Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].O[C:16]1[CH:20]=[C:19]([CH3:21])[O:18][N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:16]1[CH:20]=[C:19]([CH3:21])[O:18][N:17]=1
Reactant: Cc1cc(O)no1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(-c3ccccc3)noc2C)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.6 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (378 mg, 2.0 mmol) in THF (7 mL) was added 3-hydroxy-5-methylisoxazole (200 mg, 2.0 mmol) and triphenylphosphine (629 mg, 2.0 mmol) at room temperature under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 1.1 mL, 2.5 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. Concentration and purification by chromatography (silica, heptane:ethyl acetate=6:4 to 0:1) afforded the title compound (214 mg, 40%) as a colourless oil. MS: m/e=271.0 [M+H]+.
Reaction SMILES: C(OC([CH:8]([NH2:35])[C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][S:13][C@@H:12]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:10])=O)(C)(C)C.C1(C2C=CC=CC=2C2N[C@H]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])CS2)C=CC=CC=1.C(OC(NCC(O)=O)=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>>[C:56]([O:55][C:53]([NH:35][CH2:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:14][S:13][C@@H:12]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:10])=[O:54])([CH3:59])([CH3:58])[CH3:57]
Reactant: CC(C)(C)OC(=O)[C@@H]1CSC(c2ccccc2-c2ccccc2)N1
Reactant: CC(C)(C)OC(=O)C(N)C(=O)N1[C@@H](c2ccccc2-c2ccccc2)SC[C@H]1C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)NCC(=O)O
Product: CC(C)(C)OC(=O)NCC(=O)N1[C@@H](c2ccccc2-c2ccccc2)SC[C@H]1C(=O)OC(C)(C)C

Procedure:
C tert-Butyl (2R,4R)-3-(2-tert-butoxycarbonyl-aminoacetyl)-2-(2-phenylphenyl)-4-thiazolidinecarboxylate may be prepared in a manner similar to that described in Example 1C, but starting with 5.44 g of tert-butyl (2RS,4R)-2-(2-phenylphenyl)-4-thiazolidinecarboxylate, 2.8 g of 2-tert-butoxycarbonylaminoacetic acid and 3.3 g of N,N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica [eluent: cyclohexane/ethyl acetate (80:20 by volume)]. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure at 40° C. 4.42 g of tert-butyl (2R,4R)-3-(2-tert-butoxycarbonylaminoacetyl)-2-(2-phenylphenyl)-4-thiazolidinecarboxylate are thereby obtained in the form of a white foam, which is used in the subsequent syntheses without further treatment.
Reaction SMILES: CN(C=[O:5])C.O=O.[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH2:14])=[CH:11][CH:10]=1.[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>Cl[Pd]Cl.Cl[Cu].O>[C:17]1([C:13]([C:12]2[CH:15]=[CH:16][C:9]([CH3:8])=[CH:10][CH:11]=2)([OH:5])[CH3:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)C=O
Reactant: C=Cc1ccc(C)cc1
Reactant: Br[Mg]c1ccccc1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: O=O
Solvent: O
Product: Cc1ccc(C(C)(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Sequential reaction of a Wacker-Tsuji oxidation followed by Grignard reduction. A PDMS thimble containing PdCl2 (0.100 g, 0.564 mmol) and CuCl (0.564 g, 5.64 mmol) was placed in a 2-necked Schlenk flask with a stir bar. DMF (3.96 mL) and H2O (0.56 mL) were added to the inside of the PDMS thimble and the flask was capped with a rubber septum. A balloon filled with O2 was affixed to the septum and the reaction mixture was stirred at room temperature for 1 hour. p-Methylstyrene (0.742 mL, 5.64 mmol) was added to the reaction mixture and allowed to stir under an O2 atmosphere for 24 hours. The PDMS thimble was swelled with hexanes (30 mL) for 0.5 hours with a stir bar added to the exterior of the PDMS thimble. Phenylmagnesium bromide (3M in Et2O, 18.8 mL, 56.4 mmol) was added to the exterior of the thimble and stirred under N2 for 12 h. The exterior solvent was removed and the PDMS thimble was swelled with Et2O (4×50 mL). The combined solvents were transferred to a separatory funnel and 3N HCl (200 mL) was added. 3N HCl (200 mL) was used two more times to extract from the organic layer then the organic layer was dried over Na2SO4 and filtered. The organic solvents were concentrated in vacuo. 1-Phenyl-1-p-tolyl-ethanol (0.737 g, 62% yield) was isolated by column chromatography using hexanes/EtOAc (95/5). NMR spectra agree with those reported in the literature. 1H NMR (300 MHz, CDCl3, δ): 7.33 (d, J=8.1 Hz, 2H), 7.17 (m, 5H), 7.03 (d, J=8.1 Hz, 2H), 2.62 (s, 1H), 2.25 (s, 3H), 1.81, (s, 3H). 13C NMR (75.48 MHz; CDCl3, δ): 148.1, 145.0, 136.2, 128.6, 127.9, 126.6, 125.7, 125.6, 75.8, 30.6, 20.8.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[ClH:14].Cl.[Cl:16][C:17]1[CH:33]=[CH:32][C:20]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][SH:31])[CH2:24][CH2:23]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:16].[ClH:14].[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[SH:31][CH2:30][CH2:29][CH2:28][N:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:33][CH:32]=3)[CH2:23][CH2:24]2)[OH:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N=C=O)cc1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(NC(O)=[SH]CCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Yield: 56.8 %

Procedure:
The procedure described in Example 2 was followed, using 1.0 g of 4-n-butylphenyl isocyanate, 2.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.85 g (28% of theory) of N-(4-n-butylphenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 243°-246° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][OH:7])=[O:5])[CH3:3].CO.[CH3:10][C:11]([CH:13]=O)=O.[OH-].[Na+]>O>[CH3:3][C:2]1[N:1]=[C:11]([CH3:13])[CH:10]=[N+:6]([O-:7])[C:4]=1[OH:5]
Reactant: C[C@H](N)C(=O)NO
Reactant: CC(=O)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c[n+]([O-])c(O)c(C)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 3.6 %

Procedure:
407 mmol (42.4 g) alanine hydroxamic acid were cooled to −10° C. in 200 ml water and methanol each, 400 mmol (57 ml 40% solution) methylglyoxal were added dropwise and subsequently the pH was adjusted to approximately pH 11 with 19 ml 30% NaOH. Heating up to 0° C. was carried out within 2 h and then pH 3 was adjusted with 20% NaOH. The solution was concentrated until dryness under vacuum distillation, the residue was heated to reflux with 50 ml ethanol, after cooling filtering was carried out and the filtrate again concentrated until dryness. 44 g of the solid residue were dissolved in 50 ml water and 15 mmol (4.06 g) FeCl3*6H2O were added, heated up to 50° C. for 30 minutes, concentrated and stored at 5° C. for 4 h. The precipitated solid was filtered off and dried. 3.7 g solid in 50 ml water and 10 ml ethanol were adjusted to pH 11 with 6 ml 1 M NaOH, stirred over night and centrifugalized. The supernatant was decanted, pH 3 was adjusted with 3 ml 1 M HCl and concentrated until dryness. 4.2 g solid were refluxed in 20 ml ethanol, cooled and filtered off. The filtrate was again concentrated until dryness and the obtained 2.8 g solid were suspended with 10 ml water, heated up to 50° C. and left for cooling over night. The suspension was centrifugalized, the supernatant decanted and concentrated until dryness. 2.0 g (3.5% yield) of the title compound were obtained.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([CH:10]([NH:12][C:13](=[O:30])[CH2:14][O:15][C:16]3[N:21]=[C:20]4[N:22]([CH3:28])[N:23]=[C:24]([CH:25]5[CH2:27][CH2:26]5)[C:19]4=[C:18]([CH3:29])[CH:17]=3)[CH3:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:31]I.[H-].[Na+]>CN(C=O)C.CCOC(C)=O.O>[CH:25]1([C:24]2[C:19]3[C:20](=[N:21][C:16]([O:15][CH2:14][C:13]([NH:12][CH:10]([C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][N:1]([CH3:31])[C:5]5=[N:6][CH:7]=4)[CH3:11])=[O:30])=[CH:17][C:18]=3[CH3:29])[N:22]([CH3:28])[N:23]=2)[CH2:27][CH2:26]1
Reactant: Cc1cc(OCC(=O)NC(C)c2cnc3[nH]ccc3c2)nc2c1c(C1CC1)nn2C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(OCC(=O)NC(C)c2cnc3c(ccn3C)c2)nc2c1c(C1CC1)nn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
N-(1-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl)-2-(3-cyclopropyl-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)acetamide (example 6.57, 25 mg, 0.062 mmol) was dissolved in DMF (1 ml) and methyliodide (4.25 μl, 0.068 mmol) was added, followed by NaH (60% in mineral oil, 2.7 mg, 0.068 mmol). After stirring for 1 h at rt the reaction was diluted with EtOAc (1 ml) and water (2 ml) and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and the solvents were evaporated under reduced pressure. The crude product was purified on preparative TLC (DCM/MeOH 95/5) to give the product as colorless solid (15 mg, 58%). [1H-NMR (DMSO-d6, 600 MHz) δ 8.58 (d, 1H), 8.23 (s, 1H), 7.83 (s, 1H), 7.48 (d, 1H), 6.47 (s, 1H, 6.30 (d, 1H, 5.13-5.09 (m, 1H), 4.81 (d, 1H), 4.76 (d, 1H), 3.78 (s, 3H), 3.63 (s, 3H), 2.65 (s, 3H), 2.27-2.22 (m, 1H), 3.06 (d, 3H), 0.93-0.84 (m, 4H); LCMS RtL=2.901 min; [M+H]+=419.2]
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.N1CCCC1.CC(O[C:19]([NH:21][C@@H:22]([C:26]([OH:28])=O)[CH:23]1[CH2:25][CH2:24]1)=[O:20])(C)C.C(N[C@@H](C(O)=O)C(C)(C)C)(OC(C)(C)C)=O.[CH3:45][N:46]1[CH:50]=[C:49]([C:51]2[N:56]=[C:55]3[C:57](C(O)=O)=[CH:58][N:59](COCC[Si](C)(C)C)[C:54]3=[N:53][CH:52]=2)[CH:48]=[N:47]1.C1(C2N=C3C(C(O)=O)=CN(COCC[Si](C)(C)C)C3=NC=2)CC1.FC(F)(F)CO>>[C:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:26](=[O:28])[C@H:22]([NH:21][C:19]([C:57]2[C:55]3[C:54](=[N:53][CH:52]=[C:51]([C:49]4[CH:48]=[N:47][N:46]([CH3:45])[CH:50]=4)[N:56]=3)[NH:59][CH:58]=2)=[O:20])[CH:23]2[CH2:24][CH2:25]2)[CH2:2][CH2:3]1)#[N:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CC1
Reactant: N#CC1CCNCC1
Reactant: Cn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Solvent: C1CCNC1
Solvent: OCC(F)(F)F
Product: Cn1cc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCC(C#N)CC4)C4CC4)c3n2)cn1

Procedure:
Prepared according to the procedure outlined in Example 1 substituting piperidine-4-carbonitrile for pyrrolidine, Boc-D-cyclopropyl glycine for Boc-D-tert-leucine, and 2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid. N-Boc deprotection was achieved using 2,2,2-trifluoroethanol in a microwave reactor. MS: (M+H)+=433.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](O)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[C:40]([NH:43][NH2:44])(=[O:42])[CH3:41].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.C(OCC)(=O)C.CN(C=O)C>[C:40]([NH:43][NH:44][C:36](=[O:37])[CH2:35][O:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([N:18]2[C:17](=[O:39])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:29][CH2:30]1)(=[O:42])[CH3:41]
Reactant: CC(=O)NN
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)O)CC2)c2ncnn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)NNC(C)=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of [(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetic acid (0.50 g), acetohydrazide (0.085 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g), 1-hydroxybenzotriazole (0.15 g) and N,N-dimethylformaldehyde (5 mL) was stirred at room temperature for 22 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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 to give the title compound as a colorless solid (0.42 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][N:23]([CH3:26])C=O>CNCCC1C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:23]([CH3:26])[CH2:22][CH2:6][C:5]4[CH:20]=[CH:21][CH:2]=[CH:3][CH:4]=4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: CN(C)C=O
Agent: CNCCc1ccccc1
Solvent: CCO
Product: CN(CCc1ccccc1)C[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and N-methylphenethylamine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=421.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27]>>[N+:26]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:18]=3)[CH2:21][CH2:22]2)=[O:34])=[CH:36][CH:37]=1)([O-:28])=[O:27]
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: COc1cc(-c2cc(CN3CCN(C(=O)c4ccc([N+](=O)[O-])cc4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and 4-nitrobenzoyl chloride (72 mg) were reacted in the same manner as in Example 46 to obtain the title compound as a free base.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:36])[C@H:12]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=CC=1)([O-])=O.Cl.[NH2:38][C@H:39]([C:41]([NH2:43])=[O:42])[CH3:40].C(N(CC)CC)C>CN(C)C=O>[C:14]([NH:13][C@H:12]([C:11]([NH:38][C@H:39]([C:41]([NH2:43])=[O:42])[CH3:40])=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](N)C(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(N)=O
Yield: 95.4 %

Procedure:
Referring to Scheme 6, a solution of 5.0 g (0.010 mol) of Nα-BOC-Nε-CBZ-L-lysine p-nitrophenyl ester and 1.5 g (0.012 mol) of L-alanine amide hydrochloride and 1.67 ml (0.012 mol) of triethylamine in anhydrous N,N-dimethylformamide (50 ml) was stirred at room temperature for 16 hours before the solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate (200 ml) and washed with 3M NaOH (3×100 ml), water (3×100 ml), 1M HCl (2×100 ml) and finally with brine (100 ml). After drying over anhydrous sodium sulfate, the solution was filtered and concentrated in vacuo to give 4.3 g (96% yield) of Nα-BOC-Nε-CBZ-L-lysyl-L-alanine amide (6a) as a white solid. TLC: Rf 0.32 (chloroform-isopropanol 9:1); 1H NMR (d6 -DMSO) δ 1.20(d, 3H), 1.35(bm, 6H), 1.37(s, 9H), 2.97(m, 2H), 3.86(m, 1H), 4.21(m, 1H), 5.00(s, 2H), 6.95(d, 1H), 7.06(s, 1H), 7.24(t, 1H), 7.34(m, 6H), 7.78(d, 1H); 13C NMR (d6 -DMSO) δ 18.6, 22.8, 28.2, 29.2, 31.4, 40.1, 47.8, 54.5, 65.2, 78.2, 127.8, 128.4, 137.3, 155.5, 156.1, 171.7, 174.2.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=S)[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:7]=2[CH:20]=1.O.[NH2:22][NH2:23]>CO>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:22][NH2:23])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:7]=2[CH:20]=1
Reactant: NN
Reactant: CSc1ccc2c(c1)C(c1ccccn1)=NCC(=S)N2
Solvent: O
Solvent: CO
Product: CSc1ccc2c(c1)C(c1ccccn1)=NCC(NN)=N2

Procedure:
According to the procedure of Preparation 1, 7-methylthio-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-thione is reacted with hydrazine hydrate in methanol to give 7-methylthio-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl hydrazine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1CCN[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1([OH:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl[CH2:38][CH2:39]Cl>>[C:1]([O:5][C:6]([N:7]1[CH2:39][CH2:38][CH:10]([N:19]2[CH2:20][CH2:21][C:16]([OH:22])([CH3:15])[CH2:17][CH2:18]2)[CH2:9][CH2:8]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(O)CCNCC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1(O)CCN(C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reaction time: 0.5 h

Procedure:
To a suspension of piperidin-4-yl-carbamic acid tert-butyl ester (723 mg, 3.6 mmol) in DCE (20 mL) was added 4-methylpiperidin-4-ol (500 mg, 4.4 mmol). After 30 minutes, sodium triacetoxyborohydride (1.54 g, 7.3 mmol) was added portionwise. After 20 hours at ambient temperature, the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution (50 mL) and dichloromethane (75 mL). The organic phase was separated, dried (Na2SO4), filtered and evaporated in-vacuo. The resultant residue was purified by flash chromatography (silica, Biotage 100 g column, 0-10% methanol in dichloromethane) to afford crude 4-hydroxy-4-methyl-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester. This crude material was dissolved in dichloromethane (10 mL) and TFA (2 mL) added. After 30 minutes at ambient temperature, the reaction mixture was concentrated in-vacuo and the resultant residue loaded onto a 20 g SCX-2 cartridge which was washed with methanol, then 2N ammonia in methanol. Concentration of the combined basic fractions in-vacuo afforded the title compound as a colourless oil (285 mg, 40% over two steps). 1H NMR (300 MHz, CDCl3): 3.15 (d, J=12.3 Hz, 2H), 2.62-2.60 (m, 6H), 2.42-2.39 (m, 1H), 1.84 (d, J=12.6 Hz, 2H), 1.67-1.64 (m, 5H), 1.46-1.44 (m, 2H), 1.24 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([N+:20]([O-:22])=[O:21])=[C:4]([C:10]([N+:17]([O-:19])=[O:18])=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].O.O.O.O.O.O.O.O.O.[S-2:32].[Na+].[Na+].Cl[CH2:36][C:37]#[N:38]>CS(C)=O>[C:37]([CH2:36][S:32][C:2]1[C:3]([N+:20]([O-:22])=[O:21])=[C:4]([C:10]([N+:17]([O-:19])=[O:18])=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])#[N:38]
Reactant: [S-2]
Reactant: CCN(CC)c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Reactant: N#CCCl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCN(CC)c1c([N+](=O)[O-])cc(C(F)(F)F)c(SCC#N)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
The preparation of a compound bearing a cyanomethylthio group in the 3-position is conveniently carried out using an inert solvent such as dimethylsulfoxide. Thus, a mixture of 3-chloro-N,N-diethyl-2,6-dinitro-4-trifluoromethylaniline and sodium sulfide nonahydrate in a suitable solvent such as dimethylsulfoxide is stirred for a period of time at about 0° C. There is then added chloroacetonitrile and the reaction mixture is stirred overnight at ambient room temperature. The reaction mixture is poured over ice and extracted with ether. The ether is evaporated and the residue recrystallized from a suitable solvent such as ethanol to yield in this case 3-cyanomethylthio-N,N-diethyl-2,6-dinitro-4-trifluoromethylaniline having a melting point of about 77°-79° C. The structure is confirmed by NMR spectrum.
Reaction SMILES: [OH-:1].[K+].[C:3](=[O:6])([O-])[O-].[Na+].[Na+].[C:9]1([C:23]2[C:24]([C:29]3[CH:34]=[CH:33]C=[CH:31][CH:30]=3)=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:14]=[CH:13][C:12](S(O)(=O)=O)(S(O)(=O)=O)[CH2:11][CH:10]=1>O>[OH:1][C:12]1[CH:13]=[CH:14][C:9]([C:23]2[C:24]([C:29]3[CH:34]=[CH:33][C:3]([OH:6])=[CH:31][CH:30]=3)=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:10][CH:11]=1
Reactant: [OH-]
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(O)C1(S(=O)(=O)O)C=CC(c2ccccc2-c2ccccc2)=CC1
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(-c2ccccc2-c2ccc(O)cc2)cc1
Temperature: 330 °C
Reaction time: 3 h

Procedure:
A 1-1 V2A stainless steel vessel equipped with a horseshoe stirrer was charged with 600 g of potassium hydroxide and 60 g of sodium carbonate, and 250 g of the crude product described under (a) were added at 300° C a little at a time over 2 hours. The temperature was raised to 330° C, and the contents were stirred for 3 hours. The contents were then cooled down in a controlled manner by addition of water, diluted with a total of 1.6 1 of water and filtered with suction. The residue was suspended in 2 l of water, and the suspension was acidified with concentrated hydrochloric acid, heated to 90° C and filtered with suction while still hot. The residue was dried and recrystallized from N,N-dimethylformamide. Purity (HPLC) 99.8%; yield: 102.0 g (74% based on terphenyl).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:26])([F:25])[C:12]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:13]=1[C:14]([OH:16])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:49]=[C:50]([N:67]1[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1)[CH2:51][NH:52][C:53]([C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:57][CH:56]=1)=[O:54]>CN(C=O)C.O>[F:25][C:11]([F:10])([F:26])[C:12]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:13]=1[C:14]([N:70]1[CH2:69][CH2:68][N:67]([C:50](=[O:49])[CH2:51][NH:52][C:53]([C:55]2[CH:60]=[CH:59][C:58]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:57][CH:56]=2)=[O:54])[CH2:72][CH2:71]1)=[O:16]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)ccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2,5-bis-trifluoromethyl-benzoic acid (66.5 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 75 mg (51.6% yield) of biphenyl-4-carboxylicacid {2-[4-(2,5-bis-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 95.51%, 1H NMR: (DMSO) δ 8.65 (t, 1H), 8.1 (t, 3H), 8.0 (d, 2H), 7.83-7.7 (q, 4H), 7.5 (t, 2H), 7.42 (t, 1H), 4.2 (d, 2H), 3.8-3.42 (d, 6H), 3.2 (m, 2H).