Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-bromobenzene-1-sulfonyl chloride (256 mg, 1.00 mmol) in 1 mL of dichloromethane was slowly added to a vial (40 mL) containing 5 mL of a saturated aqueous solution of sodium bicarbonate, dichloromethane (5 mL) and 1-methylpiperazine (100 mg, 1.00 mmol). The reaction was stirred at room temperature overnight. The phases were separated and the organic layer was dried over magnesium sulfate. Evaporation of the solvent under reduced pressure provided the required product, which was used in the next step without further purification. ESI-MS m/z calc. 318.0, found 318.9 (M+1)+. Retention time of 1.30 minutes. 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 3.03 (t, J=4.2 Hz, 4H), 2.48 (t, J=4.2 Hz, 4H), 2.26 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:15].[H-].[Na+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=1[C:31]([F:34])([F:33])[F:32].[I-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=2[C:31]([F:33])([F:32])[F:34])[C:6]=1[CH3:15]
Reactant: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: COC(=O)Cc1c(C)[nH]c2nc(Cl)ccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2nc(Cl)ccc12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred, ice-cooled solution of (6-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (Example 99e) (0.03 g, 0.13 mmol) in DMF (1.0 ml) under an inert atmosphere of Argon is added sodium hydride (0.006 g of a 60% dispersion in mineral oil, 0.14 mmol). The reaction mixture is stirred at 0° C. for 45 minutes and then treated with 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene (Example 95a) (0.067 g, 0.21 mmol) followed by sodium iodide (0.031 g, 0.21 mmol). Stirring is continued at 0° C. for 2 hours and then the reaction mixture is poured onto water (15 ml) and extracted with DCM (5 ml). The organic portion is separated and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:8 increasing to 1:4) to yield the product which was further purified by trituration with ethyl acetate/iso-hexane to afford the titled product. (MH+475).
Reaction SMILES: C[Si](C)(C)[O-].[K+].[CH3:7][C:8]1([CH3:51])[O:13][C:12]2[CH:14]=[CH:15][C:16]([C@H:18]3[O:22]C(=O)[N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][C:35]4[CH:36]=[C:37]([NH:41][C:42]([NH:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)=[O:43])[CH:38]=[CH:39][CH:40]=4)[CH2:19]3)=[CH:17][C:11]=2[CH2:10][O:9]1.P([O-])([O-])([O-])=O>C1COCC1>[CH3:7][C:8]1([CH3:51])[O:13][C:12]2[CH:14]=[CH:15][C:16]([C@@H:18]([OH:22])[CH2:19][NH:20][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][C:35]3[CH:36]=[C:37]([NH:41][C:42]([NH:44][C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)=[O:43])[CH:38]=[CH:39][CH:40]=3)=[CH:17][C:11]=2[CH2:10][O:9]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5ccccc5)c4)C(=O)O3)ccc2O1
Agent: C[Si](C)(C)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3cccc(NC(=O)Nc4ccccc4)c3)ccc2O1
Temperature: 65 °C
Yield: 46.2 %

Procedure:
Potassium trimethylsilanolate (0.056 g) was added to a solution of N-(3-{[2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)-ethoxy]methyl}phenyl)-N′-phenylurea (0.061 g) in degassed anhydrous THF (4 ml) whilst stirring under nitrogen. The reaction mixture was heated to 65° C. for 4 h, adding additional potassium trimethylsilanolate (0.057 g) and heating for a further 2.5 h, at which point the reaction mixture was cooled to room temperature. Phosphate buffer (20 ml, pH6.5) was added and the mixture extracted with EtOAc (3×20 ml). The combined organic layers were separated and dried over Na2SO4 before filtering. Solvent evaporation in vacuo gave the title compound (0.027 g). LCMS RT=2.80 min, ES+ve 592 (MH)+.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:13]([O:15]CC1C=CC=CC=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([CH3:38])[C:35]([S:39](Cl)(=[O:41])=[O:40])=[C:34]([CH3:43])[C:33]=1[CH3:44].[OH-].[Na+]>ClCCl.[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:39]([C:35]2[C:34]([CH3:43])=[C:33]([CH3:44])[C:32]([O:31][CH3:30])=[CH:37][C:36]=2[CH3:38])(=[O:41])=[O:40])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)n2cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c3ccccc32)c(C)c1C

Procedure:
In the same manner as Example 5, Boc-Trp-OBzl (1.97 g, 5 mM) was reacted with 4-methoxy-2,3,6-trimethylbenzene-sulfonyl chloride (1.87 g, 7.5 mM) in dichloromethane in the presence of sodium hydroxide (500 mg, 12.5 mM) and cetyltrimethylammonium chloride (16 mg, 0.05 mM). The reaction product was then hydrolyzed with an aqueous solution of sodium hydroxide to give Boc-Trp(Mtr)-OH. Yield 2.05 g (79.4%); m.p. 78°-80° C.; [α]D22 -24.8° (c=0.5, DMF).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:5]=1[NH:6][C@@H:7]([CH3:10])[CH2:8][OH:9].C(O[CH:20]=[C:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.O>[Cl-].C([N+](CCCCCC)(CCCCCC)CCCCCC)CCCCC.CN(C=O)C>[F:3][C:4]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:5]=1[N:6]([CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C@@H:7]([CH3:10])[CH2:8][OH:9]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(c1ccc(F)c(F)c1F)[C@@H](C)CO)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
At room temperature, potassium hydroxide (330 mg) and tetrahexylammonium chloride (190.1 mg) were dissolved in DMF (15 ml). After adding a solution (5 ml) of (2S)-2-(2,3,4-trifluoroanilino)propanol (1 g, 99.8% ee) and diethyl ethoxymethylenemalonate (2.09g) in DMF, the resultant mixture was stirred for 1 hour. After adding water, the liquid reaction mixture was extracted with a solvent mixture of ethyl acetate and n-hexane (3:2). The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent, IPE was added to the obtained residue and the mixture was stirred at 0° C. for 1 hour. The crystals thus precipitated were collected by filtration and the moist product thus obtained was dried under reduced pressure. Thus, the title compound (1.65 g, 99.8% ee) was obtained as colorless crystals. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 63.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH2:32])=[O:31])=[CH:25][CH:24]=1.[F-].[K+].C(NCCNCC1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:32][C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=3)=[O:31])=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C(c2ccc(I)cc2)COC1(C)C
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(c2ccc(NC(=O)Nc3ccc(Cl)cc3)cc2)COC1(C)C
Temperature: 90 °C
Yield: 13.6 %

Procedure:
A stirred suspension of (RS)-4-(4-iodo-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.60 g), 4-chlorophenylurea (0.81 g), potassium fluoride (2.88 g, 40 wt % on alumina), N,N′-dibenzylethylenediamine (0.14 ml) and copper(I) iodide (0.11 g) in THF (16 ml) in a sealed tube was heated at 90° C. for 30 minutes under microwave irradiation. The mixture was then cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (RS)-4-{4-[3-(4-chloro-phenyl)-ureido]-phenyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.24 g, 14%) as a light yellow solid. MS (ISP): 392.1 ([{37Cl}M+H—C4H8]+), 390.1 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][C:13]=1[O:20][CH3:21])(=[O:3])[CH3:2].[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N+:22]([O-:24])=[O:23])[C:15]([CH:18]=[O:19])=[CH:14][C:13]=1[O:20][CH3:21])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C=O)ccc1OCCCCCCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(C=O)c([N+](=O)[O-])cc1OCCCCCCOC(C)=O
Yield: 92 %

Procedure:
A 250 mL round bottom flask was charged with 3 (10 g, 34 mmol) and was then placed in an ice bath. To this was added a 20% v/v solution of fuming nitric acid in acetic acid (40 mL total volume) at a rate of 1.0 mL/minute with stirring. At the end of addition the bath was removed, the reaction was protected from light, and stirred at room temperature for 4 hours. At this time the solution was poured over crushed ice (200 mg). Water was added and the product was extracted with ethyl acetate (3×200 mL). The combined organics were washed with brine (1×200 mL), saturated sodium bicarbonate (1×200 mL), and water (1×200 mL), dried over magnesium sulfate, and filtered. The solvent was evaporated in vacuo to give 10.6 g of 4 (92%) as an orange-red solid. Rf=0.80 (33% ethyl acetate/hexane). Mp 79.8-81.5° C. 1H NMR (400 MHz, DMSO-d6): δ7.69 (s, 1), 7.37 (s,1), 4.17 (pt, J=6.4, 6.8 Hz, 2), 4.0 (t, J=6.8 Hz, 2), 3.95 (s,3), 1.99 (s, 3), 1.77 (m, 2), 1.59 (m, 2), 1.45-1.37 (m, 4) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25]Cl)=[N:23][N:24]=2)[CH:3]=1.[CH2:27]1[C:31]2([CH2:36][NH:35][CH2:34][CH2:33][O:32]2)[CH2:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[I-].[Na+]>C(#N)C.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:35]3[CH2:36][C:31]4([CH2:27][CH2:28][CH2:29][CH2:30]4)[O:32][CH2:33][CH2:34]3)=[N:23][N:24]=2)[CH:3]=1
Reactant: C1CCC2(C1)CNCCO2
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(Br)cc21
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CN4CCOC5(CCCC5)C4)o3)cc(Br)cc21
Temperature: 70 °C
Yield: 30 %

Procedure:
6-Bromo-4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-(phenylsulfonyl)-1H-indazole (200 mg, 0.441 mmol) in acetonitrile (2 ml) was treated with 6-oxa-9-azaspiro[4.5]decane (160 mg, 0.793 mmol), DIPEA (0.154 ml, 0.8825 mmol) and sodium iodide (66 mg, 0.44 mmol). The reaction mixture was heated at 70° C. for 5 h, then cooled, diluted with DCM and washed with aqueous HCl. The organic layer was separated using a hydrophobic frit, washed with water and the solvent removed under a stream of nitrogen. The resulting residue was purified by loading onto a silica cartridge (20 g) and eluting with 0-100% ethyl acetate/cyclohexane over 40 mins. The appropriate fractions were combined and evaporated to give the title compound as a yellow solid (74 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:24]=1[NH2:25].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>>[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:24]=1[NH:25][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1c(F)cccc1F
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Nc5c(F)cccc5F)nc34)cc21
Temperature: 100 °C
Yield: 22 %

Procedure:
Prepared similarly to Example 82 using 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 51 mg, 0.171 mmol), 2,6-difluoroaniline (26.5 mg, 0.206 mmol, Aldrich), BrettPhos (Strem, Newburyport, Mass.; 5.0 mg, 8.56 μmol), and BrettPhos precat (Strem, Newburyport, Mass.; 7.3 mg, 8.56 μmol), heating at 100° C. for 3 h. Purification by silica gel (100% DCM to 20% MeOH/DCM) provided 2-(2-((2,6-difluorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (22% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.47 (t, J=6.75 Hz, 2H) 3.33-3.39 (m, 2H) 6.91-6.95 (m, 2H) 7.14 (d, J=9.00 Hz, 1H) 7.28-7.32 (m, 1H) 7.33 (d, J=4.50 Hz, 1H) 7.35-7.40 (m, 1H) 7.44-7.54 (m, 1H) 7.62 (d, J=6.85 Hz, 1H) 8.01-8.06 (m, 1H) 8.18 (d, J=9.00 Hz, 1H) 9.31 (s, 1H) 11.90 (br. s., 1H). 19F NMR (376 MHz, DMSO-d6) δ ppm −117.35 (2F, s). MS (ESI, pos. ion) m/z: 391.2 (M+1).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:53])[NH:7][C@@H:8]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=3)[N:20]=[C:19]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)[CH:18]=2)[CH2:13][C@H:12]1[C:34]([NH:36][C@@H:37]([CH2:46][CH2:47][CH3:48])[C@H:38]([OH:45])[C:39]([NH:41][CH:42]1[CH2:44][CH2:43]1)=[O:40])=[O:35])=[O:10])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[C:1]([NH:5][C:6](=[O:53])[NH:7][C@@H:8]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=3)[N:20]=[C:19]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)[CH:18]=2)[CH2:13][C@H:12]1[C:34]([NH:36][C@@H:37]([CH2:46][CH2:47][CH3:48])[C:38](=[O:45])[C:39]([NH:41][CH:42]1[CH2:44][CH2:43]1)=[O:40])=[O:35])=[O:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)[C@H](O)C(=O)NC1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)C(=O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-N-((2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidine-2-carboxamide (2.0 g, 2.72 mmol) in methylene chloride (10 mL) was added the Dess-Martin Periodinane reagent (2.29 g, 5.44 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Completion of the reaction was monitored by TLC analysis. Upon completion the reaction mixture was diluted with water (100 mL) and the organic layer was separated. The aqueous layer was washed with methylene chloride (2×30 mL), and the combined organic layers were washed with saturated sodium bisulfite (20 mL) followed by sodium bicarbonate solution (20 mL), and dried over sodium sulfate. The solution was filtered, the filtrate concentrated under reduced pressure, and the resulting residue was stirred with hexane (10 mL). The solid was filtered and dried to provide 1.75 g (87.8%) of (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-N-((S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidine-2-carboxamide as white solid (HPLC purity: 97.3% by area; HPLC retention time: 22.58 minutes).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[CH2:25][CH2:24][C:23]4([CH3:30])[CH3:29])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>>[CH3:29][C:23]1([CH3:30])[C:22]2[C:26](=[CH:27][CH:28]=[C:20]([C:16]3[N:15]=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:19]=[CH:18][CH:17]=3)[CH:21]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CC4)n2)CC1
Agent: Cl
Product: CC1(C)CCc2ccc(-c3cccc(N4CCNCC4)n3)cc21

Procedure:
The compound is prepared analogously to FS201 starting from the product from step c (424 mg, 1.04 mmol). The product is the hydrochloride.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:4]1)#[N:2].[OH-].[Na+]>C(O)C.[Ni]>[NH2:2][CH2:1][CH:3]1[CH2:6][C:5]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(C#N)C2
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(CN)C2

Procedure:
To a solution of 1.40 g (5.59 mmol) of tert-butyl 2-cyano-7-azaspiro[3.5]nonane-7-carboxylate (Chem. Pharm. Bull.; 52 (6), 675-687, 2004), in 10 mL of a 1N solution of sodium hydroxide in ethanol. 0.164 g (2.80 mmol) of Raney nickel is then added. The reaction medium is placed in a Parr flask under a hydrogen atmosphere (60 psi) at room temperature for 2 hours. The resulting mixture is filtered through a Büchner funnel and the filtrate is then concentrated under reduced pressure. Dichloromethane is added, the aqueous phase is separated out and extracted three times with dichloromethane, and the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporating off the solvent, 1.212 g of product are obtained in the form of a colourless oil, which is used without further purification in the following step.
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1.[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][N:40]([CH2:12][CH:13]3[O:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][CH2:14]3)[C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCC1COc2ccccc2O1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Agent: N#Cc1ccc(CCl)cc1
Product: Cc1nc(N2CCN(CC3COc4ccccc4O3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 3 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with 2-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as an oil in 3% yield: 1H NMR (300 MHz, CDCl3) δ 7.35-7.31 (m, 5H), 6.88-6.87 (m, 4H), 5.89 (br s, 1H), 4.57 (d, J=6.0 Hz, 2H), 4.43-4.39 (m, 1H), 4.33-4.28 (m, 1H), 4.17-3.97 (m, 3H), 3.86-3.53 (m, 4H), 2.63 (s, 3H); MS (ES+) m/z 465.2 (M+1).
Reaction SMILES: C(OCCC1C(=S(=O)=O)C(N)C(=CC=1)O[CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:12](O)=[O:13])C.S(Cl)([Cl:35])=O>C1C=CC=CC=1>[C:12]([Cl:35])(=[O:13])[CH2:11][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCC(OC1=CC=C(CCOCC)C(=S(=O)=O)C1N)C(=O)O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCC(=O)Cl
Yield: 100 %

Procedure:
4.5 g of intermediate B obtained by the example (b) was dissolved in 50 ml of benzene and stirred at the room temperature, and 7 ml of thionylchloride was then added therein. After stirred to make reflus for three hours, concentration was made, and 4.7 g (100%) of brown oil have been obtained.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH2:6]([O:8][C:9](=[O:20])[CH:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH2:18])[C:13]1=[O:19])[CH3:11])[CH3:7].CN1CCOCC1>ClCCl>[CH2:6]([O:8][C:9](=[O:20])[CH:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:2]([O:4][CH3:5])=[O:3])[C:13]1=[O:19])[CH3:11])[CH3:7]
Reactant: CCOC(=O)C(C)N1CCCC(N)C1=O
Reactant: COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)C(C)N1CCCC(NC(=O)OC)C1=O
Yield: 75 %

Procedure:
Methyl chloroformate (192 μL, 2.5 mmol) was added to a solution of 2-(3-amino-2-oxo-piperidin-1-yl)-propionic acid ethyl ester (353 mg, 1.6 mmol) and 4-methylmorpholine (907 μL, 8.24 mmol) in dichloromethane (10 mL). After 15 minutes the mixture was diluted with dichloromethane (20 mL) and washed with water (10 mL), and aqueous hydrogen chloride (0.5 N, 10 mL). The organic phase was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to provide 2-(3-methoxycarbonylamino-2-oxo-piperidin-1-yl)-propionic acid ethyl ester (332 mg, 1.2 mmol, 75%). C12H20N2O5 calculated 272.1 observed [M+1]+ 273.0; rt=1.82 min.
Reaction SMILES: F[B-](F)(F)F.N1(O[C:16](N(C)C)=[N+:17](C)[CH3:18])C2C=CC=CC=2N=N1.C(O)(=O)C1C=CC=CC=1.[N:32]1[C:36]2[CH:37]=[CH:38][C:39]([C:41]([N:43]3[CH2:50][CH2:49][C@:48]4([CH3:53])[C@H:51]([CH3:52])[C@H:44]3[CH2:45][C:46]3[CH:57]=[CH:56][C:55]([C:58]([OH:60])=O)=[CH:54][C:47]=34)=[O:42])=[CH:40][C:35]=2[NH:34][CH:33]=1.C(N(C(C)C)C(C)C)C.CNC>CN(C)C=O>[CH3:16][N:17]([CH3:18])[C:58]([C:55]1[CH:56]=[CH:57][C:46]2[CH2:45][C@@H:44]3[C@@H:51]([CH3:52])[C@:48]([CH3:53])([C:47]=2[CH:54]=1)[CH2:49][CH2:50][N:43]3[C:41]([C:39]1[CH:38]=[CH:37][C:36]2[N:32]=[CH:33][NH:34][C:35]=2[CH:40]=1)=[O:42])=[O:60]
Reactant: C[C@@H]1[C@H]2Cc3ccc(C(=O)O)cc3[C@]1(C)CCN2C(=O)c1ccc2nc[nH]c2c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Agent: O=C(O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1[C@H]2Cc3ccc(C(=O)N(C)C)cc3[C@]1(C)CCN2C(=O)c1ccc2nc[nH]c2c1
Reaction time: 8 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (90 mg) is added to a solution of (2R,6R,11S)-3-(3H-benzoimidazole-5-carbonyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-carboxylic acid benzoic acid (0.10 g) and ethyldiisopropylamin (53 μL) in dimethylformamide (2 mL). The resulting solution is stirred at ambient temperature for 20 min before dimethylamine (40% in H2O, 60 μL) is added. The solution is stirred overnight. The mixture is concentrated under reduced pressure and the residue is purified by HPLC on reversed phase (H2O/MeCN/NH3) to give the product as a solid.