Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH3:21])[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[OH:29][C:6]1[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10](=[O:22])[N:11]2[CH3:21]
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2C)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)nc(-c3cccnc3)c21
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A mixture of 5-hydroxy-1-methyl-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (34 mg, 0.088 mmol), β-alanine (626 mg, 7.03 mmol) and NaOMe solution (10.5 mL, 5.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 26 mg of the title compound as an off-white solid. MS: (+) m/z 445.26 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:26])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)(=O)C.ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)([O-])O.[Na+]>[CH2:27]([NH:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:26])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1cccc(NC(=O)CN2CCC(Cc3ccccc3)CC2)c1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1cccc(NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
To a stirred solution of 0.32 g (1 mmol) of N-(3-amino-phenyl)-2-(4-benzyl-piperidin-1-yl)-acetamide (Example 175), 0.1 ml (1 mmol) of benzaldehyde, 0.12 ml (2 mmol) of acetic acid in 10 ml of dichloroethane 0.32 g (1.5 mmol) of sodium triacetoxyborohydride is added in small portions below 20° C., and the reaction mixture is stirred at room temperature for 2 hours. Then 20 ml of 8% sodium hydrogencarbonate solution is added to the mixture. The organic layer is separated and the water phase is extracted three times with 10 ml of dichloromethane. The combined organic layers are washed with 20 ml of water and dried over sodium sulfate, concentrated, the residue is treated with diethylether and the precipitated crystals are filtered off to yield 0.26 g (63%) of the title compound. Melting Point: 112-114° C. (ethyl acetate)
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][C:23](=[O:36])[NH:24][C:25]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:26]=4[N:27]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[O:36]=[C:23]1[CH2:22][C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)=[N:27][C:26]2[CH:28]=[CH:29][C:30]([C:32]([F:34])([F:35])[F:33])=[CH:31][C:25]=2[NH:24]1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)c1

Procedure:
The title compound was prepared from 3′-(4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-biphenyl-3-sulfonic acid tert-butylamide (Example 4) (177 mg, 0.3 mmol) and TFA (5 mL) according to the general procedure I step 2. Obtained as an off-white solid (122 mg, 77%). MS (ISP) 460.0 [(M+H)+]; mp 170° C. (dec).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12]/[N:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[N+]([C:23]([CH2:50][CH2:51][CH2:52][CH3:53])=[CH:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][C:26]=1[C:38]([N:40]1[CH2:49][CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41]1)=[O:39])([O-])=O>>[C:32]([O:31][C:29]([C:28]1[CH:36]=[CH:37][C:25]([C:24]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=3)[C:23]=2[CH2:50][CH2:51][CH2:52][CH3:53])=[C:26]([C:38]([N:40]2[CH2:49][CH2:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:41]2)=[O:39])[CH:27]=1)=[O:30])([CH3:33])([CH3:34])[CH3:35]
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Reactant: CCCCOc1ccc(N/N=C/C(=O)OCC)cc1
Product: CCCCOc1ccc(-n2nc(C(=O)OCC)c(-c3ccc(C(=O)OC(C)(C)C)cc3C(=O)N3CCc4ccccc4C3)c2CCCC)cc1
Yield: 69.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(4-butoxyphenyl)hydrazono)acetate (51 mg, 0.19 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (90 mg, 0.19 mmol) were converted to the title compound (90 mg, 68%) as a pale yellow oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.11 (dd, J=8, 2 Hz, 1H), 8.07-8.05 (m, 1H), 7.46-6.88 (m, 9H), 5.02-4.98 (m, 1H), 4.48-4.38 (m, 1H), 4.33-4.28 (m, 2H), 4.18-3.98 (m, 3H), 3.58-3.32 (m, 1H), 2.85-2.50 (m, 4H), 1.85-1.79 (m, 2H), 1.61 (s, 9H), 1.59-1.51 (m, 2H), 1.31 (t, J=8 Hz, 1.5H), 1.23 (t, J=8 Hz, 1.5H), 1.13-0.95 (m, 7H), 0.65-0.60 (m, 3H); MS(ESI+) m/z 680.3 (M+H)+.
Reaction SMILES: C([C:4]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH:10](CCl)[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=O)C.[N+:25]([O-])([OH:27])=[O:26]>C(Cl)Cl>[N+:25]([C:15]1[C:16]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH2:10][CH2:11][N:12]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[C:13]=2[CH:14]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1cccc2c3c(ccc12)N(C(=O)C(F)(F)F)CC3CCl
Solvent: ClCCl
Product: O=C(N1CCc2c1cc([N+](=O)[O-])c1ccccc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A solution of 109 (1.0 g, 2.8 mmol) in CH2Cl2 (20 mL) was treated with fuming HNO3 (6 mL). The mixture was stirred at room temperature for 30 min, and quenched with ice. The mixture was extracted with CH2Cl2 (3×50 ml) dried, and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with EtOAc/petroleum ether (from 1:4 to 1:1) to give 6-acetyl-1 chloromethyl)-5-nitro-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole (111) (640 mg, 57%) as a brown solid: mp 182-184° C. (EtOAc/petroleum ether); 1H NMR (CDCl3) δ 9.18 (s, 1H), 9.06 (d, J=1.4 Hz, 1H), 8.28 (dd, J=8.8, 1.6 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 4.68-4.63 (m, 1H), 4.57-4.49 (m, 1H), 4.48-4.30 (m, 1H), 3.93-3.87 (m, 1H), 3.65-3.58 (m, 1H), 2.70 (s, 3H); 13C NMR 200.4, 154.7 (q, JC-F 39.2 Hz), 148.7, 139.2, 138.2, 130.9, 130.4, 127.7, 127.5, 125.9, 119.6, 115.7, 115.6 (q, JC-F 288H), 52.7, 45.4, 42.7, 28.5. Anal. (C17H12ClF3N2O4) C, H, N.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][SH:8].[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N+]([O-])=O)=[CH:18][N:17]=1)=[O:15].C(O)(=O)C>CN(C)C=O>[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([Cl:3])[CH:5]=2)=[CH:18][N:17]=1)=[O:15]
Reactant: SCc1cccc(Cl)c1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(SCc2cccc(Cl)c2)cn1
Reaction time: 0.25 h

Procedure:
To the stirred suspension of 1.73 g of sodium hydride in 30 ml of dimethylformamide the solution of 12.7 g of m-chlorobenzylmercaptan is added during 2 minutes and stirring is continued for 15 minutes. Thereupon the solution of 12.25 g of 5-nitro-pyridine-2-carboxylic acid methyl ester in 75 ml of dimethylformamide is added all at once. The mixture is stirred for 1 hour on the steam bath and allowed to stand at room temperature overnight. It is poured onto ice and acetic acid, the suspension obtained filtered and the residue recrystallized from 95% aqueous ethanol, to yield the 5-(m-chlorobenzylmercapto)-2-pyridinecarboxylic acid methyl ester melting at 75°-77°.
Reaction SMILES: N#N.[F:3][C:4]1[CH:5]=[C:6]([C:10]2[S:14][CH:13]=[N:12][C:11]=2[C:15]([OH:17])=O)[CH:7]=[CH:8][CH:9]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1>[F:3][C:4]1[CH:5]=[C:6]([C:10]2[S:14][CH:13]=[N:12][C:11]=2[C:15]([Cl:26])=[O:17])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1ncsc1-c1cccc(F)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ncsc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid (55 mg, 0.25 mmol) in toluene (1.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.08 mL, 0.86 mmol) and the resulting yellow solution was stirred at rt for 30 min. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 5-(3-fluoro-phenyl)-thiazole-4-carbonyl chloride.
Reaction SMILES: [CH2:1]([C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:18])=O>>[CH2:1]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:18])=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCc1ccc(C(=O)O)cc1
Product: CCCCCCc1ccc(C(=O)Cl)cc1

Procedure:
A solution of 3 g of para-n-hexyl benzoic acid is refluxed in 7 ml of thionyl chloride for 2 hours. The thionyl chloride is eliminated by distillation under atmospheric pressure, followed by the distillation of the acid chloride under reduced pressure and under a dry nitrogen stream. This gives a product with a boiling point of 153° C. under 1.2 mm Hg.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.Br.[NH:11]([C:13]1[NH:14][CH2:15][CH2:16][N:17]=1)[NH2:12].[OH-].[Na+]>>[N:12]1([NH:11][C:13]2[NH:17][CH2:16][CH2:15][N:14]=2)[CH:3]=[CH:7][CH:6]=[CH:5]1
Reactant: NNC1=NCCN1
Reactant: COC1CCC(OC)O1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: c1ccn(NC2=NCCN2)c1

Procedure:
By reacting 3.7 g. (0.0280 mole) of 2,5-dimethoxy-tetrahydrofuran with 5 g. (0.0276 mole) of 2-hydrazino-4,5-dihydro-1H-imidazole hydrobromide according to the process reported in Example 3, and adding at the end of the reaction a 10% aqueous solution of sodium hydroxide, the title compound is obtained as the free base. Yield 1.5 g. M.p. 183°-4°C. (from acetone.) The maleate melts at 142°-5°C (from acetone).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:14]1([C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH:2]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Ic1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2csc3ccccc23)cc1
Yield: 112.2 %

Procedure:
A solution of benzothiopheneboronic acid (1 g, 5.61 mmol) in ethanol (23 mL) was added to a mixture of iodobenzene (560 μL, 5 mmol), palladium tetrakis(triphenylphosphine) (460 mg, 0.4 mmol) and sodium carbonate (2.38 g, 22.4 mmol) in a mixture of toluene (15 mL) and water (15 mL). The reaction mixture was refluxed for 6 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate (30 mL) and water (10 mL). The biphasic mixture was acidified with an aqueous solution of hydrochloric acid 1N until pH 2. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the organic layer was washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane) to afford the desired product (3a) as a yellow solid (1.18 g, 5.61 mmol, 100%).
Reaction SMILES: [Na+].[I-:2].CN[C@@H]1CCCC[C@H]1NC.Br[C:14]1[C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[S:17][CH:18]=1.C1(C)C=CC=C(C)C=1>CCCCCC.[Cu]I.COCCOCCOC>[I:2][C:14]1[C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[S:17][CH:18]=1
Reactant: Brc1csc2ccccc12
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: Cc1cccc(C)c1
Solvent: CCCCCC
Solvent: COCCOCCOC
Product: Ic1csc2ccccc12
Temperature: 130 °C
Reaction time: 22 h
Yield: 93.4 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %/), NaI (300 mg, 2.00 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.10 mmol, 10 mol %), 3-bromobenzo[b]thiophene (131 μL, 1.00 mmol), m-Xylene (0.80 mL), and diglyme (0.20 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 130° C. for 22 h. The resulting suspension was allowed to reach room temperature, diluted with hexane (10 mL), and filtered through silica gel (2×2 cm) eluting with hexane (50 mL). The filtrate was concentrated, and the residue was purified by flash chromatography on silica gel to provide 3-iodobenzo[b]thiophene (243 mg, 93% yield) as a pale yellow liquid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:20][C:21](OC(C)=O)=[O:22]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:22])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(OCC(F)(F)C(F)(F)F)cc1O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(OCC(F)(F)C(F)(F)F)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
A solution of 2-hydroxy-4-(2,2,3,3,3-pentafluoropropoxy)benzoic acid (obtained in example 6) (0.45 g, 1.6 mmol) in pyridine (3 mL) was cooled to 0° C. and Ac2O (0.25 mL) was added. The resulting mixture was stirred for 15 min at 0° C. and for 2 h at room temperature. The mixture was then concentrated and the residue was treated with H2O (10 mL) and stirred until precipitation (2 h). The solid was collected by filtration and was purified by chromatography on silica-gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 0.2 g of the desired product as a white solid (38% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([NH:48][CH:49]2[CH2:51][CH2:50]2)[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>O1CCCC1>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([N:48]([C:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[N:3][CH:4]=2)=[O:10])[CH:49]2[CH2:50][CH2:51]2)[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Reactant: O=C(O)c1cnc(Cl)nc1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2cnc(Cl)nc2)C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2-chloropyrimidine-5-carboxylic acid (2.00 g), ethyldiisopropylamine (6.39 mL), and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (4.21 g) in tetrahydrofuran (15 mL) is stirred for 45 min at room temperature prior to the addition of 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester (2.94 g). The resulting mixture is stirred at room temperature for 1 h. The solvent is evaporated in vacuo and the residue purified by HPLC(H2O/MeOH/TFA). LC (method 3): tR=1.89 min; Mass spectrum (ESI+): m/z=381/383 (Cl) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:8][C:6]=2[N:7]=1.NN.O>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:5]2[S:10][C:9]([CH2:11][NH2:12])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: NN
Solvent: CO
Solvent: O
Product: NCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
To a solution of 2-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)isoindoline-1,3-dione 31 (100 mg, 0.24 mmol) in MeOH (7 mL) was added H2NNH2.H2O (24 μL, 0.48 mmol). The reaction was heated at reflux for 1 h. After cooling to room temperature the reaction was quenched with water (10 mL) and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo to afford (2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 (0.05 g, 73%). MS (Q1) 285 (M)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([CH2:7][Cl:8])=[O:6].[CH3:10]OC(OC)OC>>[CH3:1][O:2][C:3](=[O:9])/[CH:4]=[C:5](/[O:6][CH3:10])\[CH2:7][Cl:8]
Reactant: COC(=O)CC(=O)CCl
Reactant: COC(OC)OC
Product: COC(=O)/C=C(\CCl)OC
Temperature: 150 °C
Yield: 75 %

Procedure:
31.0 g (0.2 mol) of 4-chloroacetoacetic acid methyl ester is mixed with 106.0 g (1.0 mol) of orthoformic acid trimethyl ester. 30.0 g of Amberlyst-15 ion exchange resin is added under argon with stirring. Under vigorous formation of gas, the reaction temperature rises to 40° C. After 5 hours of stirring, no educt can any longer be detected in thin-layer chromatography. It is filtered from the ion exchange resin and the residue is distilled in a water jet vacuum. The distillate is mixed with 1.0 g of p-toluene sulfonic acid monohydrate and slowly heated to 150° C., and methanol is distilled off. The reaction mass is then distilled in a water jet vacuum. 24.7 g of a colorless liquid with a boiling point bp12 =93° C. is obtained. Further data concerning the compound is:
Reaction SMILES: [Cl:1][C:2]([Cl:23])([Cl:22])[CH:3]1[O:8][CH:7]([C:9](Cl)([Cl:11])[Cl:10])[C:6]2[CH:13]=[C:14]([C:17](OCC)=[O:18])[CH:15]=[CH:16][C:5]=2[O:4]1.O.[NH2:25][NH2:26]>C(O)C>[Cl:10][C:9]([Cl:11])=[C:7]1[C:6]2[CH:13]=[C:14]([C:17]([NH:25][NH2:26])=[O:18])[CH:15]=[CH:16][C:5]=2[O:4][CH:3]([C:2]([Cl:23])([Cl:22])[Cl:1])[O:8]1
Reactant: NN
Reactant: CCOC(=O)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc2c(c1)C(=C(Cl)Cl)OC(C(Cl)(Cl)Cl)O2

Procedure:
A mixture of ethyl 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxylate (6.4 g.), 100% hydrazine hydrate (3 ml.) and ethanol (30 ml.) was warmed on the steam bath for 30 hours. The reaction mixture was cooled, and then evaporated to dryness under reduced pressure. The oily residue was triturated with petroleum ether (b.p. 60°-80° C.) and the solid product thus obtained was crystallised from ethanol, to give 4-dichloromethylene-2-trichloromethylbenzo[1,3]dioxin-6-carbohydrazide, m.p. 182°-183° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][C:5]1[NH:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1.[CH2:15]([O:17][CH2:18][CH2:19]Cl)[CH3:16]>>[CH2:15]([O:17][CH2:18][CH2:19][N:13]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=[C:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH3:14])[CH3:16]
Reactant: CN(C)CCc1nc2cccnc2[nH]1
Reactant: CCOCCCl
Product: CCOCCn1c(CCN(C)C)nc2cccnc21
Yield: 17 %

Procedure:
A mixture formed by 3.9 g 2,3-diaminopyridine and 6.1 g 3-dimethylaminopropionic acid hydrochloride in 40 g polyphosphoric acid, is heated at 160° C. for 5 hours. Reaction mixture is cooled to room temperature, dissolved in water, then made alkaline adjusting the pH to 10 with NaOH and extracted several times with chloroform. Organic extracts are collected together, evaporated to dryness and the residue, crystallized from acetonitrile, gives 1.4 g 2-(2-dimethylaminoethyl)-3H-imidazo [4,5-b] pyridine melting at 109°-112° C. Operation is further processed as described in Example 1 using 2-(2-dimethylaminoethyl)-3H-imidazo [4,5-b] pyridine and 2-ethoxyethyl chloride and after purification by chromatography on silicagel column (CHCl3 --CH3OH 9:1), 3-(2-ethoxyethyl)-2-(2-dimethylaminoethyl)-3H-imidazo [4,5-b] pyridine is obtained as an oil with a yield of 17%.
Reaction SMILES: C(O)(=[O:3])C.O.[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[CH3:7]>O1CCOCC1>[O:8]=[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:7]=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: O=CC(=O)c1ccccc1
Temperature: 80 °C
Yield: 142 %

Procedure:
Add SeO2 (4.6 g; 0.042 mol; 1.0 equiv), acetic acid (1.2 mL; 0.021 mol; 0.5 equiv), water (1.5 mL; 0.083 mol; 2.0 equiv) in 1,4-dioxane (15 mL) and stir at 80° C. until the solution becomes clear. Cool the reaction to RT, add acetophenone (5.0 g; 0.042 mol; 1.0 equiv) and stir at 80° C. for 18 h. Cool the reaction to RT, filter through Celite®, wash the residue with EA, and dry over anhydrous sodium sulfate. Evaporate the organic layer, purify over 50 g silica using EA in hexane to produce the title compound (4.0 g, 72.7%). MS (ES+): m/z=135 (M+H)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[C:12]3[CH:18]=[CH:19][CH:20]=[N:21][C:11]=3[S:10][CH2:9][C:8]2=1.[CH3:22]I>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:22])[C:13]1[C:12]3[CH:18]=[CH:19][CH:20]=[N:21][C:11]=3[S:10][CH2:9][C:8]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)CSc1ncccc1-3
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c1c(n2C)-c2cccnc2SC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaH (60%, 41 mg, 1.03 mmoL) was added into 8-methoxy-6,11-dihydro-5-thia-4,11-diaza-benzo[a]fluorene (250 mg, 0.933 mmoL) in DMF (3 mL) at 0° C. After 10 minutes, MeI (0.064 mL, 0.93 mmoL) was added dropwise into the reaction at 0° C. The reaction mixture was slowly warmed to room temperature over 2 hours. The reaction mixture was then partitioned between EtOAc and saturated NH4Cl. The aqueous phase was extracted two times with EtOAc. The organic layer from each extraction was combined, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, hexanes:EtOAc 1:1 as eluent) to yield the title compound as a white solid.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[N:20]1([C:29]([C:31]2[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=2)=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>CN(C=O)C.O>[N:20]1([C:29]([C:31]2[CH:32]=[CH:33][C:34]([CH2:35][N:10]3[C:11]4[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=4[N:8]=[CH:9]3)=[CH:37][CH:38]=2)=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: O=C(c1ccc(CCl)cc1)n1ccc2ccccc21
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)n3ccc4ccccc43)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 54.5 %

Procedure:
To a solution of theophylline (1.80 g) in DMF (20 ml) were added potassium carbonate (1.66 g) and 4-[(1-indolyl)carbonyl]benzyl chloride (2.70 g) and the mixture was stirred at room temperature for 22 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was distilled off to provide the title compound as colorless powder (2.25 g, 54%).