Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.C(N(CC)CC)C.[CH2:38]([N:45]=[C:46]=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[CH2:38]([NH:45][C:46]([N:26]1[C:24]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:2]=[CH:1][CH:6]=[C:5]([Cl:7])[C:4]=4[Cl:8])[CH2:10][CH2:11]3)[CH:25]=2)[CH2:30][CH2:29][C:27]1=[O:28])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of aripiprazole (1.5 g, 3.35 mmol) in dichloromethane (33 mL) was added triethylamine (0.56 mL, 4.01 mmol) and benzyl isocyanate (0.82 mL, 6.69 mmol). The reaction was stirred at room temperature for 48 hours. The reaction was quenched with water and extracted with dichloromethane (3×20 mL). The organics were combined, washed with brine (20 mL), dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica eluting with 0-10% tetrahydrofuran in ethyl acetate. The product was triturated in heptane to remove aliphatic impurities and then filtered and dried to afford Compound-79 (0.575 g) as a colorless solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4].Cl.Cl[CH2:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH2:15][C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)=[CH:7][CH:6]=1)[CH3:4]
Reactant: CCc1ccc(O)cc1
Reactant: ClCCc1c[nH]cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Product: CCc1ccc(OCCc2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
180 mg (60% in oil; 4.5 mmol) of sodium hydride are slowly added to a solution of 1.1 g (9 mmol) of 4-ethylphenol in 7 ml of dimethylformamide and the mixture is stirred at room temperature for 2 hours. 150 mg (0.9 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride and tetrabutylammonium iodide (catalyst) are added and the mixture is stirred at 80° C. for 3 days. The solvent is concentrated and 50 ml of diethyl ether are added. The precipitate is separated by filtration and the filtrate is evaporated under reduced pressure to give a residue which is subjected to column chromatography through silica gel (first eluent ethyl acetate, second eluent 95/5 ethyl acetate/methanol). The title compound is then purified by preparative chromatography and then converted to the oxalate which, after crystallization from an ethanol/diethyl ether mixture, melts at 178° C.
Reaction SMILES: C([NH:11][CH:12]([C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[CH2:17][CH2:16][N:15]=1)[CH3:13])(OCC1C=CC=CC=1)=O.[BrH:28].C(O)(=O)C>>[BrH:28].[BrH:28].[NH2:11][CH:12]([C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[CH2:17][CH2:16][N:15]=1)[CH3:13]
Reactant: COc1cc2c(cc1OC)C(C(C)NC(=O)OCc1ccccc1)=NCC2
Agent: Br
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)C(C(C)N)=NCC2
Temperature: 25 °C

Procedure:
40 g 1-(1-carbobenzoxyaminoethyl)-3,4-dihydro-6,7-dimethoxyisoquinoline are dissolved in 450 ml 40% HBr/acetic acid. The mixture is maintained at room temperature for 1 hour and then concentrated in a vacuum to give a crystalline residue of 1-(1-aminoethyl)-3,4-dihydro-6,7-dimethoxyisoquinoline dihydrobromide which is washed with ether before further use (M.Pt. 234°-235°).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[Br:10]Br>CCOCC.[Fe]>[Br:10][C:6]1[CH:7]=[C:2]([F:1])[C:3]([CH3:9])=[CH:4][C:5]=1[F:8]
Reactant: Cc1cc(F)ccc1F
Reactant: BrBr
Agent: [Fe]
Solvent: CCOCC
Product: Cc1cc(F)c(Br)cc1F
Temperature: -5 °C
Reaction time: 3 h

Procedure:
A mixture of 2,5-difluorotoluene (25 g, 0.20 mol) and iron powder (11 g, 0.2 mol) was cooled to −5° C. Bromine was added dropwise such that the internal temperature of the reaction did not rise above 0° C. After stirring for 3 hours, the mixture was diluted with ether, filtered and washed with aqueous sodium thiosulfate solution. The aqueous layer was extracted with ether, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Distillation at atmospheric pressure gave 34 g of 1-bromo-2,5-difluoro-4-methyl-benzene as a colorless oil (b.p. 180 oC). 1H NMR (300 MHz, CDCl3) δ 7.20 (dd, 1H, J=6.0, 8.5 Hz), 6.93 (m, 1H), 2.23 (s, 3H) ppm.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:35])[CH:14]([CH2:18][S:19]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)(=[O:21])=[O:20])[CH:15]([CH3:17])[CH3:16])(C)(C)C>ClCCl>[Br:34][C:31]1[CH:32]=[CH:33][C:28]([N:25]2[CH2:26][CH2:27][N:22]([S:19]([CH2:18][CH:14]([CH:15]([CH3:17])[CH3:16])[C:13]([OH:35])=[O:12])(=[O:21])=[O:20])[CH2:23][CH2:24]2)=[CH:29][CH:30]=1
Reactant: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 353.2 %

Procedure:
Trifluoroacetic acid (10 ml) was added slowly to a solution of 2-[4-(4-Bromophenyl)piperazine-1-sulfonylmethyl]-3-methylbutyric acid tert-butyl ester (2 26 g) in dichloromethane (50 ml). After stirring at room temperature for 3.5 h, the solvents were removed under vacuum, and the residue azeotroped twice with 1:1 dichloromethane/hexane (30 ml). The residue was then dissolved in 1 M sodium hydroxide (20 ml) and washed with diethyl ether (50 ml). The aqueous phase was then acidified to pH 3-4 with citric acid and extracted with dichloromethane (60 ml, then 2×20 ml). The combined dichloromethane extracts were then washed with water (20 ml), saturated brine (20 ml), dried (MgSO4) and the solvents removed under reduced pressure to provide the title compound as a white solid (3 81 g, 79%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=O)[N:9]=1)(=[O:3])[CH3:2].[CH:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[CH:14][CH:12]=[O:13])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C=O)cs1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc(C=CC=O)cs1
Yield: 64.8 %

Procedure:
A mixtuxe of 2-acetylamino-4-formylthiazole (6.05 g), formylmethylidenetriphenylphosphorane (10.82 g) and chloroform (360 ml) was refluxed for 4 hours. The precipitates were collected by filtration and washed with chloroform to give 2-acetylamino-4-(2-formylvinyl)thiazole (4.52 g).
Reaction SMILES: [CH:1]1([CH2:5][C@H:6]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:7](N(OC)C)=[O:8])[CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]1([CH2:5][C@H:6]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH:7]=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: CON(C)C(=O)[C@H](CC1CCC1)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](C=O)CC1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To the solution of (S)-tert-butyl 3-cyclobutyl-1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (4.3 g, 15 mmol) in anhydrous tetrahydrofuran (100 mL) under argon at −78° C., was slowly added lithium aluminum hydride (1M in tetrahydrofuran, 15 mL, 15 mmol). After 2 hours, the reaction mixture was quenched by slowly adding 1N HCl (15 mL) and the reaction mixture was warmed up to room temperature after the addition was complete. The reaction mixture was diluted with ethyl acetate (500 mL), washed with 1N HCl, water, then brine, and dried over magnesium sulfate. Removal of the solvents under reduced pressure gave (S)-tert-butyl 1-cyclobutyl-3-oxopropan-2-ylcarbamate (2.95 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: N#CCc1cccc(N)c1
Yield: 80.5 %

Procedure:
A solution of 3-nitrobenzeneacetonitril (8.0 g) in EtOH (100 ml) was hydrogenated at 1 atm and room temperature over 5% palladium on carbon (0.8 g) for 4 hrs. The catalyst was removed by filtration through Hyflo and the filtrate was evaporated. The residue was chromatographed, eluting with EA:Hexane (1:2) to give the title compound (5.25 g) as an orange oil. T.I.c. hexane:EA (2:1) Rf 0.45; NMR (300 MHz, CDCl3) d 3.792H,s); 3.9(2H,br); 6.7(3H,m); 7.2(H,M).
Reaction SMILES: [CH2:1](/[C:8](=[CH:13]\[C:14]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[C:29](=[O:30])[C:28](=[O:31])[C:27]=3[O:32]C(C)C)=[CH:22][CH:21]=2)[C:17]([CH2:36][CH2:37][CH2:38][CH3:39])=[N:16][C:15]=1[Cl:40])/[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C>[CH2:1](/[C:8](=[CH:13]\[C:14]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[C:27](=[O:32])[C:28](=[O:31])[C:29]=3[OH:30])=[CH:22][CH:21]=2)[C:17]([CH2:36][CH2:37][CH2:38][CH3:39])=[N:16][C:15]=1[Cl:40])/[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc(Cl)c(/C=C(\Cc2ccccc2)C(=O)OC)n1Cc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Solvent: CC(=O)O
Product: CCCCc1nc(Cl)c(/C=C(\Cc2ccccc2)C(=O)O)n1Cc1ccc(-c2c(O)c(=O)c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (E)-methyl 2-benzyl-3-[2-butyl-4-chloro-1-[4-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)benzyl]-1H-imidazol-5-yl ]propenoate (1.2 g; preparable as described in Example 30(d)) and aqueous acetic acid (50%; 20 ml) was heated at 95°-100° C. for 6 hours. The solvents were evaporated under reduced pressure and the residue obtained was triturated with diethyl ether (2 ×20 ml). The resulting solid was dissolved in industrial methylated spirit (20 ml). Aqueous sodium hydroxide solution (0.5M, 22 ml) was added and the resulting mixture was stirred for 1 hour at ambient temperature and neutralised with hydrochloric acid (5M). The solvent was evaporated under reduced pressure and the residue obtained was extracted with aqueous sodium hydroxide solution (1M; 60 ml) and then acidified with hydrochloric acid (5M). The resulting precipitate was collected, washed with water (2×10 ml) and then dried to give (E)-2-benzyl-3-[2-butyl-4-chloro-1-[4-(2-hydroxy-3,4-dioxocyclobut-1 -en-1-yl)benzyl]-1H-imidazol-5-yl]propenoic acid, an active compound of the present invention, as a solid (0.54 g; m.p. 155°-160° C.).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([OH:11])[C@@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@H:6]1[NH:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])(=[O:3])[CH3:2].Cl>O.[OH-].[Na+].C(Cl)(=O)C=C>[C:1]([NH:4][C@@H:5]1[C@@H:10]([OH:11])[C@@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@H:6]1[NH:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:6](=[O:7])[CH:5]=[CH2:10])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1NC(=O)CCCCCN
Agent: C=CC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=CC(=O)NCCCCCC(=O)N[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1NC(C)=O
Reaction time: 4 h
Yield: 64.5 %

Procedure:
The free base 51 (400 mg) was dissolved in a mixture of 1 mL water, 1 mL 2N sodium hydroxide solution and 0.1 mL of acryloyl chloride and the reaction mixture was stirred for 4 hr. The reaction mixture was acidified with 1N HCl and the volatiles were removed from the solution under vacuum. The resulting residue was chromatographed using 5% methanol in dichloromethane to give 52 as a colorless foam (150 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[N:16]=[C:15]2[CH:27]=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[N:16]=[C:15]3[CH:27]=[O:28])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1nn(C2CCCCO2)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 78.1 %

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (258 mg, 1.83 mmol, 1.00 equiv), (R/S) 5-hydroxy-1-(oxan-2-yl)-1H-indazole-3-carbaldehyde (300 mg, 1.22 mmol, 0.67 equiv) and Cs2CO3 (1.2 g, 3.68 mmol, 2.01 equiv) in 1,4-dioxane (25 mL) was stirred at 100° C. for 4 h. The reaction mixture was cooled to room temperature and then diluted with 50 mL of H2O. The resulting mixture was extracted with 3×200 mL of ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-13% of ethyl acetate in petroleum ether to give 350 mg (52%) of (R/S) 5-(4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde as a light yellow solid. 1H-NMR (300 MHz, CDCl3): δ 10.3 (s, 1H), 8.23-8.18 (m, 2H), 8.01 (s, 1H), 7.78-7.75 (m, 1H), 7.27-7.23 (m, 1H), 7.04-7.00 (m, 1H), 5.89-5.85 (m, 1H), 4.06-4.01 (m, 1H), 3.85-3.77 (m, 1H), 2.60-2.52 (m, 1H), 2.21-2.17 (m, 2H), 1.86-1.74 (m, 3H) ppm.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]3[CH:12]=[N:11][NH:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].C[N:25]1CCCC1=O>CCOC(C)=O>[NH2:25][N:10]1[C:8]2[N:9]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=2[CH:12]=[N:11]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2[nH]ncc12
Reactant: CN1CCCC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C2CC2)nc2c1cnn2N
Reaction time: 0.33 h

Procedure:
Ethyl 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (200 mg, 0.865 mmol) was dissolved in N-Methyl-2-pyrrolidone (NMP) (8 mL), followed by addition of potassium tert-butoxide (116 mg, 1.038 mmol). After 20 minutes stirring, 0-{[4-(methyloxy)phenyl]carbonyl}hydroxylamine 1-[(aminooxy)carbonyl]-4-(methyloxy)benzene (289 mg, 1.730 mmol) was added and the mixture stirred at room temperature for 16 h. The contents were diluted with EtOAc, and then washed with brine, and saturated NaHCO3. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography (eluent: 0 to 50% EtOAc). The final product as collected as 106 mg (50%). LCMS E-S (M+H)=274.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.14 (m, 4H), 1.41 (t, J=7.07 Hz, 3H), 2.34-2.47 (m, 1H), 4.44 (q, J=7.07 Hz, 2H), 6.39 (s, 2H), 7.64 (s, 1H), 8.09 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([Si:32]([CH3:33])([CH3:35])[CH3:34])=[CH:30][CH:31]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:20][CH:21]=1
Reactant: C[Si](C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Product: C[Si](C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1

Procedure:
5-Chloro-6-fluoro-1H-indole-7-carboxylic acid [2-(4-chloro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amide was prepared in analogy to example 1 from 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and [2-(4-chloro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine. MS (ISP) 513.3/515.3 (100/69) (M+H)+.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][NH:9]C(=O)OC(C)(C)C)(=[O:5])=[O:4])[CH3:2].[ClH:17]>O1CCOCC1>[ClH:17].[CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][NH2:9])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCS(=O)(=O)CCCN
Reaction time: 2 h

Procedure:
Intermediate 39 (0.275 g) was dissolved in 4M hydrogen chloride in dioxane (3 ml), and the solution was allowed to stand at 22° C. for 2 h. The solvent was evaporated in vacuo to give the title compound as a white solid (186 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[CH2:22]([NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[C:30]([F:43])[CH:29]=1)=[O:26])[CH3:23].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.O.COCCOC>[CH2:22]([NH:24][C:25](=[O:26])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:5]3[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=3[N:7]=2)=[C:30]([F:43])[CH:29]=1)[CH3:23]
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(=O)OCC)C3)c(F)c1
Yield: 19.7 %

Procedure:
A solution of ethyl 2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 27) (156 mg, 0.498 mmol), 1-ethyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 28) (174 mg, 0.567 mmol), [1,1′-Bis (diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (20 mg, 0.0249 mmol) and sodium carbonate (148 mg, 1.39 mmol) in 2 ml of a 7:3:1 mixture of DME:H2O:EtOH respectively was heated in the microwave at 115° C. for 45 minutes. The reaction was concentrated in vacuo and the residue re-dissolved in a mix of MeOH/DCM. It was loaded onto an SCX cartridge and washed with two column volumes of MeOH/DCM before being eluted with 2M NH3 in MeOH and concentrated in vacuo to give a solid. The solid was triturated in acetone and filtered to yield the title compound (45 mg, 20%).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:12]([C:13](O)=O)=C[NH:10][C:7]2=N[CH:9]=1)([O-])=O.C[N:17](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.N1C2C(=CC=CN=2)C=C1.C(O)(C(F)(F)F)=O.C(Cl)Cl>CN(C=O)C>[NH:17]1[C:12]2[C:6](=[CH:5][CH:4]=[CH:9][CH:13]=2)[CH:7]=[N:10]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1c[nH]c2ncc([N+](=O)[O-])cc12
Agent: F[B-](F)(F)F
Agent: c1cnc2[nH]ccc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 0 %

Procedure:
To the Rink resin (corresponding to fragment A9 of table I, 11 g, 0.85 mmol/g, 9.35 mmol) in anhydrous DMF (15 ml), 5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (2.9 g, 14.03 mmol), TBTU (4.5 g, 14.03 mmol) and DIPEA (3.62 g, 28.05 mmol) were added. The reaction mixture was shaken at room temperature for 20 hours and then the resin was isolated by filtration. The resin was washed sequentially with DMF (25 ml), DCM (25 ml), DMF (25 ml), DCM (25 ml), MeOH (25 ml), DCM (25 ml), MeOH (25 ml), DCM (25 ml), MeOH (25 ml), TBME (25 ml×2) and dried in vacuo to give the resin bound 7-azaindole (12.5 g). 0.01 g of the resin were cleaved (1 ml of 40% TFA/DCM) to give an off-white solid (0.0014 mg, 82%).
Reaction SMILES: [N+:1]([C:4]1[CH2:5][O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.C([BH3-])#N.Cl>[Zn]>[NH2:1][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1
Reactant: O=[N+]([O-])C1=Cc2ccccc2OC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Zn]
Product: NC1COc2ccccc2C1

Procedure:
The compounds of this invention are prepared by various means. The compounds of this invention wherein R3 is hydrogen, R1 is hydrogen, ethyl or propyl, cyclopropylmethyl or cyclobutylmethyl and R2 is --CH2 cycloalkylC3-8, alkylC2-8, --(CH2)q --R4, or --CH2CH2O(CH2)rCH3 are prepared by refluxing one equivalent of a salicyl aldehyde of formula C-1 (see Chart 1) with one and one-half equivalents of 2-nitroethanol in amylacetate in the presence of one and one-half equivalents of din-propylamine hydrochloride followed by azeotropic distillation for 12 hours in a Dean-Stark apparatus to give the 3-nitrochromene of formula C-3. The 3-nitrochromene is reduced with cyanoborohydride or zinc and HCl to give the 3-aminochromane of C-4. The 3-aminochromane of C-4 can be acylated with an appropriate acid halide, e.g., acid chloride, of the formula RyCOhalide wherein Ry is alkylC1-7, --(CH2)tR4 wherein t is 1 or 2, cycloalkylC3-8 or --CH2O(CH2)mCH3 wherein R5 and m have the meanings in Formula I to give the chromane amides of formula C-5. Also the aminochromane of formula C-4 can be treated with methyl iodide to give the compound of formula C-6 wherein R14 is hydrogen and R15 is methyl or can be treated with formaldehyde in water in the presence of NaBH3CN and a few drops of glacial acetic acid at pH5 to give the corresponding dimethylated compounds. The compounds of formulas C-5 and C-6 can be converted to the corresponding compounds of formulas C-7 and C-8 wherein R is F, Cl, CF3, NR5R6, NR7C(=O)R8, NR9C(=O)OR10, or NR11C(=O)NR12R13 as follows:
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[C:18]3=[C:19]4[CH:25]=[CH:24][NH:23][C:20]4=[N:21][CH:22]=[C:17]3[NH:16][N:15]=2)[CH2:9]1>N1C=CC=CC=1>[CH:1]1([S:4]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:18]4=[C:19]5[CH:25]=[CH:24][NH:23][C:20]5=[N:21][CH:22]=[C:17]4[NH:16][N:15]=3)[CH2:9]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: c1cc2c(ncc3[nH]nc(C4CCCNC4)c32)[nH]1
Solvent: c1ccncc1
Product: O=S(=O)(C1CC1)N1CCCC(c2n[nH]c3cnc4[nH]ccc4c23)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.2 %

Procedure:
Cyclopropanesulfonyl chloride (0.076, 0.54 mmol) was added to a solution of 1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.13 g, 0.54 mmol) in pyridine (5 mL), and the mixture was stirred at room temperature for about 4 h. The solvent was removed in vacuo and the residue purified by RP-HPLC (Table 2, Method q) to yield 1-(1-(cyclopropylsulfonyl)piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.019 g, 0.055 mmol, 10%) as a white solid: LC/MS (Table 2, Method n) Rt 1.75 min; m/z: 346 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][SH:4](=[O:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.C1(C)C=C(C)C=C(C)C=1S([NH:31]O)(=O)=O>ClCCl>[NH2:31][N:7]1[C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[SH:4](=[O:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:3][C:2]1=[NH:1]
Reactant: NC1=Nc2ccc(Cl)cc2[SH](=O)(c2ccccc2)N1
Reactant: Cc1cc(C)c(S(=O)(=O)NO)c(C)c1
Solvent: ClCCl
Product: N=C1N[SH](=O)(c2ccccc2)c2cc(Cl)ccc2N1N
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To 18.2 g of 3-amino-7-chloro-1-phenyl-1,2,4-benzothiadiazine-1-oxide is slowly added with stirring a solution of 16.1 g of mesitylene sulfonylhydroxylamine in 90 ml dichloromethane at 0° C. Stirring is continued for one hour at room temperature. Thereafter the precipitate is sucked off and washed with diethylether carefully. To the dry precipitate (30.4 g), suspended in 200 ml dioxane, 60 ml of 20% aqueous sodium hydroxide is added with stirring at 0° C. Stirring is continued for three hours at room temperature. Thereafter the precipitate is sucked off and the filtrate is poured into ice water. The precipitate is sucked off and crystallized from ethanol. A 16.0 g of colorless 4-amino-7-chloro-3,4-dihydro-3-imino-1-phenyl-1,2,4-benzothiadiazine-1-oxide, m. pt. 168° C., are obtained. A 6.5 g thereof in 25 ml ethyl oxalate chloride is heated for five hours to 80° C. The excess of acid chloride is distilled and the residue partitioned in dichloromethane/aqueous sodium hydrogencarbonate. The organic solvent is distilled in vacuo and the residue crystallized from ethanol, recrystallized from toluene and again from ethanol. A 3.5 g colorless crystals are obtained, m. pt. 239° C.