Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N=C=NC(C)C)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:21][C:20](=[N:22][O:23][CH3:24])[CH2:19][C@H:18]1[C:25]([OH:27])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].[C:28](=[N:31]O)([NH2:30])[CH3:29]>C(Cl)Cl.C1COCC1>[CH3:24][O:23][N:22]=[C:20]1[CH2:21][N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])[C@H:18]([C:25]2[O:27][N:31]=[C:28]([CH3:29])[N:30]=2)[CH2:19]1
Reactant: CC(N)=NO
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CON=C1C[C@@H](c2nc(C)no2)N(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 59 %

Procedure:
Diisopropylcarbodiimide (3.16 g, 25.17 mmol) was added to a solution of (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2, 6.50 g, 25.17 mmol) and acetamidoxime (Intermediate 7, 1.86 g, 25.17 mmol) in DCM (55 ml) and stirred overnight at room temperature (DCM-insoluble amidoximes were pre-dissolved in THF, to which was added a solution of DIC and Intermediate 2 in DCM). After filtering at the pump, and evaporation in vacuo, the residue was dissolved in pyridine (60 ml) and refluxed for one hour, then cooled and allowed to stand overnight, then evaporated in vacuo. The crude product was then dissolved in DCM (50 ml) and washed with sat. NaHCO3(aq) (2×50 ml) and then 1M HCl(aq) (2×50 ml), dried over magnesium sulphate and evaporated in vacuo (crude yield 70%). Silica gel chromatography, eluting with 15% ethyl acetate in hexanes gave the desired compound, tert-butyl (2S,4EZ)-4-(methoxyimino)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-1-pyrrolidinecarboxylate (4.4 g, 60% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:21](O)[CH2:22][O:23][Si:24]([CH3:30])([CH3:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([NH:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:11]=[C:10]1[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@@H:21]([CH2:22][O:23][Si:24]([CH3:30])([CH3:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[N:12]1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)NOCc1ccccc1)C(O)CO[Si](C)(C)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of THF (1.5 L) containing 2-[(tert-butoxy)carbonylamino]-3-hydroxy-N-(phenylmethoxy)-4-(1,1,2,2-tetramethyl-1-silapropoxy)butanamide (9.8 g, 21.56 mmol), triphenylphosphine (17.5 g, 66.8 mmol) and diethyl azodicarboxylate (11.26 g, 64.7 mmol) was stirred at room temperature for 2 h. The solvent was evaporated in vacuo and the residue was purified under column chromatography using a mixture of ethyl acetate and hexane (1/4) as eluent to obtained 7.25 g of the desired product.
Reaction SMILES: [NH2:1][C@@H:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.[C:35]([C:39]1[CH:40]=[C:41]([CH:44]=[C:45]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:46]=1[OH:47])[CH:42]=O)([CH3:38])([CH3:37])[CH3:36]>C1C=CC=CC=1.ClCCl>[C:48]([C:45]1[CH:44]=[C:41]([CH:40]=[C:39]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:46]=1[OH:47])[CH:42]=[N:1][C@@H:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)([CH3:50])([CH3:51])[CH3:49]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: ClCCl
Solvent: c1ccccc1
Product: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)[C@H]2SC1

Procedure:
A solution of diphenylmethyl 7β-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (9.89 g) and 3,5-di-t-butyl-4-hydroxybenzaldehyde (5.62 g) in a mixture of benzene (160 ml) and dichloromethane (40 ml) is refluxed for 1 hour in the presence of a molecular sieve to give a solution of diphenylmethyl 7β-(3,5-di-t-butyl-4-hydroxy-benzylidene)amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[C:20]([C:21]([F:24])([F:23])[F:22])=[N:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:25]C)[CH:17]=2)[N:12]=1)[C:5]([OH:7])=[O:6].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[C:20]([C:21]([F:23])([F:24])[F:22])=[N:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:25])[CH:17]=2)[N:12]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccc2nc(-c3ccc(C(=O)O)cc3Cl)c(C(F)(F)F)nc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2nc3ccc(O)cc3nc2C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
A mixture of 3-chloro-4-(6-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)benzoic acid (150 mg, 0.392 mmol) and BBr3 (3 mL) in anhydrous DCM (30 mL) was stirred at 25° C. overnight. The resulting mixture was quenched with water (30 mL), extracted with EtOAc (50 mL×3), dried over Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% TFA as additive) to give Compound VI-1 (26 mg, yield 18%) as a solid. 1H NMR (DMSO-d6 400 MHz): δ 11.22 (brs, 1H), 8.14 (d, J=9.2 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 8.04 (dd, J=8.0, 1.6 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.70 (dd, J=9.2, 1.8 Hz, 1H), 7.47 (d, J=1.8 Hz, 1H). MS (ESI): m/z 369.0 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2]
Reactant: Sc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(Sc2ccccc2)cc1C(F)(F)F

Procedure:
A solution of 2-nitro-5-chlorobenzotrifluoride (33.8 g, 0.15 mole), benzenethiol (16.6 g, 0.15 mole) and ethanol (150 ml) is heated to its reflux temperature under nitrogen. To this solution is slowly added a solution of sodium hydroxide (6 g, 0.15 mole) and water (7 ml) at such a rate that refluxing continues with no external heating. the solution is then heated at its reflux temperature for an additional two hours, filtered hot and the filtrate cooled. The resulting precipitate is collected by filtration and recrystallized from hexene to afford a yellow solid, m.p. 65°-67° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]1([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C:9]1([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2.20 g of 2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in 50 ml DCM was added 1.15 ml of benzaldehyde, followed by the addition of 2.61 g of sodium triacetoxyborohydride in small portions. The reaction was stirred at r.t. overnight. To the reaction was then added water. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. 3.30 g (100%) of the title compound were obtained and used without further purification.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]#[N:25])[CH:20]=3)[NH:15][C:14]=2[CH2:13][CH2:12]1)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:10][C@@H:11]1[CH2:12][CH2:13][C:14]2[NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:24]#[N:25])=[CH:20][C:21]=3[C:22]=2[CH2:23]1
Reactant: N#Cc1ccc2[nH]c3c(c2c1)C[C@H](NC(=O)OCc1ccccc1)CC3
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc2[nH]c3c(c2c1)C[C@H](N)CC3
Reaction time: 18 h
Yield: 48 %

Procedure:
Combine (R)-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid benzyl ester (Preparation 62) (7.1 mmol, 2.44 g) in anhydrous ethanol (100 mL). To the stirred solution add 5% palladium/carbon (600 mg). Purge and fill the reaction vessel with hydrogen (3×) and stir the reaction mixture under hydrogen at atmospheric pressure for about 18 h. Filter the reaction mixture through a Celite® and wash the cake with methanol. Strip the filtrate to dryness and isolate the first crop via crystallization from ethyl acetate/methanol/hexanes to yield 720 mg of pure product. Strip the crystallization mother liquors to dryness, purify and isolate additional product via flash chromatography (25% methanol/dichloromethane isocratic) for a total yield of 1.17 g (78%). LCMS 100% (m/e) 212 (M+1, APES-pos), 210 (M−1, APES-neg); 1H NMR (DMSO, 400 MHz): δ 11.29 (s, 1H), 7.81 (d, 1H, J=0.9 Hz), 7.36 (dd, 1H, J=8.4, 0.9 Hz), 7.30 (dd, 1H, J=8.4, 1.8 Hz), 3.11-3.02 (m, 1H), 2.87 (dd, 1H, J=15.4, 4.8 Hz), 2.79-2.70 (m, 2H), 2.28 (dd, 1H, J=15.4, 8.4 Hz), 1.97-1.89 (m, 1H), 1.78 (s, 2H), 1.66-1.54 (m, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[C:9]([CH3:15])=[C:8]4[CH:16]=[CH:17][N:18]=[CH:19][C:7]4=[C:6]([CH3:20])[C:5]=3[C:4]=2[CH:3]=1.C([O-])(O)=O.[Na+].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)(=O)C>[C:26]([O:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[C:9]([CH3:15])=[C:8]4[CH:16]=[CH:17][N:18]=[CH:19][C:7]4=[C:6]([CH3:20])[C:5]=3[C:4]=2[CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c2ccncc2c(C)c2c1[nH]c1ccc(O)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)Cl
Product: CC(=O)Oc1ccc2[nH]c3c(C)c4ccncc4c(C)c3c2c1
Reaction time: 0.17 h
Yield: 75 %

Procedure:
A solution of 9-hydroxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole (10 g.) in acetic anhydride (75 ml.) and acetyl chloride (25 ml.) was stirred at room temperature for 2 hours. The reaction mixture was poured into excess NaHCO3 solution and stirred for 10 minutes. The resulting precipitate was removed by filtration and was washed well with water. The dried solids (10 g.; 86%) were dissolved in tetrahydrofuran and the solution was charcoaled. Crystallization from tetrahydrofuran-ethyl acetate mixture afforded 9-acetoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole (8.3 g.; 75%), m.p. 303°-304°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(OCc2ccccc2)c(Cl)c1
Yield: 73 %

Procedure:
In a 250 mL flask equipped with a reflux condenser, 2-chloro-4-nitrophenol 4.65 g (26.6 mmol), benzyl bromide 2.97 mL (27.0 mmol, 1 eq), K2CO3 9.4 g (54 mmol, 2 eq) and DMF (60 mL) were added and then heated to reflux. The procedure was conducted as Example 1, the residue was purified by column chromatography to obtain the title compound as brown solid, total yield: 73%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.I[CH:42]([CH3:44])[CH3:43]>>[CH:42]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1)([CH3:44])[CH3:43]
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Reactant: CC(C)I
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC(C)C)cc3)cc21

Procedure:
Analogously to Method F, 0.05 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1 carboxylate and 0.0316 g of 2-iodopropane are reacted at 50° C. The title compound is obtained as an orange oil. Rf=0.34 (1:1 EtOAc-heptane). Rt=5.78.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>CO.[Pd]>[NH2:12][C:4]1[C:5]([CH3:11])=[C:6]([CH:10]=[C:2]([F:1])[CH:3]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1c(N)cc(F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (E1) in MeOH (0.5 M), Pd on carbon (10 wt %, 0.2 eq.) was added. The reaction mixture was equipped with H2 atmosphere and the resulting suspension was stirred at RT for 24 h. The precipitated was filtered off and the filtrate was evaporated to dryness to yield the title compound as a brown powder that was used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 8.39 (1H, bs), 7.98 (1H, dd, J=11.1 and 2.8 Hz), 6.85 (1H, dd, J=9.1 and 2.8 Hz), 3.21 (2H, s), 2.19 (3H, s).
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CS([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[O:20])[CH2:14][CH2:13]1)(=O)=O>>[CH:1]1([S:4]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=3)=[O:20])[CH2:14][CH2:13]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reactant: O=S(=O)(Cl)C1CC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC1CCN(S(=O)(=O)C2CC2)CC1
Yield: 68 %

Procedure:
Cyclopropylsulfonyl chloride (68.5 mg, 0.487 mmol) was reacted with PTU (70 mg, 0.244 mmol) as the same manner as the synthesis of 1-(1-(methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (65 mg, 0.166 mmol, 68% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.78 (s, 1H), 7.57 (s, 4H), 6.38 (d, J=7.5 Hz, 1H), 4.19 (d, J=Hz, 1H), 3.52 (d, J=12.3 Hz, 2H), 2.99 (t, J=11.4 Hz, 2H), 2.58 (m, 1H), 1.91 (d, J=12.6 Hz, 2H), 1.46 (m, 2H), 0.96 (m, 4H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]3=[N:20][CH:21]=[C:22]([F:24])[CH:23]=[C:18]3[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[F:24][C:22]1[CH:23]=[C:18]2[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:19]2=[N:20][CH:21]=1
Reactant: CC(C)n1nc(-c2ccc(OCc3ccccc3)cc2)c2ncc(F)cc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)n1nc(-c2ccc(O)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-6-fluoro-1-(1-methylethyl)-1H-pyrazolo[4,3-b]pyridine (130 mg) and 10% Pd—C (100 mg) in EtOH (20 mL) was stirred at room temperature for 1 h under H2 atmosphere, filtered and evaporated. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give the title compound (76 mg).
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:13][CH2:14][CH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:7]([S:8]([NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:32][CH:33]=1)(=[O:10])=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CCN)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccccc1COc1ccc(CCNS(=O)(=O)Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 19.4 %

Procedure:
Alpha-toluenesulfonyl chloride (38 mg, 0.199 mmol) and methyl 2-{[4-(2-aminoethyl)phenoxy]methyl}benzoate hydrochloride (64 mg, 0.199 mmol) were mixed in DCM (3 ml). PS-DIEA (3.66 mmol/g, 272 mg, 0.997 mmol) was added. The mixture was shaken at room temperature over a weekend. It was then loaded on a column (ISOLUTE® SI, 1 g/6 ml) and eluted with DCM. The product fractions were combined and evaporated. Oil product (17 mg) was obtained, yield 19%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:15]=3[N:16]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(=O)([O-])[O-].[K+].[K+].Cl[C:39]1[CH:44]=[CH:43][N:42]=[C:41]([NH:45][C:46]([CH:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)=[O:47])[CH:40]=1>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][C:18]([O:21][C:39]4[CH:44]=[CH:43][N:42]=[C:41]([NH:45][C:46]([CH:48]5[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]5)=[O:47])[CH:40]=4)=[CH:17][C:15]=3[N:16]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(Nc2nc3cc(O)ccc3s2)c1
Reactant: CN1CCC(C(=O)Nc2cc(Cl)ccn2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCC(C(=O)Nc2cc(Oc3ccc4sc(Nc5cccc(C(C)(C)C)c5)nc4c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The mixture containing 2-(3-tert-butylphenylamino)benzo[d]thiazol-5-ol (1 eq), potassium bis(trimethylsilyl)amide (4 eq), and potassium carbonate (1.2 eq) in dimethylformamide was stirred at room temperature for 10 minutes. N-(4-chloropyridin-2-yl)-1-methylpiperidine-4-carboxamide (1.4 eq) was then added and mixture subjected to microwave at 220° C. for 20 minutes. Reaction partitioned between ethyl acetate and water. Organic layer separated, washed with brine, dried over sodium sulfate and concentrated to give crude product. Purification by HPLC to yield N-[4-({2-[(3-tert-butylphenyl)amino]-1,3-benzothiazol-5-yl}oxy)pyridin-2-yl]-1-methylpiperidine-4-carboxamide. HPLC=4.74 min; MS: MH+=516.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:23]=[CH:22][C:15]([CH2:16]OS(C)(=O)=O)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29](=[O:37])[NH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25].C(=O)(O)[O-].[K+]>CN(C=O)C>[C:24]([O:28][C:29](=[O:37])[NH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH2:16][C:15]2[CH:22]=[CH:23][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[CH:13][CH:14]=2)[CH2:33][CH2:32]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CS(=O)(=O)OCc1ccc(NC(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 41.9 %

Procedure:
Methanesulfonic acid 4-benzyloxycarbonylamino-benzyl ester (0.35 g, 2.5 mmol) was added to a suspension of piperidin-4-yl-carbamic acid tert-butyl ester (0.15 g, 0.76 mmol) and potassium bicarbonate (0.35 g, 2.5 mmol) in DMF (10 ml) and the reaction heated to 60° C. and stirred at this temperature for 16 hours under a nitrogen atmosphere. After this time, the reaction mixture was cooled to room temperature and the solvent removed. The resulting residue was diluted with EtOAc (50 ml) and washed with water (10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated and the resulting residue was triturated with EtOAc, the resulting precipitate collected by filtration and dried under vacuum to give the title compound (0.14 g, 37% yield) as a white solid. Tr=1.58 min, m/z (ES+) (M+H)+ 440.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC(CO[C:20]2[N:24]([CH3:25])[N:23]=[CH:22][C:21]=2[CH:26]=[O:27])=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:25][N:24]1[C:20]([N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)=[C:21]([CH:26]=[O:27])[CH:22]=[N:23]1
Reactant: Cn1ncc(C=O)c1OCc1ccc(Cl)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1ncc(C=O)c1N1CCN(c2ccccc2)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
A mixture of 1-phenylpiperazine (3.40 g), 5-[(4-chlorobenzyl)oxy]-1-methyl-1H-pyrazol-4-carbaldehyde (600 mg), triethylamine (1.20 mL) and dimethylformamide (7.0 mL) was stirred at 120° C. for 8 hours, and then at a room temperature for 17 hours. Thereafter, the reaction solution was concentrated under a reduced pressure, and water was then added thereto. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated saline, and was then dried over anhydrous sodium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=80:20 to 10:90), so as to obtain the title compound (669 mg) in the form of a light yellow solid.
Reaction SMILES: O[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.FC(F)(F)C(O)=O>>[C:14]1([C:2]2[CH2:3][NH:4][CH2:5][CH:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2ccccc2)CNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 3-hydroxy-3-phenylpyrrolidine-1-carboxylate (0.36 g, 0.0014 mol) and trifluoroacetic acid (2.0 mL, 0.026 mol) was stirred under nitrogen at room temp for 1 h. The volatile was removed under vacuum and evaporated with toluene twice. The residue was used in next step w/o further purification. LCMS: 146.1 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:20][C:21]1[N:22]=[CH:23][N:24](CC2C=CC=CC=2)[CH:25]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])=[C:8]([CH3:19])[CH:7]=1)=[O:4].[H][H]>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:1][C@H:2]([CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[O:13])=[C:8]([CH3:19])[CH:7]=1)=[O:4]
Reactant: Cc1cc(NC(=O)[C@H](N)Cc2cn(Cc3ccccc3)cn2)ccc1C(=O)N1CCCC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(NC(=O)[C@H](N)Cc2c[nH]cn2)ccc1C(=O)N1CCCC1

Procedure:
350.0 mg (0.81 mmol) (R)-2-amino-3-(1-benzyl-1H-imidazol-4-yl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-propionamide are dissolved in 10.0 ml acetic acid and combined with 150.0 mg Pd(OH)2. The mixture is hydrogenated in a Parr apparatus at ambient temperature at 3 bar hydrogen pressure for eight hours. Then the catalyst is filtered off and the filtrate is evaporated down i. vac.
Reaction SMILES: N#N.[CH2:3]1[CH2:13][CH2:12][N:11]2[C:6](=NCC[CH2:10]2)[CH2:5][CH2:4]1.BrCCCC#[N:19]>CCOCC>[N:11]1([CH2:12][CH2:13][CH2:3][CH2:4][NH2:19])[CH2:10][CH2:5][CH2:6]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: N#CCCCBr
Agent: N#N
Solvent: CCOCC
Product: NCCCCN1CCC1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of trimethylene imine (300 mg, 5.25 mmol) and DBU (0.79 mL, 5.23 mmol) in dry Et2O (4 mL) was added 4-bromobutyronitrile (0.54 mL, 5.27 mmol) at 0° C. The reaction mixture was stirred at rt until completion of the reaction. The mixture was filtered and concentrated under reduced pressure. The crude nitrile was redissolved in dry THF (4 mL) and treated with LiALH4 (230 mg, 6.06 mmol) at 0° C. The reaction mixture was warmed up to rt and stirred at this temperature until completion of the reaction. Aq. 1N NaOH (2 mL) was then added, the layers separated and the aq. layer extracted with EA (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude 4-(azetidin-1-yl)butan-1-amine as a pale yellow oil. GC-MS-conditions 01: tR=1.35 min; [M+H]+=129.00.