Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[N:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]=12)([O-:5])=[O:4].S(O[CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)(C1C=CC(C)=CC=1)(=O)=O.O>C1COCC1>[N+:3]([C:6]1[CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:26][CH:27]3[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:31][CH2:32]3)[C:10]=12)([O-:5])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=[N+]([O-])c1cnn2c1NCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCN2CCn3ncc([N+](=O)[O-])c32)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 16.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) was added portionwise to a stirred solution of 7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazole (0.125 g, 0.81 mmol) in anhydrous THF (10 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred for 10 min. before a solution of tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (0.31 g, 0.81 mmol) in THF (5 mL) was added portionwise over 10 min. The reaction was stirred for 6 hr at room temperature followed by 18 hr at 50° C. Further sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) was added and stirring continued at 60° C. for a further 24 h. The reaction was cooled and water was added dropwise. The mixture was extracted with EtOAc and the combined organics were dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (0-100% EtOAc/isohexane) to give tert-butyl 4-(2-(7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-1-yl)ethyl)piperidine-1-carboxylate as a yellow oil (50 mg, 17%). 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 4.24-4.16 (m, 2H), 4.25-3.97 (m, 2H), 3.83-3.77 (s, 2H), 3.27 (s, 2H), 3.22 (t, J=6.8 Hz, 2H), 2.72-2.62 (s, 2H), 1.73-1.65 (m, 3H), 1.46-1.44 (m, 9H) 1.40-1.05 (m, 2H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH2:22]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc1OC

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3,4-dimethoxyaniline gave N2-(3,4-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.90 (d, 1H, J=6.6 Hz), 7.59 (bs, 1H), 7.30 (s, 1H), 7.20-7.10 (m, 2H), 7.00-6.75 (m, 4H), 6.59 (bd, 1H, J=7.8 Hz), 3.87 (s, 3H), 3.84 (s, 3H); 19F NMR (CDCl3): −47229; LCMS: ret. time: 17.77 min.; purity: 78%; MS (m/e): 357 (MH|).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:7][C:6]=12.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].C(N(CC)CC)C>CN(C)C=O>[F:12][C:11]([F:14])([F:13])[C:10]1[N:5]2[N:4]=[CH:3][C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[C:6]2[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:9]=1
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)c1
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 102.2 %

Procedure:
A mixture of 3-iodo-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (6.49 g, 14.2 mmol), trimethylsilylacetylene (3.54 mL, 25.6 mmol) and triethylamine (3.94 mL, 28.4 mmol) in N,N-dimethylformamide (15 mL) was stirred for 10 min at room temperature while being purged with Argon, then PdCl2(PPh3)2 (100 mg, 1 mol %), PPh3 (37 mg, 1 mol %) and CuI (8 mg, 0.3 mol %) were added. Stirring was continued at 90° C. for 4.5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (150 mL), washed with water (2×50 mL) and brine (70 mL), dried (MgSO4) and evaporated to give 7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (6.2 g, 102%) as a light brown solid, which was dissolved in THF (30 mL) and MeOH (70 mL), while stirring at 0° C. potassium carbonate (200 mg, 1.45 mmol) was added and the mixture was stirred at 0° C. for 5 h. The mixture was diluted with ice water (200 mL) and extracted with TBME (3×200 mL). The combined organic layers were washed with brine (300 mL), dried (MgSO4) and evaporated. The crude product was further purified by silica gel column chromatography (heptane/EtOAc 9:1) followed by trituration with heptane to give 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (3.23 g, 63%) as an orange solid. MS (EI) 355.0[(M)+]; mp 154° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:31][O:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]Cl>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:17][C:16]=1[C:3]1[C:2]([O:1][CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([O:34][CH2:33][O:32][CH3:31])[CH:36]=2)=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:14])([CH3:15])[C:5]=2[CH:4]=1
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Reactant: COCOc1cccc(CCl)c1
Product: COCOc1cccc(COc2cc3c(cc2-c2cc(C=CC(=O)O)ccc2OC)C(C)(C)CCC3(C)C)c1
Yield: 89.3 %

Procedure:
In a manner similar to that of Example 1(a), by reaction of 2.5 g (6.12 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) with 1.26 g (6.73 mmol) of 3-methoxymethoxybenzyl chloride obtained above, 2.90 g (85%) of the expected compound were obtained in the form of a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][NH2:12])[C:4]=2[O:3][CH2:2]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])[C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1cccc2c1OCO2
Product: CC(=O)NCCc1cccc2c1OCO2

Procedure:
In close analogy to the procedure described above, 2-benzo[1,3]dioxol-4-yl-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[CH2:7][C:8]([O:10][CH3:11])=[O:9].[NH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]>CCOCC>[CH3:11][O:10][C:8](=[O:9])[CH2:7][NH:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=1
Reactant: N#Cc1cccc(N)c1
Reactant: COC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)CNc1cccc(C#N)c1
Reaction time: 6 h

Procedure:
A mixture of sodium bicarbonate (35.5 g), methyl chloroacetate (28 ml) and 3-aminobenzonitrile (25 g) were stirred under nitrogen at 80°-100° for 6 h. Heating at 90° was continued overnight, and the mixture was then cooled and poured into ether (400 ml). The solid precipitate was filtered off and the filtrate was retained. The solid was dissolved in dichloromethane (400 ml) and washed with water (200 ml) followed by dilute hydrochloric acid (200 ml). The organic phase was dried and concentrated in vacuo to give the title compound as a solid (13.8 g), m.p. 91.5°-92.5°. The previously obtained filtrate was washed with water (100 ml), dilute hydrochloric acid (200 ml) and water (100 ml), then dried and concentrated in vacuo. The resultant solid was triturated with ether to give a further batch of the title compound (11.7 g).
Reaction SMILES: [Cl:1][CH:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[NH:3]1.[NH2:13][C:14]1[CH:18]=[C:17]([CH:19]2[CH2:21][CH2:20]2)[NH:16][N:15]=1.C(N(CC)CC)C>C(O)C>[Cl:1][CH:2]1[N:11]=[C:10]([NH:13][C:14]2[NH:15][N:16]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[CH:18]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[NH:3]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: ClC1=NC(Cl)NC2=C1CCCC2
Solvent: CCO
Solvent: CCN(CC)CC
Product: ClC1N=C(Nc2cc(C3CC3)n[nH]2)C2=C(CCCC2)N1
Temperature: 120 °C

Procedure:
2,4-Dichloro-1,2,5,6,7,8-hexahydro-quinazoline (1 g, 4.93 mmol) and 3-amino-5-cyclopropylpyrazole (0.606 g, 4.93 mmol) in ethanol (8 ml) was treated with triethylamine (1.24 ml, 8.87 mmol) and the mixture heated at 120° C. for 3 days, cooled and filtered to give (0.72 g, 51%) as a colourless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:18][CH:19]([O:25][CH:26]([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]=1[OH:8].[I:29]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[I:29][C:2]1[CH:3]=[C:4]([CH2:18][CH:19]([O:25][CH:26]([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]=1[OH:8]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)C(Cc1cc(Br)c(O)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(Cc1cc(I)c(O)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.9 %

Procedure:
253 mg of ethyl 3-(3-bromo-5-[(tertiary butoxycarbonyl)amino]methyl-4-hydroxyphenyl)-2-isopropoxypropionate was dissolved in 3 ml acetonitrile, and 157 mg of N-iodosuccinimide was added thereto. After stirring at room temperature for 2.5 hours, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium thiosulfate, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 100 mg of ethyl 3-(3-iodo-5-[(tertiary butoxycarbonyl)amino]methyl-4-hydroxyphenyl)-2-isopropoxypropionate was obtained from fractions eluted with hexane-ethyl acetate (4:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].[Br:13]Br.O>C(Cl)Cl>[Br:13][CH:10]([CH3:11])[C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:12]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(F)cc1F
Solvent: O
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
In methylene chloride (300 ml) was dissolved 2',4'-difluoropropiophenone (55 g), to which was added bromine (50 g) dropwise, while stirring, during 30 minutes. The mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added water (200 ml), and the methylene chloride layer was washed three times, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off to leave 2-bromo-2',4'-difluoropropiophenone (77 g) as a pale yellow oily product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]1([S:36](Cl)(=[O:38])=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:36]([C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][CH:27]=4)(=[O:38])=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc5ccccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and naphthalene-1-sulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: C(N[C:6]([C:8]1[N:9]=[C:10]2[CH:21]=[N:20][N:19]([CH2:22][CH3:23])[C:11]2=[N:12][C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:7])CCC.[OH-:24].[Na+]>C(O)C>[CH2:15]([NH:14][C:13]1[N:12]=[C:11]2[N:19]([CH2:22][CH3:23])[N:20]=[CH:21][C:10]2=[N:9][C:8]=1[C:6]([OH:7])=[O:24])[CH2:16][CH2:17][CH3:18]
Reactant: [OH-]
Reactant: CCCCNC(=O)c1nc2cnn(CC)c2nc1NCCCC
Agent: [Na+]
Solvent: CCO
Product: CCCCNc1nc2c(cnn2CC)nc1C(=O)O

Procedure:
23.5 g. of N-butyl-6-butylamino-1-ethyl-1H-pyrazolo-[3,4-b]pyrazine-5-carboxamide (0.0735 mol.) suspended in 230 ml. of sodium hydroxide (2.5 N) and 460 ml. of ethanol are heated at reflux for 48 hours. Then the solution is evaporated to a volume of about 60-80 ml. The sodium salt of the acid precipitates. Acidification of the pulp with dilute hydrochloric acid with stirring provides 6-butylamino-1-ethyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid which is filtered off, washed with water and dried at 75°, yield 17.7 g. (91%), m.p., 97°-98° (hexane). The ester is prepared by reacting the foregoing acid with alcoholic hydrochloric acid at room temperature for 4 days. After this period, the ethanol is evaporated, the residue treated with dilute ammonia in order to remove unreacted acid and then dried at 40°. Recrystallization from ligroin yields 6-butylamino-1-ethyl-1H-pyrazolo[3,4-b]-pyrazine-5-carboxylic acid ethyl ester, m.p. 64.5°-65.5°.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.C(OC([NH:25][C@H:26]1[C@H:29]([CH2:30][CH3:31])[N:28]([S:32]([O-:35])(=[O:34])=[O:33])[C:27]1=[O:36])=O)(C)(C)C.ClCCl>C(O)=O>[NH2:25][C@H:26]1[C@H:29]([CH2:30][CH3:31])[N:28]([S:32]([OH:35])(=[O:33])=[O:34])[C:27]1=[O:36]
Reactant: CC[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1S(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O=CO
Product: CC[C@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Reaction time: 16 h
Yield: 34.7 %

Procedure:
(trans)-3-t-Butoxycarbonylamino-4-ethyl-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (6.75 g) in 40 ml of 98% formic acid is stirred for 3 hours at ambient temperature. Dichloromethane (60 ml) is added and the mixture is refrigerated for about 16 hours. The resulting precipitate is separated by filtration and then dried in vacuo to yield 0.85 g of the title compound, melting point 185° C., dec.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1([F:46])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20](C1CCCCO1)[N:19]=[C:18]2[C:30]1[NH:34][C:33]2[CH:35]=[C:36]([CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:37]=[CH:38][C:32]=2[N:31]=1)=[O:13]>C(Cl)Cl>[F:46][C:9]1([F:8])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[C:30]1[NH:31][C:32]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)=[CH:35][C:33]=2[N:34]=1)=[O:13]
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccc(CN4CCOCC4)cc3[nH]1)nn2C1CCCCO1)C1CC1(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]nc(-c3nc4cc(CN5CCOCC5)ccc4[nH]3)c2c1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
TFA (0.15 mL, 1.86 mmol) was added to solution of 2,2-difluoro-N-(3-(6-(morpholinomethyl)-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)cyclopropane carboxamide (10 mg, 0.018 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature, and then the solvent was removed by vacuum. Purification by flash column chromatography (5% CH3OH/CH2Cl2) afforded the title compound (4 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.49 (d, 1H, J=1.6 Hz), 7.69 (dd, 1H, J=1.6 and 8.8 Hz), 7.63-7.58 (m, 3H), 7.28 (m, 1H), 3.71 (m, 4H), 3.67 (m, 2H), 2.79-2.70 (m, 1H), 2.52 (m, 4H), 2.36-2.32 (m, 1H), 2.15-2.06 (m, 1H); ESI-MS [M+H]+: 453.2.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.[H][H]>O1CCOCC1.[Pd]>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
30 g (71 mmol) of tert-butyl [4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]methylcarbamate in 500 ml of dioxane are placed in a reactor. The reaction medium is degassed, followed by addition of g (1 equivalent by mass) of 10% palladium-on-charcoal. The system is placed under 3 bar of hydrogen and heated at 50° C. for seven hours. The reaction medium is filtered through Celite and evaporated, and the residue obtained is purified by chromatography on a column of silica with an fluent mixture of dichloromethane and methanol (98/2). After evaporation of the solvents, 18 g (60%) of the expected product are collected.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].C(C(C)=O)C.[CH3:15][O:16][C:17]1[C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[C:20]([C:27](Cl)=[O:28])=[CH:19][CH:18]=1>O>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:27]([C:20]1[C:21]2[O:26][CH2:25][CH2:24][O:23][C:22]=2[C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:28])[CH3:2]
Reactant: CCN1CCCC1CN
Reactant: COc1ccc(C(=O)Cl)c2c1OCCO2
Solvent: CCC(C)=O
Solvent: O
Product: CCN1CCCC1CNC(=O)c1ccc(OC)c2c1OCCO2
Yield: 103.4 %

Procedure:
87 g of 1-ethyl-2-aminomethyl pyrrolidine and 775 cm3 of methyl ethyl ketone were introduced into a balloon flask provided with an agitator and a thermometer and then, in portions, 155 g of 8-methoxy-1,4-benzodioxane-5-carbonyl chloride was added, with the temperature being maintained at from 5°-10° C. After agitation the mixture was dissolved with 1,500 cm3 of water and then the methyl ethyl ketone was distilled. The remaining solution was filtered and then treated with sodium hydroxide. The oil was decanted and then extracted with methylene chloride. The solution was dried on potassium carbonate and then the methylene chloride was distilled under vacuum. 224.5 g of N-(1-ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5-carboxamide was produced. 197.5 g of the base produced was dissolved in 760 cm3 of absolute alcohol, and then 67 g of oxalic acid in solution in 195 cm3 of absolute alcohol was added. The crystals formed were dried off, washed with absolute alcohol and then dried. 208.5 g of N-(1-ethyl-2-pyrrolidylmethyl)-8-methoxy-1,4-benzodioxane-5-carboxamide oxalate was produced (M.P. 129°-130° C.; yield: 82%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](C(OC(C)(C)C)=O)[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:25][C:21]1[CH:20]=[C:19]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH2:1])[CH:4]=3)[NH:8][N:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CN)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 88.7 %

Procedure:
To a solution of 300 mg of tert-butyl 5-(aminomethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate in 1 ml methylene chloride was added 2 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 6.5 hours. After removing the solvent by filtration, to the residue was added 20 ml of ethyl acetate. The mixture was sequentially washed with saturated aqueous sodium hydrogencarbonate solution (×2) and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 188 mg of the title compound as yellow crystals.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([N+:8]([O-:10])=[O:9])[N:3]=1.[CH2:11]([O:13][C@@H:14]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])[CH3:12]>>[CH2:11]([O:13][C@@H:14]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:6]([CH3:7])[N:5]=[C:4]([N+:8]([O-:10])=[O:9])[N:3]=2)=[CH:22][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])[CH3:12]
Reactant: Cn1nc([N+](=O)[O-])nc1Br
Reactant: CCO[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC
Product: CCO[C@@H](Cc1ccc(-c2nc([N+](=O)[O-])nn2C)cc1)C(=O)OC
Yield: 61.9 %

Procedure:
In a manner similar to that of Example 9(e), starting with 0.9 g (4.35 mmol) of 5-bromo-1-methyl-3-nitro-1H-[1,2,4]triazole and 1.9 g (6.5 mmol) of methyl 2(S)-ethoxy-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]propanoate, 0.9 g (62%) of methyl 2(S)-ethoxy-3-[4-(2-methyl-5-nitro-2H[1,2,4]triazol-3-yl)phenyl]propanoate is obtained in the form of a white solid with a melting point of 119° C.
Reaction SMILES: C1(O[C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:17]2[C:18]([O:26][CH3:27])=[N:19][C:20]([CH3:25])=[C:21]([CH2:23][CH3:24])[CH:22]=2)[CH3:16])C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH2:23]([C:21]1[CH:22]=[C:17]([CH:15]([CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:8]([N:40]2[CH2:39][CH2:38][N:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH3:29])[CH2:42][CH2:41]2)=[O:28])[C:18]([O:26][CH3:27])=[N:19][C:20]=1[CH3:25])[CH3:24]
Reactant: CCc1cc(C(C)CCCCCNC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1ccccc1N1CCNCC1
Product: CCc1cc(C(C)CCCCCNC(=O)N2CCN(c3ccccc3OC)CC2)c(OC)nc1C
Yield: 49 %

Procedure:
Phenyl-N-[6-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)heptyl]carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:9][NH2:10])=[N:5][CH:6]=[CH:7][N:8]=1.C(N(CC)C(C)C)(C)C.[CH3:20][S:21][C:22](=[O:24])Cl>ClCCl>[CH3:20][S:21][C:22](=[O:24])[NH:10][CH2:9][C:4]1[C:3]([Cl:2])=[N:8][CH:7]=[CH:6][N:5]=1
Reactant: NCc1nccnc1Cl
Reactant: CSC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSC(=O)NCc1nccnc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of C-(3-chloro-pyrazin-2-yl)-methylamine hydrochloride salt (5.13 g, 0.0285 mol) in dichloromethane (60 mL) were added N,N-diisopropylethylamine (15 mL, 0.085 mol) and carbonochloridothioic acid S-methyl ester (3.15 g, 0.0285 mol) at 0° C. After 5 min, the mixture was warmed to rt and kept at rt overnight. The mixture was diluted with dichloromethane (50 mL), washed with water (30 mL), sat. aq. NaHCO3 (2×30 mL), brine (30 mL), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel chromatography (Hex:EtOAc=70:30→50:50) to give the title compound as a light-yellow solid; 1H NMR (CDCl3, 400 MHz) δ 2.41 (s, 3H), 4.76 (d, J=4.6 Hz, 2H), 6.67 (br s, 1H), 8.34 (d, J=2.5 Hz, 1H), 8.48 (d, J=2.5 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([CH3:13])[C:3]=1[C:4]#[N:5].C(=O)(O)O.[NH2:18][C:19]([NH2:21])=[NH:20]>C(OCCO)C>[NH2:20][C:19]1[N:21]=[C:4]([NH2:5])[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([N+:10]([O-:12])=[O:11])[C:6]=2[CH3:13])[N:18]=1
Reactant: N=C(N)N
Reactant: Cc1c([N+](=O)[O-])ccc(Cl)c1C#N
Agent: O=C(O)O
Solvent: CCOCCO
Product: Cc1c([N+](=O)[O-])ccc2nc(N)nc(N)c12
Yield: 82.7 %

Procedure:
Under a nitrogen atmosphere, a stirred solution 29.5 grams (0.150 mole) of 2-chloro-6-methyl-5-nitrobenzonitrile and 54.0 grams (0.300 mole) of guanidine carbonate in 1500 mL of 2-ethoxyethanol was heated at reflux during a 3.5 hour period. After this time, the reaction mixture was concentrated under reduced pressure to a residue. The residue was stirred with 300 mL of water, and the resultant solid was collected by filtration. The solid was washed with 50 mL of water and dried under reduced pressure, yielding 27.2 grams of 2,4-diamino-5-methyl-6-nitroquinazoline. The NMR spectrum was consistent with the proposed structure. The reaction was repeated again.