Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[CH:14]OC)[C:6](=[O:17])[N:5]1[C:18](=[O:20])[CH3:19])(=[O:3])[CH3:2].Cl.[NH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([OH:30])[CH:29]=1.C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)/[C:7](=[CH:14]/[NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([OH:30])[CH:29]=2)/[C:6](=[O:17])[N:5]1[C:18](=[O:20])[CH3:19])(=[O:3])[CH3:2]
Reactant: COc1ccc(CN)cc1O
Reactant: COC=C1C(=O)N(C(C)=O)N(C(C)=O)c2ccccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN/C=C2\C(=O)N(C(C)=O)N(C(C)=O)c3ccccc32)cc1O
Temperature: 25 °C
Reaction time: 120 h
Yield: 53.6 %

Procedure:
To a suspension of 1,2-diacetyl-4-methoxymethylene-1,4-dihydro-2H-cinnolin-3-one (0.18 g, 0.66 mmol) and 5-(aminomethyl)-2-methoxyphenol hydrochloride (0.13 g, 0.66 mmol) in tetrahydrofuran (5 mL) is added triethylamine (0.21 mL). After the addition of a few drops of N,N-dimethylformamide, the reaction mixture is stirred for five days at room temperature. The solvent is then evaporated under reduced pressure to give a maroon oil, which is then purified by via semi-preparative HPLC (Prodigy ODS3 column, 40% MeCN/60% water/0.01% trifluoroacetic acid to 70% acetonitrile over 1 hour at 10 mL/min) to give (4Z)-1,2-diacetyl-4-{[(3-hydroxy-4-methoxybenzyl)amino]methylene}-1,4-dihydrocinnolin-3(2H)-one (0.14 g, 54%) as a straw-colored foam, which is crushed to a powder.
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:29])[C:12]([OH:28])=[C:13]([C:15]3[NH:16][CH:17]=[C:18]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[N:19]=3)[N:14]=[C:3]21.C(N(CC)CC)C.[CH3:37][C:38]1[O:42][N:41]=[C:40]([C:43](Cl)=[O:44])[CH:39]=1.CNC.CO>C(Cl)Cl.CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:18]2[N:19]=[C:15]([C:13]3[N:14]=[C:3]4[C:2]5([NH:1][C:43]([C:40]6[CH:39]=[C:38]([CH3:37])[O:42][N:41]=6)=[O:44])[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]5)[CH2:5][N:4]4[C:11](=[O:29])[C:12]=3[OH:28])[NH:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: NC12CCC(CC1)Cn1c2nc(-c2nc(Cc3ccc(F)cc3)c[nH]2)c(O)c1=O
Reactant: Cc1cc(C(=O)Cl)no1
Agent: CNC
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C(=O)NC23CCC(CC2)Cn2c3nc(-c3nc(Cc4ccc(F)cc4)c[nH]3)c(O)c2=O)no1
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of 10-amino-2-(4-(4-fluorobenzyl)-1H-imidazol-2-yl)-3-hydroxy-7,8,9,10-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-4(6H)-one, Example 1 (30 mg, 0.076 mmol) in CH2Cl2 (3 mL) was added triethylamine (0.063 mL, 0.455 mmol) followed by 5-methylisoxazole-3-carbonyl chloride (55.2 mg, 0.379 mmol) and the resulting mixture stirred at room temperature. After 16 h the reaction mixture was concentrated to give the crude product which was treated with 2M dimethylamine/MeOH (0.5 mL) in MeOH (2 mL) at 60° C. for 2 h. The mixture was then cooled and purified by preparative HPLC to afford the title compound (15 mg, 39%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 13.4 (1H, br. s.), 9.0 (1H, s), 7.4 (1H, br. s.), 7.4 (2H, dd, J=8.24, 5.80 Hz), 7.2 (2H, t, J=8.85 Hz), 6.6 (1H, s), 4.1 (2H, d, J=3.36 Hz), 4.1 (2H, s), 2.7-2.8 (2H, m), 2.5 (1H, br. s.), 2.0-2.0 (2H, m), 1.9-1.9 (2H, m), 1.7-1.8 (2H, m). LCMS (M+H)=505.49.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH:6](SC)[C:7](=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:15][CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.O>ClCCl>[CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7](=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc2c(c(C)c1C)NC(=O)C2SC
Agent: Cc1ccccc1S(=O)(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(c(C)c1C)NC(=O)C2
Reaction time: 3 h
Yield: 72.6 %

Procedure:
To a solution of 6,7-dimethyl-5-methoxy-3(methylthio)-1,3-dihydro-2H-indole-2-one (30 g, 126 mmol) in dichloromethane (600 mL) were added triphenylphosphine (40 g, 153 mmol) and toluenesulfonic acid monohydrate (29 g, 153 mmol) at room temperature, and the mixture was stirred for 3 hours. The reaction solution was poured into cool water, and the precipitated crystals were filtered. The crystals were washed with dichloromethane and water to obtain 17.5 g of the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=1)[N:9]=[C:8]2[NH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[N:31]=[CH:30]2)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[N:9]=[C:8]2[NH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[N:31]=[CH:30]2)(=[O:3])[CH3:2].[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[N:9]=[C:8]2[NH:26][C:30]1[C:29]2[C:33](=[CH:34][CH:35]=[CH:27][CH:28]=2)[N:32]([C:36]([O-:38])=[O:37])[N:31]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2nc(-c3cccc(N)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OC(C)=O
Product: COc1cc2nc(-c3cccc(N)c3)nc(Nc3nn(C(=O)[O-])c4ccccc34)c2cc1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of tert-butyl 5-(6-acetoxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.40 g, 0.70 mmol) in MeOH (100 mL) was added Pd/C (0.15 g) under an atmosphere of N2. The mixture was then stirred under an atmosphere of H2 (balloon pressure) for 48 h at RT. The mixture was filtered through a pad of Celite® washing with MeOH. The filtrate was concentrated in vacuo to give the desired product tert-butyl 5-((6-acetoxy-2-(3-aminophenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.23 g, 0.43 mmol, 61%). HPLC retention time 5.748 mins.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].[C:13]12([C:23](Cl)=[O:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>C(Cl)Cl.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[C:13]12([C:23](=[O:24])/[CH:12]=[C:7]3\[S:8][CH:9]=[C:10]([CH3:11])[N:6]\3[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: CCCC[n+]1c(C)csc1C
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: CS(C)=O
Solvent: CO
Solvent: ClCCl
Product: CCCCN1C(C)=CS/C1=C\C(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 1-adamantyl carbonylchloride (31.8 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR, MS and LC/MS. MS (ESI) positive ion 332 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][NH:28]3)=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([N:38]5[CH2:39][CH2:40][CH:41]([OH:44])[CH2:42][CH2:43]5)=[CH:34][CH:33]=4)[N:3]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Reactant: Nc1ccc(N2CCC(O)CC2)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Nc4ccc(N5CCC(O)CC5)cc4)nc32)cc1
Temperature: 116 °C
Yield: 13.2 %

Procedure:
A mixture of 2-chloro-N-(1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (61 mg, 0.14 mmol), 1-(4-aminophenyl)piperidin-4-ol (61 mg, 0.32 mmol) and trimethylsilyl chloride (TMSCl) (0.060 mL, 0.48 mmol) in n-butyl alcohol (2 mL) was heated at 116° C. for 96 h. The mixture was then purified by HPLC to give 1-(4-(4-(1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperidin-4-ol (11 mg).
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[C:9]([OH:23])[CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)C(=O)O1.[C:26]([O:30][C:31]([O:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[C:37]([O:36][C:35]([N:34]([O:33][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[C:6](=[O:8])[CH2:5][C:9]([CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]1)=[O:23])=[O:41])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)=C2C(=O)OC(C)(C)OC2=O)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)ON(C(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OC(C)(C)C
Reaction time: 36 h

Procedure:
A solution of tert-butyl 4-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(hydroxy)methyl]piperidine-1-carboxylate (8.99 g, 25.3 mmol) and t-butyl N-(t-butoxycarbonyloxy)carbamate (5.90 g, 25.3 mmol) in toluene (200 mL) was stirred at 65° C. for 14 h, then at rt for 36 h. The reaction mixture was concentrated and the residue was purified by flash chromatography (silica, 25% ethyl acetate/hexanes) to afford tert-butyl 4-(3-{(tert-butoxycarbonyl)[(tert-butoxycarbonyl)oxy]amino}-3-oxopropanoyl)piperidine-1-carboxylate. H NMR analysis was consistent with product but complex due to carbamate rotamers.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([OH:20])=O)=[O:13])=[CH:2]1.[N:24]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Na]>CN(C)C=O.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH:33][CH2:32][CH2:31][CH2:30][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:20])=[O:13])=[CH:2]1
Reactant: NCCCN1CCOCC1
Reactant: O=C(C=Cc1c[nH]c2ccccc12)Nc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C=Cc1c[nH]c2ccccc12)Nc1cccc(C(=O)NCCCN2CCOCC2)c1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
In 5.0 mL of dimethylformamide were dissolved 3-(3-1H-indol-3-yl-acryloylamino)-benzoic acid (150 mg, 0.49 mmol), prepared in Example 3, and 3-morpholin-4-yl-propylamine (0.11 mL, 0.73 mmol), followed by the addition of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (277.6 mg, 0.73 mmol) and N,N-diisopropylethylamine (0.13 ml, 0.73 mmol). The resulting solution was stirred at room temperature and mixed with ethyl acetate and an aqueous sodium salt solution. The organic layer was dried over anhydrous magnesium sulfate. After the filtration and concentration of the residue, the concentrate was purified using Prep-TLC (methylene chloride:methanol=10:1) to produce the subject compound as a yellow solid (8) (92.6 mg, 44%).
Reaction SMILES: [CH2:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH:10]=2)[O:5][CH:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:3]1.[I:26]I.[C:28]([S-:30])#[N:29].[K+]>C(Cl)(Cl)Cl>[I:26][CH2:1][C:2]1([N:29]=[C:28]=[S:30])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH:10]=2)[O:5][CH:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:3]1
Reactant: II
Reactant: N#C[S-]
Reactant: C=C1CC(c2ccccc2)Oc2ccc(-c3cccc(C#N)c3)cc21
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#Cc1cccc(-c2ccc3c(c2)C(CI)(N=C=S)CC(c2ccccc2)O3)c1
Reaction time: 8 h

Procedure:
To a solution of 3-(4-methylene-2-phenyl-chroman-6-yl)-benzonitrile (50 mg, 0.156 mmol) in CHCl3 (5 mL) was added I2 (93 mg, 0.367 mmol), KSCN (76 mg, 0.78 mmol) and catalyst amount t-BtNBr. The mixture was stirred overnight and used directly.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]=[O:14])=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]([C:18]([OH:20])=O)=[N:9]2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH2:44]([NH2:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(Cl)Cl>[CH2:44]([NH:51][C:18]([C:10]1[C:11]([CH:15]([CH3:16])[CH3:17])=[C:12]([CH:13]=[O:14])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:20])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NCc1ccccc1
Reactant: CC(C)c1c(C(=O)O)nn(-c2ccc(F)cc2)c1C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)c1c(C(=O)NCc2ccccc2)nn(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39 %

Procedure:
To a solution of 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid (1.25 g, 4.52 mmol) in CH2Cl2 (50 mL) at 25° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.30 g, 6.79 mmol; commercially available from Sigma Aldrich) followed by 1-hydroxybenzotriazole hydrate (1.04 g, 6.79 mmol; commercially available from Sigma Aldrich) and the reaction was stirred for 5 min at 25° C. Subsequently, benzyl amine (0.533 g, 4.98 mmol; commercially available from Sigma Aldrich) was added and the reaction was stirred for an additional 4 hrs as a fine white precipitate developed. The organic layer was washed with 1 N HCl, saturated NaHCO3 and brine. After drying and concentration, the product was purified by silica gel chromatography (20% EtOAc/Hex) to provide 1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic acid benzylamide (0.65 g, 39%): MS(APCI+): m/z366.1 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[CH:11][S:12][C:5]=2[CH2:4]1)[CH3:2].[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1F>>[ClH:13].[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[O:9][CH:7]1[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]2[S:12][CH:11]=[CH:10][C:6]1=2
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CCN1Cc2sccc2C(O)C1
Product: CCN1Cc2sccc2C(Oc2cccc(Cl)c2Cl)C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 7) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:34][C:35]1[CH:42]=[CH:41][C:38](C=O)=[CH:37][CH:36]=1.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:38]3[CH:41]=[CH:42][C:35]([CH3:34])=[CH:36][CH:37]=3)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [BH4-]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(Cc3ccc(C)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 4-Methylbenzaldehyde (0.134 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 22 mg; HRMS (FAB+, NBA) (M+H)+ 457.2853, C30H37N2O2 requires 457.2855; LC-MS: (M+H)+ 457.2, tr 6.97 min.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].CCN(CC)CC.[NH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:25][CH2:24]1.[C:43]([O-])(O)=[O:44].[Na+]>C(Cl)Cl>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:43]([NH:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH2:25][CH2:24]2)=[O:44])[C:5]1=[O:13])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: CC(C)n1c(=O)[nH]c2ccccc21
Reactant: CC(C)(C)OC(=O)C1(CN2CCC(CN)CC2)CCOCC1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1c(=O)n(C(=O)NCC2CCN(CC3(C(=O)OC(C)(C)C)CCOCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of p-nitrophenylchloroformate (4.14 g, 0.0205 mol), 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (3.62 g, 0.0205 mol, J. Med. Chem. 1999, 42, 2870-2880) and Et3N (7.81 mL, 0.0560 mol) in CH2Cl2 (100 mL) was stirred at room temperature for 4 h. Then, tert-butyl 4-{[4-(aminomethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylate (5.72 g, 0.0187 mol, step 5) was added, and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with sat. NaHCO3 aq. (300 mL), extracted with CH2Cl2 (300 mL) for three times. The combined extract was dried over Na2SO4 and concentrated. The residue was chromatographed on a column of NH-silica gel eluting with hexane/ethyl acetate (1:1) to give 9.83 g (100%) of the title compound as a yellow syrup.
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].P(Br)(Br)[Br:23]>C(Cl)Cl.CN(C=O)C>[BrH:23].[Br:23][CH:2]([C:4]1[O:5][C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: BrP(Br)Br
Reactant: Cc1ccc(-c2c(C(C)O)oc(=O)c3ccccc23)cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Br
Product: Cc1ccc(-c2c(C(C)Br)oc(=O)c3ccccc23)cn1

Procedure:
The title compound was made in a similar way as that of the intermediate C6, using 3-(1-hydroxyethyl)-4-(6-methylpyridin-3-yl)-1H-isochromen-1-one intermediate B10 (163 mg, 0.579 mmol), 1M PBr3 (0.87 mL, 0.87 mmol) in a mixture of DCM (2 ml) and DMF (3 ml) at RT. The crude was purified via reverse phase chromatography with a Biotage C18 SNAP 60 g column (Phase A, water 95%, ACN 4.9%, formic acid 0.1%); Phase B ACN 99.9%, formic acid 0.1%). The aqueous fractions were added of 50% HBraqueous and concentrated under reduced pressure to give the title compound (320 mg).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1C=CC=C[CH:3]=1.[OH:10][C:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14](=[O:22])(=[O:21])[N:13]([CH3:23])[C:12]=1[C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][N:25]=1>>[CH3:23][N:13]1[C:12]([C:24]2[O:28][C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[N:26][N:25]=2)=[C:11]([O:10][C:1](=[O:8])[CH2:2][CH3:3])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14]1(=[O:21])=[O:22]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1C(c2nnc(-c3ccccc3)o2)=C(O)c2ccccc2S1(=O)=O
Product: CCC(=O)OC1=C(c2nnc(-c3ccccc3)o2)N(C)S(=O)(=O)c2ccccc21

Procedure:
Following the procedures of Example 5, but substituting propionyl chloride for benzoyl chloride, 4-hydroxy-2-methyl-3-(2-phenyl-1,3,4-oxadiazol-5-yl)-1,2-benzothiazine 1,1-dioxide was acylated to give the title product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CCO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-(3-nitrophenyl)piperazine-1-carboxylate in EtOH (20 mL) and THF (10 mL) was added Pd/C (500 mg), the mixture was charged with H2 (1 atm) and stirred for 16 h. Pd/C was filtered off, the filtrate was concentrated to give tert-butyl 4-(3-aminophenyl)piperazine-1-carboxylate (1.71 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1)[CH3:4].[C:15]([OH:22])(=[O:21])[CH2:16][CH2:17][CH2:18][C:19]#[CH:20]>>[OH:1][CH2:2][CH:3]([NH:5][C:6]([C:7]1[CH:8]=[C:9]([C:20]#[C:19][CH2:18][CH2:17][CH2:16][C:15]([OH:22])=[O:21])[CH:10]=[CH:11][CH:12]=1)=[O:14])[CH3:4]
Reactant: CC(CO)NC(=O)c1cccc(I)c1
Reactant: C#CCCCC(=O)O
Product: CC(CO)NC(=O)c1cccc(C#CCCCC(=O)O)c1
Yield: 99 %

Procedure:
The iodobenzamide (1) (2.00 g, 6.5 mmol) was coupled with 5-hexynoic acid using method B yielding (4) (1.87 g, 6.42 mmol; 99% yield).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].[Cl:16][C:17]1[C:22]([C:23](O)=[O:24])=[C:21]([F:26])[C:20]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:19][CH:18]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:16][C:17]1[C:22]([C:23]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[CH:7][N:6]=[C:5]3[O:4][CH:1]([CH3:3])[CH3:2])=[O:24])=[C:21]([F:26])[C:20]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:19][CH:18]=1
Reactant: CC(C)Oc1ncnc2c(N)cccc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ncnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)cccc12
Yield: 17.3 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-isopropoxyquinazolin-8-amine (Intermediate-52, 100 mg, 0.49 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 184 mg, 0.64 mmol), oxalyl chloride (87 mg, 0.69 mmol), DMF (1 drop) and DIPEA (571 mg, 1.48 mmol) in CH2Cl2 (5 mL) to afford 40 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 10.73 (s, 1H), 8.78 (s, 1H), 8.76 (s, 1H), 8.15-8.12 (t, J=5.2 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.69-7.65 (t, J=8.0 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.32-7.28 (t, J=8.0 Hz, 1H), 5.60-5.54 (m, 1H), 4.28 (d, J=6.0 Hz, 2H), 1.42 (d, J=6.0 Hz, 6H), 1.11 (s, 9H); MS (m/z): 473.11 (M+H)+.