Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4].CN(C)C=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 2-methyl ester (20.0 g, 53 mmol), prepared as described by Bigge et al. (Tetrahedron Let. 1989, 30, 5193), in tetrahydrofuran (500 mL) was added N,N-dimethylformamide (50 mL). The reaction was cooled to about −78° C., and a 1M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (80 mL) was added. The reaction was stirred at about −78° C. for about 1 hour, and then benzyl bromide (9.4 mL, 79 mmol) was added. The reaction was stirred for about 30 minutes more at about −78° C., then warmed to room temperature and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were extracted twice with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 31 g of crude product. Purification by silica gel chromatography using 10-20% ethyl acetate/hexanes as eluent afforded the title compound of part 1-A (20.33 g, 82%): +APcl MS (M-55)+ 413, (M−99)+ 369; 1H NMR=400 MHz (CDCl3) δ: 7.37 (arom, m, 5H), 7.22 (arom, m, 3H), 7.00 (arom, m, 2H), 1.41 (BOC, d, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:8][C:7]=1[CH2:17][N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc(C2=CCCCC2)nc1CN1CCOCC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1oc(C2CCCCC2)nc1CN1CCOCC1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
580 mg 2-Cyclohex-1-enyl-4-morpholin-4-ylmethyl-oxazole-5-carboxylic acid ethyl ester were dissolved in 15 ml methanol. 50 mg palladium on charcoal (10%) were added and the reaction mixture was stirred under an atmosphere of hydrogen for one hour. The catalyst was filtered off through a pad of celite, the filtrate was evaporated in vacuo to obtain 570 mg 2-Cyclohexyl-4-morpholin-4-ylmethyl-oxazole-5-carboxylic acid ethyl ester as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:27])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:17]=[CH:16]3)[C:5]([F:28])=[CH:4][N:3]=1.O.C(=O)([O-])[O-].[Na+].[Na+].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>C1(C)C=CC=CC=1.O1CCOCC1>[F:28][C:5]1[C:6]([N:8]([CH3:27])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:17]=[CH:16]3)=[N:7][C:2]([C:41]2[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)Cn1ccc2cc(OCCCN(C)c3nc(Cl)ncc3F)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)Cn1ccc2cc(OCCCN(C)c3nc(-c4ccc(OC)cc4)ncc3F)ccc21
Temperature: 80 °C
Yield: 92 %

Procedure:
To a solution of methyl (5-{3-[(2-chloro-5-fluoro-4-pyrimidinyl)(methyl)amino]propoxy}-1H-indol-1-yl)acetate (Example 84, 0.1 g, 0.25 mmol) in toluene (3.75 mL), dioxane (0.75 mL), and water (0.88 mL) were added sodium carbonate (0.26 g, 2.46 mmol), 4-methoxyphenyl boronic acid (0.15 g, 0.98 mmol), and PdCl2(dppf)(CH2Cl2) (0.04 g, 0.05 mmol). The mixture was heated at 80° C. for 4 h and then concentrated under reduced pressure. The product (0.11 g, 94%) was obtained after column chromatography (67% hexanes in EtOAc). 1H NMR (300 MHz, CD2Cl2) δ 8.31 (d, 2H), 8.06 (d, 1H), 7.12-7.07 (m, 3H), 6.95-6.87 (m, 3H), 6.41 (d, 1H), 4.85 (s, 2H), 4.11 (t, 2H), 3.94 (t, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 3.35 (d, 3H), 2.26-2.20 (m, 2H).
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH3:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C>[CH2:2]([N:9]1[CH2:10][CH:11]=[C:12]([C:15]2[CH:16]=[CH:17][C:18]([C@@H:21]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[CH3:22])=[CH:19][CH:20]=2)[CH2:13][CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCC(=O)N[C@@H](C)c1ccc(-c2cc[n+](Cc3ccccc3)cc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: CCC(=O)N[C@@H](C)c1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 13.60 g (32.0 mmol) (S)-1-benzyl-4-[4-(1-propionylamino-ethyl)phenyl]-pyridinium bromide (XXI.1) in 270 mL ethanol are slowly added 2.42 g (64.1 mmol) sodium borohydride at 0° C. The mixture is stirred for 48 h at rt. After that time, the solvent is removed in vacuo and ethyl acetate is added. The mixture is extracted with 1N HCl. The aq. phase is neutralized with 4N NaOH, the precipitate is filtered off and dried at 45° C. to yield the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([C:15]1[C:16]([CH3:38])([CH3:37])[S:17](=[O:36])(=[O:35])[CH2:18][C@:19]([C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=2[CH2:31][CH2:32][CH2:33]I)([CH3:21])[N:20]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(#N)C.C(=O)=O.[NH4+].[Cl-]>C1COCC1>[C:1]([O:5][C:6](=[O:39])[N:7]([C:15]1[C:16]([CH3:38])([CH3:37])[S:17](=[O:36])(=[O:35])[C@H:18]2[CH2:33][CH2:32][CH2:31][C:23]3[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=3[C@@:19]2([CH3:21])[N:20]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2CCCI)CS(=O)(=O)C1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Cl-]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3CCC[C@@H]2S(=O)(=O)C1(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
A solution of (R)-tert-butyl-N-(5-(2-(3-iodopropyl)-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)-N-tert-butoxycarbonyl-carbamate (172 mg, 0.253 mmol) in THF (2.5 ml) was cooled down to −78° C. and lithium bis(trimethylsilyl)amide (1M solution in THF) (0.40 ml, 0.40 mmol) was added dropwise. The bright yellow mixture was stirred at −78° C. for 20 min, then transferred to −45° C. bath (acetonitrile-dry ice) and stirred for extra 5 min. Saturated NH4Cl (2 ml) solution was added, the mixture was removed from the bath and allowed to reach rt, diluted with EtOAc (5 ml) and water to dissolve solids. Organic layer was washed with brine and concentrated. The residue was purified by FC on 12 g RediSep column using 20-70% EtOAc in heptane to afford tert-butyl-N-((4aS,11bR)-10-nitro-3,3,11b-trimethyl-4,4-dioxido-3,4a,5,6,7,11b-hexahydrobenzo[3,4]cyclohepta[1,2-b][1,4]thiazin-2-yl)-N-tert-butoxycarbonyl-carbamate (105 mg, 0.190 mmol, 75% yield) as white solid. LC/MS (ESI+) m/z=574 (M+Na).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[N:7]2.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(O)(=O)C>CN(C=O)C>[CH2:21]([N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][NH:12][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[N:11][C:2]=3[CH3:1])[N:7]=2)[CH2:16][CH2:17]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1nccc2nc(NCCN3CCNCC3)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1nccc2nc(NCCN3CCN(Cc4ccccc4)CC3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of compound 8 (56.74 mg, 0.136 mmol) in DMF (10 mL) was added benzaldehyde (21.65 mg, 0.204), MP-triacetoxyborohydride (2.70 mmol/g, 302 mg, 0.816 mmol), and acetic acid (24.5 mg, 0.408 mmol). It was stirred at room temperature overnight. The resin was removed by filtration. The solvent was removed and chromatography on silica gel afforded compound 9 (46.0 mg, 93.6). 1H NMR (CD3OD, 400 MHz) δ 8.19 (d, 1H, J=5.5 Hz), 8.09 (d, 1H, J=7.5 Hz), 7.20-7.35 (m, 6H), 6.81 (d, 1H, J=7.5 Hz), 3.62-3.71 (m, 2H), 3.55 (s, 2H), 2.75 (s, 3H), 2.45-2.70 (m, 10H). LCMS (EI) m/z 362 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[NH2:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][O:24][C:25]2=[O:28])=[CH:21][CH:20]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[O:28]=[C:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([NH:18][C:13]3[N:12]=[C:11]([C:7]4[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=4)[CH:16]=[N:15][CH:14]=3)[CH:27]=2)[CH2:23][O:24]1
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Reactant: Nc1ccc2c(c1)C(=O)OC2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3ccc4c(c3)C(=O)OC4)n2)c1
Yield: 26.2 %

Procedure:
Using Method L, 2-(3-acetamidophenyl)-6-chloropyrazine (4a) (60 mg, 0.24 mmol), 6-amino-1,3-dihydroisobenzofuran-1-one (52.2 mg, 0.35 mmol), Pd(0)2 dba3 (9 mg, 0.01 mmol), BINAP (50 mg, 0.04 mmol), sodium tert-butoxide (33 mg, 0.34 mmol) and toluene (5 mL) were reacted at 85° C. for 16 hours. The same workup as for Method L was followed by washing of the resulting solid with dichloromethane (30 mL) and filtration. The insoluble solid was then washed with acetone (60 mL). The acetone was evaporated under vacuo and the resulting solid was crystallised in cold dimethylformamide: dichloromethane mixtures to give 22.7 mg of title compound. Yield: 26.2%. 1 H NMR (250 MHz, DMSO-d6) δ 2.09 (s, 3 H), 5.39 (s, 2 H), 7.45 (t, 1 H, 8.0 Hz), 7.62-7.69 (m, 2 H), 7.76 (d, 1 H, 7.9 Hz), 8.23 (s, 1 H), 8.24-8.29 (m, 2 H), 8.39 (bs, 1 H), 8.50 (s, 1 H), 9.99 (s, 1 H), 10.06 (s, 1 H); 13C NMR (62.9 MHZ, DMSO-d6) δ 24.05, 69.78, 112.78, 117.31, 120.16, 121.13, 123.36, 124.58, 125.59, 129.29, 130.73, 133.63, 136.83, 139.71, 139.94, 141.47, 147.88, 151.05, 168.47, 170.75; m/z 361.2 [(M+H)+, calcd for C20H16N4O3 360.1].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[C:14]1([CH:20]2[CH2:24][CH2:23][NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCCO)C.O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[CH:3]=[C:2]2[N:22]1[CH2:23][CH2:24][CH:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:21]1
Reactant: Cc1cc(Cl)c2cc(Cl)ccc2n1
Reactant: c1ccc(C2CCNC2)cc1
Solvent: O
Solvent: CCOCCO
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(Cl)ccc2n1

Procedure:
4,6-Dichloro-2-methylquinoline (0.1 g) and 3-phenylpyrrolidine (0.15 g) in 2-ethoxy-ethanol (1.5 mL) was heated in a microwave at 240° C. for 10 minutes. The mixture was diluted with water and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with a mixture of methanol and dichloromethane. Evaporation of the desired fractions gave the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2.C(N(CC)CC)C.O>C(#N)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[CH:16]3)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Yield: 78.3 %

Procedure:
To the solution of 2,6-dichloro-3-nitropyridine (4 g) and 5-aminoindazole (2.8 g) in acetonitrile (50 ml) was added triethylamine (3.2 ml), and then the solution was reacted at 20-25° C. for 12 hr. The reaction mixture was cooled at room temperature, added H2O 30 ml slowly, and then reacted at 20° C. for 1 hr. The reaction mixture was filtered, washed with the mixture solution(15 ml) of acetonitrile: H2O=1:1 (volume ratio) and dried at 50° C. in vacuo to obtain the desired compound (4.7 g, 78%).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=S)[NH:9][C:10]3([O:21][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]3.[NH3:23]>CO>[NH2:23][C:8]1[C:7]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:21][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:9]=1
Reactant: N
Reactant: CCOC(=O)N1CCC2(CC1)NC(=S)c1c(F)cccc1O2
Solvent: CO
Product: CCOC(=O)N1CCC2(CC1)N=C(N)c1c(F)cccc1O2
Temperature: 50 °C

Procedure:
The product of step (c) above (2.0 g, 6 mmol) was dissolved in an excess of a 7M solution of anhydrous ammonia in methanol and heated at 50° C. for 6 h. After evaporation of the solvent the residue was purified by flash chromatography on silica gel using dichloromethane/methanol (98:2) as eluent to give the title compound as a solid (1.8 g), m.p. 114-116° C. Mass spectrum (+ve CI)m /z 308 (M+ +H). Found: C, 58.63; H, 5.84; N, 13.67. Required for C15H18FN3O3 : C, 58.62; H, 5.90; N, 13.67%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][CH2:14][C@H:15]([N:17]([CH3:19])[CH3:18])C)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH3:20]O>>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C@H:14]([CH3:20])[CH2:15][N:17]([CH3:18])[CH3:19])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: C[C@H](CNc1ccnc2cc(Cl)ccc12)N(C)C
Reactant: CO
Agent: Cl
Product: C[C@H](CN(C)C)Nc1ccnc2cc(Cl)ccc12

Procedure:
Analogously to Example 33c, starting from (R)-2-amino-1-chloro-N-(7-chloro-quinolin-4-yl)-propane hydrochloride there is prepared (R)-N1 -(7-chloro-quinolin-4-yl)-N2,N2 -dimethyl-propane-1,2-diamine hydrochloride; white crystals; m.p.: >260° C., [a]D =-132° (c=1.0, MeOH).
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Br[C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1>>[S:1]1[C:5]([C:14]2[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=2)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Reactant: OB(O)c1cc2ccccc2s1
Product: c1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Yield: 76 %

Procedure:
By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from benzo[b]thiophene-2-boronic acid and 1-[2-(4-bromophenoxy)ethyl]pyrrolidine in 76% yield as a white solid following flash chromatography (SiO2; 36:4:60 THF-TEA-hexanes).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[C:5]([OH:18])=[C:6]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:9][S:8][C:7]=12.C[C:27]([N:29](C)C)=O>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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[C-]#N.[Zn+2].[Zn]>[C:27]([C:2]1[N:3]=[C:4]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[C:5]([OH:18])=[C:6]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:9][S:8][C:7]=12)#[N:29]
Reactant: CC(=O)N(C)C
Reactant: O=C(O)CNC(=O)c1nc(Br)c2snc(-c3ccc(F)cc3)c2c1O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(-c3ccc(F)cc3)nsc12
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of {[7-bromo-3-(4-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carbonyl]-amino}-acetic acid (105 mg, 0.246 mmol), Pd2(dba)3 (22.5 mg, 0.0246 mmol), dppf (27.2 mg, 0.0492 mmol), Zn(CN)2 (28.9 mg, 0.246 mmol), Zn dust (1.6 mg, 0.0246 mmol), and DMA (0.49 mL) was stirred at 120° C. for 1 h. After cooling to r.t. the mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Elution with 0-20% MeOH/CH2Cl2/0.1% HCOOH gave the title compound as a white solid (21.8 mg): MS (m/z) 371.1 (M−1).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH3:11])[CH:4]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH3:11])[CH:4]=1
Reactant: COc1ccc(C#N)c(C)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(O)ccc1C#N
Temperature: 0 °C
Reaction time: 120 h
Yield: 103.9 %

Procedure:
A solution of 4-methoxy-2-methylbenzonitrile (5.0 g, 33.97 mmol) in DCM (150 mL) is cooled down to 0° C. before adding dropwise a 1M solution of BBr3 in DCM (136 mL, 136 mmol). The reaction mixture is allowed to reach rt and stirring is then continued at 45° C. for 5 days. Ice water (500 mL) is then added and the reaction mixture is stirred for 1 h before sat. aq. NaHCO3 (250 mL) is added. The mixture is extracted with DCM (200 mL then 4×100 mL) and the combined org. extracts are dried over MgSO4, filtered and evaporated to give the title compound as a brown solid (4.7 g). LC-MS: tR=0.76 min. 1H NMR (D6-DMSO): δ 2.38 (s, 3H), 6.73 (dd, J=8.5, 2.0 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 10.49 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].C([O:13][CH2:14][CH3:15])(=O)C>>[C:14]([O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5])(=[O:13])[C:15]1[CH:7]=[CH:6][CH:2]=[CH:3][CH:4]=1
Reactant: C#CCC(O)CCCC
Reactant: CCOC(C)=O
Product: C#CCC(CCCC)OC(=O)c1ccccc1

Procedure:
From fractions 13-20 is obtained 75 mg. of colorless oil, identical to 4-hydroxy-1-octyne, [α]D25 =-17°±1.0° (C=0.77, ethyl acetate). This compound has the (R)-configuration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:4]=1[NH2:5].[CH3:13][C:14](O)=[O:15].CC(OC(C)=O)=O.CCO>O.C1COCC1.O=[Pt]=O>[C:14]([NH:5][C:4]1[CH:6]=[C:7]([CH:8]=[CH:9][C:3]=1[O:2][CH3:1])[NH2:10])(=[O:15])[CH3:13]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: CC(=O)O
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(N)cc1NC(C)=O

Procedure:
2-Methoxy-5-nitroaniline was purchased and acetylated using HOAc/Ac2O in H2O/THF according to known procedures to make 2-methoxy-5-nitroacetanilide. This was reduced using catalytic hydrogenation (PtO2, H2, EtOH) to afford 3-acetamido-4-methoxyaniline which was reacted as described in Examples 1 and 2 to yield the desired glutarimide.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1F)[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:14]#[N:15]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)c(F)c1

Procedure:
Basic displacement reaction of 4-hydroxy benzaldehyde and 3,4 difluorobenzonitrile using potassium carbonate in anhydrous DMF at reflux temperatures affords the above compound.
Reaction SMILES: [NH2:1][C:2]1([CH2:20][OH:21])[C:15]2[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[C:11]([F:18])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:19])=[CH:6][CH:7]=2.CC(C)([O-])C.[Li+].Br[CH2:29][C:30]#[N:31].O>C1COCC1>[NH2:1][C:2]1([CH2:20][O:21][CH2:29][C:30]#[N:31])[C:15]2[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[C:11]([F:18])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:19])=[CH:6][CH:7]=2
Reactant: COc1cc(F)c2c(c1)C(N)(CO)c1cc(Br)ccc1O2
Reactant: N#CCBr
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c2c(c1)C(N)(COCC#N)c1cc(Br)ccc1O2

Procedure:
A solution of (9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methanol (9.83 g, 27.8 mmol) in THF (46.3 mL) was sequentially treated with lithium t-butoxide (1 M in THF) (30.5 mL, 30.5 mmol) and 2-bromoacetonitrile (2.90 mL, 41.6 mmol) at RT. After 2.5 hours reaction time, additional 0.5 equivalent lithium t-butoxide and 2-bromoacetonitrile (1.5 mL) were added. After 4 hours reaction time, an additional 0.25 equivalent lithium t-butoxide and bromoacetonitrile (0.75 mL) were added. After 5 hours reaction time another 0.25 equivalent of lithium t-butoxide and bromoacetonitrile (0.75 mL) were added to the mixture. Water (100 ml) was added and solvents were removed under reduced pressure. The aqueous residue was filtered, the solid was washed twice with water, dried under reduced pressure and re-suspended in ethanol. The solid was filtered off, washed with ethanol and dried under reduced pressure to afford 2-((9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methoxy)acetonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH2:16])[CH:10]=2)=[O:5])[CH3:2].N1C=CC=CC=1.[F:23][C:24]([F:41])([F:40])[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([C:37](Cl)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:37]([C:32]1[C:31]([C:28]3[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:40])[F:41])=[CH:26][CH:27]=3)=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:38])[CH:10]=2)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cnc2cc(N)ccc2c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Yield: 159.1 %

Procedure:
7-Amino-quinoline-3-carboxylic acid ethyl ester (8.6 g, 39.8 mmol) was combined with pyridine (12.9 ml, 159 mmol) and 4-N,N-dimethylamino-pyridine (0.5 g, 4 mmol) in 100 ml of chloroform. The mixture was stirred as 4′-trifluoromethyl-biphenyl-2-carbonyl chloride (22.64 g, 79.5 mmol) was added as a solution in 100 ml of chloroform. After heating at reflux for 2 h, the mixture was concentrated under vacuum, the residue taken up in ethyl acetate (600 ml) and washed sequentially with a 1 N aqueous hydrochloric acid solution (2×200 ml), water, and brine. The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to yield 29.4 g of a red oil. This oil was purified by chromatography on silica, eluting sequentially with a 70:30 dichloromethane/hexanes solution, followed by dichloromethane, then a 10:90 ethyl acetate/dichloromethane solution. Concentration under vacuum of the product containing fractions afforded 13.15 g of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3.[CH2:11]=[CH:12][C:13]1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]1([CH:5]2[CH2:4][CH:8]3[CH2:7][CH:6]2[CH:10]=[CH:9]3)[CH:2]=[CH:3][CH:13]=[CH:12][CH:11]=1
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C1=CC2CC1CC2c1ccccc1
Temperature: 150 °C

Procedure:
Dicyclopentadiene (180 g), styrene (140 g), toluene (36 g), and N,N-diethylbydroxylamine (0.35 g) (added as a polymerization inhibitor) were added to a stainless steel reactor. The mixture was heated to 150° C. for 6 hours. The low boiling fraction was removed from the resulting reaction mixture on the roto-vap. The remaining higher boiling fraction was fractionally distilled. The fraction distilling at 130° C. @ 4 mm Hg was analyzed by GC and found to be 96% 5-phenylnorbornene.