Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]3[O:39][CH2:38][C:37](=[O:40])[NH:36][C:35]=3[CH:41]=2)O1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:32]=[CH:33][C:34]4[O:39][CH2:38][C:37](=[O:40])[NH:36][C:35]=4[CH:41]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Reactant: CC1(C)OB(c2ccc3c(c2)NC(=O)CO3)OC1(C)C
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4ccc5c(c4)NC(=O)CO5)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one. LCMS (M+H)+=471.0/473.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH:7]([C:11](=[O:13])[CH3:12])[C:8](=[O:10])[CH3:9])[CH3:2].[CH2:15]([O:17][C:18](=[O:26])/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:16].N12CCCN=C1CCCCC2.C(O)(=O)C>N12CCCN=C1CCCCC2.C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]([C:8](=[O:10])[CH3:9])([C:11](=[O:13])[CH3:12])[CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:26])[CH3:2]
Reactant: CCOC(=O)CCC(C(C)=O)C(C)=O
Reactant: CCOC(=O)/C=C/C(=O)OCC
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCC(C(C)=O)(C(C)=O)C(CC(=O)OCC)C(=O)OCC
Reaction time: 24 h
Yield: 53.6 %

Procedure:
25.7 g of 4-acetyl-5-oxohexanoic acid ethyl ester and 0.3 g of 1,8-diazabicyclo-[5.4.0]-undec-7-ene were mixed, and 35 g of fumaric acid diethyl ester was added at room temperature over 40 minutes. After stirring for 24 hours, the amount of 1,8-diazabicyclo-[5.4.0]-undec-7-ene was doubled and stirring continued until conversion was complete. 0.5 g of acetic acid and 50 ml of diethyl ether were added, and the solution was extracted with an aqueous potassium carbonate solution and water. Fractional distillation of the dry organic layer yielded 25.6 g of 4,4-diacetyl-5-(ethoxycarbonyl)-heptanedioic acid diethyl ester (boiling point: 170° C./0.002 mbar; purity: 93%; colorless). Content of the active structural element C3O2: 18%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:19][CH:20]=C)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:26]CC1.S(=O)(O)[O-].[Na+].I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.C(O)(C)(C)C.O.C1COCC1.[Cl-].[Na+].O.O=[Os](=O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:19][CH:20]=[O:26])[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: C=CC[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(F)cc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
tert-Butyl [(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]methylcarbamate (1.8 g, 6.1 mmol) was dissolved in a mixture of acetone (32 mL), tert-butanol (16 mL) and water (8 mL). The solution was stirred at room temperature during addition of OsO4 (0.64 mL of 2.5% in tert-butanol, 0.06 mmol) and 4-methylmorpholine N-oxide (3.2 g, 27 mmol). The mixture was stirred at room temperature for 4 h. A saturated aqueous solution of sodium bisulfite (60 mL) was added and the mixture stirred for 20 min and then diluted with water (100 mL). The solution was extracted twice with CH2Cl2 and the combined organic solutions were washed with brine. The solvent removed by evaporation and the residue (2.4 g) was dissolved in a mixture of THF (28 mL) and water (12 mL) whereupon sodium periodate (1.44 g, 6.7 mmol) was added. The solution was stirred at room temperature for 4.5 h and then diluted with water and brine. The mixture was extracted twice with CH2Cl2 and the combined organic solutions were dried over MgSO4. The solvent was removed by evaporation and there was obtained 1.58 g (87%) of tert-butyl [(2S)-2-(4-fluorophenyl)-4-oxobutyl]methylcarbamate. 1H NMR (500 MHz, CDCl3): 1.4 (s, 9H), 2.6-2.8 (m, 5H), 3.2-3.6 (cm, 3H), 7.0 (m, 2H), 7.1 (b, 2H), 9.7 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:19])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[C:6]=1[Cl:7].[Mg+2].[Cl-].[Cl-].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:19])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15]([OH:18])([C:27]3[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=3)[CH2:14][CH2:13]2)[C:6]=1[Cl:7]
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: Cc1nc(Cl)c(Cl)n1CCCCN1CCC(=O)CC1
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CCN(CCCCn3c(C)nc(Cl)c3Cl)CC2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 1.0 g (3.3 mmol) of 4,5-dichloro-2-methyl-1-(4-(4-oxo-1-piperidyl)butyl]-1H-imidazole in 10 ml of anhydrous tetrahydrofuran is added to a suspension of 1.08 g (11.4 mmol) of MgCl2 in 15 ml of anhydrous THF at −40° C. and under a nitrogen atmosphere. The mixture is stirred for 5 minutes and then, at −40° C., 6.8 ml of a 1.0M solution of 4-methylphenylmagnesium bromide are added. The resulting suspension is stirred for 15 minutes at −40° C. and for 3 hours at room temperature. An aqueous ammonium chloride solution is then added and the tetrahydrofuran is evaporated. The resulting aqueous phase is extracted with chloroform. The chloroform phase is washed with water, dried with anhydrous sodium sulfate and evaporated to dryness, a crude product being obtained which is purified by chromatography on silica gel, giving 1.02 g (2.6 mmol) of 4,5-dichloro-1-{4-[4-hydroxy-4-(4-methylphenyl)-1-piperidyl]butyl}-2-methyl-1H-imidazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[N:14]=[CH:13][O:12][N:11]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][C:10]2[NH:14][CH2:13][O:12][N:11]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(SCc2ncon2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(SCC2=NOCN2)cc1

Procedure:
3-(4-Methylphenylthiomethyl)-1,2,4-oxadiazole (1.65 g, 0.008 mol) was dissolved in methanol (25 ml). AT 0° and with stirring, sodium borohydride (0.91 g, 0.024 mol) was added in portions over 30 min. The mixture was then stirred at 0° overnight and water then added to give a solid which on recrystallisation from from isopropanol gave 4.5-dihydro-3-(4-methylphenylthiomethyl)-1,2,4-oxadiazole, m.p. 85°.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH:27]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:6][CH2:7]1
Reactant: Cc1ccc(C=O)cc1F
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc(C)c(F)c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To 10 mL of a chloroform solution containing 500 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 206 mg of 3-fluoro-4-methylbenzaldehyde, 100 mg of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 526 mg of sodium triacetoxyborohydride was added, and stirred for 15 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.44 g of 1-(2-(4-(3-fluoro-4-methylbenzylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: C([O-])(=[O:3])C.[NH4+].[CH2:6]([O:8][C:9]([C:11]1[C:12](Cl)=[N:13][C:14]2[C:18]([C:19]=1[Cl:20])=[CH:17][S:16][CH:15]=2)=[O:10])[CH3:7]>C(O)(=O)C>[CH2:6]([O:8][C:9]([C:11]1[C:12](=[O:3])[NH:13][C:14]2[C:18]([C:19]=1[Cl:20])=[CH:17][S:16][CH:15]=2)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1c(Cl)nc2cscc2c1Cl
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(Cl)c2cscc2[nH]c1=O
Temperature: 140 °C
Yield: 97 %

Procedure:
Ammonium acetate (0.644 mg, 8.3 mmol) was added to a stirred solution of 5,7-dichloro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester (38) (2.1 g, 7.6 mmol) in glacial acetic acid at room temperature. The solution was heated at 140° C. for 6 h. The hot solution was poured over ice. The solids formed were filtered, washed by water, and dried to yield 1.9 g (97%) of 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester as white solids. MP 157° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.2 Hz, 3H), 4.32 (q, J=7.2 Hz, 2H), 7.06 (d, J=3.6 Hz, 1H), 8.20 (d, J=3.2 Hz, 1H) ppm; MS m/z=258 amu (M++1).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][N:14]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[O:8][CH:9]=1)=O.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:2][CH2:3][C:5]1[N:6]=[C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][N:14]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[O:8][CH:9]=1
Reactant: COC(=O)c1coc(-c2cccc3c2ccn3C(=O)OC(C)(C)C)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)n1ccc2c(-c3nc(CO)co3)cccc21
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-[4-(methoxycarbonyl)-1,3-oxazol-2-yl]-1H-indole-1-carboxylate (512 mg) in DCM (10.2 mL) was added dropwise 1M DIBAL in DCM solution (4.2 mL) at 0° C. and the mixture was stirred at the same temperature for 1.5 hours. 1M DIBAL in DCM solution (0.60 mL) was added dropwise to the mixture. The mixture was stirred at 0° C. for 1.5 hours. To the resulting solution was added dropwise 1M Rochelle salt aqueous solution (25.0 mL) and the suspension was stirred at ambient temperature for overnight. The suspension was diluted with chloroform (50.0 mL) and filtered through a bed of celite. The layers were separated and the organic layer was washed with 0.5 M Rochelle salt solution, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=2:1) to give tert-butyl 4-[4-(hydroxymethyl)-1,3-oxazol-2-yl]-1H-indole-1-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH2:24])[CH:19]=[N:20][C:21]=1[O:22][CH3:23].N1C=CC=CC=1>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:24][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH:19]=[N:20][C:21]=1[O:22][CH3:23]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COc1cc(N)cnc1OC
Solvent: c1ccncc1
Product: COc1cc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cnc1OC
Yield: 38.3 %

Procedure:
The title compound (1.56 g, 4.60 mmol) was prepared from 2-nitrobenzenesulfonyl chloride (2.66 g, 12.0 mmol), 5,6-dimethoxy-3-pyridinamine (2.04 g, 13.2 mmol) and pyridine (2.9 mL, 36.0 mmol) using the methods of (IntA1), step 1.
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])#[N:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:4](=[O:5])[C:3]([C:1]#[N:2])=[CH:17][N:18]([CH3:19])[CH3:20])=[CH:7]1
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)c1c[nH]c2ccccc12
Product: CN(C)C=C(C#N)C(=O)c1c[nH]c2ccccc12

Procedure:
1-indol-3-yl-2-cyano-3-dimethylaminopropen-1-one was prepared from 3-(cyanoacetyl) indole (4.0 g, mmol) and dimethylformamide dimethylacetal (4.1 mL, 23.9 mmol) as a yellow solid (2.4 g), m.p. 187-188°. δH (d6 DMSO) 11.73 (1H, bs), 8.26 (1H, s), 8.12 (1H, dd, J 6.8, 1.3 Hz), 7.98 (1H, s), 7.47-7.44 (1H, m), 7.20-7.09 (2H, m), 3.35 (3H, s) and 3.26 (3H, s).
Reaction SMILES: [CH2:1]([C:4]1[NH:12][C:7]2=[N:8][CH:9]=[CH:10][N:11]=[C:6]2[N:5]=1)[CH2:2][CH3:3].Br[CH2:14][C:15]1[CH:34]=[CH:33][C:18]2/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:20]2=[C:21]([CH:24]=1)[O:22][CH2:23][C:17]1[CH:16]=[C:15]([CH2:14][N:12]3[C:7]4=[N:8][CH:9]=[CH:10][N:11]=[C:6]4[N:5]=[C:4]3[CH2:1][CH2:2][CH3:3])[CH:34]=[CH:33][C:18]=1/[C:19]/2=[C:29](/[CH3:32])\[C:30]#[N:31]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: CCCc1nc2nccnc2[nH]1
Product: CCCc1nc2nccnc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 73.7 %

Procedure:
[step 2] Using 2-propyl-1H-imidazo[4,5-b]pyrazine (68 mg, 0.42 mmol) obtained in step 1 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (153 mg, 0.43 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (136 mg, 74%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Mg]Br.O>C1COCC1>[Cl:1][C:2]1[C:11]([CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH3:16])[OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: COc1ccccc1[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2nc(Cl)c(C(O)c3ccccc3OC)cc2c1
Temperature: -78 °C

Procedure:
2-Chloro-6-methoxyquinoline-3-carbaldehyde (2.66 g, 12 mmol) was dissolved in THF (40 mL) under nitrogen and cooled to −78° C. At this temperature, a solution of 2-methoxyphenyl magnesium bromide (1M, 12.1 mL, 13.32 mmol) in THF was added by drops. Then the mixture was heated slowly to room temperature. The batch was mixed with water and extracted several times with ethyl acetate. The combined organic phases were washed with water until neutral, dried (sodium sulfate) and concentrated. Yield: 3.9 g (11.8 mmol, 99%).
Reaction SMILES: Br[C:2]1[C:11]([CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:10][C:9]2[C:8]([CH3:24])([CH3:23])[CH2:7][CH2:6][C:5]([CH3:26])([CH3:25])[C:4]=2[CH:3]=1.[Cu][C:28]#[N:29]>CN1CCCC1.[OH-].[NH4+]>[C:28]([C:2]1[C:11]([CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])=[CH:10][C:9]2[C:8]([CH3:24])([CH3:23])[CH2:7][CH2:6][C:5]([CH3:26])([CH3:25])[C:4]=2[CH:3]=1)#[N:29]
Reactant: N#C[Cu]
Reactant: CC1(C)CCC(C)(C)c2cc(CCCO[Si](C)(C)C(C)(C)C)c(Br)cc21
Agent: CN1CCCC1
Agent: [NH4+]
Agent: [OH-]
Product: CC1(C)CCC(C)(C)c2cc(CCCO[Si](C)(C)C(C)(C)C)c(C#N)cc21
Temperature: 175 °C
Yield: 60.7 %

Procedure:
To a solution of 9.0 g (20.5 mmol) of 2-bromo-3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene in 70 mL of N-methyl pyrollidine was added 7.36 g (82 mmol) of copper (I) cyanide and the reaction mixture was heated to 175° C. After 16 hours the reaction mixture was cooled to room temperature and diluted with 10% aqueous ammonium hydroxide. The resulting salts were removed by filtration and washed with hot ethyl acetate. The filtrate was extracted with ethyl acetate and the combined organic fractions were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient elution: 3-25% ethyl acetate/hexane) to give 4.8 g (61%) of 2-cyano-3-(3-t-butyldimethylsiloxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:16][C:17]1[CH:22]=[C:21]([C:23]2[O:24][C:25]3[N:26]=[C:27]([S:36][CH3:37])[N:28]=[C:29]([O:32][CH2:33][CH2:34][CH3:35])[C:30]=3[N:31]=2)[CH:20]=[C:19]([CH3:38])[C:18]=1[OH:39].O>CN(C)C=O>[CH3:16][C:17]1[CH:22]=[C:21]([C:23]2[O:24][C:25]3[N:26]=[C:27]([S:36][CH3:37])[N:28]=[C:29]([O:32][CH2:33][CH2:34][CH3:35])[C:30]=3[N:31]=2)[CH:20]=[C:19]([CH3:38])[C:18]=1[O:39][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CCCOc1nc(SC)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1nc(SC)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12

Procedure:
3.20 g of potassium carbonate and then 0.93 ml of tert-butyl bromoacetate were added to a solution of 2.00 g of 2,6-dimethyl-4-(5-methylsulfanyl-7-propoxyoxazolo[5,4-d]pyrimidin-2-yl)phenol in 20 ml of N,N-dimethylformamide. The mixture was reacted at 60° C. for 1 h and then allowed to cool and poured into water. The precipitate obtained was filtered off with suction and dried under reduced pressure. This gave 2.45 g of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8](=[O:10])[NH2:9])[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].[CH:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1.Cl>O.O1CCCC1.C(OCC)(=O)C>[C:8]([CH2:7][CH2:6][C@H:2]([NH:1][C:20]([CH:17]1[CH2:19][CH2:18]1)=[O:21])[C:3]([OH:5])=[O:4])(=[O:10])[NH2:9]
Reactant: O=C(O)C1CC1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)CC[C@H](NC(=O)C1CC1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (S)-2-Amino-4-carbamoyl-butyric acid (100 mg, 0.684 mmol) in water (16 mL) are added Na2CO3 (218 mg, 2.052 mmol) and a solution of cyclopropylcarboxylic acid (62.1 uL, 0.684 mmol) in tetrahydrofuran (8 mL). After stirring at rt during 2 h, ethyl acetate is added and the pH is decreased to 3 by addition of aqueous 1N HCl. The aqueous phase is evaporated, the residue is mixed with methanol and filtrated. The filtrate is evaporated to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.Cl.[CH3:23][O:24][NH2:25].N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[N:25][O:24][CH3:23])[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCC(F)(F)F)c1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CON=C(CCC(F)(F)F)c1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A mixture of 1-(5-(4-chlorophenyl)pyridin-2-yl)-4,4,4-trifluorobutan-1-one (821.7 mg), O-methylhydroxylamine hydrochloride (656 mg) and pyridine (5.239 mL) was stirred at room temperature overnight, and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (842.7 mg).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.O[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][N:5]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(C(F)(F)F)n2)CC1
Yield: 45.3 %

Procedure:
To a tetrahydrofuran solution (1.0 mL) of 3-(trifluoromethyl)-1H-pyrazole (272 mg, 2.00 mmol), tert-butyl 4-hydroxy-piperidine-1-carboxylate (402 mg, 2.00 mmol), and triphenylphosphine (629 mg, 2.40 mmol), diisopropyl azodicarboxylate (1.36 mL, 2.60 mmol, toluene solution) was added at room temperature and the resultant solution was stirred at room temperature for 22 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by preparative liquid chromatography to obtain the title compound (289 mg, yield 45%).
Reaction SMILES: [C:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][S:13][C:12]2=[CH:17][N+:18]([O-:20])=[O:19])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]N1C(=O)CCC1=O>>[C:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][S:13][C:12]2=[C:17]([Br:21])[N+:18]([O-:20])=[O:19])(=[O:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])C=C1SCCCN1S(=O)(=O)Cc1ccccc1
Product: O=[N+]([O-])C(Br)=C1SCCCN1S(=O)(=O)Cc1ccccc1

Procedure:
was prepared, as a yellow solid, m.p.: 143° C. (with decomposition), by treating (5A) with N-bromosuccinimide according to the procedure described in Example 1.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:16]1[C:21](=[O:24])[NH:22][CH3:23])=[O:14])([CH3:11])([CH3:10])[CH3:9].[CH3:25][S:26](Cl)(=[O:28])=[O:27].[Cl-].[Na+]>O1CCCC1>[C:8]([O:12][C:13]([N:15]1[CH2:19][C@H:18]([O:20][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:17][C@H:16]1[C:21](=[O:24])[NH:22][CH3:23])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CNC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
7.11 ml of triethylamine were added, whilst ice-cooling, to a solution of 11.29 g of (2S, 4R)-1-(t-butoxycarbonyl)-2-methylcarbamoyl-4-hydroxypyrrolidine [prepared as described in step (1) above] dissolved in 120 ml of dry tetrahydrofuran, and then 3.93 ml of methanesulfonyl chloride were added to the resulting mixture, and the mixture was stirred at 0° to 5° C. for 30 minutes and then at 15° C. for 30 minutes. It was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, giving 11.58 g of the title compound as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]([CH3:20])([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([NH2:19])=[S:18])[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:22](I)[CH3:23]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]([CH3:9])([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[NH:19])[S:18][CH2:22][CH3:23])[CH:11]=1)[CH3:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(NC(N)=S)c1
Product: CCSC(=N)Nc1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1
Yield: 97 %

Procedure:
Using the compound obtained in Example 3 as a starting material and also using ethyl iodide as a reagent, reaction was performed as in Example 29 to give 110 mg of the titled compound (yield, 97%).
Reaction SMILES: Cl.C[O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].BrC1C=CC(OC)=CC=1C(O)=O>>[NH2:6][C@H:5]([C:4]([OH:14])=[O:3])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: COc1ccc(Br)c(C(=O)O)c1
Agent: Cl
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
N-(2-Bromo-5-methoxybenzoyl)-4-[(2,4-dimethyl-3-pyridinyl)carbonyl]amino]-L-phenylalanine was prepared from 4-[(2,4-dimethyl-3-pyridyl)carbonyl]amino]-L-phenylalanine methyl ester hydrochloride and 2-bromo-5-methoxybenzoic acid using the general method described in example 107. MS (M+H) 526 (1 Br).