Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:26](=[O:28])[CH3:27])=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Reaction time: 1 h
Yield: 78 %

Procedure:
4-Nitro-3-piperidin-1-yl-phenylamine (64 mg, 0.28 mmol, as prepared in the previous step) and DIEA (122 μL, 0.700 mmol) in 4 mL of CH2Cl2 was treated with acetyl chloride (28 μL, 0.40 mmol). The reaction was stirred for 1 h, diluted with CH2Cl2 (25 mL), washed with water (50 mL), and dried (Na2SO4). Concentration of the solvent in vacuo afforded 51 mg (78%) of N-(4-nitro-3-piperidin-1-yl-phenyl)-acetamide. Using a procedure similar to Example 3, step (c), 4-nitro-3-piperidin-1-yl-phenylamine (51 mg, 0.21 mmol) was stirred with 5% Pd—C (35 mg) under H2 to afford 40 mg (61%) of the title compound as a dark semi-solid. Mass spectrum (ESI, m/z): Calcd. for C13H19N3O, 234.1 (M+H), found 234.2.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)N=[CH:3][CH:2]=1.[CH3:15]C1C=CC=CN=1.CC1C=NC=CC=1.CC1C=CN=CC=1>>[CH:9]1[C:8]2[C:7](=[N:6][C:5]3[C:14]([CH:13]=2)=[CH:1][CH:2]=[CH:3][CH:15]=3)[CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc2c(c1)cnc1ncccc12
Reactant: Cc1ccccn1
Solvent: Cc1cccnc1
Solvent: Cc1ccncc1
Product: c1ccc2nc3ccccc3cc2c1

Procedure:
4,5-phenanthroline, 2-methylpyridine; 3-methylpyridine; 4-methylpyridine;
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:15]([C:19]1[N:20]=[C:21]([SH:24])[S:22][CH:23]=1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[N:20]=[C:21]([S:24][CH2:2][C:3]([N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][CH2:6]2)=[O:4])[S:22][CH:23]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1csc(S)n1
Reactant: O=C(CCl)N1CCCc2ccccc21
Product: CC(C)(C)c1csc(SCC(=O)N2CCCc3ccccc32)n1
Yield: 37 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 4-tert-butylthiazole-2-thiol as the nucleophile to yield 34 (37%): MS: m/z+347.2 [M+H]+. Anal. Calcd (found) for C18H22N2OS2: C, 62.39; (62.60), H, 6.40; (6.43), N, 8.08; (8.06), S, 18.50; (18.39).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:10])[CH2:8][OH:9])[C@H:4]([C:11]([NH2:13])=[O:12])[CH2:3]1.Cl.CN(C)C.C(N(CC)CC)C.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C.O>[C:26]1([S:32]([O:9][CH2:8][C:7]([N:5]2[CH2:6][C@@H:2]([F:1])[CH2:3][C@H:4]2[C:11]([NH2:13])=[O:12])=[O:10])(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)CO
Agent: CN(C)C
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 80 %

Procedure:
Process A: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (381 mg) and trimethylamine hydrochloride (191 mg) were suspended in acetonitrile (10 mL) and triethylamine (0.56 mL) was added to the suspension. While this mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added drop wise. The mixture was stirred for 1 hour at the same temperature, after which water (5 mL) was added and the mixture was extracted with ethyl acetate (2×40 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1) to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a white solid (528 mg, 80% yield). Process B: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (381 mg) was suspended in acetonitrile (10 mL). To this suspension, N,N,N′,N′-tetramethyl-1,3-propanediamine (34.0 μL) and triethylamine (0.56 mL) were added. While the mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added dropwise. The mixture was then stirred at the same temperature for 1 hour, followed by the addition of saturated brine (5 mL) and extraction with ethyl acetate (2×40 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1) to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a white solid (599 mg, 91% yield). Process C: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (100 mg) and triethylamine (74 mg) were suspended in acetonitrile (1 mL). While the suspension was cooled in an ice bath, benzenesulfonic anhydride (188 mg) was added and the mixture was stirred for 10 minutes. Subsequently, the mixture was stirred at room temperature for 1 hour, followed by the addition of water (2 mL) and extraction with ethyl acetate (2×4 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a brown oil (147 mg, 85% yield).
Reaction SMILES: O[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[NH+:8](COCC[Si](C)(C)C)[NH:9][CH:10]=[C:3]12.[Si]([C:23]#[N:24])(C)(C)C>C(Cl)Cl>[NH:8]1[C:4]2[C:3](=[N:2][C:7]([C:23]#[N:24])=[CH:6][CH:5]=2)[CH:10]=[N:9]1
Reactant: C[Si](C)(C)CCOC[NH+]1NC=C2C1=CC=CN2O
Reactant: C[Si](C)(C)C#N
Solvent: ClCCl
Product: N#Cc1ccc2[nH]ncc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 115.6 %

Procedure:
To a solution of 4-hydroxy-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridinium (1.59 g, 6 mmol) in DCM (130 mL) was added TMSCN (1.13 mL, 9 mmol). After 5 min at rt, (Me)2N(C(O)Cl (0.83 mL, 9 mmol) was added. The reaction mixture was stirred at rt for 4 days, after which it was diluted with DCM, washed with brine, and dried. Concentration followed by purification through column afforded 1H-pyrazolo[4,3-b]pyridine-5-carbonitrile (1 g, 61%).
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)=[CH:29][CH:28]=1.NC1C=NC(C)=CC=1.C(N(C(C)C)CC)(C)C>C(#N)C>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:34]([NH:33][C:30]3[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=3)=[O:35])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(NC(=O)Oc2ccccc2)cn1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Agent: Cc1ccc(N)cn1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cc4)c3)CC2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(3-(4-(Trifluoromethyl)phenoxy)benzylidene)piperidine hydrochloride (200 mg, 0.541 mmol, from Example 53, Step 5) and phenyl 6-methylpyridin-3-ylcarbamate (123 mg, 0.541 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-amino-6-methylpyridine) and diisopropylethylamine (0.20 mL, 1.15 mmol) were combined in acetonitrile (5 mL) and stirred at room temperature. After 16 h, the reaction was concentrated and the residue was purified by silica gel chromatography (50-100% EtOAc:CH2Cl2) to afford the title compound (220 mg) as a white solid. MS APCI M+ 468.2, 375.2, 334.1 M− 466.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.41-2.45 (m, 2H) 2.46 (s, 3H) 2.54 (td, J=5.90, 1.26 Hz, 2H) 3.50-3.55 (m, 2H) 3.58-3.65 (m, 2H) 6.43 (s, 1H) 6.91-6.96 (m, 2H) 7.06-7.12 (m, 3H) 7.20 (d, J=8.52 Hz, 1H) 7.35-7.42 (m, 1H) 7.59-7.68 (m, 2H) 7.77 (dd, J=8.45, 2.62 Hz, 1H) 8.43 (d, J=2.78 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:8]([C:21]([O:23]C)=[O:22])=[CH:7][C:6]=2[CH:25]=1.[OH-].[Na+].O.Cl>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:8]([C:21]([OH:23])=[O:22])=[CH:7][C:6]=2[CH:25]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2ccc(OC)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2CCC(C(=O)O)=Cc3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.5 %

Procedure:
To a solution of methyl 7-bromo-1-(4-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (920 mg) in a mixture of tetrahydrofuran (70 ml) and methanol (70 ml) was added 1N sodium hydroxide solution (23 ml), and the mixture was stirred at room temperature for 1 day. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was recrystallized from hexane-ethyl acetate to give 7-bromo-1-(4-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (644 mg) as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([Cl:25])[CH:27]=3)[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C2C(=O)Nc3cc(Cl)ccc32)CC1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 60 °C

Procedure:
A mixture of rac-4-(6-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.21 g, 0.6 mmol) (from Example 12b supra), 3-chlorobenzyl bromide (0.15 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 8 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, 3% then 10% ethyl acetate in dichloromethane as solvent). Combined fractions were recrystallized from dichloromethane-hexanes to give rac-4-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester as white crystals. (Yield 0.14 g, 49.1%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[NH2:16][C:17]1[NH:21][N:20]=[CH:19][C:18]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:13]([NH:16][C:17]2[NH:21][N:20]=[CH:19][C:18]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Reactant: Nc1[nH]ncc1-c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1[nH]ncc1-c1ccccn1
Temperature: 25 °C

Procedure:
A mixture comprising 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 2) (0.179 g, 0.624 mmol), 5-amino-4-(pyridin-2-yl)-1H-pyrazole (0.1 g, 0.624 mmol), HATU (0.237 g, 0.624 mmol) and N-methylmorpholine (0.123 ml, 1.249 mmol) in DMF (5 ml) was stirred at 80° C. for 2.5 hours. After cooling to RT, the mixture was diluted with water (40 ml) and the resulting yellow precipitate was filtered under vacuum and washed with water (20 ml). MeOH (150 ml) was added to the solid and the suspension ultrasonicated to give a fine suspension. The suspension was filtered under vacuum and the solid was rinsed with MeOH (20 ml) and dried under vacuum at 45° C. for 1.5 hours to afford the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.C(OC(=O)C)(=O)C.[N+:20]([O-])([OH:22])=[O:21]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:20]([O-:22])=[O:21])[CH:7]=1
Reactant: COCCOc1ccc(N)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: COCCOc1ccc(N)c([N+](=O)[O-])c1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
4-(2-Methoxyethoxy)aniline (500 mg) was added to acetic anhydride (2.38 g) and the mixture was cooled down to 10° C. HNO3 (65% in water, 0.62 mL) was added slowly in order to keep the temperature of the reaction mixture below 15° C. After the end of the addition, the reaction mixture was allowed to warm to RT over 1 h, was quenched with ice-cold water and stirred for 10 min. The resulting suspension was filtered off and dried in high vacuo. The resulting yellow powder was dissolved in dioxane (1.4 mL), treated with 6N HCl (1.4 mL) and the reaction mixture was stirred at 70° C. for 3 h. After cooling down to RT, water was added and the pH was adjusted to 10 with 1M NaOH. The layers were separated and the aq. phase was extracted with EA. The combined org. layers were washed with brine, dried (Na2SO4) and evaporated in vacuo to afford 303 mg of yellow solid. LC-MS (B): tR=0.99 min; [M+H]+: 213.05.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:26]([O:25][C:23]([N:17]1[CH2:22][CH2:21][N:20]([C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=3)=[CH:16][CH:15]=2)[CH2:19][CH2:18]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccncc3)cc2)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In N,N-dimethylformamide (40 ml), 4-(4-pyridyl)benzoic acid hydrochloride (654 mg) and tert-butyl 1-piperazinecarboxylate (569 mg) were suspended. To the resulting suspension, 1-hydroxybenzotriazole (374 mg) and N-methylmorpholine (336 pl) were added. The resulting mixture was ice cooled, followed by the addition of 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (796 mg). After stirring at room temperature for 7 hours, the solvent was distilled off. The residue was purified by chromatography on a silica gel column (2% methanol-dichloromethane), followed by washing with hexane, whereby the title compound (905 mg, 89%) was obtained.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]=[O:19])=[CH:14][NH:15]2)=[CH:11][CH:10]=1.I[CH:21]([CH3:23])[CH3:22]>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]=[O:19])=[CH:14][N:15]2[CH:21]([CH3:23])[CH3:22])=[CH:11][CH:10]=1
Reactant: CC(C)I
Reactant: COc1ccc2c(C=O)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C=O)cn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
Cesium carbonate (558 mg, 1.71 mmol) was added to a stirred room temperature of 6-methoxy-1H-indole-3-carbaldehyde (100 mg, 0.57 mmol) in DMF (1.0 mL) and the mixture was stirred at room temperature for 15 minutes. Then 2-iodopropane (0.114 mL, 1.14 mmol) was added and the solution was stirred for 80° C. for 2 hours. The solution was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (2×15 mL) and saturated sodium bicarbonate (5 mL), washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title intermediate (108 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:4]=1[C:14]1[NH:15][C:16]2[C:17]([N:22]=1)=[N:18][CH:19]=[CH:20][CH:21]=2.[OH:23]O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:4]=1[C:14]1[NH:15][C:16]2[C:17]([N:22]=1)=[N+:18]([O-:23])[CH:19]=[CH:20][CH:21]=2
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ncccc2[nH]1
Reactant: OO
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2c(ccc[n+]2[O-])[nH]1

Procedure:
3.19 g of 2-(2-methoxy-4-methanesulfonyloxy-phenyl)imidazo[4,5-b]pyridine were dissolved in 25 ml of and then 5 ml of 30% hydrogen peroxide were added dropwise thereto. The mixture was refluxed for one hour and concentrated to about one-tenth of its volume. The residue was poured onto ice and digested until it had crystallized throughout. Yield: 2.1 g (63% of theory). Melting point: 110°-125° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][C@@H:8]2[CH2:12][CH2:13][CH2:14][C@H:7]12)C.[NH3:16]>CO>[O:11]=[C:10]1[N:6]([CH2:5][C:4]([NH2:16])=[O:3])[C@H:7]2[CH2:14][CH2:13][CH2:12][C@H:8]2[CH2:9]1
Reactant: N
Reactant: CCOC(=O)CN1C(=O)C[C@@H]2CCC[C@@H]21
Solvent: CO
Product: NC(=O)CN1C(=O)C[C@@H]2CCC[C@@H]21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of cis-hexahydro-2-oxo-cyclopenta-[b]pyrrole-1(2H)-acetic acid ethyl ester (3.25 g, 0.0154 mole) in methanol (200 ml) is saturated with anhydrous ammonia and stirred at ambient temperature 24 hours. The solution is concentrated at reduced pressure to yield a solid. Recrystallization from acetonitrile yields pure cis-hexahydro-2-oxo-cyclopenta[b]pyrrole-1(2H)-acetamide with a mp 142.5°-143.5° C.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19](=[O:21])[NH2:20])[NH:13]2)C1C=CC=CC=1.C(O)CO.COC.[H][H]>[Pd].CO>[OH:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19](=[O:21])[NH2:20])[NH:13]2
Reactant: [H][H]
Reactant: Cc1cc(OCc2ccccc2)c2cc(C(N)=O)[nH]c2c1
Agent: [Pd]
Agent: COC
Solvent: CO
Solvent: OCCO
Product: Cc1cc(O)c2cc(C(N)=O)[nH]c2c1
Yield: 93 %

Procedure:
8.5 g of the thus obtained 4-benzyloxy-2-carbamoyl-6-methyl indole are hydrogenated in a composition of 100 ml methanol and 50 ml ethylene glycol-dimethyl ether during addition of 1.0 g 10% Pd/C up to the absorption of the theoretical amount of hydrogen. The catalyst is aspirated and the filtrate is evaporated in vacuum. There is obtained 5.4 (~93% of theory) 4-hydroxy-2-carbamoyl-6-methyl indole as a light yellow syrup.
Reaction SMILES: [CH:1]1([N:4]([CH:31]2[CH2:33][CH2:32]2)[C:5]([C:7]2[N:28]([CH2:29][CH3:30])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][CH:22]=[C:23]([C:25]([OH:27])=O)[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:34][N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:36].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>CN(C=O)C>[CH:1]1([N:4]([CH:31]2[CH2:32][CH2:33]2)[C:5]([C:7]2[N:28]([CH2:29][CH3:30])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][CH:22]=[C:23]([C:25]([N:35]([CH3:36])[CH3:34])=[O:27])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C(=O)O)cs3)nc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C(=O)N(C)C)cs3)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
To 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-4-carboxylic acid (example 12A, 44 mg, 0.095 mmol) in DMF (2 ml) was added HATU (108 mg, 0.284 mmol), DIPEA (0.066 mL, 0.378 mmol), and dimethylamine (0.013 mL, 0.189 mmol). The reaction was stirred at rt for 3 h, then the solvent was removed in vacuo. The residue was purified by preparative HPLC to give 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-4-ylamino)-N,N-dimethylthiazole-4-carboxamide (10 mg, 21% yield) as a brown solid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][CH2:4][C:5]([NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])=[O:6].O.Cl>CO>[Cl:3][CH2:4][C:5]([NH:7][C@@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[OH:18])=[O:6]
Reactant: O=C(CCl)NC1CCc2ccccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(CCl)N[C@@H]1CCc2ccccc2[C@H]1O
Yield: 100 %

Procedure:
Sodium borohydride (0.93 g, 24.6 mmol) was added to a solution of 2-chloro-N-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (2.9 μg, 12.2 mmol) in methanol (30 ml). When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by the addition of water and pH was adjusted to 5-6 with 3N aqueous hydrochloric acid. The solution was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 2-chloro-N-((1RS,2RS)-trans-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-acetamide (2.92 g, 12.2 mmol, 100%) as white crystals.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH2:9])[CH2:4][O:3]1.[Cl:11][C:12]1[C:13]([F:31])=[C:14]([F:30])[C:15]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[Cl:29])=[C:16]([CH:20]=1)[C:17](O)=[O:18].OC(CO)CONC(=O)C1C=CC(F)=C(F)C=1NC1C=CC(I)=CC=1F>C(O)C>[Cl:11][C:12]1[C:13]([F:31])=[C:14]([F:30])[C:15]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[Cl:29])=[C:16]([CH:20]=1)[C:17]([NH:9][O:8][CH2:7][C@H:5]([OH:6])[CH2:4][OH:3])=[O:18]
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1Cl
Agent: O=C(NOCC(O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Solvent: CCO
Product: O=C(NOC[C@H](O)CO)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1Cl

Procedure:
Prepared from (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine and 5-chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid by the procedure described for N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide: m.p. 155-156° C.; [α]=−5.1° (c=3.5 mg/mL, ethanol); 1NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1), 8.83 (s, 1H), 7.76 (s, 1H), 7.66 (d, 1H, J=6.8 Hz), 7.47 (d, 1H, J=8.5 Hz), 6.68 (t, 1H, J=6.6 Hz), 4.83 (bs, 1H), 4.60 (bs, 1H), 3.89-3.92 (m, 1H), 3.68-3.76 (m, 2H), 3.30 (2H, partially hidden by HDO); MS (APCI+)=533.0/535.0; Anal.calcd/found for C16H13Cl2F2IN2O4: C, 36.05/36.04; H, 2.46/2.25; N, 5.25/5.10; F, 7.13/7.18; Cl, 13.30, 13.50; I, 23.80, 24.02.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]([NH:19][CH:20]1[CH:27]2[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:30]>C(O)(=O)C.O1CCOCC1>[ClH:30].[CH:21]12[CH2:29][CH:25]3[CH2:24][CH:23]([CH2:28][CH:27]([CH2:26]3)[CH:20]1[NH:19][C:17](=[O:18])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH2:8])[CH2:22]2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: N[C@@H](Cc1ccccc1)C(=O)NC1C2CC3CC(C2)CC1C3

Procedure:
To a stirred solution of 100 g (0.25 mole) of the title product of Example 1 in 827 ml of acetic acid was added 413 ml (2.5 mole) of 6.07N hydrogen chloride in dioxane. After about thirty minutes the solution was concentrated in vacuo to a viscous oil. Trituration with diethyl ether afforded a solid which was collected by filtration, washed with diethyl ether, and air dried. Repetition of the trituration with diethyl ether afforded the title compound as an analytically pure solid. [α]D +47.5°; [α]365 +186.3° (methanol).