Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].Cl.[NH2:16][CH:17]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:18]1=[O:19].C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:10]=[C:8]1[C:7]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=2)[C:11](=[O:12])[N:16]1[CH:17]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:18]1=[O:19]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NC1CCC(=O)NC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)C(=O)N1
Yield: 54.3 %

Procedure:
A mixture of 4-nitrophthalic anhydride (1.7 g, 8.5 mmol), α-aminoglutarimide hydrochloride (1.4 g, 8.5 mmol) and sodium acetate (0.7 g, 8.6 mmol) in glacial acetic acid (30 mL) was heated under reflux for 17 hours. The mixture was concentrated in vacuo and the residue was stirred with methylene chloride (40 mL) and water (30 mL). The aqueous layer was separated, extracted with methylene chloride (2×40 mL). The combined methylene chloride solutions were dried over magnesium sulfate and concentrated in vacuo to give 1.4 g (54%) of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline as a light brown solid. An analytical sample was obtained by recrystallization from methanol: mp 228.5-229.5° C.; 1H NMR (DMSO-d6) δ11.18(s, 1H), 8.69-8.65(d,d J=1.9 and 8.0 Hz, 1H), 8.56(d, J=1.9 Hz, 1H), 8.21(d, H=8.2 Hz, 1H), 5.28(d,d J=5.3 and 12.8 Hz, 1H), 2.93-2.07(m, 4H); 13C NMR (DMSO-d6) δ172.66, 169.47, 165.50, 165.23, 151.69, 135.70, 132.50, 130.05, 124.97, 118.34, 49.46, 30.85, 21.79; Anal. Calcd for C13H9N3O6: C, 51.49; H, 2.99; N, 13.86. Found: C, 51.59; H, 3.07; N, 13.73.
Reaction SMILES: C([Li])CCC.C[Si](C)(C)N[Si](C)(C)C.[C:15]([O:18][CH2:19][CH3:20])(=[O:17])[CH3:16].[CH3:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[O:23].Cl>CCCCCC.O1CCCC1>[OH:23][C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=1)([CH3:21])[CH2:16][C:15]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(C)(O)c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
19.9 ml (31.89 mmol) of a 1.6N solution of n-butyllithium in hexane were added dropwise to a solution of 6.7 ml (31.89 mmol) of hexamethyldisilazane in 50 ml of tetrahydrofuran at 0° C., and the mixture was stirred for 15 min and then cooled to −78° C. 3.12 ml (31.89 mmol) of ethyl acetate were added, the mixture was stirred for 1 h and, after addition of 5.00 g (26.57 mmol) of 4-trifluoromethylacetophenone, dissolved in 20 ml of tetrahydrofuran, stirred at −78° C. for a further hour. 1N hydrochloric acid was added to the reaction solution, and the phases were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8/2) to result in 7.14 g (97% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>ClCCl>[CH:17]1([C:20]([CH:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])=[O:21])[CH2:19][CH2:18]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)C2CC2)C(=O)O1
Temperature: 0 °C
Yield: 82.2 %

Procedure:
A mixture of 2,2-dimethyl-1,3-dioxan-4,6-dione (20.0 g) and pyridine (22,0 g) in dichloromethane (200 ml) was stirred and cooled to 0° C. in an ice bath. A solution of cyclopropylcarbonyl chloride (16.0 g) in dichloromethane (50 ml) was added dropwise with stirring in an atmosphere of nitrogen whilst maintaining the temperature below 3° C. by external cooling. The mixture was stirred at 0° C. for 1 hour and at ambient temperature for 2 hours. The resultant orange suspension was washed with hydrochloric acid (2M, 2×50 ml), water (2×50 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was dissolved in ether (150 ml) and the solution was treated with decolourizing charcoal and filtered. The filtrate was evaporated to dryness to give 5-cyclopropylcarbonyl-2,2-dimethyl-1,3-dioxan-4,6-dione (24.2 g) as a yellow solid mp 44°-46° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([OH:45])=[C:39]([S:41]([OH:44])(=[O:43])=[O:42])[CH:40]=1>C(Cl)Cl.C1COCC1>[OH:45][C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])=[CH:40][C:39]=1[S:41]([OH:44])(=[O:42])=[O:43]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1ccc(O)c(S(=O)(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: N[C@@H](CCC(=O)Nc1ccc(O)c(S(=O)(=O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boc-Glu-OtBu (100 mg, 0.33 mmol) was dissolved in methylene chloride (1 mL) and THF (1 mL). CDI (65 mg, 1.1 mmol) was added thereto and stirred at room temperature for 30 minutes. Then, 5-amino-2-hydroxybenzene sulfonic acid salt (77 mg, 0.33 mmol) was added thereto and stirred overnight at room temperature. After removing a solvent, purification was conducted in accordance with the purification process A. The obtained intermediate was dissolved in 2 mL of TFA and stirred at room temperature for 3 hours, and a solvent was removed therefrom. The obtained product was purified in accordance with the purification process A to obtain a title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.Br[CH2:16][CH:17]([OH:19])[CH3:18].BrC(C)CO.C(N(CC)CC)C>C(#N)C>[OH:19][CH:17]([CH3:18])[CH2:16][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(O)CBr
Agent: CC(Br)CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 70 °C

Procedure:
tert-Butyl piperidin-4-ylcarbamate (2.0 g, 10.0 mmol), 1-bromopropan-2-ol (2.8 g, 20.0 mmol, commercial product which also contained 30% of the regioisomer 2-bromopropan-1-ol), triethylamine (4.2 mL, 30.0 mmol), and acetonitrile (15 mL) were combined in a microwave vial and heated to 70° C. for 4 hours. The reaction mixture was concentrated to dryness. The crude product was partitioned between ethyl acetate/water. The aqueous phase was re-extracted 2× with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. The product was purified by flash chromatography on silica gel eluting with a gradient of 20-30% methanol in dichloromethane to give 1.7 g of the desired product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([S:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=1)=[O:8].[C:32]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([S:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([C:39]3[CH:40]=[CH:41][C:36]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:37][CH:38]=3)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=1)=[O:8]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Sc2cc(C)c(Br)c(C)c2)s1
Product: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Sc2cc(C)c(-c3ccc(C(C)(C)C)cc3)c(C)c2)s1

Procedure:
This compound is made by the general method as exemplified in Preparation 77 using 3-({5-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester chiral Isomer 2 and 4-t-butyl-phenyl boronic acid as the starting materials. MS(ES): 592.2 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[C:2]=S.[Cl:10][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[CH2:23][C:24]([NH:26][NH2:27])=[O:25])[CH2:17][CH2:16]1>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:14][N:15]1[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:28])[CH2:23][C:24]2[O:25][C:2]([NH:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[N:27][N:26]=2)[CH2:19][CH2:20]1
Reactant: S=C=Nc1ccccc1
Reactant: NNC(=O)CC(=O)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: CN(C)C=O
Product: O=C(Cc1nnc(Nc2ccccc2)o1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Isothiocyanato-benzene (0.1 ml) and N-[1-(3,4-dichlorobenzyl)-piperidin-4-yl]-2-hydrazinocarbonyl-acetamide (0.10 g) were stirred together in dimethylformamide (2 ml) at ambient temperature for 2 hours. AM resin (0.162 g, Novabiochem, 2% DVB 1.57 mmol/g) was added and the resulting mixture was stirred at ambient temperature for 16 hours. N-cyclohexylcarbodiimide N-methyl polystyrene HL (0.319 g, Novabiochem, 1.69 mmol/g) was added and the resulting mixture was stirred at 80° C. for 24 hours, then allowed to cool. The reaction mixture was then filtered, washing with dimethylformamide (2×2 ml). The combined filtrates were evaporated and the residue was purified by reverse phase HPLC to give the title compound as a white solid. (0.045 g, m.pt 191-217° C., MS [M+H]+ (APCI+) 460/462).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:5]=1[CH:22]=[O:23]>CN(C)C=O.O>[Cl:3][C:4]1[N:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:7]=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:5]=1[CH2:22][OH:23]
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Yield: 95 %

Procedure:
2.8 g of sodium borohydride are added to a suspension of 46.4 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-carboxaldehyde in 700 ml of dimethylformamide and 100 ml of water, the temperature possibly rising to 35°. After 30 minutes purification is carried out with active charcoal, precipitation is carried out with 700 ml of water and the precipitate is well washed. 5-Chloro-3-p-chlorophenyl-4-hydroxymethyl-1-phenyl-pyrazole is obtained with a 95 % yield; F 152.5°-153.5° (from acetone).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:28])[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:24]([N+:25]([O-])=O)=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl>CCO.[Pd]>[NH2:25][C:24]1[C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)=[O:28])=[CH:18][CH:17]=2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3[N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N)cc2)cc1

Procedure:
The product from Example 2 (720 mg, 2.18 mmol) was hydrogenated (balloon apparatus) as a solution in 30 mL of 1:1 EtOH:CH2Cl2 over 10% Pd/C overnight at room temperature. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.04–8.08 (m, 2H), 7.95 (dd, J=4.4 Hz, 1.7 Hz, 1H), 7.70–7.84 (m, 2H), 7.36–7.40 (m, 2H), 7.19 (dd, j=8.2 Hz, 1.7 Hz, 1H), 7.11 (dd, J=8.1 Hz, 4.4 Hz, 1H), 1.29 (s, 9H); MS (ESI+) m/z 346 (M+H)+.
Reaction SMILES: C(O[C:6](=[O:31])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]2[CH:27]([OH:28])[C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:29][CH3:30])[CH:24]=4)[N:19]=[CH:18][C:17]=3[O:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40](C(O)=O)[CH:41]=[CH:42][C:36]=2[S:35][CH2:34]1>>[CH3:30][O:29][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[O:16][CH2:15][CH:14]([C@H:11]3[CH2:12][CH2:13][C@H:8]([NH:7][C:6]([C:40]4[CH:41]=[CH:42][C:36]5[S:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=5[CH:39]=4)=[O:31])[CH2:9][CH2:10]3)[C:27](=[O:28])[C:26]2=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc3c(c2c1)C(O)C([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Product: COc1ccc2ncc3c(c2c1)C(=O)C([C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CO3

Procedure:
The titled compound is prepared as a white lyophilizated powder following Scheme 6 and in analogy to Example 15 using [trans-4-(4-hydroxy-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:12](=[O:30])[C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)=[CH:15][CH:14]=2)[CH2:3]1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl>[C:31]([NH:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:12](=[O:30])[C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)=[CH:17][CH:18]=2)[CH2:3]1)(=[O:33])[CH3:32]
Reactant: NC1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NC1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To 3-amino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.44 g) are added dichloromethane (5 ml) and acetic anhydride (0.12 g) and the mixture is stirred for 1 hour. The reaction mixture is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane→dichloromethane:methanol=50:1) to give 3-acetylamino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.3 g) as colorless amorphous.
Reaction SMILES: O=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH2:14]>C(O)C.C(O)(=O)C>[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[CH2:6][S:5][CH2:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: Nc1ccc(I)cc1F
Reactant: COC(=O)C1CSCC1=O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C1=C(Nc2ccc(I)cc2F)CSC1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
To a mixture of methyl 4-oxotetrahydrothiophene-3-carboxylate (1.75 g, 11 mmol) (commercially available or prepared using procedures similar to those described in Rossy et. al. J Org. Chem 1980, 45(4), 617-2) in 15 mL of ethanol was added 2-fluoro-4-iodoaniline (2.6 g, 11 mmol) followed by addition of several drops of acetic acid. The mixture was refluxed for 3 hrs. The mixture was cooled to room temperature and the product precipitated. This product was filtered off, washed with ethyl acetate, ether, dried in vacuo to afford the methyl 4-[(2-fluoro-4-iodophenyl)amino]-2,5-dihydrothiophene-3-carboxylate (1.7 g, 42%). 1H NMR (d6-DMSO): 9.80 (s, 1H), 7.71 (d, 1H), 7.49 (dd, 1H), 7.24 (t, 1H), 4.10 (t, 2H), 3.79 (t, 2H), 3.69 (s, 3H); MS (EI) for C12H11FINO2S: 380 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.O.O.O.C([O-])(=O)C.[Na+].[Br:17]Br.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[C:7]([Br:17])=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: Cc1cnc(N)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cnc(N)c(Br)n1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To acetic acid (1500 ml.), 2-amino-5-methylpyrazine (1 mole) and 326.5 g. sodium acetate trihydrate are slowly added 1.1 mole bromine in 180 ml. acetic acid at 2° C. in the absence of light. The mixture is stirred about 15 hours at 20° C., stripped of acetic acid in vacuo, poured into ice, made alkaline with sodium hydroxide, filtered, the residue extracted with ether, the extract stripped and the 2-amino-3-bromo-5-methylpyrazine crystallized from a suitable solvent.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>CO.O>[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[C:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=1
Reactant: O=C1CCNCC1
Reactant: Clc1cccc2cc[nH]c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Clc1cccc2c(C3=CCNCC3)c[nH]c12

Procedure:
Potassium hydroxide (6.89 g, 0.12 mol) was dissolved in methanol (30 mL). To the solution were added 7-chloroindole (4.65 g, 0.031 mol), 4-piperidone hydrochloride hydrate (9.48 g, 0.061 mol). The mixture was stirred at reflux temperature under nitrogen for about a day, and was cooled and diluted with 50 mL of water, added dropwise. The solid was collected, washed with water and vacuum dried. Yield 5.6 g (78%) as a yellow solid. mp 197°-201° C. FDMS m/e=232 (M+) .
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[N:4][C:5](F)=[CH:6][CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[N:4][C:5]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: Fc1ccc(F)c(-c2n[nH]c3ncccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(F)c(-c3n[nH]c4ncccc34)n2)CC1
Temperature: 140 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A mixture of 3-(3,6-difluoropyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.430 mmol) and 1-methylpiperazine (100 uL, 0.901 mmol) and DIPEA (75 uL, 0.434 mmol) in NMP (1 ml) was allowed to stir at 140° C. overnight. The reaction mixture was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (35 mg, 15% Yield).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=C.C(O)(=[O:31])CCCCCCC/C=C\CCCCCCCC>C(O)(=O)C>[C:2]([C:1]([O:11][CH3:12])=[O:10])(=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: C=C(C(=O)OC)c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccccc1
Yield: 88 %

Procedure:
The co-oxidation reaction was carried out in manner as described in Example 16, except that methyl atropate was used in lieu of oleic acid. As a result, acetic acid was obtained at a yield of 95% and methyl benzoylformate was obtained at a yield of 88%.
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].CCOCC>C1COCC1>[CH3:17][N:18]([CH:20]=[C:9]1[CH2:8][C:7](=[O:12])[NH:6][C:5]2[CH:13]=[CH:14][C:2]([I:1])=[CH:3][C:4]=2[C:10]1=[O:11])[CH3:19]
Reactant: O=C1CCC(=O)c2cc(I)ccc2N1
Reactant: COC(OC)N(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)C=C1CC(=O)Nc2ccc(I)cc2C1=O
Temperature: 70 °C

Procedure:
To a solution of 7-iodo-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-a) (1.67 g, 5.54 mmol) in THF (15 mL) was added dimethylformamide dimethylacetal (4.0 mL, 27.7 mmol) and the reaction mixture heated to 70° C. for 1 h. The reaction mixture was cooled to 22° C., treated with Et2O (50 mL), and the resulting precipitate filtered and dried in vacuo to give v-a (1.64 g, 83%) as a brown powder: MS m/z═357 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[S:11][C:12]([CH3:14])=[CH:13][C:3]=12.[NH3:15]>CC(O)C>[NH2:15][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[S:11][C:12]([CH3:14])=[CH:13][C:3]=12
Reactant: Cc1cc2c(Cl)c([N+](=O)[O-])cnc2s1
Reactant: N
Solvent: CC(C)O
Product: Cc1cc2c(N)c([N+](=O)[O-])cnc2s1
Yield: 93 %

Procedure:
To a stirred solution of 1.60 g of 4-chloro-5-nitro-2-methylthieno[2,3-b]pyridine 3 in 50 ml of 2-propanol is introduced excess amount of anhydrous ammonia at 55° C. during 3 hours. The reaction mixture is concentrated in vacuo. The residue is washed with ether and suspended in 7 ml of 1N sodium hydroxide solution with stirring. The resulting crystals are collected by filtration and washed with water and a small amount of ethanol to yield 1.37 g (93%) of Compound 4 as orange crystals melting at 238°-240° C.
Reaction SMILES: C(S1C=C(C)NC1(C1N(C2C=NC=CC=2)C=NC=1)C1C=CC=CC=1)C1C=CC=CC=1.C([N:38]1[C:42]([C:43]2[S:47][C:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[N:45][C:44]=2[CH3:54])=[CH:41][N:40]=[C:39]1[C:55]1[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=1)C1C=CC=CC=1.[H][H]>CO>[CH3:54][C:44]1[N:45]=[C:46]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[S:47][C:43]=1[C:42]1[NH:38][C:39]([C:55]2[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=2)=[N:40][CH:41]=1
Reactant: Cc1nc(-c2ccccc2)sc1-c1cnc(-c2cccnc2)n1Cc1ccccc1
Reactant: [H][H]
Agent: CC1=C[SH](Cc2ccccc2)C(c2ccccc2)(c2cncn2-c2cccnc2)N1
Solvent: CO
Product: Cc1nc(-c2ccccc2)sc1-c1cnc(-c2cccnc2)[nH]1
Reaction time: 70 h

Procedure:
The title compound is prepared from 5-(1-benzyl-2-(pyridin-3-yl-1H-imidazol-5-yl)-4-methyl-2-phenylthiazole (Example 71) in a similar manner as described in Tetrahedron Letters, 2008, 64(26), 6060-6072. In this case, 5-(1-benzyl-2-(pyridin-3-yl)-1H-imidazol-5-yl)-4-methyl-2-phenylthiazole in methanol is debenzylated by hydrogenation under an atmospheric pressure of hydrogen using a balloon with vigorous stirring for 70 h under reflux. The reaction mixture is filtered through Celite, filtered and concentrated under reduced pressure. The residue is chromatographed on silica to give the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[N:8]=[C:9]([CH3:26])[N:10]2[C:15]=1[C:14](=O)[NH:13][C:12]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[N:11]2.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1>N1C=CC=CC=1>[CH3:6][C:7]1[N:8]=[C:9]([CH3:26])[N:10]2[C:15]=1[C:14]([N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)=[N:13][C:12]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[N:11]2
Reactant: c1nc[nH]n1
Reactant: Cc1nc(C)n2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c(=O)c12
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1nc(C)n2nc(-c3ccc([N+](=O)[O-])cc3)nc(-n3cncn3)c12
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
2.53 g (1.54 ml, 16.51 mmol) of phosphoryl chloride are added dropwise under argon to a solution of 1.57 g (5.50 mmol) of 5,7-dimethyl-2-(4-nitrophenyl)imidazo-[5,1-f][1,2,4]triazin-4-(3H)one from example 8A in 10 ml of dry pyridine at 0° C., and the mixture is stirred for 30 min at 20° C. Subsequently, 3.42 g (49.53 mmol) of 1,2,4-triazole are added, and the mixture is stirred overnight at RT. The reaction mixture is concentrated, the residue is treated with aqueous sodium hydrogencarbonate solution, and the mixture is extracted using dichloromethane. The organic phase is dried (sodium sulfate) and the solvent is removed in vacuo. The residue is purified by flash chromatography (eluent: dichloromethane/methanol 100:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH3:23])=[C:14]([CH2:24][OH:25])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28](Br)[CH3:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH3:23])=[C:14]([CH2:24][O:25][CH2:28][CH3:29])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCBr
Reactant: CCc1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [H-]
Agent: [Na+]
Product: CCOCc1cc2c(nc1CC)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to example 1, intermediate d) from (4R,9aR)-6-ethyl-7-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 20, intermediate b), sodium hydride and ethyl bromide.