Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:30]([O:11][CH:4]1[C:5]2[C:10](=[N:9][CH:8]=[CH:7][N:6]=2)[C:2](=[O:1])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)(=[O:34])[CH:31]([CH3:33])[CH3:32]
Reactant: O=C1c2nccnc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)OC1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 29.8 %

Procedure:
The procedure is as in Example 7, but starting with 5-hydroxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (6.3 g) in methylene chloride (80 cc), triethylamine (5.05 g), isobutyryl chloride (4.25 g) and 4-dimethylaminopyridine (50 mg). The solid obtained is washed with tetrahydrofuran. 6-(7-Chloro-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl isobutyrate (2.3 g), m.p. 260°-262° C., is thereby obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7](=O)[NH:8]2)=[CH:4][C:3]=1[O:13][CH3:14].O>C1COCC1>[CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc2c(c(C)c1C)NC(=O)C2
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(c(C)c1C)NCC2
Temperature: 60 °C
Yield: 50.4 %

Procedure:
To a solution of 6,7-dimethyl-5-methoxy-1,3-dihydro-2H-indole-2-one (17.5 g, 91.5 mmol) in THF (500 mL) was added dropwise 1M-borane THF complex salt (306 mmol) at 0° C., and the mixture was stirred at 60° C. 3 hours. After ice-cooling, the mixture was added dropwise to water (100 mL). THF was distilled off under reduced pressure, concentrated hydrochloric acid (100 mL) was added, and the mixture was stirred under reflux for 2 hours. After neutralizing with 12N sodium hydroxide under ice-cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and purified by small amount silica gel column chromatography (ethyl acetate). The solvent was distilled off under reduced pressure, followed by recrystallization from hexane, to obtain 8.18 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:43](Cl)(=[O:46])[CH2:44][CH3:45]>O1CCCC1>[C:1]([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:43](=[O:46])[CH2:44][CH3:45])=[CH:32][CH:33]=2)[N:15]=1)([CH3:8])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(N)cc2)nc1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc(CN(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)c2ncc(CC)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-[(4-{2-[(4-Aminobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (120 mg) synthesized in Example 439-2 was dissolved in tetrahydrofuran (2.5 mL), triethylamine (40 mL) and propionyl chloride (22 μL) were added thereto, and the mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, the residue was directly purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (100 mg) as a colorless oil.
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]1[CH2:16][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:14](=[O:25])[NH:13]1)=[O:11])C1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>CO.[Pd]>[OH:8][NH:9][C:10]([C@H:12]1[CH2:16][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:14](=[O:25])[NH:13]1)=[O:11]
Reactant: COc1ccc([C@@H]2C[C@H](C(=O)NOCc3ccccc3)NC2=O)cc1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H]2C[C@H](C(=O)NO)NC2=O)cc1
Yield: 96.3 %

Procedure:
A solution of (2R, 4S)-4-(4-methoxyphenyl)-5-oxopyrrolidine-2-carboxylic acid benzyloxyamide (150 mg, 0.44 mmol) in methanol (15 mL) was treated with 5% palladium on barium sulfate (40 mg) and hydrogenated in a Parr™ shaker at 3 atmospheres pressure for 2.5 hours. The catalyst was removed by filtration and the solvent was evaporated to provide a solid. The title compound (106 mg, 96%) was isolated by crystallization from a mixture of ethyl acetate and hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:44][C:45]1[CH:46]=[CH:47][C:48]([F:61])=[C:49]([C:51]2([CH:58]3[CH2:60][CH2:59]3)[NH:56][C:55](=[S:57])[CH2:54][O:53][CH2:52]2)[CH:50]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH:58]1([C:51]2([C:49]3[CH:50]=[C:45]([NH:44][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=4)=[O:10])[CH:46]=[CH:47][C:48]=3[F:61])[CH2:52][O:53][CH2:54][C:55](=[S:57])[NH:56]2)[CH2:60][CH2:59]1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: Nc1ccc(F)c(C2(C3CC3)COCC(=S)N2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)c(C2(C3CC3)COCC(=S)N2)c1)c1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-chloro-pyridine-2-carboxylic acid (0.136 g, 0.86 mmol) in dichloromethane (15 ml), was treated with Huenig's base (0.30 ml, 1.73 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.328 g, 0.86 mmol) at room temperature. After 15 minutes of stirring, (RS)-5-(5-amino-2-fluoro-phenyl)-5-cyclopropyl-morpholine-3-thione (0.177 g, 0.66 mmol) was added and stirring continued for one hour. For the workup, the light yellow solution was poured on an ice-cold saturated solution of sodium hydrogen-carbonate, then extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel using a 9:1-mixture of dichloromethane and ethyl acetate as the eluent. The 5-Chloro-pyridine-2-carboxylic acid [3-((RS)-3-cyclopropyl-5-thioxo-morpholin-3-yl)-4-fluoro-phenyl]-amide was obtained as an off-white solid (0.245 g, 90% of theory). Mass (calculated) C19H17ClFN3O2S [405.879]; (found) [M+H]+=406.
Reaction SMILES: [C:1]1([C:13]([OH:15])=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[C:16]([NH:24][NH2:25])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]1([C:13]2[O:15][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:24][N:25]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C(O)c1cn2c3c(cccc13)CCC2
Reactant: NNC(=O)c1ccccc1
Product: c1ccc(-c2nnc(-c3cn4c5c(cccc35)CCC4)o2)cc1

Procedure:
2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-5-phenyl-1,3,4-oxadiazole was synthesized as outlined in General Procedure J using 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid and benzohydrazide. The crude product was purified using reverse phase chromatography (HPLC, C-18) using trifluoroacetic acid as a modifier to give the desired product 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-5-phenyl-1,3,4-oxadiazole as a yellow solid. Mp=155-157° C.; 400 MHz 1HNMR (DMSO-d6) δ 8.31 (s, 1H), 8.13-8.10 (m, 2H), 7.90 (d, J=8.0 Hz, 1H), 7.65-7.63 (m, 3H), 7.21 (t, J=6.8 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 4.31 (t, J=5.6 Hz, 2H), 2.99 (t, J=6.0 Hz, 2H), 2.21-2.18 (m, 2H); LCMS [M+H]: 302.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25](O)=[O:26])[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:29])([CH3:28])[CH2:22][N:23]3[CH2:24][C:25]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:26])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: C1COCCN1
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Product: CC1(C)CN(CC(=O)N2CCOCC2)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Yield: 86 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and morpholine in 86% yield.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)c3ccc(F)cc3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of tert-butyl 4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylate (8.2 g, 21.24 mmol) in dioxane (50 mL) was added HCl in dioxane (4 M, 20 mL). The reaction mixture was stirred at RT overnight. LCMS showed the reaction was completed. The mixture was concentrated to get the title compound as a light yellow solid (5.5 g, 90%). MS (ES+) C15H15FN4O requires: 286. found: 287 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]=[N+]=[N-])[CH3:2].Cl.[Cl-].C(OC(COCCOCCOCC[NH3+])=O)C>C(O)C.[Pd]>[NH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18]
Reactant: CCOC(=O)COCCOCCOCCN=[N+]=[N-]
Agent: [Pd]
Agent: CCOC(=O)COCCOCCOCC[NH3+]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)COCCOCCOCCN
Temperature: 25 °C

Procedure:
To a solution of {2-[2-(2-Azido-ethoxy)-ethoxy]-ethoxy}-acetic acid ethyl ester (0.30 g, 1.15 mmol, 1 eq) in ethanol (7 mL) was added 1M HCl (2.30 mL, 2.30 mmol, 2 eq) and 30.0 mg of Pd/C (10%). The flask was then evacuated and filled with H2. The mixture was stirred under H2 atmosphere at room temperature until the starting material disappeared on the TLC plate and in mass spectra. The solution was filtered through celite and concentrated in vacuo to give a pale yellow syrup. The obtained 2-[2-(2-ethoxycarbonylmethoxy-ethoxy)-ethoxy]-ethyl-ammonium chloride can be stored at −18° C. for several months. Work-up to get the free amine should only be performed immediately before the next step. To obtain the free amine 350 mg (1.29 mmol) of the respective hydrochloride were dissolved in chloroform. The organic layer was washed with sat. aq K2CO3 and H2O, and the solvent was evaporated in vacuo at room temperature to give a colorless oil. Yield: 210 mg (0.89 mmol, 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>C(O)COCCO.CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Agent: [Pd]
Solvent: CO
Solvent: OCCOCCO
Product: Nc1ccc2ccncc2c1

Procedure:
A mixture of 7-nitro-1,2,3,4-tetrahydro-isoquinoline (1.5 g, 8.38 mmole) and 10% Pd/C (300 mg) in diethylene glycol (5 mL) was reacted in a Smith Synthesizer under microwave radiation at 220° C. for 25 min. The resulting mixture was diluted with MeOH and filtered. The filtrate was concentrated and diluted with CH2Cl2, washed with sat. aq. NH4Cl and dried over Na2SO4. After filtration and concentration, the title compound was isolated through flash chromatography (eluted with CH2Cl2:MeOH 9:1) as an orange solid. MS: (ES+) 145 (M+H). Calc'd. for C9H8N2—144.07.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([Cl:19])[C:17]=1[CH3:18])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([Cl:19])[C:17]=1[CH3:18])[C:12]([Cl:22])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Cl)cc(C(=O)O)cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: Cc1c(Cl)cc(C(=O)Cl)cc1OCc1ccccc1

Procedure:
350 mg 3-benzyloxy-5-chloro-4-methyl-benzoic acid in 10 ml acetonitrile are combined with 0.60 ml thionylchloride and gently refluxed for 15 minutes. Then the reaction mixture is evaporated down and evaporated again with toluene. The acid chloride is further reacted without any further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]3[CH2:16][NH:15][C:14](=O)[CH2:13][O:12]3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]3[O:12][CH2:13][CH2:14][NH:15][CH2:16]3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cc(C3CNC(=O)CO3)ccc21
Solvent: C1CCOC1
Product: Cn1ncc2cc(C3CNCCO3)ccc21
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 6-(1-methyl-1H-indazol-5-yl)morpholin-3-one (17.8 mg, 0.077 mmol) in THF was added BH3 in THF (1M, mmol). The resulting mixture was stirred at room temperature for 10 hr. The crude compound was evaporated to dryness and used for the next step without further purification. LCMS-ESI+: calc'd for C12H15N3O: 218.1 (M+H+); found: 218.2 (M+H+).
Reaction SMILES: O[C:2]1[C:7]2[C:8]([CH3:16])=[N:9][C:10]3[N:11]([N:12]=[C:13]([CH3:15])[CH:14]=3)[C:6]=2[N:5]=[CH:4][C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:2]1[C:7]2[C:8]([CH3:16])=[N:9][C:10]3[N:11]([N:12]=[C:13]([CH3:15])[CH:14]=3)[C:6]=2[N:5]=[CH:4][C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1Cl
Reaction time: 5 h

Procedure:
13.4 g. of 6-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester (0.05 mol.) and 100 ml. of phosphorous oxychloride are refluxed with stirring for 5 hours. The excess of chlorinating agent is distilled off and the dark residue is poured into ice-water. 6-Chloro-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester precipitates, yield 6.4 g. (42%), m.p. 143°-145° (ethyl acetate).
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(COS(C)(=O)=O)C(=O)N(CC(C)C)N=1.[F:26][C:27]1[CH:53]=[CH:52][C:30]([CH2:31][N:32]2[C:37](=[O:38])[C:36]([C:39]([O:41]C)=[O:40])=[CH:35][C:34]([C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([F:51])[CH:44]=3)=[N:33]2)=[CH:29][CH:28]=1>>[C:39]([C:36]1[C:37](=[O:38])[N:32]([CH2:31][C:30]2[CH:29]=[CH:28][C:27]([F:26])=[CH:53][CH:52]=2)[N:33]=[C:34]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([F:51])[CH:44]=2)[CH:35]=1)([OH:41])=[O:40]
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(Cc2ccc(F)cc2)c1=O
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Product: COc1ccc(-c2cc(C(=O)O)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Yield: 97.7 %

Procedure:
Following the procedure of Example 1 (7), 2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as a yellow powder (yield: 97.7%).
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(O)(=O)=O)=[CH:3][CH:2]=1.[CH3:12][C@@:13]12[C@@:21]([OH:26])([C:22]([CH2:24][OH:25])=[O:23])[C@H:20]([OH:27])[CH2:19][C@H:18]1[C@@H:17]1[CH2:28][CH2:29][C:30]3[C@@:36]([CH3:37])([C@H:16]1[C@@H:15]([OH:38])[CH2:14]2)[CH:35]=[CH:34][C:32](=[O:33])[CH:31]=3.C(=O)CCC>C(#N)C>[CH3:6][CH2:1][CH2:2][CH:3]1[O:26][C@:21]2([C:22]([CH2:24][OH:25])=[O:23])[C@@H:20]([CH2:19][C@@H:18]3[C@:13]2([CH3:12])[CH2:14][C@H:15]([OH:38])[C@H:16]2[C@H:17]3[CH2:28][CH2:29][C:30]3[C@:36]2([CH3:37])[CH:35]=[CH:34][C:32](=[O:33])[CH:31]=3)[O:27]1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC=O
Solvent: CC#N
Product: CCCC1O[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)C=C[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)O1

Procedure:
The reaction is carried out in a nitrogen atmosphere. 15,4 g p-toluenesulphonic acid is dissolved into 200 ml acetonitrile. To the solution 50,0 g 16α-hydroxyprednisolone and 17.6 ml butanal are added. The temperature rises to 25° C. After 30 min most of the material is dissolved. Shortly thereafter the product starts to crystallize. After 3 hours the reaction is stopped by the addition of 75 ml aqueous saturated sodium hydrogen carbonate solution, whereupon the product crystallizes. The dried product is dissolved in methylene chloride and methanol and is crystallized by the addition of ligroine (b.p. 40-65) giving crude budesonide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]2[C:3]=1[C:4]([CH:13]=O)=[CH:5][NH:6]2.C1(P(=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC#N>[C:11]([C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]2[C:7]=1[NH:6][CH:5]=[C:4]2/[CH:13]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])#[N:12]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(F)c2c(C=O)c[nH]c12
Solvent: CC#N
Product: CCOC(=O)/C=C/c1c[nH]c2c(C#N)ccc(F)c12
Yield: 74.5 %

Procedure:
To a mixture of 4-fluoro-3-formyl-1H-indole-7-carbonitrile (D42) (9.0 g) in CH3CN (120 mL) was added ethyl (triphenylphosphoranyliden)acetate (25.0 g). The reaction was heated at reflux overnight. After the mixture was filtered, the filtrate was concentrated and purified by preparative TLC to afford ethyl (2E)-3-(7-cyano-4-fluoro-1H-indol-3-yl)-2-propenoate (D43) (9.2 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.[Cl:17][CH2:18][CH2:19]Br>>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[N:9]([CH2:19][CH2:18][Cl:17])[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Reactant: ClCCBr
Product: COc1cc2c(cc1OC)CC(=O)N(CCCl)C=C2

Procedure:
This compound was prepared analogous to Example 1(a) by reacting 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one with 1-chloro-2-bromo-ethane.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:22]1[O:26][C:25](=[O:27])[CH2:24][CH2:23]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:38]([O:45][C:46]1[CH:53]=[CH:52][C:49]([CH2:50]I)=[CH:48][CH:47]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O)(=O)CC>C1COCC1.CN1C(=O)N(C)CCC1.C(OCC)(=O)C.O>[C:1]([NH:8][C@H:9]([C@H:22]1[O:26][C:25](=[O:27])[C@H:24]([CH2:50][C:49]2[CH:52]=[CH:53][C:46]([O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:47][CH:48]=2)[CH2:23]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: ICc1ccc(OCc2ccccc2)cc1
Reactant: COCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CCC(=O)O2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCC(=O)O
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: COCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](Cc3ccc(OCc4ccccc4)cc3)C(=O)O2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under an N2 atmosphere, 3,6 g (9,48 mmol) of 5(S)-[1(S)-(Boc-amino)-2-[p-(2-methoxyethoxy)phenyl]ethyl]dihydrofuran-2-(3H)-one, dissolved in 17.3 ml of THF and 1.9 ml of DMPU, are deprotonated, at -70° C., with 18.58 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and, after 15 min, alkylated with 3.07 g (9.48 mmol) of p-benzyloxybenzyl iodide (Example 1d)) in 6 ml of THF. After 30 min at -75° C., the mixture is protonated with 3.53 ml (47.4 mmol) of propionic acid and 3.53 ml of water and warmed to 0° C. The reaction mixture is diluted with 95 ml of ethyl acetate and the whole is washed with 10% citric acid solution, sat. NaHCO3 solution and saline. The aqueous phases are extracted with 2 portions of ethyl acetate. The organic phases are dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane/ethyl acetate, 1:1) and crystallization from ethyl acetate/hexane yields the pure title compound: TLC Rf (C)=0.38; tRet (II)=18.0 min; FAB-MS (M+H)+ =576.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26])=O>>[F:19][C:16]([F:18])([F:17])[C:13]1[N:11]2[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=4)[C:25]#[N:26])[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Reactant: N#Cc1cccc(C=O)c1
Product: N#Cc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4c3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine with 3-formylbenzonitrile was carried out according to General Synthetic Method 9. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 3-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]piperazin-1-yl]methyl]benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]3[C:19]([N:20]=2)=[C:18]2[N:21]([C:25]4[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=4)[C:22](=[O:24])[NH:23][C:17]2=[CH:16][N:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].I[CH3:35]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]3[C:19]([N:20]=2)=[C:18]2[N:21]([C:25]4[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=4)[C:22](=[O:24])[N:23]([CH3:35])[C:17]2=[CH:16][N:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CI
Reactant: COc1ccc(-c2ccc3ncc4[nH]c(=O)n(-c5cn(C)nc5C)c4c3n2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3ncc4c(c3n2)n(-c2cn(C)nc2C)c(=O)n4C)cc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 8-(3,4-dimethoxy-phenyl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-1,3-dihydro-1,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-one (Example 249, 50 mg, 0.120 mmol) and NaH 55% (8 mg, 0.183 mmol) in DMF (1.2 ml) was stirred at rt for 20 min. Then iodomethane (0.011 ml, 0.180 mmol) was added and the RM was stirred at rt for 2.25 h. After that, the RM was quenched with saturated aqueous NaHCO3, the suspension was then filtered, the cake was washed with water and dried in the vacuum oven to give the title compound as an off-white solid. (HPLC: tR 2.67 min (Method A); M+H=431 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.38 (d, 1H), 8.24 (d, 1H), 7.96 (s, 1H), 7.62-7.54 (m, 1H), 7.42-7.38 (m, 1H), 7.02 (d, 1H), 3.85 (s, 6H), 3.81 (s, 3H), 3.59 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N+:18]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])[CH3:3].[OH-].[Na+].ClCCl>[Pd].C(O)C>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH2:18])=[CH:9][CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)c1ccc(Nc2ccncc2N)cc1
Reaction time: 3.5 h

Procedure:
4-(4-Acetylphenyl)amino-3-nitropyridine hydrochloride (2.0 g, 71.8 mmol) was partitioned between aqueous sodium hydroxide and dichloromethane (3×20 ml). The combined organic phases were washed with water (20 ml) and concentrated under reduced pressure to give a solid. Ethanol (20 ml) was added, and the solution was hydrogenated over 5% palladium on carbon (0.2 g) at 50 p.s.i. (345 kPa) for 3.5 hours. The catalyst was filtered off, and the solvent removed under reduced pressure to give a brown solid, (1.8 g) which was used directly for the next reaction without purification, m.p. 165°-166° C. (after recrystallisation from ethanol).