Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:12]2[CH2:13][C:14]([CH2:16][C@H:9]1[CH2:10][CH2:11]2)=O)=[O:7])([CH3:4])[CH3:3].[NH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH3:26][O:25][C:23]([C:22]1[CH:27]=[CH:28][C:19]([CH2:18][NH:17][CH:14]2[CH2:16][CH:9]3[N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH:12]([CH2:11][CH2:10]3)[CH2:13]2)=[CH:20][CH:21]=1)=[O:24]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNC2CC3CCC(C2)N3C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A solution of N-Boc nortropinone (2.4 g, 10.9 mmol) and methyl 4-aminomethylbenzoate (1.6 g, 10.9 mmol) in dichloroethane (20 mL) was stirred as acetic acid (0.85 g, 14.2 mmol) was added. After 1 hour, sodium triacetoxyborohydride (2.7 g, 13.1 mmol) was added and the reaction was stirred for 17 hours. The reaction was treated with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2×). The combined organic extracts were dried and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexane gave 3.6 g of 1,1-dimethylethyl 3-[[[4-(methoxycarbonyl)phenyl]methyl]amino]-8-azabicyclo[3.2.1]octane-8-carboxylate.
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.C([Mg]Cl)(C)C.[SiH4].[CH:12]([Si:15]([CH:19]([CH3:21])[CH3:20])([O:17][CH3:18])Cl)([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH:12]([Si:15]([CH:1]([CH3:2])[CH3:5])([CH:19]([CH3:21])[CH3:20])[O:17][CH3:18])([CH3:14])[CH3:13]
Reactant: C1CCOC1
Reactant: CO[Si](Cl)(C(C)C)C(C)C
Agent: CC(C)[Mg]Cl
Agent: [SiH4]
Solvent: Cc1ccccc1
Product: CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To the mixture of the silanes containing diisopropylmethoxychlorosilane as obtained from the disproportionation reaction in (b) above, was added 150 ml of toluene to dissolve the mixture, thereby to obtain a toluene solution of the said silane mixture. The THF solution of isopropyl magnesium chloride (Grignard reagent) as prepared in (a) above was added dropwise through a dropping funnel to the toluene solution of said silane mixture at 40° C.-50° C. over 1 hour. Then the resulting mixture was stirred at 70° C. for 4 hours. Thus, the Grignard reagent was reacted with the diisopropylmethoxychlorosilane contained in the said toluene solution, to produce triisopropylmethoxysilane. To the resulting reaction solution was added dropwise 40 ml of a saturated aqueous ammonium chloride solution to dissolve the magnesium salt in the latter. The organic layer was separated from the aqueous layer and the organic layer, was distilled to afford 28 g of triisopropylmethoxysilane as a fraction boiling at 85° C.-86° C./20 mm Hg. The yield was 73%.
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([F:16])([F:14])[F:15])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:5]1
Reactant: [N-]=[N+]=NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 3-azido-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-benzo[e][1,4]diazepine-2-one (crude from above) in 1.3 L THF was added triphenylphosphine (109 g, 0.417 mol) and water (150 mL). This was stirred overnight at ambient temperature. The reaction was then concentrated under reduced pressure, taken up in 1N HCl (1500 mL), and extracted with ethyl ether (2×500 mL). The combined organics were back extracted with 1N HCl (1×300 mL). The combined aqueous layers were back extracted with ethyl acetate (100 mL) and then basefied with sat. NaHCO3 (100 mL) and 50% NaOH until pH=10. This was extracted with ethyl acetate (2×500 mL). The combined ethyl acetate fractions were dried over Na2SO4, evaporated under reduced pressure and crystallized from ethyl ether to give the title compound as a powder. MP=141°-143° C.;
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH2:10]([NH:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]1)[CH2:11][CH2:12][CH3:13]>O1CCOCC1>[Cl:3][C:2]1[N:1]=[C:8]([N:14]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:15]2[CH2:16][C:17]([CH3:23])([CH3:24])[NH:18][C:19]([CH3:22])([CH3:21])[CH2:20]2)[N:7]=[C:5]([N:14]([CH:15]2[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:21])([CH3:22])[CH2:20]2)[CH2:10][CH2:11][CH2:12][CH3:13])[N:4]=1
Reactant: CCCCNC1CC(C)(C)NC(C)(C)C1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: C1COCCO1
Product: CCCCN(c1nc(Cl)nc(N(CCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1

Procedure:
To a solution of 18.4 g of cyanuric chloride in 200 ml of dioxane was added dropwise, with stirring, a solution of 43.6 g of 4-butylamino-2,2,6,6-tetramethylpiperidine in 100 ml of dioxane at 20°-25° C. The mixture was stirred at the same temperature for 2 hours, after which it was stirred at 60°-70° C. for 2 hours. At the end of this time, the dioxane was distilled off and the residue was poured into a 10% aqueous solution of potassium carbonate and extracted with ethyl acetate. The extract was dried over anhydrous potassium carbonate, and then the ethyl acetate was distilled off. The resulting oil was purified by column chromatography through silica gel, eluted with a 20:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine, to give the title compound in the form of crystals melting at 40°-42° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:22]([O-])=[O:23])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9]2)=[N:4][CH:3]=1.[CH3:25]C(C[AlH]CC(C)C)C>C(Cl)Cl>[CH3:25][CH:22]([C:7]1[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9][C:10]2[C:5]([CH:6]=1)=[N:4][CH:3]=[C:2]([F:1])[CH:11]=2)[OH:23]
Reactant: CS(=O)(=O)c1ccccc1-c1nc2cc(F)cnc2cc1C(=O)[O-]
Reactant: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(O)c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Reaction time: 4 h

Procedure:
To a solution of 7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridine-3-carboxylate (1.2 g, 3.33 mmol) in DCM (27 mL) was added DIBAL-H (34 mL, 33.3 mmol) at −78° C. The reaction mixture was stirred for 4 h at same temperature. The reaction mixture was quenched with satd solution of ammonium chloride and extracted with EtOAc. The organic layer was concentrated in vacuo to give methyl (7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)methanol: LC-MS (ESI) m/z 333.1 [M+H]+. It was carried on crude for next step.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[C:16]1([CH:26]=O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([O:38][CH3:39])=[O:37])[CH:31]=1)=O>>[CH2:9]([N:8]1[C:3]2=[N:1][N:2]([CH2:26][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[C:28]([C:30]3[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([O:38][CH3:39])=[O:37])[CH:31]=3)=[C:4]2[C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: COC(=O)c1cc(C=O)n(C)c1
Reactant: O=Cc1cccc2ccccc12
Product: COC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2cccc3ccccc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 1-naphthaldehyde, followed by methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate. Mass: 500.38 (M+H).
Reaction SMILES: [NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]2)=[N:11][CH:12]=1)=[O:5])[NH2:2].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]=[C:40]=S)=[CH:35][CH:34]=2)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40]3[O:24][C:3]([C:4]([NH:6][C:7]4[CH:8]=[CH:9][C:10]([N:13]5[CH2:14][CH2:15][CH:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:18]5)=[N:11][CH:12]=4)=[O:5])=[N:1][N:2]=3)=[CH:35][CH:34]=2)=[CH:28][CH:27]=1
Reactant: S=C=Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: COC(=O)CC1CCN(c2ccc(NC(=O)C(=O)NN)cn2)CC1
Product: COC(=O)CC1CCN(c2ccc(NC(=O)c3nnc(Nc4ccc(Oc5ccc(Cl)cc5)cc4)o3)cn2)CC1

Procedure:
Prepared using the procedures described above for Example 631 except using methyl [1-(5-{[hydrazino(oxo)acetyl]amino}pyridin-2-yl)piperidin-4-yl]acetate (Intermediate 77) and 1-chloro-4-(4-isothiocyanatophenoxy)benzene.
Reaction SMILES: C(N1CCCC(C(OCC)=O)C1)(=O)C1C=CC=CC=1.[CH3:20][CH:21]1[NH:26][CH2:25][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]1.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38](Cl)=[O:39]>>[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38]([N:26]1[CH:21]([CH3:20])[CH2:22][CH2:23][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25]1)=[O:39]
Reactant: CCOC(=O)C1CCC(C)NC1
Reactant: O=C(Cl)Cc1cccs1
Agent: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Product: CCOC(=O)C1CCC(C)N(C(=O)Cc2cccs2)C1
Yield: 59.8 %

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with ethyl 6-methyl-3-piperidinecarboxylate (263.1 mg; 1.54 mmol) and 2-thiopheneacetyl chloride (190 μl; 1.54 mmol). The crude product was distilled at 210° C./0.1 torr, giving ethyl 1-(2-thiopheneacetyl)-6-methyl-3-piperidinecarboxylate (272.2 mg) as a light yellow oil. MS m/z (positive ion) 591(dimer+; 25) 296 (MH+; 100).
Reaction SMILES: [CH:1]1([N:4]2[CH:9]3[CH2:10][CH2:11][CH2:12][CH:5]2[CH2:6][C:7](=O)[CH2:8]3)[CH2:3][CH2:2]1.Cl.[NH2:15][OH:16]>C(O)C>[CH:1]1([N:4]2[CH:9]3[CH2:10][CH2:11][CH2:12][CH:5]2[CH2:6][C:7](=[N:15][OH:16])[CH2:8]3)[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CC2CCCC(C1)N2C1CC1
Agent: Cl
Solvent: CCO
Product: ON=C1CC2CCCC(C1)N2C1CC1

Procedure:
A mixture of the above described 9-cyclopropyl-9-aza-bicyclo[3.3.1]nonan-3-one (890 mg, 5.0 mmol) in ethanol (20 mL) and hydroxylamine hydrochloride (366 mg, 5.3 mmol) was refluxed for 6 h. The reaction mixture was evaporated totally, the residue extracted with ethyl acetate and sodium bicarbonate solution, the organic layers dried over Na2SO4, filtered and the solvents evaporated to give the title compound as a white solid. (890 mg, 100%); MS: m/e=195.2 (M+H+).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[CH:34]=1)=O.[OH-].[Na+].O>C(O)C>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[CH:34]=1
Reactant: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C(F)(F)F)cn3c2)c1)c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cn2cc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 107.8 %

Procedure:
To a solution of N-[3-({2-[(trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide (400 mg, 0.787 mmol) produced in Example A1(vi) in ethanol (4.0 mL) was added 1N aqueous sodium hydroxide solution (8.0 mL), and the mixture was stirred at room temperature for 12 hr. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), fractions containing the object product was concentrated under reduced pressure, and the residue was washed with ethyl acetate/diisopropyl ether (1:4) to give the title compound (350 mg, quantitative) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH2:13][C:14](=[O:16])[S:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: Sc1ccccc1
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(CC(=O)Sc2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 10-mL, one-necked, round-bottomed flask was charged with 2.5 mL dichloromethane, (3,4,5-trimethoxyphenyl)acetic acid (566 mg, 2.5 mmol), DMAP (31 mg, 2.5 mmol) and thiophenol (1.0 mL, 9.9 mmol). The mixture was cooled in an ice bath while DCC (619 mg, 3.0 mmol) was added and stirred for 5 min. The reaction was allowed to warm up to room temperature and additionally stirred for 3 h.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH2:7]([C:9]1[C:14]([OH:15])=[C:13](O)[CH:12]=[CH:11][C:10]=1[CH2:17][C:18]#[N:19])[CH3:8].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:7]([C:9]1[C:14]([O:15][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:13]([O:4][CH2:1][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:12]=[CH:11][C:10]=1[CH2:17][C:18]#[N:19])[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: CCc1c(CC#N)ccc(O)c1O
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(CC#N)ccc(OCc2ccccc2)c1OCc1ccccc1
Reaction time: 8 h

Procedure:
Solid potassium carbonate (1.94 g) was added at room temperature to a solution of the product from stage (i) (1 g) in dry dimethylformamide. Benzyl bromide (2.41 g) was added. The mixture was stirred overnight. Ice and water were added. The mixture was extracted with ether. The extracts were washed with water, dried and evaporated. The oil obtained was purified by FCC using ether/hexane (1:1) as eluent, to give the title compound as a yellow oil which crystallised slowly (1.82 g) m.p. 44°-47.5°.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].CCN(CC)CC.[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([Si:16]([CH3:18])([CH3:17])[O:4][CH2:1][C:2]#[CH:3])([CH3:15])([CH3:14])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of prop-2-yn-1-ol (168 g, 3 mol), Et3N (412 g, 4.08 mol) in CH2Cl2 (3500 mL) was added a solution of TBSCl (543 g, 3.45 mol) in CH2Cl2 (500 mL) at 0° C. Then the reaction mixture was warmed up to room temperature and stirred overnight. The mixture was washed by water (3000 mL), dried over Na2SO4, and concentrated to give crude product, which was purified by flash chromatography (petroleum ether) and distillation to give compound S-1 as a yellow liquid. (110 g, 43%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:14]3[C:15](=[O:29])[N:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:17]4[N:18]=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[NH:12][N:11]=2)=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].O>N1C=CC=CC=1>[CH3:30][S:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[C:14]3[C:15](=[O:29])[N:16]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:17]4[N:18]=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[NH:12][N:11]=2)=[CH:4][CH:3]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a solution of 3-[2-(4-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (38 mg, 0.10 mmol, prepared in Example 13) in pyridine (2 ml) was added methanesulfonyl chloride (18.5 mg, 0.16 mmol, 1.6 eq.), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was admixed with water, and filtered to give precipitates which were dried to afford 3-[2-(4-methanesulfonylaminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (43 mg, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[C:19]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])=[O:13])[N:4]=1>CO.CN(C)C=O.[Pd].[O-][V](=O)=O.[Na+]>[NH2:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([NH:14][C:12]([NH:11][C:5]2[N:6]=[C:7]([O:9][CH3:10])[N:8]=[C:3]([O:2][CH3:1])[N:4]=2)=[O:13])(=[O:16])=[O:17])[C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC)n1
Agent: O=[V](=O)[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1c(N)cccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC)n1
Reaction time: 0.17 h

Procedure:
50 mg (113 μmol) of methyl 2-[([(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]-carbonylamino)sulfonyl]-6-nitrobenzoate are suspended in a mixture of 3 ml of methanol/dimethylformamide (5:1), admixed with 10 mg. of palladium on activated carbon (5%) and 1 mg (8.20 μmol) of sodium (meta)vanadate and, hydrogenated under atmospheric pressure and at room temperature for 3 h. The mixture is then filtered off, the filtrate is concentrated and the residue is taken up in water and adjusted to pH 1.5 using 3 N aqueous hydrochloric acid solution. The precipitate is stirred in an ice-bath for 10 min and then filtered off with suction and dried under reduced pressure. This gives 41 mg (87% of theory) of methyl 2-amino-6-[([(4,6-dimethoxy-1,3,5-triazin-2-yl)amino]carbonylamino)sulfonyl]benzoate of m.p. 129-134° C. (decomp.).
Reaction SMILES: [H-].[Na+].C(OCCOCCO)C.Cl[C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15].[C:24](=[S:26])=[S:25]>>[SH:26][C:24]1[S:25][C:13]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=2[N:15]=1
Reactant: S=C=S
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCCOCCO
Product: FC(F)(F)c1ccc2sc(S)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a mixture of sodium hydride (0.98 g, 40.91 mmol) and diethylene glycol monoethyl ether (25 mL) was added 2-chloro-5-(trifluoromethyl)aniline (5.00 g, 25.57 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at rt for 30 minutes, and then carbon disulfide (3.89 g, 51.13 mmol) was added. The reaction mixture was then heated at 140° C. for 6 hours. After cooling the solution to rt, the product was precipitated by addition of conc. HCl, collected by filtration, and recrystallized from isopropyl ether to afford 2-mercapto-5-(trifluoromethyl)benzothiazole (2.65 g, 44%). 1H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 1H), 7.61 (d, 1H), 7.94 (d, 1H).
Reaction SMILES: FC1C=C(C[C@@H](C2N(C3C=CC(OC)=CC=3)C=CN=2)N)C=C(F)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:36][CH:35]=[N:34][C:33]=2[CH:37]([NH:47]S(C(C)(C)C)=O)[CH2:38][C:39]2[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[CH:40]=2)=[CH:28][CH:27]=1>>[ClH:25].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:36][CH:35]=[N:34][C:33]=2[CH:37]([NH2:47])[CH2:38][C:39]2[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[CH:40]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)S(=O)NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1
Agent: COc1ccc(-n2ccnc2[C@@H](N)Cc2cc(F)cc(F)c2)cc1
Product: Cl
Product: NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5E of Example 5 utilizing 33F. MS (m/z) 335.1 [M+H]+.
Reaction SMILES: C(C1OC2C=CC(Br)=CC=2C=1)C1C=CC=CC=1.C(Cl)(=O)C1C=CC(OC)=CC=1.[CH2:29]([C:36]1[O:37][C:38]2[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][C:39]=2[C:40]=1[C:41](=[O:50])[C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[C:56]([N:60]1[CH2:63][CH:62](CCl)[CH2:61]1)([CH3:59])([CH3:58])[CH3:57]>>[CH2:29]([C:36]1[O:37][C:38]2[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][C:39]=2[C:40]=1[C:41](=[O:50])[C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:61]2[C-:62]=[CH:63][N+:60]=2[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:44][CH:43]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)oc3ccc(Br)cc23)cc1
Reactant: CC(C)(C)N1CC(CCl)C1
Agent: Brc1ccc2oc(Cc3ccccc3)cc2c1
Agent: COc1ccc(C(=O)Cl)cc1
Product: CC(C)(C)[N+]1=C(COc2ccc(C(=O)c3c(Cc4ccccc4)oc4ccc(Br)cc34)cc2)[C-]=C1

Procedure:
2-Benzyl-5-bromobenzofuran is acylated with p-anisoyl chloride as described above, the resulting 2-benzyl-5-bromo-3-(4-methoxybenzoyl)benzofuran is dimethylated and the product thus formed is reacted with N-t-butyl-3-chloromethylazetidine as described in Example 3 to give the title compound.
Reaction SMILES: C([Li:5])CCC.[CH2:6]([C:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH:8]=[CH2:9]>C1COCC1>[CH2:6]([C:10]1([Li:5])[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH2:7][CH:8]=[CH2:9]
Reactant: C=CCCC1=CC=CC1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: [Li]C1(CCC=C)C=CC=C1
Reaction time: 1 h

Procedure:
47.5 millimoles of butyllithium mixed with a C6 alkane are added slowly to 47.5 millimoles of the γ-butenylcyclopentadiene prepared in the preceding stage (b), in 50 ml of THF at 0° C. and are stirred for 1 hours. The γ-butenylcyclopentadienyllithium solution thus produced is added to 19 millimoles of hafnium tetrachloride in 50 ml of THF at 0° C. and is stirred for 65 hours. The volatile compounds are removed under vacuum and the residue is extracted with ether and filtered. The product is precipitated in the form of a white solid by slowly cooling the solution to −50° C. and recrystallizing from ether at −12° C.
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8](Cl)[N:7]=[CH:6][N:5]=1>C(OCC)C.CO>[Cl:3][C:4]1[N:5]=[CH:6][N:7]=[C:8]([NH2:2])[C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: Nc1ncnc(Cl)c1[N+](=O)[O-]
Reaction time: 2 h
Yield: 74.9 %

Procedure:
A solution of 28% aqueous ammonium hydroxide (670 mL, 5.35 mol, 1.04 equiv) was added in a drop-wise fashion to a rapidly stirred solution of the 4,6-dichloro-5-nitropyrimidine solid (1000 g, 5.16 mol, 1.00 equiv) in diethyl ether (4000 mL) and methanol (670 mL). The addition was carried out over a period of 2 hours. Upon completion of addition, the resulting yellow solid was filtered off, washed with water and hexane, and dried under reduced pressure to give the title compound as a yellow solid (yield: 675 g). This crude solid was used in the next step without any further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 7.91 (broad s, 2H). MS (EI) for C4H3ClN4O2: 175 (MH+).