Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:18][C@@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([O:29]C)[CH:23]=[CH:24][CH:25]=2)[CH2:20]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>CN1CCOCC1.C(OCC)(=O)C.O>[Si:5]([O:18][C@H:19]1[CH2:20][C:21]2[C:22]([OH:29])=[CH:23][CH:24]=[CH:25][C:26]=2[CH2:27][CH2:28]1)([C:1]([CH3:3])([CH3:4])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc2c1C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC2
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)[Si](O[C@@H]1CCc2cccc(O)c2C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of Example 26B (0.9 g, 2.2 mmol) in N-methylmorpholine (7 mL) was treated with potassium carbonate (0.3 g, 2.2 mmol) and thiophenol (0.23 mL, 2.24 mmol), and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate, and the combined organic extract was washed three times with water and once with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel (5 to 20% ethyl acetate-hexane, eluant) to afford 0.45 g (52% yield) of the title compound as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 9.11 (br, 1H), 7.64 (m, 4H), 7.41 (m, 6H), 6.85 (t, J=7.6 Hz, 1H), 6.45-6.56 (m, 2H), 4.06 (m, 1H), 2.70-2.86 (m, 2H), 2.45-2.54 (m, 2H), 1.73 (m, 2H), 0.97 (s, 9H). MS (DCI+) m/z 403 (M+H)+, 420 (M+NH4)+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([NH2:10])([CH3:9])[CH3:8])[CH:4]=[N:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[I-].C[N+]1(C)[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1.C([O-])([O-])=O.[Na+].[Na+]>O.C(O)C>[N:1]1[CH:6]=[C:5]([C:7]([N:10]2[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)([CH3:9])[CH3:8])[CH:4]=[N:3][CH:2]=1
Reactant: C[N+]1(C)CCC(=O)CC1
Reactant: CC(C)(N)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(c1cncnc1)N1CCC(=O)CC1
Yield: 34.1 %

Procedure:
To a stirred mixture of 2-(5-pyrimidinyl)-2-propylamine (660 mg), ethanol (9 mL) and K2CO3 (665 mg) heated to reflux was added dropwise over 30 min, a solution of 1,1-dimethyl-4-oxopiperidinium iodide (1.9 g) in water (36 mL). When the addition was complete, the mixture was heated under reflux for an additional 2 h, cooled, basified to pH 10 with Na2CO3 and extracted with ethyl acetate (3 .Yen.100 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. Column chromatography over silica gel, eluting with a methylene chloride; 5% methanol gave 360 mg of 1-(2-(5-pyrimidinyl)-prop-2-yl)-4-oxopiperidine as an oil: 1H NMR (400 MHz, CDCl3) 9.13 (s, 1H), 8.95 (s, 2H), 2.79 (t, 4H), 2.44 (t, 4H), 1.47 (s, 6H).
Reaction SMILES: [CH2:1]([C:9]1[N:10]([CH2:22][CH2:23][O:24][CH2:25][C:26]#[CH:27])[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([C:9]1[N:10]([CH2:22][CH2:23][O:24][CH2:25][C:26]#[C:27][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C#CCOCCn1c(CCCCCCCC)nc2cnc3ccccc3c21
Reactant: Ic1ccccc1
Product: CCCCCCCCc1nc2cnc3ccccc3c2n1CCOCC#Cc1ccccc1
Reaction time: 0.75 h
Yield: 71.7 %

Procedure:
Using the general method of Example 12 Part A, 2-octyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (4.84 g, 13.32 mmol) was reacted with iodobenzene (1.7 mL, 14.65 mmol) at 40° C. After 45 minutes the reaction was judged complete. The volatiles were removed under reduced pressure and the resulting oil purified by chromatography over silica gel (98/2 (dichloromethane/methanol) to provide 4.2 g of 2-octyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline as a pale yellow solid.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C=CC=CC=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:42])=[C:30]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[N:36][CH:37]=2)[CH:31]=1.C1C(=O)N([Br:50])C(=O)C1>CCOC(C)=O>[Br:50][CH2:42][C:29]1[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][C:30]=1[C:32]1[CH:33]=[CH:34][C:35]([C:38]([O:40][CH3:41])=[O:39])=[N:36][CH:37]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(-c2cc(Cl)ccc2C)cn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(Cl)ccc2CBr)cn1

Procedure:
Solid benzoyl peroxide (496 mg, 2.0 mmol) was added to a benzene solution (50 mL) of methyl 5-(5-chloro-2-methylphenyl)picolinate (3.6 g, 13.6 mmol) and NBS (2.7 g, 15.0 mmol) and the resulting mixture was refluxed. After 16 h the resulting mixture was cooled, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:21][CH2:22]2)=[CH:13][CH:12]=1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CCC(c2ccc(Br)cc2)CC1
Product: Brc1ccc(C2CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-bromophenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(4-bromophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[C:17]3[N:33]=[CH:32][S:31][C:18]=3[N:19]=[C:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[N:21]=2)[CH:6]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[CH3:14])[CH:8]=1.CC[N:36]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[C:17]3[N:33]=[CH:32][S:31][C:18]=3[N:19]=[C:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH2:36])=[O:27])=[CH:24][CH:23]=3)[N:21]=2)[CH:6]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[CH3:14])[CH:8]=1
Reactant: COc1cc(Nc2nc(-c3ccc(C(=O)O)cc3)nc3scnc23)cc(N2CCC[C@@H]2C)c1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc(-c3ccc(C(N)=O)cc3)nc3scnc23)cc(N2CCC[C@@H]2C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
The mixture of (S)-4-(7-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid, EDCI (56 mg, 0.29 mmol), HOBt (39 mg, 0.29 mmol) and Et3N (39 mg, 0.39 mmol) in DCM (20 mL) was stirred at room temperature for 3 hrs, then ammonia was bubbled into this mixture for 3 h. The mixture was filtered and the filtrate was concentrated to give a residue which was purified by column chromatography (DCM:MeOH=50:1) to afford (S)-4-(7-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamide (12 mg, 10%) as yellow solid. 1H NMR (300 MHz, DMSO): δ 9.99 (s, 1H), 9.40 (s, 1H), 8.49 (s, 1H), 8.46 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 7.49 (s, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 5.88 (s, 1H), 3.93-3.90 (m, 1H), 3.79 (s, 3H), 3.43-3.40 (m, 1H), 3.18-3.15 (m, 1H), 2.06-1.98 (m, 3H), 1.69 (s, 1H), 1.15 (d, 3H, J=6.0 Hz). LC-MS: 461 [M+H]+, tR=1.6 min. HPLC: 95.06% at 214 nm, 95.01% at 254 nm, tR=5.55 min.
Reaction SMILES: Cl.[C:2]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[C:25]([NH:36][CH2:37][CH2:38][CH2:39][OH:40])[CH:24]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]>O1CCOCC1>[C:2]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[C:25]([NH:36][CH2:37][CH2:38][CH2:39][OH:40])[CH:24]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1NCCCO
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cccc3c2c2ccccc2n3-c2ccc(C(=O)O)c(NCCCO)c2)cn1
Temperature: 100 °C
Yield: 30.4 %

Procedure:
8 ml of 1N hydrochloric acid are added to a solution of 0.7 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(3-hydroxypropyl)amino]benzoate in 10 ml of dioxane. The reaction mixture is heated at 100° C. in a microwave for 2 hours and then concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of dichloromethane and methanol (96/4 by volume), so as to give 190 mg of 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(3-hydroxypropyl)amino]benzoic acid in the form of a pale yellow powder the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:10][CH3:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(Br)cn1
Temperature: 160 °C
Yield: 89 %

Procedure:
2,5-Dibromo-pyridine (3.0 g, 12.7 mmol) and sodium thiomethoxide (0.84 g, 12 mmol) were dissolved in 18 ml anhydrous N,N-dimethylformamide. The mixture was heated at 160° C. under nitrogen for 6 hrs. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The aqueous layer was extracted with ethyl acetate several times. The combined extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0→6% EtOAC/Hexane) to give 5-Bromo-2-methylsulfanyl-pyridine as a white solid (2.18 g, 84% yield). 1H-NMR (400 MHz, CDCl3): δ 2.55 (s, 3H), 7.09 (dd, 1H, J=0.71=8.6), 7.59 (dd, 1H, J=2.4, J=8.6), 8.50 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH2:15][N:14]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si](C(C)C)(C(C)C)C(C)C)[CH:23]=1)[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.O.CCOC(C)=O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH2:15][N:14]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)CCN(Cc1cccc(O[Si](C(C)C)(C(C)C)C(C)C)c1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1OCc1ccccc1)CCN(Cc1cccc(O)c1)C2

Procedure:
A solution of 6-(benzyloxy)-7-methoxy-2-(3-(triisopropylsilyloxy)benzyl)-1,2,3,4-tetrahydroisoquinoline (2.7 g, 5 mmol) in THF (50 mL) was cooled to 0° C. and 1M TBAF/THF (5.5 mL, 5.5 mmol) added drop wise. The solution was stirred at 0 C. for 1 h 30 min and water (20 mL) added as well as EtOAc (80 mL). The organic layer was washed with water, brine, dried with MgSO4, filtered and concentrated under reduced pressure. The resulting solid was washed with hexane, filtered and dried. 1.7 g (90%), white powder, mp=78-79° C.; Rf: 0.12 (Hexane/EtOAc 3:1), 1H NMR (270 MHz, CDCl3) δ 2.63-2.78 (4H, m, 2×CH2), 3.52 (2H, s, CH2), 3.58 (2H, s, CH2), 3.79 (3H, s, CH3O), 5.08 (2H, s, OCH2), 6.48 (1H, s, ArH), 6.60 (1H, s, ArH), 6.68 (1H, dd, J 8.2 and 2.5 Hz, ArH), 6.82 (1H, d, J 2.5 Hz, ArH), 6.88 (1H, d, J 7.7 Hz, ArH), 7.15 (1H, dd, J 8.2 and 7.7 Hz, 1H, ArH), 7.26-7.47 (5H, m, ArH). 13C NMR (67.5 MHz, CDCl3) δ 12.7((CH3)2CHSi), 18.0 ((CH3)2CHSi), 28.8 (CH2), 50.7 (CH2), 55.9 (CH2), 56.1 (CH3O), 62.7 (CH2), 71.2 (OCH2), 110.1 (CH(Ar)), 114.3 (CH(Ar)), 118.6 (CH(Ar)), 120.8 (CH(Ar)), 126.4 (C(Ar)), 127.4 (CH(Ar)), 127.6 (C(Ar)), 127.8 CH(Ar)), 128.6 (CH(Ar)), 129.2 (CH(Ar)), 137.4 (C(Ar)), 140.0 (C(Ar)), 146.6 (C(Ar)), 147.9 (C(Ar)) and 156.1 (C(Ar)). LC/MS (APCI+) tr=5.12 min m/z 376.59 (M++H); MeOH/H2O 50/50 to 95/5 (5 min); HPLC tr=3.26 min (100%). (CH3CN/H2O 90/10)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12])=[O:6])=[O:4]>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]([C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])=[O:6])=[O:4]
Reactant: COC(=O)C(=O)Nc1cccc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: COC(=O)C(=O)Nc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
To a solution of 1.69 g of 3-[(methoxycarbonyl)carbonylamino]benzyl alcohol in 20 ml of acetone was added 3.47 g of manganese dioxide, this was stirred at room temperature for 2 hours, 3.92 g of manganese dioxide was further added, and this was stirred at room temperature for 18 hours. The reaction solution was filtered with Celite, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 0.53 g of 3-[(methoxycarbonyl)carbonylamino]benzaldehyde [Compound No. (w)] as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH:17]([CH3:21])[C:18]([O-:20])=[O:19])=[CH:11][C:10]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Li+]>O1CCCC1.O>[CH2:1]([O:8][C:9]1[C:10]([F:22])=[CH:11][C:12]([CH2:16][CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:13][C:14]=1[F:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cc1cc(F)c(OCc2ccccc2)c(F)c1)C(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(Cc1cc(F)c(OCc2ccccc2)c(F)c1)C(=O)O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-methylpropanoate (752) (1.09 g, 3.26 mmol) in tetrahydrofuran (10 mL), water (10 mL), and methanol (20 mL) was added lithium hydroxide (547 mg, 13.04 mmol) and the solution was stirred overnight at 80° C. The reaction was concentrated, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-methylpropanoic acid (753).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12]([N:14]([CH3:28])[C:15](=[O:27])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH3:26])[CH:18]=2)=[O:13])=[CH:3]1>CN(C=O)C.[C].[Pd]>[CH3:28][N:14]1[C:15](=[O:27])[CH:16]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH3:26])[CH:18]=2)[CH:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[C:12]1=[O:13]
Reactant: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cn(C)c3ccccc23)C1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: CN1C(=O)C(c2cn(C)c3ccccc23)C(c2cn(C)c3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.8 %

Procedure:
To a solution of 2,3-bis(1-methyl-1H-indol-3-yl)-N-methylmaleimide (50 mg, 0.14 mmol) in DMF (1 mL) was added a small amount of 10% palladium-carbon, and the whole was stirred at room temperature for 1 day under hydrogen atmosphere. The palladium-carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=2:1) to obtain 1-methyl-3,4-bis(1-methyl-1H-indol-3-yl)-2,5-dioxopyrrolidine (28 mg, 55.7%) as pale red solids. 1H-NMR(CDCl3): δ 3.28(s, 3H), 3.44(s, 6H), 4.81(s, 2H), 6.63(s, 2H), 6.85-7.00(m, 2H), 7.04-7.11(m, 4H), 7.22-7.26(m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:17]#[N:18])[C:10]([CH3:16])=[C:11]([CH:14]=[CH2:15])[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][N:27]([CH3:33])[C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:17]#[N:18])[C:10]([CH3:16])=[C:11]([CH:14]=[CH2:15])[C:12]=3[N:30]3[CH2:31][CH2:32][C@H:28]([N:27]([CH3:33])[CH3:26])[CH2:29]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: C=Cc1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C=Cc1c(C)c(C#N)c2nc(C3CC3)oc2c1N1CC[C@H](N(C)C)C1
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 89.2 %

Procedure:
2-Cyclopropyl-7-fluoro-5-methyl-6-vinyl-1,3-benzoxazole-4-carbonitrile (I-180) (100 mg, 0.41 mmol) was dissolved in dimethyl sulfoxide (2 ml), then at room temperature, triethylamine (86 μl, 0.62 mmol) and (3S)-3-(dimethylamino)pyrrolidine (68 μl, 0.54 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 4.5 hours. After cooling to room temperature, the reaction liquid was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=9:1) to obtain a roughly-purified product (123 mg, 89%) as a pale brown solid. This was recrystallized from diisopropyl ether and hexane to obtain the entitled compound (79 mg) as a white solid.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.Br[C:27]1[CH:28]=[C:29]2[C:35]([CH:36]([C:38]3[CH:39]=[C:40]4[C:45](=[CH:46][CH:47]=3)[N:44]=[CH:43][CH:42]=[CH:41]4)[CH3:37])=[N:34][O:33][C:30]2=[N:31][CH:32]=1.C([Sn](CCCC)(CCCC)[C:53]1[N:54]=[CH:55][S:56][CH:57]=1)CCC>CN(C=O)C>[S:56]1[CH:57]=[C:53]([C:27]2[CH:28]=[C:29]3[C:35]([C@@H:36]([C:38]4[CH:39]=[C:40]5[C:45](=[CH:46][CH:47]=4)[N:44]=[CH:43][CH:42]=[CH:41]5)[CH3:37])=[N:34][O:33][C:30]3=[N:31][CH:32]=2)[N:54]=[CH:55]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: CC(c1ccc2ncccc2c1)c1noc2ncc(Br)cc12
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CN(C)C=O
Product: C[C@H](c1ccc2ncccc2c1)c1noc2ncc(-c3cscn3)cc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a pressure vessel was added 2-(dicyclohexylphosphino)biphenyl (12 mg, 0.42 mmol), 6-(1-(5-bromoisoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline (0.10 g, 0.28 mmol), 4-(tributylstannyl)thiazole (0.16 g, 0.42 mmol) in anhydrous DMF (3 mL). The vial was flushed with argon, sealed and stirred at 90° C. for two hours. The mixture was concentrated and purified by MPLC (eluted with a gradient of 0 to 10% methanol in dichloromethane) to yield the racemic product as an off-white solid. The desired enantiomer (>99% cc) was obtained via SFC. MS m/z=359.0 [M+1]+ Calc'd for C20H14N4OS: 358.4
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:14].[C:15]([C:17]1[N:21]([CH3:22])[C:20](B(O)O)=[CH:19][CH:18]=1)#[N:16].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]([C:17]1[N:21]([CH3:22])[C:20]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=2[F:14])=[CH:19][CH:18]=1)#[N:16]
Reactant: CCNS(=O)(=O)c1ccc(Br)c(F)c1
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCNS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)c(F)c1
Reaction time: 16 h
Yield: 24.3 %

Procedure:
According to general procedure B, 4-bromo-N-ethyl-3-fluorobenzenesulfonamide (166 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-3-fluorobenzenesulfonamide (44 mg, 24%) was provided after purification. HRMS: calcd for C14H14FN3O2S, 307.07907; found (EI, M+.), 307.0792. HPLC purity 99.5% at 210-370 nm, 8.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[CH2:14][C@@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])=[CH:4][C:3]=1[F:27].[OH-].[Na+].[NH2:30]O.Cl>CO.O.C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:22][NH:30][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])=[CH:4][C:3]=1[F:27]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2cc(F)c(Cl)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(Cl)c(F)c1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
Cis-methyl 2-(4-chloro-3,5-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.445 g, 3.58 mmol) was dissolved in MeOH (14 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.150 g, 3.76 mmol) dissolved in water (1.4 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.230 mL, 3.76 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (18.49 mL, 110.93 mmol) and the mixture was stirred at 80° C. for 20 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. The compounds were detected by UV at 220 nm. Cis-methyl 2-(4-chloro-3,5-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.831 g, 62.3%) was yielded as colorless solid. 1H NMR (600 MHz, cdcl3) δ 1.80-1.87 (m, 1H), 2.04-2.15 (m, 1H), 2.19-2.28 (m, 1H), 2.30-2.36 (m, 1H), 3.00-3.09 (m, 1H), 3.30-3.39 (m, 1H), 3.66 (s, 3H), 4.07-4.16 (m, 1H), 4.98-5.05 (m, 1H), 5.59 (s, br., 1H), 6.80 (d, 2H). MS m/z 273 (M+H)+
Reaction SMILES: [CH2:1](I)[CH3:2].[CH3:4][CH2:5][C@@H:6]([C@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])[CH3:7].O>>[CH2:1]([O:10][C:9](=[O:11])[C@H:8]([C@H:6]([CH2:5][CH3:4])[CH3:7])[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH3:2]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCI
Solvent: O
Product: CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC

Procedure:
The title compound was prepared by the method of Example 8 using ethyl iodide (0.4 mL, 5 mmol) instead of methyl iodide and BOC--L--Ile--OH--0.5 H2O (1.0 g, 4 mmol) instead of the title product of Example 1. Concentration afforded the title compound (1.1 g) as a water white liquid and the structure verified by NMR.