Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[C:16]([O:23][CH3:24])=[CH:15][C:10]=2[C:11](OC)=[O:12])=O)=[CH:4][CH:3]=1.[NH3:27]>CO>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]2[N:27]=[C:11]([OH:12])[C:10]3[C:9](=[C:18]([O:19][CH3:20])[C:17]([O:21][CH3:22])=[C:16]([O:23][CH3:24])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1NC(=O)c1ccc(Cl)cc1
Solvent: CO
Product: COc1cc2c(O)nc(-c3ccc(Cl)cc3)nc2c(OC)c1OC
Temperature: 100 °C

Procedure:
A suspension of 28.5 g of methyl 2-(4-chlorobenzoylamino)-3,4,5-trimethoxybenzoate in 200 ml of methanol was treated with 150 ml of liquid ammonia and heated at 100° C. for 5 h in an autoclave. On cooling, a precipitate deposited, which was filtered off with suction and dried under reduced pressure. Yield: 25 g. M.p.: 289° C.
Reaction SMILES: [CH3:1][C:2]([C:6]1[N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[CH:18]=[CH:19][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:21][C:8]=2[N:7]=1)([CH3:5])[CH2:3][CH3:4].[NH:26]1[CH:30]=[CH:29][CH:28]=[N:27]1>CN(C1C=CN=CC=1)C.CC#N>[CH3:1][C:2]([C:6]1[N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[CH:18]=[CH:19][C:20]([S:22]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)(=[O:24])=[O:23])=[CH:21][C:8]=2[N:7]=1)([CH3:5])[CH2:3][CH3:4]
Reactant: c1cn[nH]c1
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cccn3)ccc2n1CC1CCOCC1
Yield: 98 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride e (287 mg, 0.746 mmol) (see following Steps B, C, D and E for preparation), pyrazol (152 mg, 2.24 mmol) and DMAP (182 mg, 1.49 mmol) in MeCN (15 mL). The crude product was purified by MPLC using Hex/EtOAc (3:7) on silica gel to give 305 mg (98%) of a white solid as the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ 0.73 (t, J=7.52 Hz, 3 H), 1.37-1.52 (m, 4 H), 1.54 (s, 6 H), 1.90 (q, J=7.49 Hz, 2 H), 2.20-2.34 (m, 1 H), 3.24-3.34 (m, 2 H), 3.87-3.90 (m, 2 H), 4.34 (d, J=7.62 Hz, 2 H), 6.47 (dd, J=2.73, 1.56 Hz, 1 H), 7.73 (dd, J=1.56, 0.59 Hz, 1 H), 7.76 (dd, J=8.79, 0.39 Hz, 1 H), 7.86 (dd, J=8.8, 1.8 Hz, 1 H), 8.22-8.27 (m, 1 H), 8.31 (dd, J=2.73, 0.59 Hz, 1 H); MS (ESI) (M+H)+=417.3; Anal. Calcd for C21H28N4O3S+0.1H2O (418.35): C, 60.29; H, 6.79; N, 13.39. Found: C, 60.32; H, 6.58; N, 13.77.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][CH:30]=1)[CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[CH:19]=[C:20](CC(O)=O)[CH:21]=[CH:22][CH:23]=2)=[N:12]1)=[O:5])[CH3:2].[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])=[O:37])([CH3:34])([CH3:33])[CH3:32].CN1CC[O:48][CH2:47][CH2:46]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:5])[NH:6][C:7]1[CH:30]=[CH:29][CH:28]=[C:9]([CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH2:46][C:47](=[O:48])[NH:43][CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])=[CH:20][CH:19]=3)=[N:12]2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3cccc(CC(=O)O)c3)ccc2=O)c1
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CC(=O)NCCCCNC(=O)OC(C)(C)C)cc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.5 mmol of 3-[1-(3-ethoxycarbonylaminobenzyl)-6-oxo-1,6-dihydropyridazin-3-yl]phenylacetic acid are suspended in 2 ml of DMF, and 0.6 mmol of N-tert-butyloxycarbonyl-1,4-diaminobutane, 1 mmol of 4-methylmorpholine, 70 mg (0.5 mmol) of 1-hydroxybenzotriazole and 1 mmol of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride are added. The reaction mixture is stirred at room temperature for 24 h and purified by means of preparative HPLC.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:22][C:23](=[O:35])[C@@H:24]([O:33][CH3:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH3:21].[Br:36][CH2:37][CH2:38][CH2:39]O>C1(C)C=CC=CC=1.C1COCC1>[CH2:20]([O:22][C:23](=[O:35])[C@@H:24]([O:33][CH3:34])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:39][CH2:38][CH2:37][Br:36])=[CH:30][CH:31]=1)[CH3:21]
Reactant: OCCCBr
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (4.77 mmol, 1250 mg) in 50 mL of dry toluene was treated at 0° C. with diisopropilazodicarboxylate (4.77 mmol, 964.5 mg) and stirred for about 20 minutes. A solution of (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester (Example 283, Step 1) (4.46 mmol, 1000 mg) and 3-bromo-propan-1-ol (4.77 mmol, 663 mg) in 10 mL of dry THF was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness under vacuum and purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 6:1). The fraction with Rf 0.4 corresponding to the coupled compound was combined and concentrated to dryness to afford a yellow oil. MS (ES) for C15H21BrO4 [M+Na]+: 367.2.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH3:8][C:9]([OH:12])([CH3:11])[CH3:10].[C:13]([O:17][C:18]([N:20]([CH2:50][CH2:51][O:52][CH2:53][CH2:54][NH:55][CH3:56])[C@@H:21]1[CH2:28][N:27]2[C:29]3[CH:30]=[C:31]([C:42]([O:44][CH3:45])=[O:43])[CH:32]=[CH:33][C:34]=3[C:35]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:26]2[C:25]2[CH:46]=[CH:47][CH:48]=[CH:49][C:24]=2[O:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(CC)CC>C(Cl)Cl.CCOCC>[C:13]([O:17][C:18]([N:20]([CH2:50][CH2:51][O:52][CH2:53][CH2:54][N:55]([S:2]([NH:5][C:6]([O:12][C:9]([CH3:11])([CH3:10])[CH3:8])=[O:7])(=[O:4])=[O:3])[CH3:56])[C@@H:21]1[CH2:28][N:27]2[C:29]3[CH:30]=[C:31]([C:42]([O:44][CH3:45])=[O:43])[CH:32]=[CH:33][C:34]=3[C:35]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:26]2[C:25]2[CH:46]=[CH:47][CH:48]=[CH:49][C:24]=2[O:23][CH2:22]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CNCCOCCN(C(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(CCOCCN(C)S(=O)(=O)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COc1ccccc1-3
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Chlorosulfonyl isocyanate (1.2 eq) was dissolved in dry DCM (0.2M) and 1.3 eq of a 2M solution of t-BuOH in ether was added at 0° C., after stirring for 1 h a 1 M solution of methyl (7R)-7-((tert-butoxycarbonyl){2-[2-(methylamino)ethoxy]ethyl}amino)-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (1 eq) and NEt3 (3 eq) in dry DCM was added dropwise, and stirring was continued for 30 min at 0° C. and then at RT for 2 h. All volatiles were evaporated in vacuo and the residue was taken in EtOAc, washed with 1N HCl and brine, dried and concentrated; the crude material was purified by FC (Biotage, gradient of PE/EtOAc 1:1 to 1:3) to afford 40% of the title compound. (ES+) m/z 785 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[NH:22][CH3:23])[C:4](=[O:15])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].[CH2:29](Br)[CH:30]1[O:34][CH2:33][CH2:32][CH2:31]1>ClCCl.CN(C)C=O>[CH3:2][N:3]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[N:22]([CH3:23])[CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][O:34]1)[C:4](=[O:15])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: BrCC1CCCO1
Reactant: CN[C@@H]1CCCC[C@H]1N(C)C(=O)Cc1cccc2sccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CC1CCCO1)[C@@H]1CCCC[C@H]1N(C)C(=O)Cc1cccc2sccc12
Reaction time: 20 h
Yield: 31.6 %

Procedure:
A solution of trans-(±)-N-methyl-N-[2-(methylamino)cyclohexyl]benzo[b]thiophene-4-acetamide monohydrochloride (120 mg, 0.34 mmol) in dichloromethane (10 ml) was treated with saturated aqueous sodium bicarbonate to liberate the parent amine. The oil was dissolved in dimethyl formamide and treated with tetrahydrofurfuryl bromide (68 mg, 0.41 mmol) and sodium bicarbonate (43 mg, 0.5 mmol). The resulting mixture was stirred in an oil bath at 95°-110° C. for 20 hours then concentrated in vacuo, poured into saturated aqueous sodium bicarbonate (15 ml) and extracted with dichloromethane (2×15 ml). Silica gel chromatography (70:30:1 ethyl acetate-hexanetriethylamine) furnished trans-(±)-N-methyl-N-(2-(methyl[(tetrahydro-2-furanyl)methyl]amino)cyclohexyl)-benzo[b]thiophene-4-acetamide as a colourless oil (43 mg, 32%); m/e: 400 (M+), 329, 286, 195, 147; t.l.c. analysis of this product (50:50:1 ethyl acetate-hexane-triethylamine, multiple development) indicated that it consisted of two components.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].BrC1C=CC(C(F)(F)F)=NC=1.[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)=[O:28])[CH:25]=2)[N:20]=[C:19]([O:35][CH3:36])[C:18]=1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1.Cl>C1COCC1.C(Cl)Cl.O>[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)([OH:28])[CH2:1][CH3:2])[CH:25]=2)[N:20]=[C:19]([O:35][CH3:36])[C:18]=1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([S:44]([CH3:47])(=[O:45])=[O:46])=[CH:42][CH:43]=1
Reactant: CC[Mg]Br
Reactant: COc1nc2ccc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: FC(F)(F)c1ccc(Br)cn1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)(c1ccc2nc(OC)c(Cc3ccc(S(C)(=O)=O)cc3)c(Cl)c2c1)c1cncn1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Ethyl magnesium bromide solution (3 M in Et2O, 0.1 mL, 0.334 mmol) was added slowly to a solution of 5-bromo-2-(trifluoromethyl)pyridine (0.075 g, 0.334 mmol) in dry THF (3 mL). The resulting cloudy solution was stirred at room temperature for 20 minutes, cooled to 0° C. and then (4-chloro-2-methoxy-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (0.056 g, 0.119 mmol, Intermediate 7: step e) in dry DCM (1 mL) was added. The resulting suspension was stirred at room temperature for 10 minutes then heated in a 60° C. oil bath, for 6 hours, then at 80° C. for an additional 12 hours. The mixture was cooled to room temperature, then H2O was added followed by 6 N aqueous HCl to bring the contents to a neutral pH. The solvents were removed under reduced pressure and the product extracted out with CH2Cl2 (2×). The combined organic extract was dried (Na2SO4), filtered, evaporated in vacuo and chromatographed (0-10% MeOH in DCM) to provide a yellow solid by-product. Further purification by RP-HPLC (water/acetonitrile/0.1% TFA) of this by-product provided the title compound as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.80 (s, 1H), 8.32 (d, J=2.0 Hz, 1H), 7.84 (d, J=7.6 Hz, 4H), 7.51 (d, J=8.6 Hz, 3H), 4.44 (s, 2H), 4.07 (s, 3H), 3.53 (s, 3H), 3.07 (s, 3H), 2.26-2.48 (m, 2H), 0.83 (t, J=7.0 Hz, 3H); MS (ESI) 500 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([Cl:18])(=O)C>>[Cl-:18].[CH:7](=[N+:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)Cl
Reactant: O=Cc1ccccc1
Reactant: C1CCNCC1
Product: C(c1ccccc1)=[N+]1CCCCC1
Product: [Cl-]

Procedure:
The reaction of 19.8 ml (0.200 mol) piperidine and 10.1 ml (0.100 mol) benzaldehyde in accordance with general synthesis instructions 2 and subsequent reaction with 6.0 ml (0.100 mol) acetyl chloride in accordance with general synthesis instructions 3 gave 11.7 g (corresponding to 56% of the yield calculated by theory) 1-benzylidene-piperidinium chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:15])[CH2:9][CH2:10][C:11]([O:13]C)=O)=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:15][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)CC[C@@H](O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC[C@H](c2ccc(F)cc2)O1
Temperature: 40 °C
Reaction time: 16 h
Yield: 111 %

Procedure:
To a solution of (R)-methyl 4-(4-fluorophenyl)-4-hydroxybutanoate (1.7 g, 8.0 mmol) in DCM (40 mL) was added 8 drops TFA at room temperature. The reaction mixture was warmed to 40° C. and stirred for 16 h. Evaporation of the solvent gave a light yellow oil from which the product was isolated by Flash chromatography eluting with 0% to 30% ethyl acetate/hexane to give 1.6 g of the title compound as a colorless oil.
Reaction SMILES: C(OC1C=C(C=CC=1)CN(C1C=CC(C#N)=CC=1)N1C=NN=C1)C1C=CC=CC=1.[H-].[Na+].[C:32]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][N:41]2[CH:45]=[N:44][N:43]=[CH:42]2)=[CH:36][CH:35]=1)#[N:33].[Br:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][C:48]=1[O:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][O:57]1>CN(C=O)C.CCOC(C)=O>[O:57]1[CH2:58][CH2:59][CH2:60][CH2:61][CH:56]1[O:55][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][C:47]=1[Br:46])[CH2:51][N:40]([C:37]1[CH:36]=[CH:35][C:34]([C:32]#[N:33])=[CH:39][CH:38]=1)[N:41]1[CH:42]=[N:43][N:44]=[CH:45]1
Reactant: BrCc1ccc(Br)c(OC2CCCCO2)c1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: N#Cc1ccc(N(Cc2cccc(OCc3ccccc3)c2)n2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(Cc2ccc(Br)c(OC3CCCCO3)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
The title compound was prepared by adapting the method for 4-[(3-benzyloxybenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole using the following modifications. To a stirred suspension of NaH (60% dispersion in oil, 0.27 g, 6.78 mmol) in anhydrous DMF (10 mL) was added a solution of 4-[(4-cyanophenyl)amino]-4H-[1,2,4]triazole (1.26 g, 6.78 mmol) in anhydrous DMF (5 mL) and the mixture stirred at r.t. for 0.5 h. A solution of 4-bromo-3-(tetrahydropyran-2-yloxy)benzyl bromide (2.61 g, 7.46 mmol) in anhydrous DMF (5 mL) was then added and the mixture heated at 80-90° C. for 3 h. The mixture was cooled, diluted with EtOAc (50 mL), washed with water (4×100 mL), brine (100 mL) and dried (Na2SO4). Concentration in vacuo and subsequent purification by flash column chromatography [SiO2, EtOAc (100%)] gave 4-[(3-(tetrahydropyran-2-yloxy)-4-bromobenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole as a yellow oil (3.05 g, 99%); δH (270 MHz, CDCl3) 1.61-1.99 (m, 6H), 3.55-3.59 (m, 1H), 3.73 (m, 1H), 4.75 (d, J=14.6, 1H), 4.90 (d, J=14.6, 1H), 5.41 (m, 1H), 6.64 (AA′BB′, 2H), 6.69 (dd, J=8.2, 2.2, 1H), 7.00 (d, J=2.2, 1H), 7.49 (d, J=7.9, 1H), 7.57 (AA′BB′, 2H), 8.15 (s, 2H); LRMS (FAB+) m/z (rel. intensity) 456.1 (54, [C21H20N5O281Br+H]), 454.1 (54, [C21H20N5O279Br+H]); LC-MS (APCI+): tR=2.0 min, m/z 456.1 (94, [C21H20N5O281Br+H]), 454.1 (100, [C21H20N5O279Br+H]); HPLC: tR=2.21 min (94%); HRMS (FAB+): Found 454.08627 C21H21N5O279Br requires 454.08786.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:19][C:20]([C:22]2[N:26]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[N:25]=[C:24]([NH:36][C:37]([C:39]3[N:43]([CH2:44][C:45]4[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=4)[N:42]=[C:41]([N+:53]([O-:55])=[O:54])[CH:40]=3)=[O:38])[CH:23]=2)=[O:21])[CH:6]=1)=[O:4].[OH-].[Li+]>CO.C1COCC1.O>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:9]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]([NH:19][C:20]([C:22]3[N:26]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[N:25]=[C:24]([NH:36][C:37]([C:39]4[N:43]([CH2:44][C:45]5[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=5)[N:42]=[C:41]([N+:53]([O-:55])=[O:54])[CH:40]=4)=[O:38])[CH:23]=3)=[O:21])=[N:8]2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])nn3Cc3ccc(OC)cc3)nn2Cc2ccc(OC)cc2)nn1Cc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(NC(=O)c3cc(NC(=O)c4cc([N+](=O)[O-])nn4Cc4ccc(OC)cc4)nn3Cc3ccc(OC)cc3)cc2C(=O)O)cc1

Procedure:
A 1.00 g (1.33 mmol, 1.00 equiv) amount of 1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-nitro-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxylic acid methyl ester [O2N-Pz(PMB)-Pz(PMB)-Pz(PMB)-OMe] and 81 mg of lithium hydroxide (3.38 mmol, 2.54 equiv) were stirred in a mixture of methanol/THF/water (5:5:1) for 18 h. The crude product is prepared according to general procedure A to yield the compound as a colorless solid. Yield: 0.92 g (1.25 mmol, 94%).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH3:11])[NH:6][C:5](=[O:12])[CH:4]=1)[CH3:2].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH3:11])[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[C:5](=[O:12])[CH:4]=1)[CH3:2]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(CC)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1nc(CC)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
To a solution of 6-ethyl-2-propylpyrimidin-4(3H)-one (5.0 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (9.0 g) in acetonitrile (150 mL) was added potassium carbonate (8.32 g), and the mixture was stirred at 50° C. for 12 hr. The insoluble material was filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (4.95 g, 46%) as a colorless viscous substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:19]=[N:20][N:21]([CH3:23])[CH:22]=3)[C:16](=O)[C:15]3[C:14]([C:25](OCC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.[OH2:30].[NH2:31][NH2:32]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:31][NH:32][C:25](=[O:30])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[N:19]=[N:20][N:21]([CH3:23])[CH:22]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1cn(C)nn1)C(c1ccc(F)cc1)N2
Reactant: O
Product: Cn1cc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(F)cc2)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,3-triazol-4-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (113 mg, 0.28 mmol) in 85% hydrazine monohydrate (4 mL) stirred for 3 hr at room temperature. The mixture was filtered and washed with water, petroleum ether and ethyl acetate to give the crude product, which was purified by prep-HPLC to give the title compound (41 mg, yield 39%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.93 (s, 3H), 4.50-4.52 (d, J=7.6 Hz, 1H), 4.96-4.98 (d, J=7.6 Hz, 1H), 7.09-7.15 (m, 3H), 7.35-7.42 (m, 4H), 7.55-7.57 (t, J=7.6 Hz, 1H), 7.72 (s, 1H); LC-MS (ESI) m/z: 363 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=O)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=O)[CH:5]=[CH:6][C:7]=1[F:8].CC(O)=O.C[N:35](C)C=O>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[N:35]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[CH:20]=2)=[CH:24][CH:25]=1
Reactant: CN(C)C=O
Reactant: O=C(CC(CC(=O)c1ccccc1O)c1ccc(F)c(F)c1)c1ccc(Cl)cc1
Solvent: CC(=O)O
Product: Oc1ccccc1-c1cc(-c2ccc(F)c(F)c2)cc(-c2ccc(Cl)cc2)n1
Temperature: 100 °C

Procedure:
A mixture of 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-5-(4-chlorophenyl)-1,5-pentanedione on Wang resin (2.0 g, 1.76 mmol), NH4OAc (0.80 g), and AcOH (1.0 mL) in dimethylformamide (20 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA, and lyophilized to give 2-[6-(4-chloro-phenyl)-4-(3,4-difluoro-phenyl)-pyridin-2-yl]-phenol; mp 146-148° C.; 1H NMR (DMSO-d6) d 6.75 (m, 1 H), 7.00 (m, 2 H), 7.35 (m, 2 H), 7.57 (m, 1 H), 7.69 (d, J=8.6 Hz, 2 H), 7.95 (d, J=8.6 Hz, 1 H), 8.18 (d, J=8.6 Hz, 2 H), 8.32 (m, 2 H), 14.00 (s, 1 H); IR (KBr) 1606 cm−1; MS [M+1] m/z=394. Anal. calcd for C23H14ClF2NO: C, 70.15; H, 3.58; N, 3.50; Found: C, 69.98; H, 3.51; N, 1.80.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Cl.C(N(CC)CC)C>C(#N)C>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1ccccn1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
Under anhydrous conditions (positive nitrogen pressure, presence of 3Å molecular sieves), a mixture of N-hydroxyphthalimide (10.0 g, 0.061 mole), 2-picolylchloride hydrochloride (10.0 g, 0.061 mole), and triethylamine (18.5 g, 0.183 mol) in 100 ml of anhydrous acetonitrile was refluxed for 6 hours. After overnight stirring at ambient temperature, TLC showed that the starting materials were practically consumed. The solvent was evaporated and the residue dissolved in 200 ml of EtOAc. The solution was washed with 1N NaOH (100 ml), water (2×200 ml), brine (1×200 m ml) and dried (MgSO4). After removal of the solvent, the crude product was recrystallized from EtOAc/hexane to afford 11.4 g (73.6%) of title product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10](C#C[Si](C)(C)C)[CH:11]=1)[O:8][C:7]([CH3:19])([CH3:18])[CH2:6][C:5]2([CH3:21])[CH3:20].[C:22](=[O:25])([O-])[O-].[K+].[K+].[CH3:28]O>>[C:11]([C:2]1[CH:3]=[C:4]2[C:9](=[C:22]([OH:25])[CH:28]=1)[O:8][C:7]([CH3:18])([CH3:19])[CH2:6][C:5]2([CH3:20])[CH3:21])#[CH:10]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(C#C[Si](C)(C)C)c2O1
Reactant: CO
Agent: [K+]
Product: C#Cc1cc(O)c2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 80 °C
Yield: 99 %

Procedure:
A solution of 6-bromo-8-trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman (Intermediate 18, 0.47 g, 1.56 mmol) in methanol (5 mL) was treated with potassium carbonate (0.2 g, 1.45 mmol) and the resulting reaction mixture was heated at 80° C. for 3 h. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as a brown oil (0.35 g, 99%).
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:27][Cl:28].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[ClH:28].[ClH:28].[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:27][C:26]3[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:14][CH2:15]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(C(CCN2CCNCC2)c2ccccc2)cc1
Reactant: COc1cc(CCl)cc(OC)c1OC
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc(OC)c1OC
Product: Cl
Yield: 76.7 %

Procedure:
N-3,3-Diphenylpropylpiperazine in the amount of 14.0 g (0.05 mole), 10.8 g (0.05 mole) of 3,4,5-trimethoxybenzylchloride, and 5.05 g (0.05 mole) of triethylamine were dissolved in 100 ml of xylene, and the same procedure as that of Example 1 was followed to obtain 20.4 g of 1-(3,3-diphenylpropyl)-4-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (76.7% yield) with a melting point of 178°C.