Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH3:24])[CH:6]=1.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH3:24])[S:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([F:26])([F:38])[F:39])(=[O:36])=[O:35])[CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN(C)S(=O)(=O)c2ccccc2C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-methylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and 2-(trifluoromethyl)benzenesulfonyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(O)O.ClC1C=CC([N+]([O-])=O)=CC=1O>>[N:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[CH:3][CH:4]=2)[N:12]=[N:11][CH:10]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Brc1ccc(-n2ncnn2)cc1
Agent: O=[N+]([O-])c1ccc(Cl)c(O)c1
Product: O=C(O)c1ccc(-c2ccc(-n3ncnn3)cc2)cc1

Procedure:
The title compound was prepared from 2-(4-bromophenyl)tetrazole (D72, 0.2 g) and 4-boronobenzoic acid (0.15 g) as described in Description 15 (0.17 g, 72%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[NH:11][CH2:12][CH2:13][N:14]=1>C1(C)C=CC=CC=1>[C:2]1([CH:1]=[CH:9][C:10]2[NH:14][CH2:13][CH2:12][N:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC1=NCCN1
Solvent: Cc1ccccc1
Product: C(=Cc1ccccc1)C1=NCCN1

Procedure:
A solution of 5.3 g (50 mmol) of benzaldehyde and 4.2 g (50 mmol) of 2-methyl-4,5-dihydro-1H imidazole in 50 ml toluene was refluxed in a Dean-Stark apparatus. Within 8 h 0.9 ml of water had been separated and the reaction was almost complete as detected by TLC. After cooling the crystalline precipitate was filtered off, treated with cold tert.-butylmethylether, and dried in vacuo.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([NH:15][C:16]3[C:17]4[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[S:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[NH3:29]>CO.CN(C=O)C>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([O:8][C:9]2[C:14]([NH:15][C:16]3[C:17]4[C:24]([CH3:25])=[C:23]([C:26]([NH2:29])=[O:27])[S:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:7]1
Reactant: N
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](O)CC3)c12
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](O)CC3)c12

Procedure:
Prepared analogously to 1.4 from 0.1 g 4-[2-(trans-4-hydroxy-cyclohexyloxy)-pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia in methanol (7M) in DMF. Separated from cis isomer by chromatography.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][Si:19]([CH2:22][Mg]Cl)([CH3:21])[CH3:20].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(O)(=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1
Reactant: C[Si](C)(C)C[Mg]Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C[Si](C)(C)C)c([N+](=O)[O-])c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A solution of (3-nitro-phenyl)-carbamic acid tert-butyl ester (1.20 g, 5.04 mmol) in THF (50 mL) was added ((trimethylsilyl)methyl)magnesium chloride (1.48 g, 10.1 mmol) at −70° C. under nitrogen gas. The solution was then stirred at −70° C. for one h. A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.74 g, 12.1 mmol) in THF (30 mL) was added, the reaction was warmed to 0° C. and the reaction was allowed to stir at 0° C. for another hour. The reaction mixture is poured into an aqueous solution of acetic acid (50 mL, 5%v/v) and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown oil. Flash chromatography (80/20 hexanes/ethyl acetate) afforded (3-nitro-4-trimethylsilanylmethyl-phenyl)-carbamic acid tert-butyl ester (1.20 g, 73%) as a light oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=2)[CH2:11][N:12]([CH2:25][CH3:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:4][N:3]=1.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[CH2:25]([N:12]([CH2:11][C:10]1[CH:27]=[CH:28][CH:29]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:7]=2)[CH:9]=1)[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:26]
Reactant: CCN(CCCNC(=O)c1ccccc1)Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: CCN(CCCNC(=O)c1ccccc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 44 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 510.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].Cl.[Cl:12][CH2:13][C:14](=N)OCC>C(O)C>[Cl:12][CH2:13][C:14]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[N:10]=1
Reactant: CCOC(=N)CCl
Reactant: N#Cc1ccc(N)c(N)c1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc2nc(CCl)[nH]c2c1
Yield: 54.9 %

Procedure:
3.42 g of 3,4-diaminobenzonitrile and 4.06 g of ethyl chloroacetoimidate hydrochloride were dissolved in 100 ml of ethanol, and the solution was refluxed under heating for 3 hours. After cooling and distilling off the solvent, the resulting residue was dissolved in ethyl acetate, washed with water, and then dried. After distilling off the solvent, the crystals thus precipitated were collected by filtration to obtain 2.7 g of 2-chloromethyl-5-benzimidazolecarbonitrile.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6][CH:5]=2.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:26]([O:28][CH3:29])=[O:27])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[H-].[Na+].Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:28][C:26]([C:23]1([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][N:3]3[C:4]4[C:9](=[CH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6][CH:5]=4)[C:10]([CH3:11])=[C:2]3[CH3:1])=[CH:22][CH:21]=2)[CH2:25][CH2:24]1)=[O:27]
Reactant: Cc1[nH]c2ccc(C(=O)O)cc2c1C
Reactant: COC(=O)C1(c2ccc(CBr)cc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccc(Cn3c(C)c(C)c4cc(C(=O)O)ccc43)cc2)CC1
Reaction time: 8 h
Yield: 41.6 %

Procedure:
To a solution of 2,3-dimethyl-1H-indole-5-carboxylic acid (500 mg, 2.3 mmol) in anhydrous DMF (20 mL) was added methyl 1-(4-(bromomethyl)phenyl)cyclopropanecarboxylate (620 mg) followed by NaH (230 mg). The resulting solution was allowed to stir overnight under argon atmosphere. The remaining NaH was hydrolyzed by the careful addition of a 0.5 N HCl solution. The mixture was diluted with ethyl acetate, washed with a 0.5 N HCl solution and brine, dried on MgSO4, and concentrated. The crude residue was purified by chromatography on silica gel (Hexane/Ethyl acetate 5/5) to afford an orange powder (361 mg). ESI-MS (m/z): 378 [MH]+
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]([F:33])([F:32])[C:24]([NH:26][CH2:27][CH:28]1[CH2:31][NH:30][CH2:29]1)=[O:25].N1C=CC=CC=1>C(N(CC)CC)C>[F:33][C:23]([F:22])([F:32])[C:24]([NH:26][CH2:27][CH:28]1[CH2:29][N:30]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:31]1)=[O:25]
Reactant: O=C(NCC1CNC1)C(F)(F)F
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC(CNC(=O)C(F)(F)F)C3)c(F)cc2c1=O
Yield: 89.8 %

Procedure:
A solution of 0.8 g (2.8 mmoles) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.92 g (4.2 mmoles) of 3-trifluoroacetamidomethylazetidine hydrochloride, 8 ml of pyridine and 1.7 g of triethylamine is heated under reflux for 3 hours. It is then evaporated under vacuum, diluted with water and filtered. 1.12 g (88.9%) of 7-(3-trifluoroacetamidomethyl-1-azetidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 145°-150° C.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:23]1[N:24]=[C:25]([NH2:41])[C:26]2[N:27]=[CH:28][N:29]([C:39]=2[N:40]=1)[C@@H:30]1[O:38][C@H:35]([CH2:36][OH:37])[C@@H:33]([OH:34])[C@H:31]1[OH:32]>>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[C:3][C:23]3[N:24]=[C:25]([NH2:41])[C:26]4[N:27]=[CH:28][N:29]([C:39]=4[N:40]=3)[C@@H:30]3[O:38][C@H:35]([CH2:36][OH:37])[C@@H:33]([OH:34])[C@H:31]3[OH:32])[CH2:5][CH2:6]2)=[O:11])=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCC1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Product: Nc1nc(C#CCC2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Batch: AB-9-149. 4-nitrophenyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-97 (0.630 g, 2.185 mmol) was added to a solution of 2-iodoadenosine (0.727 g, 1.849 mmol) according to general procedure 2. Yield: 1.192 g, 65%. %. 1H NMR (CD3OD) δ 8.26 (m, 1H), 8.25-7.34 (2×m, 4H), 5.94 (d, 1H), 4.72 (m, 2H), 4.32-4.14 (2×m, 3H), 3.91-3.71 (2×d, 2H), 3.17-2.90 (2×bt, 4H), 2.48 (d, 5H), 1.45 (m, 5H). m/z MH+=554.15. HPLC rt=7.3 mm.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:9]([CH3:10])[CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1)=O.C(C1N(C)C=C(C#N)C=1)(=O)C.[OH:24][CH2:25][C:26]([NH:29][C:30]([NH2:32])=[S:31])([CH3:28])[CH3:27]>C(O)C>[OH:24][CH2:25][C:26]([NH:29][C:30]1[S:31][CH:2]=[C:3]([C:5]2[N:9]([CH3:10])[CH:8]=[C:7]([C:11]#[N:12])[CH:6]=2)[N:32]=1)([CH3:28])[CH3:27]
Reactant: CC(C)(CO)NC(N)=S
Reactant: Cn1cc(C#N)cc1C(=O)CBr
Agent: CC(=O)c1cc(C#N)cn1C
Solvent: CCO
Product: Cn1cc(C#N)cc1-c1csc(NC(C)(C)CO)n1

Procedure:
The above prepared 2:1 mixture of 5-(2-bromo-acetyl)-1-methyl-1H-pyrrole-3-carbonitrile and 5-acetyl-1-methyl-1H-pyrrole-3-carbonitrile in ethanol (50 mL) was treated with N-(2-Hydroxy-1,1-dimethylethyl)thiourea, prepared in step 2 of Example 52, and heated under reflux. The mixture was filtered while still hot, and the precipitate washed with ethanol, and then partitioned between 1 N sodium carbonate and ethyl acetate. The organic layer was washed with water, dried (anhydrous MgSO4) and evaporated to afford 5-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}-1-methyl-1H-pyrrole-3-carbonitrile (1.10 g, 3.98 mmol), as a yellow oil. ANLC 100% at 210-370 nm, 7.8 min; 100% at 248 nm, 7.8 min, the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for C13H16N4OS [M+H]+, 277.11176; found (ESI, [M+H]+), 277.1126.
Reaction SMILES: FC(F)(F)S(O[CH2:7][CH2:8][N:9]([CH2:22][CH2:23]OS(C(F)(F)F)(=O)=O)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])(=O)=O.Cl.[NH2:35][C:36]1([C:39]([O:41][CH3:42])=[O:40])[CH2:38][CH2:37]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([N:9]1[CH2:8][CH2:7][N:35]([C:36]2([C:39]([O:41][CH3:42])=[O:40])[CH2:38][CH2:37]2)[CH2:23][CH2:22]1)(=[O:11])=[O:12])([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCOS(=O)(=O)C(F)(F)F)CCOS(=O)(=O)C(F)(F)F
Reactant: COC(=O)C1(N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)C1(N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CC2)CC1
Temperature: 60 °C

Procedure:
A solution of N,N-bis-(2-trifluoromethanesulfonyloxyethyl)-2-nitrobenzenesulfonamide (1.83 g, 3.30 mmol) from Example 16B and methyl 1-aminocyclopropane-1-carboxylate HCl (0.50 g, 3.30 mmol) in anhydrous acetonitrile (10 mL) was treated with sodium carbonate (1.40 g, 13.2 mmol) and heated overnight at 60° C. (J. A. Kozlowski, et al., Bioorg. Med. Chem. Lett. 12: 791-794, 2002). Reaction diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase HPLC on a Biotage pre-packed silica gel column eluting with 3:1 hexane:ethyl acetate to afford the title compound. MS (ESI) m/z 370 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][C:4]=1[CH2:11]Br.C[O:14][P:15]([O:18][CH3:19])[O:16][CH3:17]>C1(C)C=CC=CC=1>[C:3]1([CH2:2][P:15](=[O:14])([O:18][CH3:19])[O:16][CH3:17])[CH:8]=[CH:7][C:6]([CH2:9][P:15](=[O:14])([O:18][CH3:19])[O:16][CH3:17])=[CH:5][C:4]=1[CH2:11][P:15](=[O:14])([O:18][CH3:19])[O:16][CH3:17]
Reactant: COP(OC)OC
Reactant: BrCc1ccc(CBr)c(CBr)c1
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1ccc(CP(=O)(OC)OC)c(CP(=O)(OC)OC)c1)OC

Procedure:
A solution of 1,2,4-tris(bromomethyl)benzene (Preparation 4, 0.532 g, 0.0015 M) and trimethylphosphite (15 mL, 0.126 M) in dry toluene (25 mL) is stirred and heated at reflux temperature for 80 hours. Solvent and excess trimethylphosphite are removed under reduced pressure and the oily residue is chromatographed over silica gel (50 g, 40-63 μm, 10% CH3OH--CHCl3, 8 mL fractions) using 10% CH3OH--CHCl3 to elute the column. Fractions 16-22 contain the title compound (0.587 g, 0.00132 M, 88%), which is a viscous oil.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[F:20][C:21]1[C:26](B(O)O)=[CH:25][CH:24]=[CH:23][N:22]=1>>[F:20][C:21]1[C:26]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1cccnc1F
Product: O=C(O)c1cccc(COc2ccc(-c3cccnc3F)cc2)c1

Procedure:
3-[4-(2-Fluoro-pyridin-3-yl)-phenoxymethyl]-benzoic acid was prepared using the procedure described above for the synthesis of Example 4 from 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 2-fluoropyridine-3-boronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=324.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.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>[Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(F)cc1Cl
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2ccccn2)c(F)cc1Cl
Temperature: 25 °C
Yield: 67.1 %

Procedure:
To a solution of methyl 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (212 mmol) in THF (400 mL), was added 2-bromopyridine (33.4 g, 211 mmol), potassium carbonate (117 g, 848 mmol) and water (64 mL). The mixture was degassed with argon for 30 minutes. To this mixture was added tetrakis(triphenylphosphine)palladium (12.2 g, 10.6 mmol) and the mixture heated at reflux for 1.5 h. The mixture was cooled to room temperature and filtered through Celite, washing with EtOAc (1.2 L) and water (800 mL). The filtrate was diluted with saturated aqueous brine solution (200 mL) and the aqueous layer separated and extracted with EtOAc (600 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography over silica gel, eluting with EtOAc:hexane (3:17 to 1:4) and concentrated in vacuo to a slurry, which was diluted with heptane (100 mL) and cooled to 0° C. The solid was collected by filtration to afford the title compound (37.6 g, 67%).
Reaction SMILES: [CH3:1][C@H:2]1[C@:7]2([OH:30])[C@:8]34[O:28][C@H:27]5[C@@:16]6([C@@H:23]([OH:29])[C:24]([O:26]5)=[O:25])[C@H:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:18][C@H:12]([C@@:13]36[C@@H:14]([OH:15])[C@@H:6]2[O:5][C:3]1=[O:4])[O:11][C:9]4=[O:10].[C:31]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH3:1][C@H:2]1[C@:7]2([OH:30])[C:8]34[O:28][CH:27]5[C@@:16]6([C@@H:23]([O:29][CH3:31])[C:24]([O:26]5)=[O:25])[C@H:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:18][C@H:12]([C@:13]36[C@H:14]([OH:15])[CH:6]2[O:5][C:3]1=[O:4])[O:11][C:9]4=[O:10]
Reactant: C[C@@H]1C(=O)O[C@H]2[C@H](O)[C@@]34[C@H]5C[C@@H](C(C)(C)C)[C@]36[C@@H](OC(=O)[C@@H]6O)O[C@@]4(C(=O)O5)[C@@]12O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CO[C@H]1C(=O)OC2OC34C(=O)O[C@@H]5C[C@@H](C(C)(C)C)[C@@]21[C@]53[C@H](O)C1OC(=O)[C@@H](C)[C@@]14O
Yield: 54.6 %

Procedure:
To a suspension of ginkgolide B (0.030 g, 0.071 mmol) and K2CO3 (0.030 g, 0.212 mmol) in acetonitrile (0.5 mL) was added iodomethane (0.020 g, 0.141 mmol). The reaction mixture was heated under reflux for 30 min. This reaction resulted in a mixture of 10-methoxy-ginkgolide B and 1-methoxy ginkgolide B in a ratio of 4 to 1. 10-Methoxy-ginkgolide B was separated using an HPLC semi-preparative C18 column (7.8 mm×30 cmL) with a mobile phase of MeOH/H2O (40:60) at a flow of 2 mL/min to give the final product as a white solid (0.017 g, 56%). 1H NMR (400 MHz, CD3OD): δ1.14 (s, tert-butyl), 1.24 (d, J=7.1, CH3), 1.90 (dd, J=14.2, 4.6, 8-H), 2.06 (td, J=13.9, 4.3, 7α-H), 2.25 (dd, J=13.6, 4.6, 7β-H), 3.05 (q, J=7.1, 14-H), 3.80 (s, OCH3), 4.24 (d, J=7.4, 1-H), 4.57 (d, J=7.4, 2-H), 4.93 (s, 10-H), 5.43 (d, J=4.1, 6-H), 6.10 (s, 12-H). 13C NMR (75 MHz, CD3OD): δ7.6, 7.0, 29.6 (3 C), 32.9, 37.6, 41.8, 48.8, 68.6, 70.5, 71.5, 74.4, 80.4, 82.2, 84.8, 90.9, 98.2, 110.3, 171.1, 173.0, 175.4. [Hu, L., Chen, Z., Xie, Y., Jiang, Y., & Zhen, H. (2000) Bioorg. Med. Chem. 8, 1515-1521]
Reaction SMILES: C[Zn]C.[C:4]1(C)C=CC=CC=1.Br[C:12]1[C:17]([F:18])=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22].[NH4+].[Cl-]>O1CCOCC1.CO>[F:18][C:17]1[C:12]([CH3:4])=[C:13]([N+:21]([O-:23])=[O:22])[CH:14]=[CH:15][C:16]=1[O:19][CH3:20]
Reactant: COc1ccc([N+](=O)[O-])c(Br)c1F
Reactant: Cc1ccccc1
Agent: C[Zn]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc([N+](=O)[O-])c(C)c1F
Temperature: 55 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Dimethylzinc (67 ml of a 2M toluene) was slowly added to a mixture of 2-bromo-3-fluoro-4-methoxy-1-nitro-benzene (12.0 g) and palladium-(diphenylphosphinoferrocenyl)-dichloride-methylene dichloride complex (1.65 g) in dioxane (300 ml) at 40° C. The mixture was stirred at 55° C. during 2 hours. After cooling to room temperature, MeOH (80 ml) was slowly added followed by aqueous NH4Cl soln. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude oil was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 9/1) to provide 2-fluoro-1-methoxy-3-methyl-4-nitro-benzene (10.5 g, 90% purity) as a light yellow solid used as such in Step 3. 1H NMR (CDCl3) δ ppm: 7.89 (1H, dd); 6.86 (1H, dd); 3.96 (3H, s); 2.53 (3H, d).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3]1.[H-].[Na+].Cl[C:16]1[CH:27]=[CH:26][C:19]([C:20]([N:22]([O:24][CH3:25])[CH3:23])=[O:21])=[CH:18][N:17]=1>CN(C=O)C>[C:11]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([OH:1])=[C:10]2[C:16]1[CH:27]=[CH:26][C:19]([C:20]([N:22]([O:24][CH3:25])[CH3:23])=[O:21])=[CH:18][N:17]=1)#[N:12]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(-c2c(O)[nH]c3ccc(C#N)cc23)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a solution of 473 mg (2.99 mmol) of 2-oxoindoline-5-carbonitrile in DMF (10 mL) were added 229 mg (5.73 mmol) of sodium hydride (60% on mineral oil) as a solid. After stirring the resulting suspension for 60 min at RT, a solution of 500 mg (2.49 mmol) of 6-chloro-N-methoxy-N-methylnicotinamide from example 1.1 in DMF (10 mL) was added slowly and the mixture was stirred for 80 min at 120° C. The reaction was cooled down to RT and a saturated solution of NH4CL (40 mL) was added and the resulting precipitate was collected by filtration. The precipitate was washed with water and hexane and afterwards dried in a vacuum oven. Yellow solid. Amount 265 mg. Yield 33%.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:18][CH2:19]Cl)[C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)=[O:6].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:22]1([N:21]2[CH2:19][CH2:18][N:4]([C:5]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]4)=[O:6])[CH2:3][CH2:2]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCc2cc(C(=O)N(CCCl)CCCl)ccc2N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(C(=O)N3CCN(c4ccccc4)CC3)ccc2N1
Yield: 37.2 %

Procedure:
A mixture consisting of 15.9 g of 6-[bis-(2-chloroethyl)aminocarbonyl]-3,4-dihydrocarbostyril, 5.5 g of aniline and 70 ml of methanol was refluxed for 15 hours. After cooled the reaction mixture, 3.06 g of sodium carbonate was added to the reaction mixture and the reaction mixture was further refluxed for 8 hours. The reaction mixture was cooled and crystals precipitated in the reaction mixture were collected by filtration, and recrystallized from isopropanol to obtain 6.3 g of 6-(4-phenyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 200°-201° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:23]2[CH:22]=[N:21][C:20]([O:19][CH3:18])=[N:25][CH:24]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: COc1ncc(B(O)O)cn1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ncc(-c2cncc(Cl)c2N2CCC(C(N)=O)CC2)cn1

Procedure:
General procedure E was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (75 mg, 0.27 mmol), 2-methoxypyrimidine-5-boronic acid (53 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium(0) (16 mg, 5 mol %), acetonitrile (3 mL) and 0.5 M sodium carbonate (0.77 mL, 0.38 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, EtOH, 96:4-82:18, biotage 25+S) to furnish the title compound as an off white solid (20 mg, 21%), along with recovered 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide as a white solid (32 mg, 43% RSM), LC-MS (ESI, 4 min) Rt 1.76 min, m/z 348 (100%, [M+H]+); m/z (ESI) C16H18N5O2Cl requires 347.1149, found [M+H]+ 347.1147.