Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1)=[O:4].C([O-])(=O)C.[Na+].C(O)(=O)C.[Br:25]Br>C(Cl)Cl>[CH3:1][N:2]([CH3:15])[C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:12])([CH3:14])[CH3:13])[C:7]=1[Br:25])=[O:4]
Reactant: CN(C)C(=O)Nc1cc(C(C)(C)C)no1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)C(=O)Nc1onc(C(C)(C)C)c1Br
Temperature: 0 °C
Yield: 99.9 %

Procedure:
To a mixture of 1,1-dimethyl-(3-t-butyl-5-isoxazolyl)-urea (0.70 g), anhydrous sodium acetate (0.30 g) and glacial acetic acid (3.3 ml), bromine (0.53 g) is added dropwise in 10 minutes with ice cooling and stirring and the resultant mixture is stirred for 15 minutes. The reaction mixture is poured into ice water (30 ml) and shaken with methylene chloride. The organic layer is washed with saturated aqueous sodium bicarbonate solution and then water and evaporated to remove the solvent. The residue is recrystallized from benzene to give 1,1-dimethyl-3-(3-t-butyl-4-bromo-5-isoxazolyl)urea (0.96 g) as crystals melting at 175.5° to 176.5° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=3)[NH:9][C:8]=2[CH2:7]1)[CH3:5].[H-].[Na+].ClC[CH2:34][O:35][CH3:36]>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[C:4]([S:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21])([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=3)[N:9]([CH2:34][O:35][CH3:36])[C:8]=2[CH2:7]1)[CH3:5]
Reactant: COCCCl
Reactant: COC(=O)C(C)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCn1c2c(c3cc(Cl)ccc31)CCC(C(C)(C(=O)OC)S(=O)(=O)c1ccccc1)C2
Reaction time: 2 h

Procedure:
350 mg (0.81 mmol) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester (from example 3) in 10 mL of THF at 0° C., were treated with 39 mg (0.89 mmol, 1.1 eq) of NaH (55% in oil) portionwise within 30 min. 0.10 mL (1.22 mmol, 1.5 eq) of 1-chloro-2-methoxy-ethane was added and the ice bath removed. After 2 hours, the reaction was quenched by addition of aqueous NH4Cl sat., extracted with EtOAc and the organic phases dried over Na2SO4. Evaporation of the solvent afforded (RS,SR)-2-benzenesulfonyl-2-(6-chloro-9-methoxymethyl-2,3,4,9-tetrahydro-1H-carbazol-2yl)-propionic acid methyl ester as yellow solid, MS: 493 (MNH4′). The crude material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:23]([C:25]5([CH3:29])[CH2:28][O:27][CH2:26]5)=[O:24])[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.ClC1C=C2C(C3N=C(N[C@@H]4CCNC4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.CC1(C(O)=O)COC1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]4[CH2:22][CH2:21][N:20]([C:23]([C:25]5([CH3:29])[CH2:28][O:27][CH2:26]5)=[O:24])[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C(=O)N2CC[C@H](Nc3nc(-c4c[nH]c5ncc(Cl)cc45)ncc3F)C2)COC1
Agent: CC1(C(=O)O)COC1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4CCNC4)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Product: CC1(C(=O)N2CC[C@@H](Nc3nc(-c4c[nH]c5ncc(Cl)cc45)ncc3F)C2)COC1
Yield: 44 %

Procedure:
According to the procedure for compound 482 using (R)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(pyrrolidin-3-yl)pyrimidin-4-amine hydrochloride, 8a, and 3-methyloxetane-3-carboxylic acid (50 mg, 0.46 mmol) afforded 18.6 mg (44% yield) of 473, as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:7][CH2:6]1.[N+](C1C=CC([O:30][C:31]([N:33]2[CH:37]([C:38]3[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([F:45])[CH:39]=3)[CH2:36][O:35][C:34]2=[O:46])=O)=CC=1)([O-])=O>C1COCC1>[CH3:20][O:19][C:17](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:31]([N:33]2[CH:37]([C:38]3[CH:39]=[C:40]([F:45])[CH:41]=[C:42]([F:44])[CH:43]=3)[CH2:36][O:35][C:34]2=[O:46])=[O:30])[CH2:6][CH2:7]1
Reactant: COC(=O)c1ccccc1N1CCN(CCCN)CC1
Reactant: O=C1OCC(c2cc(F)cc(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1N1CCN(CCCNC(=O)N2C(=O)OCC2c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution of 1-(3-amino-propyl)-4-(2-carbomethoxyphenyl)-piperazine (25 mg, 0.090 mmol) in 10 mL of THF, 4-(3,5-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester(30 mg, 0.082 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by 1:9 MeOH/EtOAc (Rf =0.75, MeOH/EtOAc=1:3) to obtain 2-[4-(3-{[4-(3,5-difluoro-phenyl)-2-oxo-oxazolidine-3-carbonyl]-amino}-propyl)-piperazin-1-yl]-benzoic acid methyl ester (31 mg, 69%). The compound was dissolved in CH2Cl2 (3 mL) and was treated with 1N HCl in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a yellow solid. M. P. 93-96° C.; [α]D =+45.3, (c=0.29, MeOH); Anal. Calcd. For C25H30N4O5F2Cl2.0.58 CH2Cl2 : C, 50.48; H, 5.16; N, 9.20. Found: C, 50.46; H, 5.56; N,8.91.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][C:12]=1[O:21][CH3:22].[CH3:24][O:25][C@@H:26]1[CH2:30][NH:29][C@H:28]([CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:27]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:29]2[CH2:30][C@@H:26]([O:25][CH3:24])[CH2:27][C@H:28]2[CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[O:20])=[CH:13][C:12]=1[O:21][CH3:22]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Cl
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Cl)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 86.6 %

Procedure:
A mixture of 4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (398 mg, 1.19 mmol), methyl 4-[(2S,4S)-4-methoxy-2-pyrrolidinyl]methoxybenzoate (317 mg, 1.19 mmol), EDC.HCl (342 mg, 1.79 mmol), HOBT (242 mg, 1.79 mmol) and Et3 N (0.83 ml, 5.95 mmol) in DMF (5 ml) was stirred at room temperature for 13 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl3/Aectone (10/1)CHCl3/MeOH (20/1)], to give methyl 4-[(2S,4S)-1-[4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-methoxy-2-pyrrolidinyl]methoxybenzoate (600 mg, 87%) as a colorless amorphous solid 1H-NMR (CDCl3) δ 1.99–2.06 (m, 1H), 2.34 (d, J=13.9 Hz, 1H), 3.30 (s, 3H), 3.59 (d, J=7.4 Hz, 1H), 3.62 (d, J=3.2 Hz, 2H), 3.83 (s, 3H), 3.88 (s, 3H), 4.00–4.18 (m, 3H), 4.42–4.51 (m, 2H), 6.82–7.07 (m, 7H), 7.28 (d, J=8.3 Hz, 1H), 7.35 (dd, J=7.9, 1.5 Hz, 1H), 7.94–8.00 (m, 3H), 8.18(d, J=8.3 Hz, 1H); MS (ESI) m/z 582 (M++1), 584 (M++3).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].[CH2:6]([OH:8])[CH3:7].[ClH:9]>>[ClH:9].[NH:5]=[C:1]([O:8][CH2:6][CH3:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CCO
Reactant: CC(C)C#N
Agent: Cl
Product: CCOC(=N)C(C)C
Temperature: 25 °C
Reaction time: 120 h
Yield: 49.5 %

Procedure:
A solution of 138.2 g (2 mol) of isobutyronitrile in 101.2 g (2.2 mol) of ethanol cooled to 0° C. was saturated with anhydrous HCl gas (total vol. of HCl=1.5 L: 2.2 mol) at a rate of 1.5 L/min for 35 minutes. The resulting mixture was tightly capped and stored in a refrigerator (-5° C.) for 5 days and then stirred at room temperature for 18 hours. The solid formed was removed by filtration and the filtrate was poured into 2 L of anhydrous ether with stirring and the resulting reaction mixture was stirred at 0°-5° C. for 30 minutes. The precipitated solid was filtered, washed with anhydrous ether, and dried in a vacuum oven (over KOH) to afford 150 g (98.9%) of 1-imino-1-ethoxyisobutane hydrochloride.
Reaction SMILES: ClC(OCC(C)C)=O.C(N(CC)CC)C.[CH3:16][C:17]1([CH3:45])[CH2:43][C:21]2[C:22]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[C:39]([OH:41])=O)[CH:34]=[CH:35][CH:36]=3)=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[S:24][C:20]=2[C:19](=[O:44])[CH2:18]1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][NH2:50]>C(Cl)Cl>[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][NH:50][C:39](=[O:41])[C:38]([NH:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([C:22]2[C:21]3[CH2:43][C:17]([CH3:16])([CH3:45])[CH2:18][C:19](=[O:44])[C:20]=3[S:24][C:23]=2[N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[CH:32]=1)=[O:42]
Reactant: CN(C)CCN
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3cccc(NC(=O)C(=O)O)c3)c2C1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCNC(=O)C(=O)Nc1cccc(-c2c(N3CCOCC3)sc3c2CC(C)(C)CC3=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.7 %

Procedure:
Isobutyl chloroformate (30 μL, 0.23 mmol) and triethylamine (30 μL, 0.23 mmol) were added to a solution of Example 292 (50 mg, 0.12 mmol) in DCM (5.0 mL) and the reaction mixture was stirred at room temperature for 1 h. N,N-Dimethylethylenediamine (60 μL, 0.58 mmol) was then added and the reaction mixture was stirred at room temperature for 72 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (pH 5.8) to give the title compound (4 mg, 6%) as a yellow solid. δH (CDCl3) 9.12 (1H, s), 8.41 (1H, br s), 7.55-7.46 (2H, m), 7.29 (1H, t, J 7.9 Hz), 7.05-7.00 (1H, m), 3.61-3.49 (6H, m), 2.90-2.77 (6H, m), 2.49 (6H, s), 2.33 (2H, s), 2.29 (2H, s), 0.90 (6H, s). LCMS (ES+) 499.3 (M+H)+.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][C:7]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:11][CH2:10][CH2:9][O:8]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)(=O)C.CCCCCC>C(OCC)C>[OH:2][CH2:3][CH2:5][CH2:6][C:7]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10][O:11]1
Reactant: COC(=O)CCC1(c2ccccc2)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: OCCCC1(c2ccccc2)OCCO1
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
A solution of 2-[2-(methoxycarbonyl)ethyl]-2-phenyl-1,3-dioxolane (5.00 g) in diethyl ether (15 ml) was added dropwise to a mixture of lithium aluminium hydride (949 mg) and diethyl ether (30 ml) at 0° C. After stirring for 30 minutes, water was added to the reaction mixture carefully and the precipitates were removed by filtration. The filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain 2-(3-hydroxypropyl)-2-phenyl-1,3-dioxolane (3.81 g, yield 87%) as a colorless oil from an ethyl acetate-hexane (2:3, v/v)-eluted fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][CH:5]3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=1[Cl:44])[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:33]=[C:34](\[C:36]3[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=3[Cl:44])/[CH3:35])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCC2Nc3ccc(Cl)cc3C2C1
Reactant: CC(=CBr)c1cc(F)c(F)cc1Cl
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Chloro-2-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (220 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-2-chloro-4,5-difluorobenzene (321 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The product was further purified by HPLC. Yield: 30 mg as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.40 (d, 1H), 7.30 (m, 1H), 7.22 (d, 1H), 7.15 (t, 1H), 7.08 (d, 1H), 6.90 (s, 1H), 4.40 (m, 2H), 3.60 (m, 2H), 3.10 (m, 2H), 3.05 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:24][CH:23]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)C(Br)c1ccc(Sc2ccc(Cl)cc2)cc1
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Sc2ccc(Cl)cc2)cc1
Yield: 62 %

Procedure:
In a manner similar to Example 16, 7.43 g of methyl α-bromo-α-[p-(p-chlorophenylthio)phenyl]acetate was reacted with 3.21 g of p-chlorophenol. Ether workup, chromatography and recrystallization from 150 ml of hexane:chloroform (15:1) yielded 5.2 g of a white solid, mp 90.5°-94.5° C.
Reaction SMILES: N#N.[C:3]([Si:7]([CH3:17])([CH3:16])[O:8][CH:9]([C:11]1[O:12][CH:13]=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4].[Li]C(C)(C)C.CN(C)[CH:25]=[O:26].[NH4+].[Cl-]>C1COCC1.CCCCC.O>[C:3]([Si:7]([CH3:17])([CH3:16])[O:8][CH:9]([C:11]1[O:12][C:13]([CH:25]=[O:26])=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncco1
Reactant: CN(C)C=O
Agent: N#N
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc(C=O)o1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazole (733 mg, 3.22 mmol) in dry THF (16 mL) was added tert-BuLi (2.62 mL of a 1.6 M solution in pentane, 4.19 mmol) at −78° C. The reaction mixture was then stirred for 1 h at −40° C. and cooled to −78° C. before N,N-dimethylformamide (0.49 mL, 6.44 mmol) was added dropwise. The reaction mixture was allowed to warm up to rt over a period of 1 h and stirred at this temperature for 2 h. Water (30 mL) and sat. aq. NH4Cl (20 mL) were added, the layers separated and the aq. layer extracted with EA (2×30 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a colorless oil. TLC:rf (4:1 hept-EA)=0.33. LC-MS-conditions 02: tR=1.08 min; [M+H]+=256.37.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:18][CH:17]4[NH:19][CH2:20][CH:12]3[CH2:13][CH:14]=[CH:15][CH2:16]4)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[O:21]1[CH2:23][CH:22]1[CH2:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][NH:30]2.CCN(C(C)C)C(C)C>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:18][CH:17]4[N:19]([CH2:23][CH:22]([OH:21])[CH2:24][O:25][C:26]5[CH:34]=[CH:33][CH:32]=[C:31]6[C:27]=5[CH:28]=[CH:29][NH:30]6)[CH2:20][CH:12]3[CH2:13][CH:14]=[CH:15][CH2:16]4)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: C1=CCC2CNC(C1)CN2c1ccc2c(c1)OCCO2
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: OC(COc1cccc2[nH]ccc12)CN1CC2CC=CCC1CN2c1ccc2c(c1)OCCO2
Temperature: 120 °C

Procedure:
7-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-7,9-diaza-bicyclo[4.2.2]dec-3-ene (15 mg, 0.055 mmol) and 4-oxiranylmethoxy-1H-indole (20 mg, 0.106 mmol) were placed in a μW tube with ethanol (2 ml), DiPEA (0.2 mL) and heated to 120° C. for 900 sec. The solvent was evaporated to yield a crude oil, which was purified via reverse phase chromatography (20% CH3CN to 90% CH3CN in water) to yield the title compound as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([C:40]#[N:41])[C@H:12]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[NH:11][C@@H:10]([C:18]([NH:20][CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([F:31])[CH:23]=3)=[O:19])[C@@H:9]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[C:4]([F:42])[CH:3]=1>CO>[Cl:38][C:34]1[C:33]([F:39])=[C:32]([C@H:9]2[C@@:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:42])([C:40]#[N:41])[C@@H:12]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[NH:11][C@@H:10]2[C:18]([NH:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([F:31])[CH:23]=2)=[O:19])[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCc2ccc(C(=O)O)c(F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: CO
Product: CC(C)(C)C[C@H]1N[C@H](C(=O)NCc2ccc(C(=O)O)c(F)c2)[C@@H](c2cccc(Cl)c2F)[C@]1(C#N)c1ccc(Cl)cc1F
Yield: 41.3 %

Procedure:
The mixture 4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid (71.1 mg. 0.115 mmol) was separated by SFC, 40% CH3OH on a Whelk-01 R,R prep column to give chiral-4-(((2S,3R,4S,5R)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)methyl)-2-fluorobenzoic acid (29.4 mg., 41.4%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 618.15. found: 618.2 and chiral 4-(((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)methyl)-2-fluorobenzoic acid (29.7 mg., 41.8%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 618.15. found: 618.2.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH2:13][C@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@H:15]1[O:27][CH3:28].[Cl:29][C:30]1[N:31]=[C:32]([C:37](OCC)=[O:38])[NH:33][C:34]=1[CH2:35][CH3:36].Cl>CN(C1C=CN=CC=1)C.CC(N(C)C)=O>[Cl:29][C:30]1[N:31]=[C:32]([C:37]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][C@H:15]2[O:27][CH3:28])=[O:38])[NH:33][C:34]=1[CH2:35][CH3:36]
Reactant: CCOC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
WSC hydrochloride (580 mg, 3.02 mmol) and DMAP (125 mg, 1.02 mmol) were added to a solution of tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained in Example (1e) (230 mg, 0.99 mmol) and ethyl 4-chloro-5-ethyl-1H-imidazole-2-carboxylate obtained in Example (1d) (85 mg, 0.49 mmol) in DMA (5 mL), and the mixture was stirred at room temperature for three hours. Dilute hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with water, saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1, ethyl acetate) to obtain 117 mg of the title compound as a pale yellow solid (62%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([Sn](C)(C)C)[CH:15]=[C:14]([NH2:23])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][N:29]2[S:35]([C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)(=[O:37])=[O:36]>CN(C=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>[F:34][C:32]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][N:29]2[S:35]([C:38]2[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=2)(=[O:36])=[O:37])=[C:25]([C:16]2[CH:15]=[C:14]([NH2:23])[C:13]3[CH:12]=[N:11][N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[C:18]=3[CH:17]=2)[CH:33]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)n2ccc3c(Br)cc(F)cc32)cc1
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1cc(-c2cc(F)cc3c2ccn3S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (0.8 g), 4-bromo-6-fluoro-1-[(4-nitrophenyl)sulfonyl]-1H-indole (0.879 g) and Pd(PPh3)4 (0.212 g) in DMF (5 ml) was heated at 120° C. for 18 h. The solvent was removed in vacuo and the residue purified by silica cartridge (100 g) using a gradient of cyclohexane and ethyl acetate to give the title compound as an orange solid, 0.42 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH3:15])[C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[N:16]O)[C:7]2=1.[OH2:18]>O1CCOCC1.CO>[F:1][C:2]1[C:14]2[N:13]([CH3:15])[C:12]3[CH2:11][CH2:10][CH2:9][NH:16][C:8](=[O:18])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: Cn1c2c(c3cccc(F)c31)C(=NO)CCC2
Solvent: C1COCCO1
Solvent: CO
Product: Cn1c2c(c3cccc(F)c31)C(=O)NCCC2
Reaction time: 1 h

Procedure:
A mixture of 8-fluoro-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one oxime (1.8 g) and polyphosphoric acid (ca. 20 ml) in dioxan (30 ml) was stirred under nitrogen at 100°-110° for 1 h. After cooling, the reaction mixture was poured into iced water (1 l) and the resulting suspension was extracted with dichloromethane. The organic extract was concentrated in vacuo to give a solid which was taken up in methanol and adsorbed onto silica. Purification by FCC eluting with System A (200:8:1) gave the title compound (850 mg), m.p. 233°-235°.