Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C[O:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:12]2[C:22](=[O:37])[N:23]([CH2:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)[CH2:24][C:11]2=[CH:10]1.C(OCC)C.O>C(Cl)Cl>[OH:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[C:12]2[C:22](=[O:37])[N:23]([CH2:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)[CH2:24][C:11]2=[CH:10]1
Reactant: COCCn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: O=C1c2c(cn(CCO)c(=O)c2N2CCOCC2)CN1CCc1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.4 %

Procedure:
Boron tribromide (0.5 ml, 0.445 mmol) and 5-(2-methoxy-ethyl)-7-morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (50 mg, 0.111 mmol, see Example 18) were dissolved in DCM (30 ml) in a round-bottomed flask. The reaction was stirred at about 0° C. for about 3 h, diethyl ether and afterwards water were added. The obtained crude material was purified by preparative HPLC to give the title compound (20 mg, 0.046 mmol, 41.3% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(=O)O[CH2:17][CH2:16][O:15]1>CN(C=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[O:13][CH2:17][CH2:16][OH:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OCCO1
Reactant: Oc1cccc(-c2ccccc2)c1
Solvent: CN(C)C=O
Product: OCCOc1cccc(-c2ccccc2)c1
Yield: 86 %

Procedure:
The title compound was prepared according to the procedure of Example 114, Step 1 starting from 3-phenylphenol (1.72 g, 10.1 mmol) and ethylene carbonate (0.80 g, 9.1 mmol) and DMF (3 mL). Semi-solid; yield 86%. MS m/z 214 (M)+.
Reaction SMILES: P(Cl)(Cl)Cl.[CH3:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:14]([C:17]1[C:29](=[O:30])[N:25]2[CH2:26][CH2:27][O:28][C:23]3[C:24]2=[C:19]([CH:20]=[CH:21][CH:22]=3)[C:18]=1[OH:31])([OH:16])=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[OH:31][C:18]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:24]=2[N:25]([CH2:26][CH2:27][O:28]3)[C:29](=[O:30])[C:17]=1[C:14](=[O:16])[N:6]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH3:5]
Reactant: CNc1ccc(F)cc1
Reactant: O=C(O)c1c(O)c2cccc3c2n(c1=O)CCO3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: CN(C(=O)c1c(O)c2cccc3c2n(c1=O)CCO3)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
Phosphorus trichloride (0.353 ml) was added dropwise to a water-cooled solution of N-methyl-4-fluoroaniline (3.04 g) in toluene (18 ml). The mixture was stirred at room temperature for 30 minutes. 6-Carboxy-2,3-dihydro-7-hydroxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (2 g) was added thereto, and the resulting mixture was stirred at 100° C. for 2 hours. Water (20 ml) and 4N sodium hydroxide (15 ml) were added thereto. The insoluble material was filtered and the filtrate was separated. The aqueous layer was acidified with hydrochloric acid and extracted with chloroform. The extract was dried over magnesium sulfate, filtered, and concentrated. The residue was recrystallized from a mixture of ethanol and isopropyl ether to give pale brown crystals of 2,3-dihydro-7-hydroxy-6-[N-(4-fluorophenyl)-N-methylcarbamoyl]-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (2.1 g).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([N:17]2[CH2:2][CH2:3][N:4]3[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]3[CH2:9]2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2n(n1)CCN(C1CC1)C2
Temperature: 30 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A mixture of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 101c (4 g, 12.9 mmol) and cyclopropanamine (7.35 g, 129 mmol) in THF (40 mL) was stirred at 30° C. overnight. After the completion of the reaction, the mixture was filtered off and the solid was washed with THF (100 mL). The filtrate was concentrated under reduced pressure to give 135a (2.68 g, 99%). MS: [M+H]+ 209.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]4[N:17]5[N:18]=[C:19]([C:22]6[CH:42]=[CH:41][C:25]([C:26]([NH:28][C@@H:29]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:30]([O:32]C(C)(C)C)=[O:31])=[O:27])=[CH:24][CH:23]=6)[CH:20]=[N:21][C:16]5=[N:15][N:14]=4)[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1>FC(F)(F)C(O)=O.C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]4[N:17]5[N:18]=[C:19]([C:22]6[CH:42]=[CH:41][C:25]([C:26]([NH:28][C@@H:29]([C:37]([CH3:38])([CH3:40])[CH3:39])[C:30]([OH:32])=[O:31])=[O:27])=[CH:24][CH:23]=6)[CH:20]=[N:21][C:16]5=[N:15][N:14]=4)[CH2:11][CH2:12]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncsc6c5)CC4)n3n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl (2S)-2-[(4-{3-[1-(1,3-benzothiazol-6-yl)cyclopropyl][1,2,4]-triazolo[4,3-b][1,2,4]triazin-6-yl}benzoyl)amino]-3,3-dimethylbutanoate (33.0 mg, 0.056 mmol) in trifluoroacetic acid (1.0 mL) and methylene chloride (1.0 mL) was stirred at RT for 2 h. The volatiles were evaporated under reduced pressure to afford the desired product which was directly used in the next step without further purification. Analytical LCMS: (M+H)+=528.0.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][OH:9])=[CH:3][CH:2]=1.[C:10]([CH2:12][C:13](O)=[O:14])#[N:11]>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:10]([CH2:12][C:13]([O:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:14])#[N:11]
Reactant: N#CCC(=O)O
Reactant: OCCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: N#CCC(=O)OCCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a solution of β-phenethyl alcohol (3.6 ml, 30.0 mmol) in DMF (30 ml) was added cyanoacetic acid (2.55 g, 30.0 mmol) in DMF (20 ml) and the whole was cooled to 0° C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimido (4.66 g, 30.0 mmol) in DMF (5 ml) and 4-dimethylaminopyridine (0.37 g, 3.0 mmol) in DMF (10 ml) were then added to the mixture in that order at 0° C. and stirring was continued for 1 hour at this temperature and 18 hours at room temperature. The reaction mixture was concentrated in vacuo and purified by column chromatography to afford phenethyl cyanoacetate (2.49 g, 13.2 mmol).
Reaction SMILES: Cl.[CH:2]([NH:5][OH:6])([CH3:4])[CH3:3].[OH-].[Na+].[Br:9][CH:10]([CH2:14][CH2:15]Br)[C:11](Cl)=[O:12]>C(Cl)Cl.O>[Br:9][CH:10]1[CH2:14][CH2:15][O:6][N:5]([CH:2]([CH3:4])[CH3:3])[C:11]1=[O:12]
Reactant: CC(C)NO
Reactant: O=C(Cl)C(Br)CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)N1OCCC(Br)C1=O
Temperature: 5 °C
Yield: 10.5 %

Procedure:
To a stirred mixture of 5.3 g (47 mmol) of N-isopropylhydroxylamine hydrochloride in 100 ml of methylene chloride cooled to 5° C. was added 3.8 g (47 mmol) of 50% sodium hydroxide solution in 20 ml of water. To this mixture was added with stirring 12.4 g (47 mmol) of 2,4-dibromobutyrylchloride and twenty minutes later an additional 7.6 g (94 mmol) of 50% sodium hydroxide solution was added. After twenty hours the organic phase was separated, dried over anhydrous magnesium sulfate and concentrated to an oil. This oil was chromatographed on silica gel with 40% ethyl acetate-hexane to afford 1.1 g of oily dihydro-4-bromo-2-isopropyl-2H-1,2-oxazin-3(4H)-one.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:28][C:29]3[CH:38]=[C:37]([CH3:39])[C:32]4[NH:33][C:34](=[O:36])[O:35][C:31]=4[CH:30]=3)[C:19](=[O:27])[N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[NH:3]1.[NH:44]1[CH2:49][CH2:48][S:47](=[O:50])[CH2:46][CH2:45]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:28][C:29]3[CH:38]=[C:37]([CH3:39])[C:32]4[NH:33][C:34](=[O:36])[O:35][C:31]=4[CH:30]=3)[C:19](=[O:27])[N:20]3[CH2:21][CH2:22][CH:23]([N:44]4[CH2:49][CH2:48][S:47](=[O:50])[CH2:46][CH2:45]4)[CH2:24][CH2:25]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[NH:3]1
Reactant: O=S1CCNCC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(=O)CC2)cc2oc(=O)[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCS(=O)CC3)CC2)cc2oc(=O)[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 80 mg (0.14 mmol) (R)-1-(4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl)-2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 32 mg (0.27 mmol) thiomorpholin-1-oxide in 5 mL DCM was stirred overnight at RT. After the solution had been cooled to 0° C., 15 μL (0.27 mmol) of AcOH and 50 mg (0.33 mmol) of sodium triacetoxyborohydride were added and the reaction mixture was stirred for 4 h at this temperature. It was evaporated down i.vac., the residue was taken up in 1 mL MeOH, filtered to remove any insoluble constituents and the crude product was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].Br[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[N:12]([CH2:15][CH2:16][O:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: CCc1nc2ccccc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1nc2ccccc2c(=O)n1CCOc1ccc(C=O)cc1
Yield: 27 %

Procedure:
The title compound (5.0 g, 27%) was prepared from 2-ethyl-4-oxo-3,4-dihydroquinazoline (9.2 g, 57.5 mmol) and 4-(2-bromoethoxy)benzaldehyde (14.5 g, 69.0 mmol) in the presence of K2CO3 (14.6 g, 115.0 mmol) as base, by a similar procedure to that described in preparation 1.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])=[CH:11][CH:10]=2)O1.[F:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33](I)[C:28]=1[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1COCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:20]([O:19][C:18]([NH:17][C@@H:15]([C:12]1[CH:11]=[CH:10][C:9]([C:33]2[C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([F:26])[CH:36]=[CH:35][CH:34]=2)=[CH:14][CH:13]=1)[CH3:16])=[O:24])([CH3:21])([CH3:22])[CH3:23]
Reactant: COC(=O)c1c(F)cccc1I
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(F)cccc1-c1ccc([C@@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 18.9 %

Procedure:
To a stirred solution of tert-butyl (1R)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethylcarbamate (1.0 g, 2.9 mmol) and methyl 2-fluoro-6-iodobenzoate (1.2 g, 4.32 mmol) in 25 mL of a 5:1 THF:water mixture was added potassium carbonate (1.2 g, 8.64 mmol), tri-o-tolylphosphine (350 mg, 1.15 mmol) and lastly palladium acetate (65 mg, 0.29 mmol). The reaction vessel was then sealed and placed into a 90° C. oil bath for overnight stirring and heating. After about 18 hours the reaction mixture was cooled to ambient temperature and then diluted with EtOAc. The organics were washed with brine (×4), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give an oil. This oil was subject to silica gel chromatography eluting with 10-60% EtOAc in hexanes to provide methyl 4′-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}-3-fluoro-1,1′-biphenyl-2-carboxylate (205 mg), found to be pure by LC/MS and proton NMR.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][CH:4]([CH2:7][CH3:8])[C:3]=1[C:9]([O:11]C)=O.C([O-])=O.[NH4+].[CH:17]([NH2:19])=O>>[CH2:7]([CH:4]1[C:3]2[C:9]([OH:11])=[N:19][CH:17]=[N:1][C:2]=2[CH2:6][CH2:5]1)[CH3:8]
Reactant: CCC1CCC(N)=C1C(=O)OC
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Product: CCC1CCc2ncnc(O)c21
Temperature: 150 °C
Yield: 71.9 %

Procedure:
Methyl 2-amino-5-ethylcyclopent-1-enecarboxylate (1.62 g, 9.57 mmol) was combined with ammonium formate (3.02 g, 47.9 mmol) and formamide (3.80 mL, 95.7 mmol), and the reaction mixture was heated to 150° C. for 16 hours. Conversion was confirmed by LCMS. The reaction was cooled to room temperature and partitioned between a 5:1 DCM/i-PrOH solution and water. The aqueous layer was extracted multiple times with the same DCM/i-PrOH solution. The combined extracts were concentrated to dryness and partitioned between DCM and brine. The organic portion was concentrated to provide 5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (1.13 g, 6.88 mmol, 71.9% yield) as an oil, which was taken to the next step without purification. MS (APCI+) [M+H]: 165.0.
Reaction SMILES: [CH2:1]([N:3]([CH2:46][CH3:47])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([C:14]1[C@H:15]([CH3:45])[C@@H:16]2[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=[O:5])[CH3:2].N1(C(C2C=CC=CC=2S)=O)CCCC[CH2:50][CH2:49]1>>[N:3]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:14]2[C@H:15]([CH3:45])[C@@H:16]3[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]3[C:18]=2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])=[O:5])[CH2:46][CH2:47][CH2:50][CH2:49][CH2:2][CH2:1]1
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Reactant: O=C(c1ccccc1S)N1CCCCCC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccccc3C(=O)N3CCCCCC3)[C@H](C)[C@H]12
Yield: 95 %

Procedure:
Following a procedure similar to that described in Example 18, but using 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 39) and 2-(1-perhydroazepinylcarbonyl) phenylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 95%. This compound was found to be the same as the compound prepared as described in Example 36 and had the same physicochemical properties.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7])[NH2:2].CN(C)[CH:13]=[C:14]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[C:15](OCC)=[O:16]>C(O)(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][N:10]=[C:3]([N:1]2[C:15](=[O:16])[C:14]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:13][NH:2]2)[CH:4]=1)#[N:7]
Reactant: CCOC(=O)C(=CN(C)C)c1cccnc1
Reactant: N#Cc1ccnc(NN)c1
Solvent: CC(=O)O
Product: N#Cc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Reaction time: 0.5 h

Procedure:
545 mg (4.06 mmol) of the compound from Example 1A and 1.07 g (4.88 mmol) of the compound from Example 2A in 15 ml of glacial acetic acid are stirred at RT for 2 h. The mixture is concentrated and the residue is taken up in 300 ml of ethyl acetate and washed repeatedly with saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is taken up in 30 ml of ethanol, 1.33 g (4.88 mmol) of a 25% strength solution of sodium ethoxide in ethanol are added at RT and the mixture is stirred for 30 min. The pH is adjusted to 5 by addition of 1 M hydrochloric acid, and the solid formed is filtered off with suction, washed with diethyl ether and dried under high vacuum.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13](=O)[CH:12]([O:17][CH3:18])[CH2:11]2)=[CH:4][CH:3]=1.C([NH2:28])C1C=CC=CC=1.S1C=CC=C1>C1COCC1.[Pd]>[F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH2:28])[CH:12]([O:17][CH3:18])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: COC1CN(CCCOc2ccc(F)cc2)CCC1=O
Reactant: NCc1ccccc1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: C1CCOC1
Product: COC1CN(CCCOc2ccc(F)cc2)CCC1N

Procedure:
A mixture of 1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinone (140 mg, intermediate 1), benzylamine (61 mg), Pd 10% on charcoal (100 mg) and a 0.02% solution of thiophene in THF was reacted under hydrogen gas for 3 hours at 50° C. The catalyst was filtered off and fresh palladium 10% on charcoal (100 mg) was added. Debenzylation of the formed intermediate took place under hydrogen atmosphere for 18 hours at 50° C. The reaction mixture was filtered and evaporated under a gentle stream of nitrogen to yield 1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine (compound I-1) having a cis/trans ratio of about 93/7.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]([C:17]3([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18]3)[NH:10][CH2:9][CH2:8][C:7]2=1.C(O)[C:27]1[CH:32]=[CH:31]C=[CH:29][CH:28]=1>>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]([C:17]3([C:21]([O:23][CH2:24][C:25]4[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=4)=[O:22])[CH2:20][CH2:19][CH2:18]3)[NH:10][CH2:9][CH2:8][C:7]2=1
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(OC)cc32)CCC1
Reactant: OCc1ccccc1
Agent: Cl
Product: COc1ccc2[nH]c3c(c2c1)CCNC3C1(C(=O)OCc2ccccc2)CCC1

Procedure:
The procedure is as in Example 23, using as substrate the product of Example 7 and as reagent benzyl alcohol.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[NH:43]1[CH2:46][CH:45]([C:47]#[N:48])[CH2:44]1>>[CH3:42][C@@H:37]1[CH2:36][N:35]([C:21]2[C:20]([CH2:19][OH:18])=[CH:33][C:24]3[C:25]([C:28]([N:43]4[CH2:46][CH:45]([C:47]#[N:48])[CH2:44]4)=[O:29])=[N:26][O:27][C:23]=3[C:22]=2[F:34])[CH2:40][C@H:39]([CH3:41])[O:38]1
Reactant: N#CC1CNC1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: C[C@@H]1CN(c2c(CO)cc3c(C(=O)N4CC(C#N)C4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and azetidine-3-carbonitrile
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CN1CCCC1=O.O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: COc1ccnc(Cl)c1
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccnc(N2CCNCC2)c1
Yield: 16.2 %

Procedure:
46 mg 2-chloro-4-methoxy-pyridine and 277 mg piperazine in 2 mL n-methyl-2-pyrrolidinone were stirred 45 min at 140° C. and 30 min at 200° C. under microwave conditions. The reaction was diluted with water and purified by HPLC to give 10 mg desired product.
Reaction SMILES: [CH2:1]([C@H:8]([NH:29][C:30](=[O:70])[C@@H:31]([N:36]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][O:49]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:43]=2)[C:37]1=[O:69])[C@@H:32]([CH3:35])[CH2:33][CH3:34])[C@H:9]([OH:28])[CH2:10][N:11]([S:16]([C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[N:26]/[OH:27])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.Cl>CO>[CH2:1]([C@H:8]([NH:29][C:30](=[O:70])[C@@H:31]([N:36]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][OH:49])[N:43]=2)[C:37]1=[O:69])[C@@H:32]([CH3:35])[CH2:33][CH3:34])[C@H:9]([OH:28])[CH2:10][N:11]([S:16]([C:19]1[CH:20]=[CH:21][C:22](/[CH:25]=[N:26]/[OH:27])=[CH:23][CH:24]=1)(=[O:18])=[O:17])[CH2:12][CH:13]([CH3:14])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN(CC(C)C)S(=O)(=O)c1ccc(/C=N/O)cc1)N1CCN(Cc2cccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN(CC(C)C)S(=O)(=O)c1ccc(/C=N/O)cc1)N1CCN(Cc2cccc(CO)n2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
A solution of the product of Example 286D (0.166 g) in methanol:dichloromethane (2 mL, 3:2) at 0° C. was treated with concentrated HCl (1 mL). The mixture was stirred at 25° C. for 30 min and partitioned into sat NaHCO3 and dichloromethane. The organic layer was separated and dried over NaSO4, filtered, and the solvents were evaporated. The residue was purified using 4% methanol/chloroform to give 69 mg (56%) of the title compound.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:18][CH2:17][CH2:16][C@H:2]1[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:4].O.O.C(O)(=O)C(O)=O>CO.[Pd]>[NH:1]1[CH2:18][CH2:17][CH2:16][C@H:2]1[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:4]
Reactant: CCCCCCCCCCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: CCCCCCCCCCNC(=O)[C@@H]1CCCN1
Yield: 118.8 %

Procedure:
5.0 g (12.9 mmoles) of Z-Pro-NH-C10H21 and 2.02 g (16 mmoles) of oxalic acid dihydrate are dissolved in 100 ml of methanol, 0.8 g of a 10% palladium-on-carbon catalyst are added, and hydrogen is bubbled through the mixture for 2 hours. The reaction mixture is heated, the catalyst is filtered off, and the filtrate is evaporated. The crystalline residue is triturated with ether and then filtered off to obtain 3.9 g (88%) of H-Pro-NH-C10H21.(COOH)2 ; m.p.: 152°-154° C., Rf3 =0.16.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[O:6][C@H:5]([C@@:7]([OH:31])([CH:29]=C)[CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:4]([CH:32]=C)[O:3]1>C(Cl)Cl>[CH3:34][C:2]1([CH3:1])[O:3][C@H:4]2[CH:32]=[CH:29][C@:7]([CH2:8][O:9][C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([OH:31])[C@H:5]2[O:6]1
Reactant: C=C[C@@H]1OC(C)(C)O[C@@H]1[C@@](O)(C=C)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC1(C)O[C@H]2C=C[C@@](O)(COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
To a stirred solution of 5 (14.55 g, 31.86 mmol) in methylene chloride (100 ml) was added tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene]-[benzylidine]ruthenium (VI) dichloride (270 mg, 0.32 mmol), and the reaction mixture was stirred at room temperature for 2 days. The volatiles were removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give 6 (12.83 g, 94%) as a white semi-solid; 1H NMR (400 MHz, CDCl3) δ 7.47-7.21 (m, 15H), 5.93 (dd, J=5.6, 1.6 Hz, 1H), 5.73 (d, J=5.6 Hz, 1H), 5.31 (d, J=5.6 Hz, 1H), 4.56 (d, J=5.6 Hz, 1H), 3.59 (d, J=9.2 Hz, 1H), 3.15 (d, J=9.2 Hz, 1H), 3.02 (s, 1H), 1.32 (s, 3H), 1.21 (s, 3H).