Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]2[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]3[S:19][CH2:18][C:12]4([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)[O:11][C:10]=32)=[CH:5][CH:4]=1.[C:24]([C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C@@H:34]2[CH2:36][O:35]2)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C@@H:34]([OH:35])[CH2:36][N:15]2[CH2:16][CH2:17][C:12]3([O:11][C:10]4[C:20]5[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]=4[S:19][CH2:18]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:21]=5)[CH2:13][CH2:14]2)=[CH:30][CH:29]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: COc1ccc2c(c1)C1=C(SCC3(CCNCC3)O1)C(=O)C2=O
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Product: COc1ccc2c(c1)C1=C(SCC3(CCN(C[C@H](O)COc4ccc(C(C)(C)C)cc4)CC3)O1)C(=O)C2=O

Procedure:
Compound 227 was synthesized using 9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Z. Mp.=153-156° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.90 (d, J=8.8 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.22 (d, J=2.4 Hz, 1H), 7.11 (dd, J=2.4, 8.8 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 4.85 (d, J=4.8 Hz, 1H), 3.96-3.92 (m, 2H), 3.92 (s, 3H), 3.86-3.81 (m, 1H), 3.07 (s, 2H), 2.81 (dd, J=10.8, 22 Hz, 2H), 2.54 (m, 1H), 2.45-2.39 (m, 3H), 1.98 (d, J=14.0 Hz, 2H), 1.84-1.76 (m, 2H), 1.25 (s, 9H); LCMS: 538 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.Cl.O.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH2:15]1
Reactant: O=C1CCNCC1
Reactant: Cc1cccc2cc[nH]c12
Agent: Cl
Solvent: O
Product: Cc1cccc2c(C3CCNCC3)c[nH]c12

Procedure:
This compound was prepared following the procedure described in Example 1 (parts A and B) starting with 1 g (7.6 mmol) of 7-methylindol and 2.9 g (19 mmol) of 4-piperidone monohydrate hydrochloride. After the usual work-up 0.8 g (50% of yield) of the desired product were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Br[CH2:11][C:12]([NH2:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:11][C:12]([NH2:14])=[O:13]
Reactant: OCc1cccc(O)c1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)COc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
To a solution of 3-hydroxybenzyl alcohol (500 mg, 4 mmol) in acetonitrile (10 mL) was added 2-bromoacetamide (1 eq) and potassium carbonate (1 eq). The resulting suspension was stirred at rt for 18 h. The solvent was removed in vacuo and the residue partitioned between EtOAc and H2O. The aqueous layer was acidified with dilute HCl (2M) and then re-extracted with EtOAc (3×50 mL). The organic phases were combined, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (EtOAc: methanol) to give 2-(3-(hydroxymethyl)phenoxy)acetamide (320 mg, 43%).
Reaction SMILES: O1C(C2C=C(N[C:13]3[N:18]=[C:17]([C:19]4[C:20]([C:28]5[CH:29]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:37]6[S:38][CH:39]=[CH:40][CH:41]=6)[CH:31]=[CH:32][CH:33]=5)=[N:21][N:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=45)[CH:16]=[CH:15][N:14]=3)C=CC=2)=CN=C1.[NH2:43][C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[CH2:49][CH:48]([NH:53][C:54](=[O:59])[C:55]([F:58])([F:57])[F:56])[CH2:47]2.Cl.C(OCC)C>CC(O)C>[F:58][C:55]([F:56])([F:57])[C:54]([NH:53][CH:48]1[CH2:47][C:46]2[C:50](=[CH:51][CH:52]=[C:44]([NH:43][C:13]3[N:18]=[C:17]([C:19]4[C:20]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:37]6[S:38][CH:39]=[CH:40][CH:41]=6)[CH:29]=5)=[N:21][N:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=45)[CH:16]=[CH:15][N:14]=3)[CH:45]=2)[CH2:49]1)=[O:59]
Reactant: Nc1ccc2c(c1)CC(NC(=O)C(F)(F)F)C2
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CC(NC(=O)C(F)(F)F)C4)n2)c1
Yield: 37.3 %

Procedure:
N-{3-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(2-thienyl)acetamide (109 mg, 0.25 mmol) (see Example 2, step B) and N-(5-amino-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (72 mg, 0.30 mmol) were combined in i-PrOH (2 mL) and 1M hydrochloric acid in diethyl ether (25 μL, 0.025 mmol) and heated at 180° C. in the microwave reactor for 20 min. The reaction product was concentrated and purified directly by silica gel flash column chromatography (30-100% EtOAc in hexanes). Purification yielded 61 mg (38%) of a brown oil. ES-LC/MS m/z=654 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.Cl[CH:19]([C:22]1([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[CH:30][CH:29]=[CH:28]3)[CH2:24][CH2:23]1)[CH:20]=O.C(N(CC)CC)C>C(O)(C)C>[N:31]1[C:32]2[C:27](=[CH:26][C:25]([C:22]3([C:19]4[N:3]5[N:4]=[C:5]([C:8]6[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=6)[CH:6]=[N:7][C:2]5=[N:1][CH:20]=4)[CH2:24][CH2:23]3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(-c2cnc(N)nn2)cc1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Temperature: 110 °C
Yield: 44.1 %

Procedure:
A mixture of methyl 4-(3-amino-1,2,4-triazin-6-yl)benzoate (160 mg, 0.70 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (200 mg, 0.83 mmol) in isopropyl alcohol (6 mL) was heated at 110° C. for 24 h. The mixture was adjusted to pH 9 by adding triethylamine and then the volatiles were removed under reduced pressure. The residue was purified by chromatography on silica gel with EtOAc in CH2Cl2 (0-60%) to afford the desired product (130 mg, 44%). LCMS: (M+H)=421.1.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].ClC(O[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16])=O>>[CH3:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:9]=1[Cl:1]
Reactant: [Cl-]
Reactant: Cc1cccc(C)c1OC(=O)Cl
Agent: [Al+3]
Product: Cc1cccc(C)c1Cl
Temperature: 200 °C

Procedure:
0.3 g of anhydrous aluminium chloride was of 2,6-dimethylphenyl chloroformate and the mixture was heated to 200° C. at normal pressure. A further 150 g of 2,6-dimethylphenyl chloroformate and a further one gram of anhydrous aluminium chloride were then metered in over a period of 2 hours and the 2,6-dimethylchlorobenzene formed was simultaneously distilled off. The reaction did not proceed to completion and a mixture of 2,6-dimethylphenyl chloroformate and 2,6-dimethylchlorobenzene was obtained. Separation by distillation gave a 74% yield of 2,6-dimethylchlorobenzene (based on the conversion).
Reaction SMILES: [C:1]1([CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(OC(=O)C)(=O)C>[C:1]1([CH:11]=[C:12]2[CH2:16][C:17](=[O:18])[O:19][C:13]2=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(=Cc1cccc2ccccc12)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(=Cc2cccc3ccccc23)C(=O)O1
Temperature: 60 °C
Yield: 70.2 %

Procedure:
A mixture of 24.5 g of 2-(1-naphthylmethylene)succinic acid in 260 ml of acetic anhydride was heated at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and to the residue was added a mixture of benzene and hexane (1:1 by volume), and precipitated crystals were collected by filtration to obtain 16.0 g of 2-(1-naphthylmethylene)succinic anhydride as orange yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([CH:10]([CH3:12])[CH3:11])=[O:21])=[CH:4][N:3]=1
Reactant: CC(C)Sc1cnc(Cl)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)S(=O)c1cnc(Cl)c(Cl)c1
Yield: 16 %

Procedure:
10 g (0.045 mol) of 2,3-dichloro-5-isopropylthiopyridine (as crude product) were reacted with 7.8 g (0.045 mol) of m-chloroperbenzoic acid in 60 ml of methylene chloride by a method similar to Example 1, Precursor β. After the crude product had been purified by means of flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:1), 1.7 g of product of value were obtained. Yield: 16%; m.p.: 62-64° C.; 1H-NMR (in d6 dimethyl sulfoxide): δ [ppm]=1.0 and 1.25 (2×d, 2×CH3); 3.2 (m, CH); 8.3 and 8.5 (2×d, pyr H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.Cl[CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:12]=[CH2:13])[CH:7]=1
Reactant: COc1ccc(Br)cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=COc1cc(Br)ccc1OC
Temperature: 65 °C
Reaction time: 2.5 h

Procedure:
Into a flame-dried 250 mL round-bottomed flask were added 5-bromo-2-methoxy-phenol (10.01 g, 49.3 mmol), 2-chloroethyl-p-toluenesulfonate (25.32 g, 107.9 mmol), CsCO3 (20.43 g, 62.7 mmol), Triton X-405 (0.57 g, 1 mmol), and THF (55 mL). The slurry was heated at 65° C. for 7 h, then cooled to room temperature. The reaction solution was cooled to 0° C., and a solution of potassium tert-butoxide (18.11 g, 1.48 mol) in 100 mL THF was added dropwise over 30 min. The reaction mixture was allowed to warm to room temperature and stirred an additional 2.5 h. The reaction was quenched by addition of a saturated aqeuous NH4Cl solution, and extracted 3× with EtOAc. The combined organic phase was treated with brine, dried over MgSO4, filtered, concentrated, and then co-evaporated 3× with toluene. The intermediate 4-bromo-1-methoxy-2-vinyloxy-benzene was obtained as an orange-tinted oil (12.2 g). 1H NMR (DMSO-d6) 7.26 (dd, J=8.8, 2.4, 1H), 7.20 (d, J=2.4 Hz, 1H), 6.77 (dd, J=13.6, 6.0, 1H), 4.63 (d, J=13.6, 1H), 4.42 (d, J=6.0, 1H), 3.76 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:17]=[N:16][N:15](C2CCN(C(OC(C)(C)C)=O)CC2)[N:14]=1)=[O:12])[CH3:9].C(OC(C1N([CH:41]2[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]2)N=NC=1)=O)C>>[N:44]1([C:13]2([C:11]([O:10][CH2:8][CH3:9])=[O:12])[CH:17]=[N:16][NH:15][NH:14]2)[CH2:45][CH2:46][CH2:41][CH2:42][CH2:43]1
Reactant: CCOC(=O)c1cnnn1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(=O)c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(N2CCCCC2)C=NNN1
Reaction time: 0.75 h

Procedure:
Trifluoroacetic acid (3 mL) was added to 1,1-dimethylethyl 4-[4-(ethoxycarbonyl)-2H-1,2,3-triazol-2-yl]-1-piperidinecarboxylate (0.41 g, 1.3 mmol) (i.e. the product of Example 32, Step A). The reaction mixture was stirred for 45 minutes. The reaction mixture was then concentrated in vacuo. The resulting mixture was treated with saturated aqueous sodium bicarbonate and the aqueous layer was extracted three times with dichloromethane. The solvent was removed with a rotary evaporator to afford 0.23 g of ethyl 4-piperidinyl-2H-1,2,3-triazole-4-carboxylate as an oil. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Br)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][N:15]([CH2:13][CH3:14])[CH2:16][CH2:17]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1cc2ccccc2c(Br)n1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc(N)cc3ccccc23)CC1
Yield: 38 %

Procedure:
3-Amino-1-bromoisoquinoline (10.3 g) and 1-ethylpiperazine (10.5 g) were reacted in the presence of potassium carbonate (13.8 g) in N,N-dimethylformamide (80 ml) at room temperature for 3 days. The reaction solution was concentrated, followed by the addition of purified water (500 ml), and the resulting mixture was stirred under ice-cooling for 1 hr. The resulting ocherous precipitates were collected by filtration, washed with a small amount of ice-water and hexane, and then dried at 50° C. under reduced pressure, to give 3-amino-1-(4-ethylpiperazin-1-yl)isoquinoline (4.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[N:7]2.C([O-])([O-])=O.[Na+].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[CH2:23]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[N:7]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cnc2cccc(O)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2cccc(OCc3ccccc3)c2c1

Procedure:
A solution of ethyl 5-hydroxyquinoline-3-carboxylate (2.17 g, 10 mmol) prepared in stage D of example 2, Na2CO3 (2.12 g, 20 mmol) and benzylbromide (1.71 g, 10 mmol) in DMF (20 mL) was stirred for 12 hours at room temperature. The reaction mixture was diluted with water (50 mL) and then extracted with AcOEt (3×25 mL). The combined organic layers were washed water, and dried over Magnesium sulfate and evaporated under reduced pressure. The obtained residue was chromatographed over silica-gel.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][CH3:14])=[N:4][CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C([Li])CCC.[CH:20](OC)=[O:21].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:13]([O:12][C:3]1[C:2]([CH:20]=[O:21])=[C:7]([C:8]([F:11])([F:10])[F:9])[N:6]=[CH:5][N:4]=1)[CH3:14]
Reactant: CCOc1ncnc(C(F)(F)F)c1Br
Reactant: COC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ncnc(C(F)(F)F)c1C=O
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 81.5 %

Procedure:
A solution of 5.76 g (21.3 mmoles) of 5-bromo-4-ethoxy-6-trifluoromethylpyrimidine dissolved in 250 ml of THF was cooled to −78° C. Thereto was dropwise added 22.6 ml of n-butyllithium (a 1.6 moles/liter n-hexane solution, 36.1 mmoles). The mixture was stirred for 40 minutes. Thereto was added 2.7 g (45.1 mmoles) of methyl formate. The resulting mixture was stirred for 1.5 hours to give rise to a reaction. After the completion of the reaction, an aqueous ammonium chloride solution was added. The mixture was extracted with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 3.82 g (yield:. 81.6%) of 4-ethoxy-6-trifluoromethylpyrimidine-5-carboaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][N+:12]([O-:24])=[C:11]([CH3:15])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2ccnc(C)c2)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc[n+]([O-])c(C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A mixture of 4-(4-methoxyphenyl)-2-methylpyridine (375 mg) and metachloroperbenzoic acid (70%, 695 mg) in chloroform is stirred at room temperature for two hours. Concentration and purification over silica gel (eluent dichloromethane/methanol from 100/0 to 90/10) affords 384 mg of 4-(4-methoxyphenyl)-2-methylpyridine 1-oxide as an orange oil used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[OH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=2)=[CH:29][CH:28]=1>CN(C)C=O>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH:34]=2)=[CH:29][CH:28]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Oc1ccc(C2=CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2ccc(O)cc2)CC1
Temperature: 20 °C
Reaction time: 12 h
Yield: 18.4 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (12 g), triethylamine (6 cc) and 4-(4-hydroxyphenyl)-1,2,3,6-tetrahydropyridine (7.5 g) in dimethylformamide (120 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 12 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (80 cc), 2-{3-[4-(4-hydroxyphenyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (3.3 g) is obtained, m.p. 198° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([CH:13]=[O:14])[CH:3]=1.[Cl:15]N1C(C)(C)C(=O)N(Cl)C1=O>>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([CH3:11])([CH3:10])[CH3:12])[N:5]=[C:4]([CH:13]=[O:14])[C:3]=1[Cl:15]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: CC(C)(C)c1nc(C=O)cc(N)c1F
Product: CC(C)(C)c1nc(C=O)c(Cl)c(N)c1F
Yield: 0.1 %

Procedure:
Using the procedure for Example 15, 4-amino-6-(tert-butyl)-5-fluoropicolinaldehyde (0.5 g, 2.55 mol), 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.276 g, 1.401 mol) CH3CN (26 mL) gave 4-amino-6-(tert-butyl)-3-chloro-5-fluoropicolinaldehyde (423 mg, 70.5%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 4.76 (d, J=7.2 Hz, 3H), 1.42 (d, J=1.6 Hz, 9H); 19F NMR (376 MHz, CDCl3) δ −132.69; 13C NMR (101 MHz, CDCl3) δ 191.27, 152.89, 149.20, 146.51, 141.75, 139.93, 36.97, 28.39; EIMS m/z 230.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1([CH2:27][C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH:31]=O)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:31]([C:30]3[CH:33]=[CH:34][CH:35]=[C:28]([CH2:27][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:29]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1cccc(CN2CCOCC2)c1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4cccc(CN5CCOCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 56.7 %

Procedure:
In a similar fashion to Compound LXXVI, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (40.0 mg, 0.118 mmol) and 3-morpholin-4-ylmethyl-benzaldehyde (26.7 mg, 0.130 mmol) were reacted to produce 35 mg (57%) of the title compound. mp: 184-185° C., 1H NMR (300 MHz, CDCl3): 8.13 (s, 1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.47 (s, 2H), 6.40 (d, J=8 Hz, 2H), 6.24 (s, 1H), 6.14 (br s, 1H), 6.10 (d, J=8 Hz, 1H), 5.28 (t, J=8 Hz, 1H), 3.74 (br s, 4H), 3.64 (s, 2H), 3.17 (s, 1H), 3.07 (s, 6H), 2.94 (s, 1H), 2.80 (d, J=8 Hz, 1H), 2.54 (s, 3H), 2.35 (d, J=8 Hz, 1H), 2.13 (s, 1H), 1.70 (d, J=8 Hz, 1H). MS: 523, 525 (M+H), HPLC: 1.84 min (G method).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[CH3:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:21]=1[NH2:22]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:21]2[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=2[CH3:19])[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2ccsc2n1
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(Nc2nc(Cl)nc3sccc23)c(C)c1
Temperature: 90 °C
Reaction time: 48 h
Yield: 13 %

Procedure:
To a solution of 2,4-dichlorothieno[2,3-d]pyrimidine (805 mg, 3.94 mmol), TFA (0.91 mL, 11.82 mmol) in TFE (11 mL) was added 2,4,6-trimethylaniline (0.15 mg, 1.1 mmol) in a sealed tube. The reaction was stirred at 90° C. for 2 d. Reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by HPLC to afford the product as a white solid (43.4 mg, 36%):
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.S(=O)(=O)(O)O.[OH-].[Na+].[N+:16]([O-])([OH:18])=[O:17]>>[N+:16]([C:5]1[S:1][CH:2]=[C:3]([C:6]([OH:8])=[O:7])[CH:4]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccsc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1csc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Thiophenecarboxylic acid (5.12 g) was added portionwise to a mixture of nitric acid (20 ml) and sulfuric acid (11.5 ml) below 5° C. The mixture was stirred at the same temperature for 30 minutes, and poured into ice water. The mixture was alkalified with 1N sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 5-nitro-3-thiophenecarboxylic acid (4.45 g) as crystals.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][N:26]=2)=[N:20][C:19]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][C:38]=2[C:39]#[N:40])=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:16]1[N:17]=[CH:18][C:19]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][C:38]=2[C:39]#[N:40])=[N:20][C:21]=1[C:22]1[O:23][C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:25][N:26]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnccc2C#N)nc1-c1nnc(-c2ccccc2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccncc1-c1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
tert-Butyl N-tert-butoxycarbonyl-N-[5-(4-cyano-3-pyridyl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]carbamate (140 mg, 0.2585 mmol) in dichloromethane (2 mL) was treated with TFA (2 mL, 25.96 mmol) and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, re-disolved in MeOH/DCM and concentrated (2×), dissolved MeOH/DCM and passed through bicarbonate cartridge, concentrated under reduced pressure to give a yellow solid. The solid was triturated with acetonitrile and filtered to give yellow solid (83 mg, 94%); 1H NMR (400.0 MHz, DMSO) d 7.69-7.77 (m, 3H), 8.07 (d, 1H), 8.24-8.26 (m, 2H), 7.80-8.40 (br s, 2H), 8.90 (d, 1H), 9.09 (s, 1H) and 9.47 (s, 1H) ppm; MS (ES+) 342.16
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:34](OC(=O)C)=[O:35]>>[CH:34]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: CC(=O)OC=O
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: O=CN1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A138) and acetic formic anhydride the title compound is obtained as colorless solid.