Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:20]C(=O)OC(C)(C)C)[C@H:9]([OH:19])[CH2:10][NH:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[NH2:20][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]([OH:19])[CH2:10][NH:11][O:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCCC1
Yield: 96.8 %

Procedure:
A combination of trifluoroacetic acid (20 mL) and tert-butyl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (2.00 g, 5.29 mmol) was stirred under Argon at ambient temperature for approximately 30 minutes. The reaction was evaporated in vacuo and the residue was partitioned between dichloromethane and aqueous sodium hydroxide (1N). After separating the layers, the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a solid which was dried under high vacuum to provide (2R,3S)-3-amino-1-[(cyclohexyloxy)amino]-4-phenyl-2-butanol (1.426 g, 97%). H1-NMR (chloroform-D3): 1.24 (m, 5H), 1.58 (m, 4H), 1.73 (m, 2H), 1.95 (m, 2H), 2.51 (m, 1H), 2.97 (m, 2H), 3.16 (m, 2H), 3.33 (m, 1H), 3.57 (m, 1H), 3.77 (m, 1H), 7.26 (m, 5H). MS(ESI): 279(M+H).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([SH:17])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br>C(O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][S:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1
Reactant: Sc1nnc(-c2ccccc2)c2ccccc12
Reactant: Clc1cccc(CBr)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Clc1cccc(CSc2nnc(-c3ccccc3)c3ccccc23)c1
Reaction time: 0.17 h
Yield: 11 %

Procedure:
To a suspension of 4-phenylphthalazine-1-thiol (1 mmol; from Example 1B) in ethanol (20 ml) is added aqueous KOH (1 molar;1 ml), and the mixture is stirred for 10 minutes to give a clear solution. 3-Chlorobenzylbromide (0.13 ml, 1 mmol) is added at room temperature, and the solution is stirred overnight. Work-up yields the title compound as a white solid (40 mg).
Reaction SMILES: CON(C)[C:4]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5].[CH3:20][Mg+].[Br-].O>C1COCC1>[C:4]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:7]1)(=[O:5])[CH3:20]
Reactant: C[Mg+]
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: -78 °C
Reaction time: 3 h
Yield: 872.3 %

Procedure:
To a solution of tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (11 g, 4.0 mmol) in THF (40 mL) was added CH3MgBr (4 mL, 12 mmol) at −78° C. The mixture was stirred at −78° C. for 3 hr. Water (20 mL) was added and the mixture was extracted by ethyl acetate (80 mL*3). The organic layer was washed with brine and dried over sodium sulfate. The crude product was concentrated and purified by column chromatography on silica gel (eluted: petroleum ether/ethyl acetate=10/1) to give tert-butyl 2-acetylmorpholine-4-carboxylate (8 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][CH2:28][O:29]C4CCCCO4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][CH2:28][OH:29])[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: OCCn1cc(-c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-fluoro-6-(6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline (Stage 254.1, 72 mg, 0.152 mmol) in DCM (2 mL) stirred at rt was added a solution of HCl in dioxane (4 M, 0.381 mL). The RM was stirred 1 h at rt, during this time the product precipitated as an oil. The supernatant DCM was discarded, the residue was taken in EtOAc and washed with a solution of 10% NaHCO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, DCM/DCM/MeOH 19:1=100:0->0:100) to afford the title compound as a off white powder (tR 3.20 min (conditions 3), MH+=389.1, 1H-NMR in DMSO-d6: 8.82 (d, 1H), 8.42 (s, 1H); 8.33 (d, 2H); 8.12-8.05 (m, 2H); 8.02 (d, 1H); 7.76 (d, 1H); 7.58 (s, 1H); 7.52 (d, 1H); 7.49-7.43 (m, 1H); 4.97 (t, 1H); 4.54 (s, 2H); 4.18 (t, 2H); 3.72 (q, 2H)).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].Cl[C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH2:6]([C@H:2]1[C:3](=[O:5])[O:4][C:9](=[O:11])[NH:1]1)[CH3:7]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@H](N)C(=O)O
Solvent: C1CCOC1
Product: CC[C@@H]1NC(=O)OC1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 511 %

Procedure:
To a suspension of (2S)-2-aminobutanoic acid (10 g) and activated carbon (116 mg) in tetrahydrofuran (50 mL) was added dropwise a solution of triphosgene (10.07 g) in tetrahydrofuran (50 mL) at room temperature, and the mixture was stirred at 50° C. for 2 hr. The same experimental process was performed twice, in each of which insoluble materials were filtered off with celite, and the filtrates were combined and concentrated under reduced pressure. The residue was washed with hexane to give the title compound as a solid (yield: 22.39 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:10](=[S:11])[N:12]=[N:13][NH:14]2)=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(N=C=S)cc1
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2[nH]nnc2=S)cc1
Yield: 59.5 %

Procedure:
4-Methoxyphenylisothiocyanate (2 g) and 1 g of sodium azide in 50 mL of ethanol is refluxed for 5 hours, cooled and concentrated as described (Canadian Journal of Chemistry 1959, p 101). The precipitate is collected by vacuum filtration and dried to give 1.5 g of 1-(4-methoxyphenyl)tetrazol-5-thione as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]2[N:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][CH2:51][C@H:52]([OH:55])[CH2:53][OH:54].C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:50][CH2:51][C@H:52]([OH:55])[CH2:53][OH:54])=[O:24])=[C:16]2[N:15]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: NC[C@H](O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@H](O)CO)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 42.3 %

Procedure:
A mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation C, 400 mg, 1.16 mmol), HATU (486 mg, 1.28 mmol), and (S)-3-aminopropane-1,2-diol (318 mg, 3.49 mmol) in dry DMF (3.0 mL) was stirred for 1-2 minutes at ambient temperature. Diisopropylethylamine (DIEA) (0.62 mL, 3.49 mmol) was added and the reaction was flushed with N2, sealed and stirred at ambient temperature for 18 hours. The reaction mixture was added to H2O (15 mL), mixed and extracted with EtOAc. The combined EtOAc extracts were washed with H2O, saturated NaHCO3 and dried over MgSO4/activated carbon. The solution was eluted through a SiO2 column eluting first with EtOAc then 10% MeOH/EtOAc. The 10% MeOH/EtOAc pool was concentrated and the residual, colorless glass was dissolved in a minimal amount of CH2Cl2. Hexane was added and the resulting white suspension was sonicated and concentrated to give the title product as a white solid (205 mg, 42%). MS (apci) m/z=418.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([SH:13])[CH2:11][SH:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[S:13][CH2:10][CH2:11][S:12]1
Reactant: O=Cc1ccccc1Cl
Reactant: SCCS
Product: Clc1ccccc1C1SCCS1

Procedure:
Following the general procedure described in Example 1, 55.3 gm (0.393 moles) of 2-chlorobenzaldehyde and 37.21 gm (0.395 moles) of 1,2-ethanedithiol gave, after distillation, 65.65 gm (0.303 moles) of a clear, colorless liquid, b.p. 121°-125° C. (0.03 mm/Hg). Elemental analysis for C9H9ClS2 :
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]=[N:7][NH:8][C:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][N:10]=2)=[CH:4][CH:3]=1>C(O)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[N:10]=[C:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][OH:11])[NH:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C=NNC2=NOCc3ccccc32)cc1
Solvent: CCO
Product: OCc1ccccc1-c1nc(-c2ccc(Cl)cc2)n[nH]1
Yield: 57 %

Procedure:
The compound of the title is prepared following the procedure described in the foregoing example starting from 4-[2-(4-chlorobenzyliden)hydrazino]-1H-2,3-benzoxazine. Yield 57%. M.p. 252°-54° C. (from ethanol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([F:14])([F:13])[CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]([F:14])([F:13])[CH2:6][N:7]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOC(=O)C(F)(F)CNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 103.8 %

Procedure:
A solution of 3.6 g (0.016 mole) of 3-cyclopentylamino-2,2-difluoro-propanoic acid ethyl ester in 3 mL of ethyl acetate was added over 5 minutes to a cooled (0 degrees) mixture of 3.2 g (0.016 mole) of 2,4-dichloro-5-nitro-pyrimidine, 5.47 g (0.064 mole) of sodium bicarbonate and 36 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure to give 6.29 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-difluoro-propanoic acid ethyl ester (IV-20) as a yellow thick oil, which contained a small portion of a regioisomer. This material was used directly in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1.[ClH:22]>>[ClH:22].[NH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([CH2:8][S:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CSc2ccccn2)C1
Agent: Cl
Product: c1ccc(SCC2CCCNC2)nc1

Procedure:
tert-Butyl 3-[(2-pyridinylsulfanyl)methyl]-1-piperidinecarboxylate (Preparation 51, 1.0 g, 3.2 mmol) in hydrogen chloride (4 M solution in dioxane, 8.1 ml) was stirred under nitrogen at room temperature. After 25 min a white solid precipitated out of solution. Diethyl ether was added and the reaction mixture was filtered and the solid washed with diethyl ether. The title compound was obtained as a solid (0.81 g, 100%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:44])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])[CH:12]=1.Cl>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:44])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:43])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:39])([C:35]([F:36])([F:37])[F:38])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=1)[CH2:41][CH3:42])[CH3:21]
Reactant: CCC(CC)(c1ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.10 mL) was added to a solution of [5-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-butyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 108-(3); 30 mg, 0.050 mmol) in methanol (0.7 mL) at room temperature, and the mixture was stirred at room temperature for four hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (28 mg, 96%).
Reaction SMILES: [C:1](=[S:16])(OC1C=CC=CN=1)OC1C=CC=CN=1.[NH:17]1[C:21]2=[N:22][CH:23]=[CH:24][C:25]([CH2:26][NH2:27])=[C:20]2[CH:19]=[CH:18]1>O1CCCC1>[N:27]([CH2:26][C:25]1[CH:24]=[CH:23][N:22]=[C:21]2[NH:17][CH:18]=[CH:19][C:20]=12)=[C:1]=[S:16]
Reactant: NCc1ccnc2[nH]ccc12
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: C1CCOC1
Product: S=C=NCc1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
O,O-di-2-pyridinyl thiocarbonate (1136 mg, 4.89 mmol) was added to a solution of (1H-pyrrolo[2,3-b]pyridin-4-yl)methanamine (720 mg, 4.89 mmol) in tetrahydrofuran (THF) (60 mL). Let stir at RT for 30 minutes and concentrated. The residue was purified via Biotage (0% to 50% gradient EtOAc:Hex; 25 g-HP-silica gel column) to obtain 690 mg of 4-(isothiocyanatomethyl)-1H-pyrrolo[2,3-b]pyridine. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.26 (s, 2H) 6.57 (dd, J=3.54, 1.77 Hz, 1H) 7.07 (d, J=4.80 Hz, 1H) 7.50-7.63 (m, 1H) 8.26 (d, J=4.80 Hz, 1H) 11.86 (br. s., 1H); MS[MH]+=190.0
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:17][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(SCCCOCc3ccccc3)nc2)C(OCc2ccc3ccccc3c2)C1
Agent: [Br-]
Agent: [Zn+2]
Product: c1ccc(COCCCSc2ncc(C3CCNCC3OCc3ccc4ccccc4c3)cn2)cc1

Procedure:
In an analogous manner to that described in Example 125(h), from tert-butyl (3RS,4RS)-4-[2-(3-benzyloxy-propylsulphanyl)-pyrimidin-5-yl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate by cleavage of the BOC group by means of anhydrous zinc bromide there was obtained 2-(3-benzyloxy-propylsulphanyl)-5-[(3RS,4RS)-3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-pyrimidine in in the form of an amorphous, colourless solid; MS: 500 (M+H)+.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].C([Li])CCC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[O:23])=[CH:17][CH:16]=1.C(O)(=O)C>O1CCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[O:23][CH:2]=[N:1][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:17][CH:16]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1ncoc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.5 %

Procedure:
To a solution of Ethyl isocyanoacetate (1.00 mL, 9.15 mmol) in Tetrahydrofuran (43 mL) at −78° C. was added 2.5 M n-Butyllithium (9.15 mmol, 9.15 mmol) in hexanes under argon. The mixture was stirred for 20 min. 4-Chlorophenylacetyl chloride (0.753 g, 3.98 mmol) in Tetrahydrofuran (11 mL, 130 mmol) was added at the same temperature. After 1 h, the temperature was raised to rt and then quenched by acetic acid (0.38 g, 6.3 mmol). The mixture was washed with saturated sodium bicarbonate and brine. The organic layer was collected and dried over sodium sulfate. After evaporation, the mixture was purified by chromatography to afford ethyl 5-(4-chlorobenzyl)-1,3-oxazole-4-carboxylate (0.83 g, 78%). LCMS: (FA) ES+ 266.3.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=O.ClC(OCC(C)C)=O.Cl.[CH3:24][NH:25][O:26][CH3:27]>C1COCC1.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([N:25]([O:26][CH3:27])[CH3:24])=[O:14]
Reactant: CNOC
Reactant: O=C(O)c1cccc2c(Br)cccc12
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)c1cccc2c(Br)cccc12
Reaction time: 0.42 h
Yield: 30 %

Procedure:
Step 1 A solution of 5-bromo-1-naphthoic acid (prepared according to the procedure of Hausamann, Chem. Ber., 1876, 9, 1519; 2.00 g, 7.97 mmol) in THF (50 mL) was treated with TEA (2.22 mL, 15.93 mmol), then with isobutyl chloroformate (1.088 g, 7.97 mmol) and the resulting suspension was stirred at rt. After 25 min, the mixture was treated with additional TEA (2.22 mL, 15.93 mmol), then with a solution of N,O-dimethylhydroxylamine hydrochloric acid salt (0.777 g, 7.97 mmol) in water (5 mL), and the mixture was stirred at rt. After 2.5 h, the mixture was concentrated and the residue was taken up in EtOAc and water. The mixture was filtered, the layers were separated, and the organic phase was washed with NaHCO3 (aq), dried and concentrated to provide 5-bromo-N-methoxy-N-methyl-1-naphthamide as a pasty solid (1.03 g, 30%) contaminated with ca. 30% isobutyl 5-bromo-1-naphthoate. Mass spectrum m/z 294, 296 (M+H)+. Without further purification, a solution of this material (1.01 g, 2.404 mmol) in THF (15 mL) was stirred on ice and treated with (4-fluorophenyl)magnesium bromide, 2M in ether (7.21 mL, 14.42 mmol). The solution was stirred on ice and allowed to slowly warm to rt. After 16 h, the mixture was treated with 1 M hydrochloric acid and extracted twice with EtOAc. The combined organic layers were dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 85:15 hexane-EtOAc) to provide (5-bromonaphthalen-1-yl)(4-fluorophenyl)methanone as a pale yellow viscous oil (658 mg, 83%). 1H NMR (400 MHz, methanol-d4) δ 8.49 (1 H, d, J=8.6 Hz), 7.95 (1 H, d, J=8.6 Hz), 7.86-7.93 (3 H, m), 7.74 (1 H, dd, J=8.5, 7.2 Hz), 7.64-7.68 (1 H, m), 7.40 (1 H, dd, J=8.5, 7.6 Hz), 7.25 (2 H, t, J=8.8 Hz). Mass spectrum m/z 329, 331 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1.[N+:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)([O-:32])=[O:31].C(OCC)(=O)C>C(#N)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]([CH2:37][C:36]2[CH:39]=[CH:40][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=2)[CH:7]=[N:8][CH:9]=1
Reactant: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)Cc1cncn1Cc1ccc([N+](=O)[O-])cc1
Temperature: 55 °C

Procedure:
To a solution of 1-(triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester (23, 274 mg, 0.736 mmol) in acetonitrile (10 ml) was added 4-nitrobenzylbromide (159 mg, 0.736 mmol) and heated to 55° C. for 16 h. After this time, the reaction was cooled to room temperature, treated with ethyl acetate (20 ml) and the resulting precipitate was filtered. The filtrate was concentrated to dryness in vacuo and the residue was redissolved in acetonitrile (4 ml) and heated to 65° C. for 3 h. After this time, the reaction mixture was evaporated to dryness and combined with initial precipitate. This residue was dissolved in methanol (5 ml) and heated to reflux for 30 min. The resulting solution was evaporated in vacuo and the residue was purified by flash chromatography (2-5% methanol/methylene chloride gradient elution) to provide 16.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[S:13]>C(#N)C>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:12]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[S:13])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2c(Cl)cccc2s1
Solvent: CC#N
Product: S=C(Nc1nc2c(Cl)cccc2s1)n1ccnc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 18.5 %

Procedure:
To 4-chlorobenzo[d]thiazol-2-amine (1.12 g, 6.07 mmol) in acetonitrile (30 mL) was added 1,1′-thiocarbonyldiimidazole (1.405 g, 7.89 mmol). The reaction mixture was stirred at 50° C. for 18 hours. The reaction was cooled to room temperature and the precipitate was filtered and washed with acetonitrile (2×50 mL). The yellow powder was dried in a vacuum oven (40° C.) for 1 hour to yield N-(4-chlorobenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide (0.33 g, 1.12 mmol, 18.5% yield) and then used in the next step without any further purification or characterization.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12](=[O:25])[NH:13][C:14]1[CH:18]=[C:17]([CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[O:16][N:15]=1)[CH2:9][CH2:10][CH3:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:20]1([CH2:19][C:17]2[O:16][N:15]=[C:14]([NH:13][C:12](=[O:25])[CH:8]([NH2:7])[CH2:9][CH2:10][CH3:11])[CH:18]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCCC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(CC2CCCC2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(N)C(=O)Nc1cc(CC2CCCC2)on1
Reaction time: 18 h
Yield: 80.7 %

Procedure:
[1-(5-Cyclopentylmethyl-isoxazol-3-ylcarbamoyl)-butyl]-carbamic acid tert-butyl ester (14.0 mmol) was dissolved in 100 mL of anhydrous dichloromethane at rt under N2. Triflouroacetic acid (140 mmol) was added and the reaction was stirred for 18 h. The crude reaction was concentrated under reduced pressure. The residual oil was redissolved in 100 mL Et2O and washed with 100 mL 1N NaOH, followed by 100 mL aqueous saturated sodium chloride solution. The organics were then dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-Amino-pentanoic acid (5-Cyclopentylmethyl-isoxazol-3-yl)-amide (11.3 mmol).