Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[N+:31]([O-:33])=[O:32])=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[O:30])=[CH:17][C:16]=2[N+:31]([O-:33])=[O:32])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Yield: 97.2 %

Procedure:
A solution of the product of Example 10B (250 mg, 0.4732 mmol) in methylene chloride (5 mL) was treated with trifluoroacetic acid (5 mL) at room temperature for 30 minutes. The solvents were removed by rotary evaporation under vacuum, and the residue taken up in ethyl acetate (100 mL) and washed with saturated aqueous sodium hydrogen carbonate (2×50 mL), water (50 mL), and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound as a light orange solid (197 mg, 97%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].C(Cl)Cl>>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(OC)cc1
Solvent: ClCCl
Product: C=CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a -78° C. cold solution of 4-allylanisol (14.6 ml, 95 mmol) in CH2Cl2 (300 ml) BBr3 (100 ml, 0.1 mol, 1 mol/l in CH2Cl2) was added dropwise. The reaction mixture was then allowed to warm up to room temperature. After 1 hour, the reaction mixture was cooled to 0° C. and quenched slowly with H2O (90 ml). The resulting aqueous phase was extracted with CH2Cl2 (2×100 ml). The combined organic phases were dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexane-ethyl acetate 9:1) to provide 4-allylphenol (11.3 g, 89%) as a purple oil, MS: m/e=134 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH:18]1[CH2:23][CH2:22][CH:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:20][CH2:19]1.[CH3:29][O:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:32]=1[OH:46]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][CH:18]2[CH2:19][CH2:20][CH:21]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH2:22][CH2:23]2)=[CH:3][C:2]([C:35]2[CH:34]=[CH:33][C:32]([OH:46])=[C:31]([O:30][CH3:29])[CH:36]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CCN(CC)C1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: CCN(CC)C1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(-c4ccc(O)c(OC)c4)cc23)CC1
Yield: 63.1 %

Procedure:
Following general procedure F, {6-bromo-4-[4-(diethylamino)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (58 mg, 0.130 mmol) was reacted with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (34 mg, 0.136 mmol) to afford the desired product (40 mg, 60%) as a yellow glass: 1H NMR (300 MHz, CD3OD) δ 9.26 (s, 0.5H), 9.17 (s, 0.5H), 8.33 (dd, J=8.2, 1.6 Hz, 1H), 8.09 (dt, J=8.8, 1.7 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.25 (dd, J=12.8, 2.1 Hz, 1H), 7.21-7.08 (m, 1H), 6.99-6.87 (m, 1H), 4.81 (s, 1H), 3.96 (d, J=3.5 Hz, 3H), 3.64-3.44 (m, 1H), 3.40-3.12 (m, 3H), 2.96-2.76 (m, 1H), 2.41 (s, 1H), 2.24 (d, J=12.4 Hz, 2H), 2.14-1.83 (m, 4H), 1.73 (t, J=9.7 Hz, 2H), 1.46-1.30 (m, 6H), 1.26-1.07 (m, 4H); ESI MS m/z 488 [C30H37N3O3+H]+; HPLC 98.9% (AUC), tR=6.24 min.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][CH2:22][C:23]#[CH:24].C(N(CC)CC)C>CN(C)C=O.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.[Cu]I>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:24]#[C:23][CH2:22][O:21][CH3:20])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCOC
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC#Cc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 85 °C
Reaction time: 12 h
Yield: 79.4 %

Procedure:
To a solution of 1-benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 7, 6.5 g, 19.3 mmol) in N,N-dimethylformamide (30 mL) was added 3-methoxy-propyne (5 mL, 57.9 mmol), tetrakis(triphenylphosphine)palladium(0) (2.2 g, 1.93 mmol), copper (I) iodide (735 mg, 3.85 mmol) and triethylamine (8.1 mL, 57.9 mmol) at room temperature. The mixture was then heated at 85° C. and stirred for 12 h. The resulting mixture was cooled to room temperature, extracted with ethyl acetate (2×250 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 20% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine as a light yellow solid (5 g, 89.1%): LC/MS m/e calcd for C17H14N2O3S [M+H]+ 327.38, observed 327.0.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16]([C:31]#[C:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:39])C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(O)C>[CH3:39][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16]([C:31]#[C:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(Oc3ccc(C(F)(F)F)cn3)c2)cc1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccccc3)cc(Oc3ccc(C(F)(F)F)cn3)c2)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
{2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (150 mg; 0.266 mmol) was dissolved in THF (2 mL) and ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for ½ h. acidified with 5% aqueous citric acid and extracted with ethyl acetate, dried and evaporated to dryness. Yield: 100 mg (75%). HPLC-MS: m/z: 535.7 (M)+; Rt: 2.78 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]2[CH2:14][CH2:13]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]3[CH2:13][CH2:14]3)[C:23](=[O:25])[O:8][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: O=C(O)c1cc(Cl)ccc1NC1CC1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1oc(=O)n(C2CC2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 270.3 %

Procedure:
A solution of 5-chloro-2-(cyclopropylamino)benzoic acid (4.70 g) and triethylamine (3.12 mL, 1 eq) in DCM (111 mL) was cooled to 0° C. and treated with triphosgene (2.31 g, 0.35 eq) in small portions. Dimethylaminopyridine (271 mg, 0.1 eq) was then added and the reaction was stirred at room temperature overnight. The crude was washed with cold 1 N HCl, and the organic portion was dried over sodium sulfate, and concentrated, then held under vacuum for 18 h delivering product (5.00 g, 95% yield). 1H-NMR (400 MHz, DMSO-d6) δ 7.88 (m, 2H), 7.68 (d, 1H), 2.90 (m, 1H), 1.16 (m, 2H), 0.80 (m, 2H). MS (ES+) m/z 260.0 (M+Na).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH:3]=1.CO[CH2:21][CH2:22]OC.C(=O)([O-])[O-].[Na+].[Na+]>[OH-].[Na+]>[N:5]1[CH:22]=[CH:21][CH:2]=[C:3]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)[CH:3]=2)[CH:4]=1
Reactant: Clc1cc(Oc2ccc3cccnc3c2)ncn1
Reactant: COCCOC
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: c1cncc(-c2cc(Oc3ccc4cccnc4c3)ncn2)c1
Temperature: 200 °C

Procedure:
To a 5 mL, microwave vial containing 7-(6-chloro-pyrimidin-4-yloxy)-quinoline, (Example 102(a)), (0.30 g, 1.2 mmol) and ethylene glycol dimethyl ether (2 mL) was added 3-diethyl (3-pyridyl)borane (0.21 g, 1.5 mmol, Aldrich), 1 N sodium carbonate (1.8 mL), and palladium(0)-tetrakis-triphenylphosphine (0.14 g, 0.15 mmol, Strem Chemical). The vial was sealed and heated at 200° C. for 20 min in a microwave synthesizer, allowed to cool to room temperature, and the reaction mixture was diluted with 1 N sodium hydroxide (25 mL) and extracted with dichloromethane (2×50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated onto silica gel. The crude material was purified by silica gel chromatography (gradient: 1–2% 2 N ammonia in methanol/dichloromethane) to obtain the title compound as an off-white solid. Mp: 155–158° C. MS (ESI, pos. ion.) m/z: 301 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:25][CH:26]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccc(C(F)(F)F)cc4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a stirred mixture of 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (1.00 g, 3.20 mmol) and 4-(trifluoromethyl)benzoyl chloride (0.67 g, 3.20 mmol) in N,N-dimethylformamide (25 mL), was added triethylamine (0.90 mL, 6.40 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (50 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (50 mL), ethyl acetate (50 mL) and dried overnight in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-trifluoromethyl-benzamide as a white solid (0.70 g, 49% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.75 min (95.6%); mp: 241-243° C.; 1H NMR (DMSO-d6) δ 1.92-2.14 (m, 1H), 2.29-2.48 (m, 1H), 2.54-2.67 (m, 1H), 2.80-3.04 (m, 1H), 4.31 (d, J=17.4 Hz, 1H), 4.45 (d, J=17.6 Hz, 1H), 4.62 (d, J=5.9 Hz, 2H), 5.11 (dd, J=5.1, 13.2 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.56 (s, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.88 (d, J=8.3 Hz, 2H), 8.11 (d, J=8.1 Hz, 2H), 9.39 (s, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.50, 31.19, 42.87, 47.13, 51.59, 122.15, 122.97, 123.90 (q, J=270 Hz), 125.38 (q, J=3.5 Hz), 127.13, 128.21, 130.47, 131.23 (q, J=31.6), 137.92, 142.42, 143.53, 165.14, 167.91, 170.98, 172.85; LCMS: MH=446; Anal Calcd for C22H18N3O4F3+0.35H2O: C, 58.50; H, 4.17; N, 9.30. Found: C, 58.55; H, 3.81; N, 9.18.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:8]([CH2:26][C:27]2[O:28][C:29]([CH2:32][CH2:33][CH3:34])=[N:30][N:31]=2)[CH:7]=1)=O>[NH4+].CO>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)(=[O:24])=[O:25])=[C:8]([CH2:26][C:27]2[O:28][C:29]([CH2:32][CH2:33][CH3:34])=[N:30][N:31]=2)[CH:7]=1
Reactant: CCCc1nnc(Cc2cc(NC(=O)C(F)(F)F)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)o1
Agent: [NH4+]
Solvent: CO
Product: CCCc1nnc(Cc2cc(N)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)o1
Yield: 61.5 %

Procedure:
A solution of 2,2,2-trifluoro-N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-3-((5-propyl-1,3,4-oxadiazol-2-yl)methyl)phenyl)acetamide (390 mg, 0.74 mmol) in 7M ammonium in MeOH (10 mL) was stirred in a sealed tube at 50° C. for 4 hours. After concentrated, the crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a yellow solid (195 mg, yield 62%). MS calcd for (C19H21BN4O5S): 428.3. MS found (ESI negative): (M−H)−=427.1. 1H NMR (DMSO-d6) δ (ppm): 10.0 (s, 1H), 9.12 (bs, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.37 (s, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.36 (d, J=8.8 Hz, 1H), 6.21 (s, 1H), 4.80 (s, 2H), 4.37 (s, 2H), 2.65 (q, 2H), 1.55 (m, 2H), 0.83 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:21]=[C:20]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)[O:19][C:4]=2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:7]=1.[Cl-].[NH4+:28].N.O>C(O)C>[NH2:28][C:2]1[C:3]2[N:21]=[C:20]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)[O:19][C:4]=2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:7]=1
Reactant: COc1ccc(CCNc2nc(Cl)c3nc(-c4ccco4)oc3n2)cc1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: COc1ccc(CCNc2nc(N)c3nc(-c4ccco4)oc3n2)cc1
Temperature: 100 °C
Yield: 48.5 %

Procedure:
7-chloro-2-(2-furyl)-5-[2-(4-methoxyphenyl)ethyl]amino-oxazolo[5,4-d]pyrimidine (0.5 g) and ammonium chloride (0.1 g) were added to a saturated solution of ammonia in ethanol (20 ml) and sealed in a Caries tube. The sealed tube was then heated at 100° C. for 18 hours. The cooled reaction mixture was poured into water (200 ml) and the resultant precipitate removed by filtration. The solid was recrystallised from methanol to afford 7-amino-2-(2-furyl)-5-[2-(4-methoxyphenyl)ethyl]amino-oxazolo[5,4-d]pyrimidine (0.23 g, 48.6%), m.p. 194°-196° C.; microanalysis, found: C, 61.5; H, 4.8; N, 19.5%; C18H17N5O3 requires: C, 61.5; H, 4.9; N, 19.9%; NMR (DMSO-d6); 2.76(t,2H ArCH2), 3.44(brq 2H, CH2NH), 3.72(s, 3H, OMe), 6.70(m, 1 H furyl-H), 6.28(brs, 1H NH), 6.84(d, 2H, ArH), 7.13(complex, 5H ArH, NH2 furyl-H), 7.89(m, 1H, furyl-H); m/e [M+H]+ 352.
Reaction SMILES: COC([CH:5]1[C:13](=[O:14])[C:9]2([CH2:12][CH2:11][CH2:10]2)[CH2:8][NH:7][C:6]1=[O:15])=O>C(#N)C.O>[CH2:12]1[C:9]2([C:13](=[O:14])[CH2:5][C:6](=[O:15])[NH:7][CH2:8]2)[CH2:10][CH2:11]1
Reactant: COC(=O)C1C(=O)NCC2(CCC2)C1=O
Solvent: O
Solvent: CC#N
Product: O=C1CC(=O)C2(CCC2)CN1

Procedure:
7,9-Dioxo-6-aza-spiro[3.5]nonane-8-carboxylic acid methyl ester (1.30 g, 6.2 mmol) in 30 ml acetonitrile/water (10:1) is refluxed for 1 hour. The reaction mixture is evaporated and the product purified by chromatography on silica. 1H-NMR (400 MHz; DMSO-d6): 8.02 (s, 1H), 3.40 (brs, 2H), 3.25 (s, 2H), 2.30-2.15 (m, 2H), 2.04-1.88 (m, 1H), 1.86-1.70 (m, 3H); LC-MS (m/z, ES+): 153 (MH+), retention time: 0.86 mins (LC-MS method 2)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].C1C(=O)N([Br:25])C(=O)C1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Br:25])[CH:13]=3)[NH:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc2c(c1)[nH]c1ccccc12
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)[nH]c1ccc(Br)cc12
Reaction time: 5 h

Procedure:
To a solution of 9H-carbazol-2-yl acetate (500 mg, 2.2 mmol) in DCM (40 mL) was added a solution of NBS in 25 mL of DCM dropwise at rt. The reaction mixture was stirred in the dark for 5 h. It was washed with water (3×50 mL) and dried over MgSO4 and concentrated. The crude product was purified by silica chromatography (EtOAc/hexane) to afford 6-bromo-9H-carbazol-2-yl acetate (WZ02025) as an off-white solid (250 mg, containing 17% dibrominated product). MS (ESI) m/z 305 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[CH3:11][NH2:12]>CO>[CH3:11][NH:12][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: ClCCOc1cccnc1
Reactant: CN
Solvent: CO
Product: CNCCOc1cccnc1
Temperature: 100 °C
Yield: 12 %

Procedure:
The 2-chloro-1-(3-pyridyloxy)ethane (2.17 g, 13.8 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH was adjusted to 1 with 10% HCl solution and impurities were extracted with chloroform (2×50 mL). The pH of the aqueous phase was raised to 6 with 10% NaOH solution and other impurities were extracted with ether (3×25 mL). The aqueous layer was basified to pH 10 with 10% NaOH solution and extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 0.253 g (12.0%) of an oil.
Reaction SMILES: C([NH:8][C@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:10]([NH:12][N:13]1[CH2:17][CH2:16][C@H:15]([N:18]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:19](=[O:27])[C@H:20]([CH3:26])[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:14]1)=[O:11])(OC(C)(C)C)=O.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[OH:48][C:42]([C:44]([F:47])([F:46])[F:45])=[O:43].[NH2:8][C@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:10]([NH:12][N:13]1[CH2:17][CH2:16][C@H:15]([N:18]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[C:19](=[O:27])[C@H:20]([CH3:26])[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:14]1)=[O:11]
Reactant: CC(=O)OC[C@@H](C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC[C@@H](C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@H](N)Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2R)-2-(BOC)amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide, prepared in Step A, in DCM (7 mL) was added TFA (7 mL). After being stirred at rt for 1 h, the reaction mixture was concentrated iii vacuo to give the title compound. The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]([C:15]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=2[CH:17]=[O:18])=[N:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.O>C1(C)C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([CH:26]=[CH2:27])[C:5]([C:15]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=2[CH:17]=[O:18])=[N:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccc(-c2nc(Cc3ccccc3)c(N)nc2Cl)c(C=O)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1nc(N)c(Cc2ccccc2)nc1-c1ccc(OC)cc1C=O
Temperature: 110 °C
Yield: 55.7 %

Procedure:
Under an argon atmosphere, to a solution of 2-(5-amino-6-benzyl-3-chloropyrazin-2-yl)-5-methoxybenzaldehyde (7) (2.28 g, 6.44 mmol) in deaerated toluene (30 mL) were successively added dichlorobis(triphenylphosphine)palladium(II) (226 mg, 322 mol), tributyl(vinyl)tin (3.75 mL, 12.8 mmol) and tetra-n-butylammonium chloride (3.50 g, 12.6 mmol) at room temperature. The mixture was heated to reflux for 1.5 hours (oil bath temperature at 110° C.). After cooling to room temperature, to the mixture was added water and the product was extracted with ethyl acetate (×3). The combined organic extract was washed successively with water (×1) and brine (×1) followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (silica gel mixed with 10 wt % potassium fluoride, n-hexane/ethyl acetate=3/1) to give 2-(5-amino-6-benzyl-3-vinylpyrazin-2-yl)-5-methoxybenzaldehyde (8) (1.24 g, 3.59 mmol, 55.5%) as a reddish brown oily substance. TLC Rf=0.27 (n-hexane/ethyl acetate=3/1); 1H NMR (500 MHz, CDCl3) δ 3.92 (s, 3H), 4.15 (s, 2H), 4.50 (s, 2H), 5.39 (dd, 1H, J=2.0, 11.0 Hz), 6.33 (dd, 1H, J=2.0, 17.0 Hz), 6.57 (dd, 1H, J=11.0, 17.0 Hz), 7.20-7.28 (m, 4H), 7.30-7.36 (m, 2H), 7.41 (d, 1H, J=8.5 Hz), 7.55 (d, 1H, J=3.0 Hz), 9.88 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 41.0, 55.7, 110.6, 120.5, 121.0, 127.2, 128.5 (2C), 129.1 (2C), 132.3, 132.9, 134.4, 136.1, 136.5, 138.7, 140.2, 145.2, 151.5, 159.8, 191.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1Br.[C:29]1(OB(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)Oc1ccccc1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1-c1ccccc1
Yield: 120.9 %

Procedure:
In a solution of 0.70 g of 2-bromo-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]benzoic acid methyl ester synthesized similarly to Step 1 of Synthetic Example 10 in 20 ml of tetrahydrofuran and 10 ml of water, 0.18 g of phenyl boric acid, 0.39 g of potassium carbonate and 0.05 g of dichlorobis(triphenylphosphine) palladium (II) were added, and stirred under reflux with heat for 1.5 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was poured in 30 ml of water, then extracted with ethyl acetate (50 ml×1). The organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate, and 0.78 g of the aimed product was obtained as brown resinous substance.
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:10][C@@H:11]([C:15]([OH:17])=[O:16])[C@@H:12]([CH3:14])[OH:13].[OH-].[Na+].C(Cl)(Cl)Cl>C1COCC1>[O:8]=[C:1]([NH:10][C@@H:11]([C:15]([OH:17])=[O:16])[C@@H:12]([CH3:14])[OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)Cl
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCCCCC(=O)N[C@@H](C(=O)O)[C@@H](C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of n-heptanoyl chloride (440 mL, 2.83 mmol) in THF (250 mL) is added dropwise, over a period of 30 min, to a cold (-5° to 0° C.), vigorously stirred mixture of D-allo-Thr (300 mg, 2.51 mmol) and 2N aq. NaOH (3.5 mL, 7.0 meq) in THF (4.0 mL). The resulting mixture is stirred for 2 h at the same temperature and overnight at room temperature. The volatiles are removed and the residue is diluted with water and acidified, using conc. HCl. The mixture is extracted with EtOAc and the combined organic solution is washed with brine, dried, filtered, and concentrated to provide crude 2c-1 (420 mg, containing 10% excess heptanoyl reagent) which solidifies upon standing. NMR δ1.28 (d, J=6.5, 3 H), 4.20 (m, 1H), 4.61 (dd, J=3.4, 6.6, 1H), 6.56 (br d, J=6.9, 1H); [α]D26 -38±2 (CHCl3).