Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]([OH:14])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[N:19]1([C:25]([NH:27][C:28]2([C:34](O)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[OH:14][CH:3]([C@@H:2]([NH:1][C:34]([C:28]1([NH:27][C:25]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:26])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)=[O:35])[CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5]
Reactant: CCCC[C@H](N)C(O)C(=O)OCc1ccccc1
Reactant: O=C(NC1(C(=O)O)CCCCC1)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)C1(NC(=O)N2CCOCC2)CCCCC1)C(O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
Subsequently, under ice-cooled condition, to 9.3 g (37 mmol) of phenylmethyl (2RS,3S)-3-amino-2-hydroxyheptanoate, 9.5 g (37 mmol) of 1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxylic acid synthesized in Reference Example 5 and 6.0 g (45 mmol) of 1-hydroxybenzotriazole in 100 ml of dichloromethane, 8.5 g (45 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added and then was stirred at the room temperature for 18 hours. The reaction solution was concentrated under reduced pressure. The residue was washed successively with water, aqueous solution of 10% of potassium hydrogensulfate, aqueous solution of saturated sodium hydrogen-carbonate and saturated brine in addition of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled away from the reaction mixture under reduced pressure. The residue was purified by the silicagel column chromatography, whereby 16.8 g of phenylmethyl (2RS,3S)-2-hydroxy-3-[N-[1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarbonyl]amino]heptanoate was obtained.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]([OH:8])[CH2:6][CH2:5][O:4][CH2:3]1.S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1>C(O)C>[O:15]=[C:12]1[N:11]=[C:10]([NH:1][C@H:2]2[C@H:7]([OH:8])[CH2:6][CH2:5][O:4][CH2:3]2)[CH2:14][S:13]1
Reactant: N[C@@H]1COCC[C@H]1O
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: O=C1N=C(N[C@@H]2COCC[C@H]2O)CS1
Yield: 49.7 %

Procedure:
To a solution of 2-amino-1,5-anhydro-2,4-dideoxy-threo-pentitol (1.09 g) in ethanol (100 mL) was added 4-thioxo-1,3-thiazolidin-2-one (1.28 g), and the mixture was heated under reflux for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (1.00 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN1C(=O)CCC1.O>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCCCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=Cc1ccc(OCCCCCCO)cc1
Reaction time: 24 h
Yield: 51.6 %

Procedure:
4-Hydroxybenzaldehyde (15 g, 122 mmol) was dissolved in 150 ml of NMP. 6-Chlorohexanol (20.16 g 146 mmol), anhydrous potassium carbonate (20.36 g, 146 mmol) and a catalytic amount of potassium iodide were added. The batch was stirred at 90 C for 24 hours. Water was added to the cooled solution, which was subsequently extracted with 3×100 mls of ethyl acetate. The combined organics were washed with 5% KOH (2×100 mls), brine solution and then dried over magnesium sulfate. The concentrated product was then recrystallized from a 1:1 mixture of ethyl acetate/hexane to give 14 g of an off-white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH2:11][C:12]([S:15]([CH2:18][CH:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])(=[O:17])=[O:16])([CH3:14])[CH3:13]>N1C=CC=CC=1>[C:1]([O:10][CH2:11][C:12]([S:15]([CH2:18][CH:19]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])(=[O:17])=[O:16])([CH3:14])[CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(CO)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(COC(=O)c1ccccc1)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
In an analogous manner to that described in paragraph (d) above, by reacting benzoyl chloride with benzyl rac-α-[[(2-hydroxy-1,1-dimethylethyl)sulfonyl]methyl]hydrocinnamate in pyridine there was obtained benzyl rac-α-[[[2-(benzoyloxy)-l,1dimethylethyl]sulfonyl]methyl]hydrocinnamate as a colourless oil, MS: 403 (M-benzyl)+.
Reaction SMILES: C[C:2]1([N:8]2[C:12]([C:13]3[S:25][C:16]4[N:17]=[CH:18][N:19]=[C:20]([S:21]([CH3:24])(=[O:23])=[O:22])[C:15]=4[CH:14]=3)=[CH:11][N:10]=[CH:9]2)C=CC=CC1.[Br:26][C:27]1[CH:32]=[CH:31][C:30](C2N=CN(C)C=2C2SC3N=CN=C(SC)C=3C=2)=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:11]2[N:10]=[CH:9][N:8]([CH3:2])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20]([S:21]([CH3:24])(=[O:22])=[O:23])[C:15]=3[CH:14]=2)=[CH:29][CH:28]=1
Reactant: CSc1ncnc2sc(-c3c(-c4ccc(Br)cc4)ncn3C)cc12
Reactant: CC1(n2cncc2-c2cc3c(S(C)(=O)=O)ncnc3s2)C=CC=CC1
Product: Cn1cnc(-c2ccc(Br)cc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 17 but using 6-[4-(4-bromophenyl)-1-methyl-1H-imidazol-5-yl]4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 67) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (example 7). Pale yellow solid (715 mg, 79%);
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27]>CC(C)=O>[CH2:1]([O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(OC)c1

Procedure:
Benzyl bromide (3.59 ml) and potassium carbonate (5.69 g) were added to an acetone (50 ml) solution of methyl 4-hydroxy-3-methoxybenzoate (5.00 g), and heated at reflux for 4 hours. After removing solid matter by filtration and concentrating the filtrate under reduced pressure, the residue was dissolved in ethyl acetate, and washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure, thereby giving 7.47 g of methyl 4-benzyloxy-3-methoxybenzoate.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH:30]=O>>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][N:14]([CH2:30][C:29]3[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:27]([O:26][CH3:25])[CH:28]=3)[CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(CN2CCc3c(-c4ccc(Cl)cc4)nn(Cc4ccccc4)c3CC2)cc1OC

Procedure:
The title compound was prepared (12 mg) from 1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 59, Step E; 0.1 mmol) using 3,4-dimethoxy-benzaldehyde (0.2 mmol) in place of formaldehyde. MS (ESI): exact mass calculated for C29H30ClN3O2, 487.20; found, m/z 488.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.44-7.43 (m, 2H), 7.30-7.29 (m, 2H), 7.25-7.22 (m, 2H), 7.20-7.18 (m, 1H), 7.03-7.02 (m, 2H), 6.86 (d, J=1.7 Hz, 1H), 6.76-6.71 (m, 2H), 5.25 (s, 2H), 3.79 (s, 6H), 3.63 (s, 2H), 2.72 (s, 4H), 2.68-2.66 (m, 4H).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].CN(C1C=CC=CN=1)C.[C:16]([C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1)#[N:17].C(N(CC)CC)C>ClCCl>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][S:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]#[N:17])[CH:19]=1)(=[O:26])=[O:25]
Reactant: NCCCBr
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Agent: Br
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(S(=O)(=O)NCCCBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of bromopropylamine hydrogen bromide (0.219 g, 1 mmol) in dichloromethane (2 ml) is treated with a solution of dimethylaminopyridine (0.004 g) in dichloromethane (0.5 ml) followed by a solution of 3-cyano-benzenesulfonyl chloride (0.2 g, 1.0 mmol) in dichloromethane (0.5 ml). Triethylamine (0.3 ml, 2.16 mmol) is added and the reaction mixture stirred at ambient temperature for 2 hours, then quenched with water and saturated aqueous NaHCO3, and extracted into dichloromethane. The organic phase is washed with aqueous 1M HCl solution and brine, dried over MgSO4 and evaporated to afford crude N-(3-bromopropyl)-3-cyano-benzenesulfonamide. (13C NMR, 100 MHz, CDCl3, 30.2, 32.6, 41.9, 114.3, 117.5, 130.7, 130.9, 131.1, 136.3, 142.1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[CH:5]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[CH2:6][O:7][CH3:8].[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[C:4]([CH3:17])([CH3:18])[CH:5]([N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:20]1=[O:21])[CH2:6][O:7][CH3:8]
Reactant: COCC(Nc1ccccc1N)C(C)(C)C(=O)OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COCC(n1c(=O)[nH]c2ccccc21)C(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a solution of 3-(2-amino-phenylamino)-4-methoxy-2,2-dimethyl-butyric acid methyl ester (550 mg, 2.1 mmol) in THF (25 mL) was added 1,1′-carbonyldiimidazole (500 mg, 3.1 mmol). The solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated. The resulting residue was purified by CombiFlash with 75% EtOAc in Hexane as the eluent to afford the desired 4-methoxy-2,2-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-butyric acid methyl ester (420 mg, 70%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4](I)=[N:5][NH:6]2.[H-].[Na+].C([Mg]Cl)(C)C.[CH2:20]([Sn:24]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])Cl)[CH2:21][CH2:22][CH3:23]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([Sn:24]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:20][CH2:21][CH2:22][CH3:23])=[N:5][NH:6]2
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Fc1cc(F)c2c(I)n[nH]c2c1
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)cc(F)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.1 %

Procedure:
To a solution of 4,6-difluoro-3-iodo-1H-indazole (2.11 g, 7.53 mmol) in THF (45 mL) at 0° C. was slowly added sodium hydride (60% in mineral oil, 362 mg, 9.04 mmol). The reaction mixture was stirred at room temperature for 10 min then cooled to −10° C. and isopropylmagnesium chloride (2.0 M in THF, 4.52 mL, 9.04 mmol) was added. The reaction mixture was stirred at −10° C. for 30 min then tributylchlorostannane (2.66 mL, 9.8 mmol) was added dropwise. Stirring was continued at −10° C. for 20 min then at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl then diluted with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 10% to 20% EtOAc/heptane (0.5% Et3N) to afford 1.94 g (58%) of 4,6-difluoro-3-tributylstannanyl-1H-indazole as a pale yellow viscous oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.03 (dd, J=8.9, 2.1 Hz, 1H), 6.60 (td, J=9.8, 2.1 Hz, 1H), 1.51-1.64 (m, 6H), 1.29-1.42 (m, 6H), 1.20-1.29 (m, 6H), 0.88 (t, J=7.4 Hz, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[O:26])=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(C(=O)N3CCOCC3)cc21
Product: CC1c2cc(C(=O)N3CCOCC3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with (1-Methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-morpholin-4-yl-methanone to provide the title compound in moderate yield.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]([NH2:22])=[O:21])[CH2:16][CH2:15]1>C1COCC1>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([NH2:22])=[O:21])[CH2:16][CH2:15]2)=[N:3][CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: NC(=O)C1CCNCC1
Solvent: C1CCOC1
Product: NC(=O)C1CCN(c2ncc([N+](=O)[O-])cc2[N+](=O)[O-])CC1
Temperature: 60 °C
Yield: 12 %

Procedure:
3 g (14.7 mmol) of 2-chloro-3,5-dinitropyridine, 10 ml of THF and 30 mmol of 4-piperidine carboxamide were placed in a round-bottomed flask. The mixture was maintained at 60° C. for 15 hours with stirring and was then poured into an ice-water mixture with stirring. The precipitate formed was filtered off by suction and dried under vacuum to constant weight. 0.522 g of yellow powder was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][CH2:12][CH2:13][OH:14])[N:4]=1.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:14][CH2:13][CH2:12][CH2:11][C:5]1[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=1)(=[O:25])=[O:24]
Reactant: COc1cc(OC)nc(CCCO)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)nc(CCCOS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(4,6-dimethoxypyrimidin-2-yl)propan-1-ol (100 mg, 0.50 mmol) in DCM (2.0 mL), Et3N (0.21 mL, 1.51 mmol) was added. After stirring for 5 min at rt, the reaction mixture was cooled to 0° C. and methansulfonylchloride (0.05 mL, 0.61 mmol) was added. The reaction mixture was stirred for 10 min at 0° C. and for 20 min at rt, then poured onto ice water. The aq. layer was extracted with DCM, the org. layer was washed with 1 N aq. HCl-solution followed by sat. NaHCO3-solution, then dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield the tiltle compound as a yellow oil which was used immediately in the next step. The LC-MS conditions B: tR=0.60 min, [M+H]+=277.09.
Reaction SMILES: [NH:1]1[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]2[N:3]=[C:2]1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1.O>CS(C)=O>[NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1c2ccccc2-c2c1cccc2C1=NC2CCCCC2N1
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccccc2-c2c1cccc2-c1nc2c([nH]1)CCCC2
Temperature: 200 °C
Yield: 64.1 %

Procedure:
In a 20 ml sealed tube, dissolve 330 mg of 4-(3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-9H-fluoren-9-one, obtained in the previous stage, in 12 ml of dimethyl sulphoxide and then heat at 200° C. for one hour. After cooling, add 30 ml of water and then extract 3 times with 100 ml of ethyl acetate. The crude solid obtained is purified by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and methanol (97/3 by volume). In this way, we obtain 210 mg of 4-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-9H-fluoren-9-one, in the form of a yellow powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:16][Si:17]([CH3:19])([CH3:18])[C:20]1[C:4]2[C:3]([CH:2]=[C:15]3[C:21]=1[C:11]([C:10]#[CH:9])=[CH:12][CH:13]=[CH:14]3)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C#C[Si](C)(C)C
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Product: C#Cc1cccc2cc3ccccc3c([Si](C)(C)C)c12
Temperature: 80 °C
Yield: 75.2 %

Procedure:
Under an argon atmosphere, 40 g (0.155 mol) of 9-bromoanthracene, 3.3 g (4.6 mmol) of bis(triphenylphosphine)palladium(II) dichloride and 0.87 g (3 mmol) of copper Iodide were dissolved in 500 ml of diisopropylamine in a 1 L 3-necked flask equipped with a stirrer, thermometer and reflux condenser. 23 g (0.233 mol) of trimethylsilyl acetylene was then slowly dropped into the resulting mixture at room temperature. The reaction mixture was slowly heated to 80° C. and refluxed for 12 hours. After the reaction was completed, the reaction mixture was cooled down to room temperature, and then the precipitated salt was filtered off. The solvent was removed under a reduced pressure, and then the residue was dissolved in methylene chloride. The organic layer was washed with water several times and then dried with anhydrous magnesium sulfate. The solvent was removed to obtain orange-colored liquid, which was purified by silica gel column chromatography using hexane as an eluent, and then recrystallized from ethanol to give yellow crystal. The yellow crystal was recovered and sufficiently dried in a vacuum oven at 40° C., to give 32 g (83.3% yield) of the desired product having a melting point of 66-68° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30].[Li+].CC([N-]C(C)C)C>>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][N:19]=3)[C:29]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CCCCc1cnccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=c1c(CCCc2cnccn2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1
Yield: 33 %

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(pyrazin-2-yl)pentanoate (1.5 eq., prepared in Synthetic Example 7) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(pyrazin-2-yl)propyl]-1,8-naphthyridin-2(1H)-one (yield, 33%). The product was purified through flash column chromatography and recrystallization (mp 194–195° C./DMF).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:10]([C:19]([O:21]CC)=[O:20])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH-].[K+]>CCO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:10]([C:19]([OH:21])=[O:20])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2)nc2c(cnn2CC)c1-c1cncc(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1ncc2c(-c3cncc(C)c3)c(C(=O)O)c(-c3ccccc3)nc21
Yield: 70.5 %

Procedure:
To a stirred solution of ethyl 1-ethyl-4-(5-methyl-3-pyridyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (257 mg) in a mixture of EtOH (2.5 ml) and water (2 ml) was added potassium hydroxide (1.32 g) and the mixture was refluxed for 12 hours. Another potassium hydroxide (439 mg) was added and the mixture was refluxed for 4.5 hours. After cooling, the reaction mixture was diluted with water and extracted with CHCl3. The aqueous layer was acidified to pH3-4 by adding HCl and extracted with CHCl3. The organic layer was washed with water, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was crystallized from EtOAc and n-hexane to give 1-ethyl-4-(5-methyl-3-pyridyl)-6-phenyl-1H-pyrazolo [3,4-b]pyridine-5-carboxylic acid (168 mg) as a light yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[CH:8]([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1.[C:18]1([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[C:8]([CH2:32][CH2:31][CH2:30][N:27]3[CH2:28][CH2:29][N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1
Reactant: COC(=O)C1Sc2cc(Cl)ccc2OCC1=O
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Product: COC(=O)C1(CCCN2CCN(c3ccccc3)CC2)Sc2cc(Cl)ccc2OCC1=O

Procedure:
Methyl 7-chloro-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate is alkylated with 3-(4-phenylpiperazin-1-yl)propylchloride in the same manner as described in Example 1 to give methyl 7-chloro-3-oxo-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate which is isolated as the hydrochloride [(white crystals), mp, 197°-199° C⟧
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][NH2:12]>O1CCOCC1>[CH2:1]([NH:8][C:9](=[S:10])[NH:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: S=C=NCc1ccccc1
Solvent: C1COCCO1
Product: NNC(=S)NCc1ccccc1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
Benzylisothiocyanate (4.0 g) is slowly added to 1.8 g of anhydrous hydrazine in 50 ml dioxane. The reaction mixture is stirred at room temperature, the dioxane is then removed in vacuo and the residue is recrystallised from ethanol to give 4-benzylthiosemicarbazide as a crystalline solid (2.5 g), m.p. 127° C.
Reaction SMILES: [CH3:1][N:2]([C@H:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[C:3](=[O:20])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[F:27][C:28]([F:42])([F:41])[C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:32]Br.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:1][N:2]([C@H:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[C:3](=[O:20])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:32][C:31]2[CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:36]=[C:29]([C:28]([F:27])([F:41])[F:42])[CH:30]=2)=[CH:15][CH:14]=1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: COC(=O)[C@@H](C)N(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(O)cc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)N(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A solution of methyl 2-UN-methyl-N-((R/S)-α-t-butoxycarbonylmethyl-4-hydroxyphenylacetyl)amino]-(R)-propionate 48d (1.5 g, 4.1 mmol) and 3,5-bistrifluoromethylbenzyl bromide (1.3 g, 4.2 mmol) in DMF (10 mL) was stirred at 60° C. overnight in the presence of K2CO3 (1.14 g, 8 mmol). After cooling to room temperature, EtOAc was added and the solution was washed with brine three times, dried over MgSO4, and concentrated. Purification on a silica gel column by eluting with 40% EtOAc/hexane afforded the product (1.46 g, 60%) as a solid. MS (CI—NH3): (M+H)+=592.