Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CN=C1.[OH:14][CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17].O>CN(C=O)C>[Si:5]([O:14][CH:15]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C:16]([O:18][CH3:19])=[O:17])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C(O)c1ccc(OC)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
TBDMSCl (1.5 g, 9.94 mmol) and imidazole (1.0 g, 14.6 mmol) were added to a solution of methyl hydroxy-(4-methoxyphenyl)acetate (Teodozyj Kolasa et al., J. Org. Chem., 1987, 22, 4978-4984) (1.3 g, 6.62 mmol) in DMF (8 mL) and the mixture was stirred at r.t. for 2 h. Water was added and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated to give the title compound (2.0 g, 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.[I:40]I>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][C:10]=1[I:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: FC(F)(F)c1ccc(OCc2ccccc2)cc1
Agent: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: FC(F)(F)c1ccc(OCc2ccccc2)c(I)c1
Temperature: 25 °C
Reaction time: 88 h
Yield: 158.2 %

Procedure:
A solution of 4(benzyloxy)benzotrifluoride (12.71 g, 50.4 mmol) in acetonitrile (300 ml) was stirred under nitrogen and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (17.75 g, 50.4 mmol) and iodine (6.4 g, 25.2 mmol) added. The mixture was stirred at room temperature for 88 h. The solvent was evaporated and the residue partitioned between ethyl acetate (400 ml) and water (400 ml). The organic layer was washed with water, dried (MgSO4) and evaporated to an orange oil which was purified by flash chromatography (silica gel, 5% ethyl acetate:isohexane) to give the title compound as an orange oil (15.07 g, 79%)
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][CH:10]([CH2:14][CH3:15])[C:11](O)=O.C>O>[Cl:9][CH:10]([C:11]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]=1)[CH2:14][CH3:15]
Reactant: CCC(Cl)C(=O)O
Reactant: Nc1cccnc1N
Solvent: O
Product: CCC(Cl)c1nc2cccnc2[nH]1
Temperature: 80 °C

Procedure:
5.0 g of 2,3-diaminopyridine in 200 g of polyphosphoric acid are heated at 120° C. for 0.5 h. The solution is cooled to 80° C. and 5.7 ml of 2-chlorobutyric acid are added. Thereafter, the reaction mixture is heated to 130° C. for 22 h. After cooling, the polyphosphoric acid is hydrolysed with 136 ml of water. After reheating to 90° C., charcoal is added under vigorous stirring. Subsequently, the suspension is filtered through a celite pad while still hot (70° C.). The filter cake is rinsed with 100 ml of water and the pH 4 using 9 M aqueous sodium hydroxide solution. The mixture is extracted three times each with 200 ml of ethyl acetate, the combined organic phases are dried using sodium sulfate, concentrated and purified by chromatography on silica gel (eluent: toluene/ethyl acetate 1:1) to give 5.19 g of the title compound as a colorless, amorphous solid. M.p. 137° C. MS: 196.0/198.0 (MH+, 100%/32%). TLC: Rf=0.50 (dichloromethane/methanol 10:1).
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:28][C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[NH:23][CH2:24][CH2:25][CH2:26][N:27]=3)[CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[OH-].[Na+].FC(F)(F)C(O)=O>CO>[CH:32]([O:31][C:29]([NH:28][C@@H:4]([CH2:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[NH:23][CH2:24][CH2:25][CH2:26][N:27]=3)[CH:16]=2)[CH2:11][CH2:10]1)=[O:8])[C:3]([OH:35])=[O:2])=[O:30])([CH3:34])[CH3:33]
Reactant: COC(=O)[C@H](CNC(=O)C1CCN(c2cccc(NC3=NCCCN3)c2)CC1)NC(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)N[C@@H](CNC(=O)C1CCN(c2cccc(NC3=NCCCN3)c2)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound of Example 43 in methanol (5 ml) is added 2M aqueous sodium hydroxide solution (5 ml), and the mixture is stirred at 25° C. overnight. The reaction solution is neutralized with trifluoroacetic acid, and purified by CHP-20 (eluent: gradient, 35% to 100% methanol/0.05% aqueous trifluoroacetic acid solution) to give the title compound (40 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][C@H:29]1[O:34][C@@H:33]([CH3:35])[CH2:32][NH:31][CH2:30]1>CN(C)C=O.C(OCC)(=O)C>[CH3:35][CH:33]1[CH2:32][N:31]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:30][CH:29]([CH3:28])[O:34]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COC(=O)c1ccc(-c2ccc(OCCCBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(OCCCN3CC(C)OC(C)C3)cc2)cc1
Yield: 45.8 %

Procedure:
A solution of methyl 4-[4′-(3-bromopropyoxy)phenyl]benzoate (1.5 g), potassium carbonate (1.2 g) and cis-2,6-dimethylmorpholine (990.6 mg) in N,N-dimethyformamide was stirred for 15 hours at room temperature, then diluted with ethyl acetate and washed with water (5x), dried over magnesium sulfate, evaporated, then purified by silica gel chromatography (20:1 dichloromethane-ethanol elution) to give methyl 4-[4′-[3-(2,6-dimethylmorpholino)propoxy]phenyl]benzoate (755 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1O)(=[O:3])[CH3:2].[CH:18](N(C(C)C)CC)(C)C.CI>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:18])=[O:10])=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)Nc1c(O)cc(C(=O)O)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Yield: 94.1 %

Procedure:
Compound 107 (1.50 g, 6.69 mmol) was dissolved in DMF (25 mL), and diisopropylethylamine (16.0, 92.7 mmol) and MeI (2.3 mL, 39 mmol) were added. The solid which formed was filtered and the filtrate was concentrated to dryness on a rotary evaporator to provide 15 (1.50 g, 94.3%) as a yellow solid: mp 123°-124° C. (ethanol). The literature (Appleton et al., 1970) reports mp 127° C.
Reaction SMILES: C([O:5][C:6](=[O:23])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[S:18][C:19]([Br:22])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Br:22][C:19]1[S:18][C:17]([S:14]([N:11]2[CH:12]=[CH:13][C:9](/[CH:8]=[CH:7]/[C:6]([OH:23])=[O:5])=[CH:10]2)(=[O:15])=[O:16])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.5 %

Procedure:
A mixture of 4.5 g (E)-3-[1-(5-bromo-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester with 85.0 ml dichloromethane and 13.0 ml TFA is stirred at ambient temperature for 24 h. The dichloromethane and TFA is evaporated and the residue is coevaporated with toluene for 3 times. By this method 3.8 g light pink solid is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc([N+](=O)[O-])ccn2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N)ccn2)CC1
Yield: 95.5 %

Procedure:
Subject a slurry of 4-(4-nitro-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 9.28 mmol) and 5% Pd/C (151 mg) in EtOAc (150 mL) to an atmosphere of hydrogen at 60 psi (Parr shaker) overnight at ambient temperature. Filter the reaction mixture through a pad of Celite® and concentrate under reduced pressure to provide the title compound as a white solid (2.6 g, 95% yield). LCMS ES+(m/z) 294 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][C@@H:11]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]([CH2:20][CH2:21][OH:22])[N:14]=[CH:13][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH2:1]([O:8][C:9]([NH:10][C@@H:11]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]([CH2:20][CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])[N:14]=[CH:13][C:12]1=2)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CCCc2c1cnn2CCO)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1ncc2c1CCC[C@H]2NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.2 %

Procedure:
To a solution of [(R)-1-(2-hydroxy-ethyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl]-carbamic acid benzyl ester (755 mg, 2.40 mmol) and pyridine (1.45 mL, 18.0 mmol) in dichloromethane was added methanesulfonyl chloride (1.40 mL, 18.0 mmol) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 6 hours. The resulting mixture was poured into ice (10 g). The organic layer was then separated and washed with 0.1 N hydrochloric acid and saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (10% methanol in dichloromethane) to afford methanesulfonic acid 2-((R)-4-benzyloxycarbonylamino-4,5,6,7-tetrahydroindazol-1-yl)-ethyl ester (880 mg, 90%) as a white solid. MS calcd. for C18H23N3O5S 393, obsd. (ESI+) [(M+H)+] 394.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[N:6]=[C:5]([S:17][CH3:18])[N:4]=1)[CH3:2].[H][H]>[Pd].CO>[CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[N:6]=[C:5]([S:17][CH3:18])[N:4]=1)[CH3:2]
Reactant: CCc1nc(SC)nn1-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1nc(SC)nn1-c1ccc(N)cc1
Yield: 91 %

Procedure:
A mixture of 41 parts of 5-ethyl-3-(methylthio)-1-(4-nitrophenyl)-1H-1,2,4-triazole and 80 parts of methanol is hydrogenated at normal pressure and at room temperature with 1 part of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from 1,1'-oxybisbutane. The product is filtered off and dried, yielding 33 parts (91%) of 4-[5-ethyl-3-(methylthio)-1H-1,2,4-triazol-1-yl]benzenamine; mp. 131.7° C.
Reaction SMILES: COC1C=C(N[CH2:12][C:13]2[CH:36]=[CH:35][C:16]([C:17]([NH:19][C:20]3[CH:25]=[C:24]([CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=[CH:22][C:21]=3[NH2:34])=[O:18])=[CH:15][CH:14]=2)C=CC=1OC>CO.C(OCC)(=O)C.[Pd]>[NH2:34][C:21]1[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][C:20]=1[NH:19][C:17](=[O:18])[C:16]1[CH:15]=[CH:14][C:13]([CH3:12])=[CH:36][CH:35]=1
Reactant: COc1ccc(NCc2ccc(C(=O)Nc3cc(C=Cc4ccccc4)ccc3N)cc2)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(C(=O)Nc2cc(CCc3ccccc3)ccc2N)cc1
Reaction time: 1 h

Procedure:
To a degassed solution of compound 127 (100 mg, 0.209 mmol) in a mixture of methanol and ethyl acetate (1:1) was added was added a catalytic amount of 10% palladium on charcoal and the mixture was put under H2 atmosphere (latm) and stirred for 1 h and filtered through celite and the filtrate was concentrated in vacuo. The mixture was separated by flash chromatography on silica gel using EtOAc/Hexanes with increasing polarity (40:60 to 60:40) as the eluent. The least polar compound 129 was isolated as a white solid (31 mg, 31% yield) and the most polar compound was further purified by crystallization from a mixture of ethyl acetate and hexanes affording compound 128 as light beige crystals (18 mg, 18% yield).
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]>C(O)(=O)C.C(O)C.[Pt]=O>[NH2:2][CH2:1][C:3]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2)CC1
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CN)(c2ccccc2)CC1
Yield: 31.7 %

Procedure:
Tert-butyl 4-cyano-4-phenylpiperidine-1-carboxylate (2.6 g, 9.08 mmol) was dissolved in 15% acetic acid/ethanol and hydrogenated at 50 psi over platinum oxide (0.052 g) for a week. HPLC showed only 50% conversion and the reaction was resubmitted to the same conditions and hydrogenated for 4 more days. The reaction was then filtered and the filtrate was evaporated. The residue was diluted with ethyl acetate and 1N hydrochloric acid. The aqueous phase was collected, basified with sodium carbonate and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (0.835 g, 32%) as an oil which was used as such for the next reaction. LC/MS (M-(t-Bu)+H)+: 235. HPLC ret. time (Condition B): 1.322 min.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1.[OH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32]([O:34][CH3:35])=[O:33].CN(C)C=O.[H-].[Na+]>O>[CH3:15][C:14]1[O:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][C:10]=1[CH2:9][CH2:8][O:7][C:6]1[CH:22]=[CH:23][C:3]([CH2:2][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:4][CH:5]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccccc1OCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.8 %

Procedure:
To a mixture of 4-[2-(4-chloromethylphenoxy)ethyl]-5-methyl-2-phenyloxazole (0.85 g), methyl 2-(2-hydroxyphenyl)acetate (0.40 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.11 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give methyl 2-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxy]phenyl]acetate as an oil (0.57 g, 57%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:7])=[C:4]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CO>[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][CH2:19][NH:18][C:4]1[N:3]=[C:2]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:17]=[CH:16][C:5]=1[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:7]
Reactant: C1CCNC1
Reactant: O=C(NCc1cccnc1)c1ccc(Cl)nc1NCCc1cccc(F)c1
Solvent: CO
Product: O=C(NCc1cccnc1)c1ccc(N2CCCC2)nc1NCCc1cccc(F)c1
Temperature: 150 °C

Procedure:
A mixture of 6-chloro-2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide (50 mg, 0.13 mmol) and pyrrolidine (94 mg, 1.3 mmol) in a sealed tube was heated to 150° C. for 10 min. LC/MS indicated the reaction was complete. The crude was diluted with MeOH, filtered, and purified on RP-HPLC using a mixture of acetonitrile and H2O to a give 2-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)-6-(pyrrolidin-1-yl)nicotinamide (20.2 mg, 37%). LRMS (M+H+) m/z 420.2.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[C:16]=3[O:17][C:6]=2[C:5]([CH:24]=[O:25])=[C:4]([OH:26])[CH:3]=1)=[O:9].[CH3:27]I.O>CN(C=O)C>[CH3:27][O:19][C:18]([C:15]1[C:16]2[O:17][C:6]3[C:5]([CH:24]=[O:25])=[C:4]([OH:26])[CH:3]=[C:2]([CH3:1])[C:7]=3[C:8](=[O:9])[O:10][C:11]=2[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=1)=[O:20]
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Reactant: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)c(C)c2c1Oc1c(C=O)c(O)cc(C)c1C(=O)O2
Temperature: 25 °C

Procedure:
Psoromic acid (1 mmol) was dissolved in DMF (10 mL), KHCO3 (2.4 mmol) was added and stirred for several minutes at room temperature. Then, CH3I (1.2 mmol) was added. The reaction mixture was maintained at 40° C. and monitored by TLC. Upon completion, the reaction mixture was poured into 50 mL of water and extracted with ethyl acetate. The organic layer was subsequently washed with saturated NaHCO3 solution and saturated brine, and dried over anhydrous MgSO4, filtered and evaporated by a rotatory evaporator. The residue was purified by column chromatography to provide a white solid product.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC[N:22]([CH:26]([CH3:28])C)[CH:23]([CH3:25])C.ClC(OCC(C)C)=O.N1CCCC1>C(Cl)Cl>[O:19]=[C:17]([N:22]1[CH2:23][CH2:25][CH2:28][CH2:26]1)[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccncc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccncc1)C(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
N-Boc-(5)-3-(pyridin-4-yl)alanine (0.500 g, 1.88 mmol) was dissolved in CH2Cl2 (15 mL) and DIEA (361 μL, 2.07 mmol) was added. The mixture was cooled to 0° C. and isobutyl chloroformate (270 μL, 2.07 mmol) was added. The mixture was stirred for 10 min and pyrrolidine (267 mg, 3.76 mmol) in CH2Cl2 (5 mL) was added. This mixture was stirred for 15 min at 4° C., 12 h at 25° C., washed successively with NaH2PO4, saturated sodium hydrogen carbonate, water and brine. The organic layer was dried over magnesium sulfate and evaporated to dryness. The residue obtained was purify by column chromatography (SiO2) using a gradient of MeOH 0-10% [v/v] in EtOAc to give tert-butyl(R)-1-oxo-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-2-ylcarbamate EBE 06172 (146 mg, 24% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[NH:31]1[CH2:37][CH2:36][C:35](=[O:38])[NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:31]5[CH2:37][CH2:36][C:35](=[O:38])[NH:34][CH2:33][CH2:32]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: O=C1CCNCCN1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CCN1

Procedure:
1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepan-5-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and [1,4]diazepan-5-one following General Procedure B.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=5)[CH:20]=4)[OH:15])=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2cccc(Cl)c2)nn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5cccc(Cl)c5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:29](Cl)(Cl)=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:21][C:29]2=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccccc2N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2c(=O)[nH]c3ccccc32)C1
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of 3(R)-(2-Amino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (52 mg, 0.18 mmol), Et3N (1.0 ml) in CH2Cl2 (1 ml) at 0° C. was added a solution of phosgene (20% in toluene, 0.1 ml). After stirring for 2 hr and evaporation of solvent, the residue was purified by chromatography (1%-2% MeOH in CH2Cl2) to give a colorless oil (34 mg, 60%). 1H-NMR (300 MHz, CDCl3) δ 7.80 (d, 1H), 4.20 (m, 3H), 3.50 (m, 1H), 2.75 (m, 1H), 2.65 (m, 1H), 2.10 (m, 1H), 1.90 (m, 1H), 1.70 (m, 1H), 1.50 (s, 9H) ppm; IR (film) 3067, 2975, 2935, 2858, 1745, 1692, 1612, 1487, 1423, 1383, 1347, 1266, 1246, 1158 cm−1; LRMS (calculated for C17H23N3O3-BOC)+ 217, found 217.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[Cl:11].[NH4+].[Cl-]>CO.[Zn]>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cccc(Br)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1cccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of 1-bromo-2-chloro-3-nitrobenzene (3.0 g, 12.7 mmol) in MeOH (127 ml) was added Zn dust (8.30 g, 127 mmol) followed by NH4Cl (6.79 g, 127 mmol) which resulted in a significant exotherm. The heterogeneous reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of Celite and concentrated to an off-white solid. To this solid was added EtOAc and the resulting mixture was sonicated for 10 minutes. The mixture was filtered through Celite and washed with EtOAc. The combine filtrates were concentrated in vacuo to afford 2.17 g (10.5 mmol, 79%) of 3-bromo-2-chloroaniline: LCMS (m/z): 205.9 (MH+); tR=0.87 minute: 1H NMR (400 MHz, CDCl3) δ 6.62-6.66 (m, 1H) 6.87 (t, J=8.0 Hz, 1H) 6.97 (d, J=7.8 Hz, 1H) 7.22 (d, J=9.0 Hz, 1H).