 of palladium(II) acetate (0.047 mmol). The mixture is heated at 65-70° C. for 4 hours, volatiles are removed by distillation and the residue is purified by column chromatography on silica gel, eluting with mixtures of ethyl acetate-hexane of increasing polarity. 3-Formyl-4-acetyloxycinnamic acid (0.095 g) is obtained as a white solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH:29]([CH2:34][CH:35]3[O:37][CH2:36]3)[C:30]([O:32]C)=[O:31])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH:28][CH:29]([CH2:34][CH:35]([OH:37])[CH2:36][S:1][C:2]3[S:3][C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=3)[C:30]([OH:32])=[O:31])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: Sc1nc2ccccc2s1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc4ccccc4s3)C(=O)O)cc2)cc1

Procedure:
Example 26 is prepared from 2-mercaptobenzothiazole and 1d using the procedure described for compound 20.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])[CH2:3]1.C(N(CC)CC)C.[F:22][CH:23]([F:27])[C:24](F)=[O:25]>C1(C)C=CC=CC=1>[F:22][CH:23]([F:27])[C:24](=[O:25])[C:10](=[CH:9][N:4]1[CH2:3][CH:2]([CH3:1])[O:7][CH:6]([CH3:8])[CH2:5]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C=CN1CC(C)OC(C)C1
Reactant: O=C(F)C(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C(=CN1CC(C)OC(C)C1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Methyl 3-(2,6-dimethylmorpholin-4-yl)acrylate (93.5%, 17.5 g, 82 mmol) and triethylamine (8.8 g, 87 mmol) were initially charged in toluene (150 ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride (10.0 g, 100 mmol) was introduced. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 hour, warmed to room temperature. The reaction mixture was washed with deionized water (100 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml), and the solvent was then removed under reduced pressure. The residue obtained was 21.4 g of an orange solid which, according to GC analysis, consisted to 90.8% of methyl 4,4-difluoro-3-oxo-2-(2,6-dimethylmorpholin-4-ylmethylidene)butyrate (yield: 85.3%). 1H-NMR (CDCl3): δ=1.2 (s, 3H), 1.25 (s, 3H), 2.95 (m, 1H), 3.25 (m, 1H), 3.5 (m, 1H), 3.75 (m, 2H), 3.8 (s, 3H), 6.6 (t, 1H), 7.85 ppm (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH:18]([C:20]3[NH:29][C:28](=[O:30])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH3:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:31]1(I)[CH2:35][CH2:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].CC#N>CN(C=O)C>[CH:31]1([O:30][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([CH:18]([CH:15]3[CH2:16][CH2:17][N:12]([S:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)(=[O:10])=[O:11])[CH2:13][CH2:14]3)[CH3:19])[N:29]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1ccc(S(=O)(=O)N2CCC(C(C)c3nc4ccccc4c(=O)[nH]3)CC2)cc1
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCC(C(C)c3nc(OC4CCCC4)c4ccccc4n3)CC2)cc1
Temperature: 70 °C

Procedure:
A mixture of 2-{1-[1-(4-Methoxy-benzenesulfonyl)-piperidin-4-yl]-ethyl}-3H-quinazolin-4-one (34 mg, 0.08 mmol), cyclopentyl iodide (18 μL, 0.16 mmol), and potassium carbonate (55 mg, 0.4 mmol) in DMF (1 mL) was heated to 70° C. for 1 day. The reaction mixture was partitioned between dichloromethane and water. The organic layer was concentrated in vacuo and the residue was purified by HPLC (in the absence of TFA) to yield the product. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J=7.6 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.75 (t, J=7.0 Hz, 1H), 7.67 (d, J=8.9 Hz, 2H), 7.46 (t, J=7.5 Hz, 1H), 6.97 (d, J=8.9 Hz, 2H), 5.63 (m, 1H), 3.68 (s, 3H), 3.80 (d, J=11.6 Hz, 1H), 3.67 (dd, J=11.2, 1.6 Hz, 1H), 2.81 (quintet, J=7.3 Hz, 1H), 2.28 (t, J=11.8 Hz, 1H), 2.17 (m, 1H), 1.93 (m, 10H), 1.44 (m, 3H), 1.29 (d, J=6.9 Hz, 3H); HPLC ret. time 3.24 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 496.3 (M+1)+
Reaction SMILES: C([N:5]1[CH2:8][C:7]([N+:12]([O-:14])=[O:13])([N+:9]([O-:11])=[O:10])[CH2:6]1)(C)(C)C.Cl[C:16]([O:18][CH3:19])=[O:17]>>[CH3:19][O:18][C:16]([N:5]1[CH2:8][C:7]([N+:12]([O-:14])=[O:13])([N+:9]([O-:11])=[O:10])[CH2:6]1)=[O:17]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)N1CC([N+](=O)[O-])([N+](=O)[O-])C1
Product: COC(=O)N1CC([N+](=O)[O-])([N+](=O)[O-])C1

Procedure:
reacting a mixture of 1-tertiarybutyl-3,3-dinitroazetidine and methyl chloroformate to form 1-(methyl oxycarbonyl)-3,3-dinitroazetidine;
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1>C1(C)C(C)=CC=CC=1>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: c1ccc2c(c1)CCN2
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCc2ccccc21

Procedure:
An initial solution of 22.6 g of 4-chloro-3-nitrobenzotrifluoride and 29.8 g of indoline in 500 ml of xylene is stirred and refluxed under N2 for 18 hours. The indoline HCl salt which separates is filtered off, and the xylene filtrate is washed with water, with 3 N HCl, with 3 N--NaOH, and finally again with water, dried over MgSO4, and concentrated to an oil on a rotovac at 60° C., first at aspirator pressure, then in vacuo. This oil is taken up in 100 ml hexane and allowed to crystallize 18 hours to yield 1-(2-nitro-4-trifluoromethylphenyl)indoline, m.p. 89°-92° C.
Reaction SMILES: [CH2:1]([C@H:3]1[NH:8][CH2:7][CH2:6][NH:5][CH2:4]1)[CH3:2].[S:9](N)([NH2:12])(=[O:11])=[O:10]>O1CCOCC1>[CH2:1]([C@H:3]1[NH:8][CH2:7][CH2:6][N:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1CNCCN1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CC[C@@H]1CN(S(N)(=O)=O)CCN1

Procedure:
To a solution of (3R)-3-ethylpiperazine (0.5 g) in dioxane (10 ml) was added sulfamide (0.373 g) and the reaction mixture was then heated at reflux in dioxane for 3 d. The reaction mixture was purified by loading onto SCX and eluting with (200 ml) MeOH/NH3. The eluent was then reduced in vacuo to yield (3R)-3-ethylpiperazine-1-sulfonamide as a white solid. A mixture of (3R)-3-ethylpiperazine-1-sulfonamide (0.260 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.438 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester ((the product of example 5 step i), 0.350 g) in dioxane (10 ml) was heated at reflux in a microwave at 100 C, 300 W, open vessel with cooling for 30 min. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield: 0.705 g
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[C:27]1([C:33]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>C(O)(=O)C>[NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH:5][C:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: NC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 3.54 g of Fmoc-Asn-OH (10 mmol) and 5.2 g of triphenylmethanol (20 mmol) in 30 ml of acetic acid and 1.9 ml of acetic anhydride (20 mmol) is stirred at 50° for 15 minutes and then a solution of 0.05 ml of conc. sulfuric acid in 5 ml of acetic acid is added. After about one hour at 50° C. a solution forms, and after 11/2 hours a precipitate starts to form. After 3 hours, 200 ml of ice-cold water are slowly added to the suspension, while cooling in ice, the mixture is briefly stirred, and the precipitate is filtered off and thoroughly washed with water. The moist material is dissolved in ethyl acetate, and the organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. Before the product starts to crystallize out, the solution is diluted with 1,2-dichloroethane, concentrated again and filtered through 50 g of silica gel. The excess triphenylmethanol is eluted with 200 ml of 1,2-dichloroethane, and then Fmoc-Asn(Trt)-OH is eluted with 500 ml each of a 98:2 and of a 96:4 mixture, of 1,2-dichloroethane and methanol. The residue after evaporation to dryness is dissolved in 10 ml of tetrahydrofuran, 30 ml of ethyl acetate are added, the solution is concentrated to 20 g, and diisopropyl ether is added to crystallize; the Fmoc-Asn(Trt)-OH obtainable in this way melts at 210°-211° (with decomposition).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C@H:18]([NH2:21])[C@H:17]([O:22][CH3:23])[CH2:16]2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[Cl:24][C:25]1[N:26]=[C:27]([C:32](O)=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C@H:18]([NH:21][C:32]([C:27]3[NH:28][C:29]([CH2:30][CH3:31])=[C:25]([Cl:24])[N:26]=3)=[O:33])[C@H:17]([O:22][CH3:23])[CH2:16]2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccc1NC(C)=O
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(NC(C)=O)c(C(=O)OC)c3)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
Methyl cis(±)-2-(acetylamino)-5-(4-amino-3-methoxypiperidin-1-yl)benzoate obtained in Example (185d) (210 mg, 0.65 mmol) and 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (113 mg, 0.65 mmol) were dissolved in DMA (3 ml). WSC hydrochloride (500 mg, 2.6 mmol) and HOBt (88 mg, 0.65 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was recrystallized from an ethyl acetate/hexane solvent to obtain 120 mg of the title compound as crystals.