Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Br:33][C:34]1[CH:39]=[C:38]([CH2:40][NH:41][CH:42]([CH3:44])[CH3:43])[CH:37]=[CH:36][N:35]=1>C(#N)C>[Br:33][C:34]1[CH:39]=[C:38]([CH2:40][N:41]([CH:42]([CH3:44])[CH3:43])[C:7]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)=[O:9])[CH:37]=[CH:36][N:35]=1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: CC(C)NCc1ccnc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)N(Cc1ccnc(Br)c1)C(=O)c1cn(C)cn1
Temperature: 25 °C
Reaction time: 23 h
Yield: 97.6 %

Procedure:
After a solution of methyl-1H-imidazole-4-carboxylic acid (1.45 g), 1-hydroxybenzotriazole hydrate (HOBT.H2O) (2.08 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (2.60 g) in acetonitrile (35 mL) was stirred at room temperature for 10 min, a solution of N-[(2-bromopyridin-4-yl)methyl]propan-2-amine (2.59 g) in acetonitrile (15 mL) was added thereto, and the resulting solution was then stirred at room temperature for 23 hr. The solvent was distilled off under reduced pressure, and the residue was then diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate solution. After extracting with chloroform, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, chloroform:methanol=98:2-82:18) and (the same column, chloroform:methanol=98:2-85:15) to afford the title compound (3.72 g).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:19])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:19])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc2c1cc(C)n2Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2n1Cc1ccccc1
Yield: 48.9 %

Procedure:
A solution of 1.25 g (5 inmol) of 4-methoxy-2-methyl-1-(phenylmethyl)-1H-indole and 20 mL of 1M BBr3 /CH2Cl2 in 50 mL of methylene chloride was stirred at room temperature for 5 hours and concentrated at reduced pressure. The residue was dissolved in ethyl acetate, washed with brine and dried (MgSO4). After concentrating at reduced pressure, the residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 577 mg (49% yield) of 4-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole, 125-127° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[CH2:6]1)=[O:4].C(N(CC)CC)C.[CH:24]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])[CH3:25].O>C1COCC1>[CH3:1][O:2][C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:33]([C:30]3[CH:31]=[CH:32][C:27]([CH:24]([CH3:26])[CH3:25])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)N1CCC(c2cccc(N)c2)C1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N1CCC(c2cccc(NS(=O)(=O)c3ccc(C(C)C)cc3)c2)C1
Reaction time: 16 h
Yield: 109.4 %

Procedure:
To a solution of 3-(3-amino-phenyl)-pyrrolidine-1-carboxylic acid methyl ester (500 mg, 2.27 mmol) and triethylamine (500 mg, 4.94 mmol) in THF (20 ml) at 10° C. 4-isopropyl-benzenesulfonylchloride (500 mg, 2.27 mmol) was added. The mixture was allowed to come to room temperature and was stirred for 16 h. The mixture was poured into water and extracted three times with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over MgSO4 and evaporated under reduced pressure to give the product as a brown oil (1 g, 100%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][C:24]1[C:28]([C:29]([OH:31])=O)=[C:27]([CH2:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:26][N:25]=1.C(N(C(C)C)C(C)C)C.[C:50]1([C:56]2([OH:62])[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C.C(Cl)(Cl)Cl>[OH:62][C:56]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:61][CH2:60][N:59]([C:29]([C:28]2[C:24]([CH3:23])=[N:25][O:26][C:27]=2[CH2:32][C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:40])=[O:31])[CH2:58][CH2:57]1
Reactant: Cc1noc(CC(=O)c2ccccc2)c1C(=O)O
Reactant: OC1(c2ccccc2)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(CC(=O)c2ccccc2)c1C(=O)N1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of TBTU (0.48 g, 1.5 mmol, 1.5 eq.) in DMF (2 mL) was added to a mixture of 3-methyl-5-(2-oxo-2-phenylethyl)isoxazole-4-carboxylic acid (0.24 g, 1 mmol, 1 eq), N-ethyl-N-isopropylpropan-2-amine (0.18 mL, 1 eq) and 4-phenylpiperidin-4-ol (0.18 g, 1 eq) in DMF (1 mL). The resulting solution was stirred at room temperature. Chloroform (25 mL) was added and the solution was washed with water and 1 M HCl, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2 1:2 heptane/EtOAc) to afford the title compound. MS (ESI, POS. ION) M/Z Calcd for C24H24N2O4: 404.1736, found 404.1732.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:9]([N:11]1[CH2:15][CH2:14][CH:13]2[NH:16][CH2:17][CH:18]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH:12]12)=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:37]([O:39][CH2:40]C)=[O:38]>C(Cl)Cl>[CH3:40][O:39][C:37]([N:16]1[CH2:17][CH:18]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH:12]2[N:11]([C:9](=[O:10])[CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:35])[CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[CH2:15][CH2:14][CH:13]12)=[O:38]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2NCC(c3c[nH]c4cc(F)ccc34)C21)C1CCCCC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A solution containing crude 49 (229 mg, 0.47 mmol) in DCM (5 mL) was cooled to 0° C. TEA (73 mg, 0.72 mmol) was added followed by ethyl chloroformate (73 mg, 0.78 mmol). After 30 min, the reaction mixture was diluted with DCM and washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (2:1 hexanes/EtOAc to 1:1 hexanes/EtOAc) to afford 226 mg (88%) of 50 as an off-white-colored foam. 1H NMR (300 MHz, CDCl3): δ8.25-8.14 (m, 1H), 8.10 (s, 1H), 7.03-6.97 (m, 1H), 6.95-6.83 (m, 1H), 5.36-5.32 (m, 1H), 4.63 (dd, J=5.4, 19.8 Hz, 1H), 4.39-4.34 (m, 1H), 4.26-4.22 (m, 1H), 4.09-4.04 (m, 2H), 3.95 (app t, J=5.7 Hz, 1H), 3.80 (s, 3H), 3.53-3.48 (m, 2H), 2.49-2.43 (m, 0.5H), 2.31-2.24 (m, 0.5H), 1.94-1.88 (m, 1H), 1.77-1.65 (m, 6H), 1.44 (s, 9H), 1.29-1.10 (m, 5H) ppm. Mass spectrum, m/z [543.4] (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[Cl:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)c1ccccc1Cl
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4Cl)c3O2)cc1
Yield: 70.2 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 2-chlorophenylboronic acid (0.306 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.380 g (70%) of (±)-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a tan solid. mp 100-103° C.; Anal. calcd. for C22H19ClO4S: C, 63.69; H, 4.62. Found: C, 63.43; H, 4.69.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH:20]([F:22])[F:21])[CH:17]=2)[C:12]([CH2:23][C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[CH:26][C:25]=2[Cl:31])=[N:11][N:10]=1>CN(C=O)C>[Cl:31][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:30])[C:24]=1[CH2:23][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:19][CH:20]([F:21])[F:22])=[CH:15][CH:14]=2)[C:9]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[N:10][N:11]=1
Reactant: c1nc[nH]n1
Reactant: FC(F)Oc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(-n3cncn3)c2c1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
A solution under N2 of 1,2,4-triazole (2.4 g, 34.8 mmoles) in DMF (100 ml) was added with NaH (1.05 g, 26.1 mmoles). The mixture was stirred at room temperature up to clarity, then added with 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-difluoromethoxy-phthalazine (6.8 g, 17.4 mmoles), prepared as described in example 99. The mixture was heated at 100° C. for 5 hours, extracted three times with CH2Cl2. The organic phase was anhydrified and dried to give a solid which was flash chromatographed (eluent: ethyl acetate/petrolatum 7:3 to 100% of ethyl acetate) to give 4.14 g of the title compound (yield: 28%). m.p.: 220-224° C.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:13]([NH:25][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCCCCCCCCCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and dodecylamine comparable as in Example A.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[C:11]([CH2:13][N:14]2[C:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]4=[O:33])=[N:24][CH:25]=3)=[CH:17][N:16]=[CH:15]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39]>CN(C=O)C>[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[C:11]([CH2:13][N:14]2[C:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]4=[O:33])=[N:24][CH:25]=3)=[CH:17][N:16]=[CH:15]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])=[O:39]
Reactant: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCN
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCNC(=O)c1cccc(Cl)c1
Reaction time: 2 h

Procedure:
2-(2-Amino-ethoxy)-4-[5-(5-chloro-2-oxo-2H-[1,2']bipyridinyl-5'-ylmethyl)-imidazol-1-ylmethyl]-benzonitrile (L-824,459, 75 mg, 0.16 mmol) was dissolved in DMF (800 μl) and treated with 3-chlorobenzoylchloride (20 μl, 0.18 mmol). The reaction mixture was stirred at room temp. for 2 hours. The solvent was removed in vacuo and the crude product purified by flash chromatography [4% MeOH(NH4OH 5%)/CH2Cl2 ] to yield the final product.
Reaction SMILES: [C:1]([CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1)(O)=[O:2].[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[CH2:7][CH:6]2[O:5][CH2:4][C:1](=[O:2])[NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)Nc2ccccc2)cc1

Procedure:
Analogously to Example 3a, 3.06 g of tert-butyl 3-carboxymethoxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 34b) and 0.63 ml of aniline are reacted. The title compound is obtained as a colourless oil. Rf=0.50 (1:1 EtOAc-heptane); Rt=5.89.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[NH:15][N:16]=2)[N:13]=1.Br[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[N:15]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[N:16]=2)[N:13]=1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: BrC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=c1n(C2CCCCC2)nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 75 °C
Reaction time: 17 h
Yield: 34.1 %

Procedure:
A suspension of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (36 mg, 0.1 mmol), bromocyclohexane (40 μL, 0.3 mmol) and solid K2CO3 (42 mg, 0.3 mmol) in anhydrous DMF (1 mL) was stirred at 75° C. for 17 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional bromocyclohexane (50 μL, 0.375 mmol) was added, the reaction was allowed to continue at 75° C. for 24 h more. After cooling to room temperature, the reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL). The separated EtOAc layer was washed with saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-60%) in hexanes to yield a yellow glassy product, which was lyophilized in acetonitrile to afford 15 mg (34%) of the title compound as a yellow powder. LC/MS (method A): retention time=4.06 min, (M+H)+=439. 1H NMR (CDCl3, 400 MHz): δ 7.18-7.50 (m, 5H), 7.19 (d,J=8.8 Hz, 2H), 7.03 (d,J=8.8 Hz, 2H), 4.47 (m, 1H), 1.26-2.04 (m, 10H).
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[S:6]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:23][C:24]1[O:28][N:27]=[C:26]([OH:29])[CH:25]=1.C(=O)([O-])O.[Na+].Cl>O.CO.CS(C)=O>[CH3:23][C:24]1[O:28][N:27]([C:12]2[CH:13]=[CH:14][C:9]([S:6](=[O:8])(=[O:7])[N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][C:11]=2[N+:16]([O-:18])=[O:17])[C:26](=[O:29])[CH:25]=1
Reactant: Cc1cc(O)no1
Reactant: CCCCN(CCCC)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: CCCCN(CCCC)S(=O)(=O)c1ccc(-n2oc(C)cc2=O)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of 600 g of N,N-dibutyl-4-chloro-3-nitrobenzenesulfonamide, 220 g of 5-methyl-3-hydroxyisoxazole, 300 g of sodium hydrogen carbonate and 1.5 liter of dimethylsulfoxide was reacted at 80° C. for 6 hours. The reaction mixture was cooled to 40° C., 1.2 liter of methanol was added thereto, and then 400 ml of concentrated hydrochloric acid was added thereto at 25° C. After stirring for 30 minutes, 800 ml of water was added thereto. The crystals thus deposited were collected by filtration, washed with water, recrystallized from methanol and dried. Yield: 613 g (86.6%). Melting point: 84° to 86° C.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:26](Cl)(=[O:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[CH2:13]([N:25]([CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[C:26](=[O:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCN
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCC)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
The compound was prepared from D-galactose, dodecylamine and stearoyl chloride analogously to Example 11.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23](O)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([F:58])=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:44]3[CH2:49][CH2:48][N:47](C(OC(C)(C)C)=O)[C@@H:46]([CH3:57])[CH2:45]3)[CH:38]=2)[CH:36]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23]([NH:29][CH2:30][C:31]3[CH:36]=[C:35]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:44]5[CH2:49][CH2:48][NH:47][C@@H:46]([CH3:57])[CH2:45]5)[CH:38]=4)[C:34]([F:58])=[CH:33][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(F)c(-c2cccc(CN3CCN[C@@H](C)C3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
A mixture of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (88 mg, 0.23 mmol), 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (107 mg, 0.25 mmol), HBTU (103 mg, 0.27 mmol) and Et3N (0.06 mL, 0.45 mmol) in DCM was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were then washed with water followed by a brine wash. The organic layer was then concentrated under vacuum to give a crude residue: LC-MS m/z 785 (M+H)+. The crude residue was dissolved in 25% TFA in DCM (2 mL) and stirred at RT for 2 h. It was purified with a Gilson HPLC (with 0.1% TFA condition), eluting with 10 to 70% CH3CN in water at a flowrate of 20 mL/min. The fractions were combined and then converted to the free base with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered and then concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]propanediamide as a solid (61 mg, 39%). LC-MS m/z 685 (M+H)+.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[C:7]([CH:9](Br)[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=O)[CH:6]=[CH:5][N:4]=1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[S:24].C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]1[S:24][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([NH2:2])[CH:8]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:25]=1
Reactant: NC(=S)c1ccccc1Cl
Reactant: Cc1cccc(C(=O)C(Br)c2ccnc(N)c2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(-c3ccccc3Cl)sc2-c2ccnc(N)c2)c1
Yield: 70 %

Procedure:
A solution of 2-(2-amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)ethanone hydrobromide (5.00 g, 12.3 mmol) and 2-chlorothiobenzamide (1.06 g, 11.9 mmol) in N,N-dimethylformamide (40 mL) was stirred for 14 hours at room temperature. Aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. The extracts were washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexaneethyl acetate=4:1 to 2:1) to obtain a crystal. This crystal was washed with isopropyl ether, to obtain a title compound (3.15 g, yield 81%).
Reaction SMILES: Cl[C:2]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>>[CH3:9][O:8][N:6]([CH3:7])[C:4](=[O:5])[C:3]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[N:13][C:2]=1[C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18]
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1Cl
Reactant: C#C[Si](C)(C)C
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1C#C[Si](C)(C)C
Yield: 60 %

Procedure:
2-Chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (1.2 g, 4.52 mmol) was reacted with (trimethylsilyl)acetylene (0.689 ml, 4.97 mmol) to give N-methoxy-N-methyl-6-trifluoromethyl-2-trimethylsilanylethynyl-nicotinamide (896 mg, 60%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:8]=[CH:9][N:10]3[C:19]4[C:14](=[C:15](C(F)(F)F)[CH:16]=[CH:17][CH:18]=4)[C:13](=[O:24])[N:12]([CH3:25])[C:11]=23)[N:3]=1.CN1C(=O)C2[C:30](=[CH:31]C=CC=2C(F)(F)F)NC1=O.CC1ON=C(C[N+]#[C-])N=1>>[CH:1]1([C:2]2[O:6][N:5]=[C:4]([C:7]3[N:8]=[CH:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13](=[O:24])[N:12]([CH3:25])[C:11]=34)[N:3]=2)[CH2:31][CH2:30]1
Reactant: Cc1nc(-c2ncn3c4cccc(C(F)(F)F)c4c(=O)n(C)c23)no1
Reactant: Cn1c(=O)[nH]c2cccc(C(F)(F)F)c2c1=O
Agent: [C-]#[N+]Cc1noc(C)n1
Product: Cn1c(=O)c2ccccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
3-(5-methyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-4-methyl-5-oxo-6-trifluoromethyl-imidazo(1,5-a)quinazoline, M.p. 251.5°-251.9° C., by reaction between 3-methyl-5-trifluoromethyl 1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and 5-methyl-3-isocyanomethyl-1,2,4-oxadiazole.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21]([C:23]5([NH:31]C(=O)OC(C)(C)C)[CH2:28][O:27]C(C)(C)[O:25][CH2:24]5)=[CH:20][C:19]=4[CH:39]=3)[N:11]=2)=[CH:6][CH:5]=1)[CH3:2].ClC1C=C(C2ON=C(C3C=CC4OC(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)=CC=4C=3)N=2)C=CC=1OCCC>>[NH2:31][C:23]([C:21]1[O:22][C:18]2[CH:17]=[CH:16][C:15]([C:12]3[N:11]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=4)[O:14][N:13]=3)=[CH:39][C:19]=2[CH:20]=1)([CH2:28][OH:27])[CH2:24][OH:25]
Reactant: CCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1
Agent: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Product: CCOc1ccc(-c2nc(-c3ccc4oc(C(N)(CO)CO)cc4c3)no2)cc1
Yield: 32 %

Procedure:
When the product of Step C was substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 32% yield, as light yellow solid. 1H-NMR (DMSO-d6) 8.09 (s, 1H); 7.96 (d, 2H, J=8.4 Hz); 7.7 (d, 1H, J=8.4 Hz); 7.15 (d, 2H, J=9 Hz); 6.98 (s, 1H); 5.1 (b, 2H); 4.13 (q, 2H, J=6.9, 13.8 Hz); 3.73 (d, 2H, J=8.1 Hz); 3.64 (d, 2H, J=8.1 Hz); 1.34 (t, 3H, J=6.9 Hz).