Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@H:13]([N+:14]([O-])=O)[CH2:12][CH:11]=[CH:10][CH2:9]1.Cl.C([O-])(O)=O.[Na+]>CO.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@H:13]([NH2:14])[CH2:12][CH:11]=[CH:10][CH2:9]1
Reactant: O=[N+]([O-])[C@@H]1CC=CC[C@H]1c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N[C@@H]1CC=CC[C@H]1c1ccccc1Cl
Temperature: 25 °C

Procedure:
To a solution of Example 1A (100 mg, 0.042 mmol) in a 2 mL solution of 1:1 aqueous concentrated HCl in methanol at 0° C., Zn dust (32 mg, 0.5 mmol) was added in several portions. The solution was allowed to warm to room temperature over three hours. Afterwards, the solution was carefully basified with saturated NaHCO3. The mixture was extracted with ethyl acetate, concentrated, taken up in dichloromethane, and filtered through Celite. Concentration of the filtrate gave the title compound. 1H NMR (300 MHz, C5D5N) δ ppm 7.41-7.43 (m, 2H), 7.24-7.28 (m, 1H), 7.12-7.14 (m, 1H), 5.70-5.73 (m, 2H), 3.49-3.54 (m, 2H), 2.55-2.58 (m, 1H), 2.37-2.41 (m, 1H), 2.14-2.24 (m, 2H). MS (ESI+) m/z 208 (M+H)+
Reaction SMILES: C(N(CC)C(C)C)(C)C.C([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=1[CH2:30][CH2:31][CH3:32])(=O)C.[CH3:33][O:34][CH2:35]Cl.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O.CO>[F:26][C:25]([F:28])([F:27])[C:20]([C:17]1[CH:18]=[CH:19][C:14]([OH:13])=[C:15]([CH2:30][CH2:31][CH3:32])[CH:16]=1)([O:29][CH2:33][O:34][CH3:35])[C:21]([F:23])([F:24])[F:22]
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1OC(C)=O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1O
Temperature: 40 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
N,N-Diisopropylethylamine (27.6 mL) was added to 2-propyl-4-[1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl]phenyl acetate (13.67 g, 39.7 mmol) in dichloromethane (160 mL), and then chloromethyl methyl ether (6.0 mL) was added. After stirring at 40° C. for 18 hours, methanol (20 mL) was added at room temperature. After stirring for 1.5 hours, potassium carbonate (11 g, 39.7 mmol) was added, followed by stirring overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 10.87 g of the title compound (yield: 79%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]2)[C:12]([CH2:18][S:19][CH2:20][CH3:21])([C:14]([F:17])([F:16])[F:15])[OH:13].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[C:7]([OH:8])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]2)[C:12]([CH2:18][S:19][CH2:20][CH3:21])([C:14]([F:16])([F:15])[F:17])[OH:13]
Reactant: CCSCC(O)(C(Nc1cccc2nc(C)ccc12)c1ccc(F)c(OC)c1F)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCSCC(O)(C(Nc1cccc2nc(C)ccc12)c1ccc(F)c(O)c1F)C(F)(F)F
Reaction time: 22 h

Procedure:
Analogously to example 10 40 mg (0.08 mmol) 2,4-difluoro-α-[(ethylsulfanyl)methyl]-3-methoxy-β-[(2-methylquinolin-5-yl)amino]-α-(trifluoromethyl)benzeneethanol in 1.6 ml dichloromethane are treated with 0.8 ml of a 1 M solution of boron tribromide in dichloromethane at −20° C. The typical work up after 22 hours at room temperature and chromatography on silica gel (acetone in hexane 50%) yields 26 mg of the desired product.
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7].N[C:28]1C=C2C(=CC=1)C(=O)OC2.C1(C2(CC(=O)C(O)=O)CCC2)C=CC=CC=1>>[C:18]1([C:16]2([CH2:15][C:14](=[O:25])[C:13]([NH:12][C:11]3[CH:2]=[C:3]4[C:8](=[CH:9][CH:10]=3)[C:6](=[O:7])[O:5][CH2:4]4)=[O:26])[CH2:24][CH2:28][CH2:17]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Reactant: Nc1ccc2c(c1)COC2=O
Agent: O=C(O)C(=O)CC1(c2ccccc2)CCC1
Product: O=C(CC1(c2ccccc2)CCC1)C(=O)Nc1ccc2c(c1)COC2=O

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid, melting point 142-146° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[CH:7]=1.Cl.[CH3:15][O:16][NH:17][CH3:18].Cl.CN(C)CCCN=C=NCC.O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11](=[O:13])[N:17]([O:16][CH3:15])[CH3:18])[N:10]=2)[CH:7]=1
Reactant: O=C(O)c1cn2cc(Br)ccc2n1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cn2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.1 %

Procedure:
850 mg of 6-bromo-2-hydroxycarbonyl-imidazo[1,2-a]pyridine, 519 mg of N-methoxy-N-methyl-amine hydrochloride, and 1.12 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were dissolved in 10 ml of pyridine, and the mixture was stirred at room temperature for 2 days. Water was added to the obtained solution, and the products were extracted with ethyl acetate. Organic layer was washed with saturated sodium chloride aqueous solution, and dried with anhydrous magnesium sulfate. Then, the solvents were distilled outunder reduced pressure. The obtained residues were purified by silicagel column chromatography (ethyl acetate) to obtain 362 mg of the above compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[N:9]=1.[C:22](O)(=[O:25])[CH:23]=[CH2:24]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: C=CC(=O)O
Reactant: Nc1cccc(Nc2nccc(Sc3ccccn3)n2)c1
Product: C=CC(=O)Nc1cccc(Nc2nccc(Sc3ccccn3)n2)c1
Yield: 42.9 %

Procedure:
In a procedure analogous to Example 15, reaction of N1-(4-(pyridin-2-ylthio)pyrimidin-2-yl)benzene-1,3-diamine (35 mg, 0.12 mmol) and acrylic acid (16 μL, 0.24 mmol) furnished the product (18 mg, 43%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:30][CH2:31][N:32]1[CH2:37][C@H:36]([CH3:38])[O:35][C@H:34]([CH3:39])[CH2:33]1.CC#N>CC(C)=O>[CH3:39][C@H:34]1[O:35][C@@H:36]([CH3:38])[CH2:37][N:32]([CH2:31][CH2:30][N:20]2[CH2:21][CH2:22][CH:17]([CH2:16][NH:15][C:13]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([O:3][CH3:2])[CH:5]=4)[NH:9][N:8]=3)=[O:14])[CH2:18][CH2:19]2)[CH2:33]1
Reactant: C[C@@H]1CN(CCCl)C[C@H](C)O1
Reactant: COc1ccc2[nH]nc(C(=O)NCC3CCNCC3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC#N
Product: COc1ccc2[nH]nc(C(=O)NCC3CCN(CCN4C[C@@H](C)O[C@@H](C)C4)CC3)c2c1
Yield: 48.3 %

Procedure:
A mixture of compound 7b (8 g, 24.6 mmoles) and potassium carbonate (17 g, 123 mmoles) in acetone (250 mL) was refluxed for 1 hour, then (2R,6S)-4-(2-chloroethyl)-2,6-di methyl morpholine (25.9 mmoles) was added dropwise. The mixture was refluxed overnight then was cooled and filtered. The resulting solid was dried and purified via preparative HPLC (channel A=CH3CN+0.1% formic acid; channel B=H2O+0.1% formic acid: flow=40 ml/min; gradient=10%-45% of eluent A in 15 minutes) providing N-[(1-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}piperidin-4-yl)methyl]-5-methoxy-1H-indazole-3-carboxamide 25 (48.3% yield)
Reaction SMILES: [Cl:1][CH2:2][C:3]1([CH3:10])[CH2:7][N:6]([CH3:8])[C:5](=[O:9])[NH:4]1.C(O[Cl:16])(C)(C)C>CO>[Cl:16][N:4]1[C:3]([CH2:2][Cl:1])([CH3:10])[CH2:7][N:6]([CH3:8])[C:5]1=[O:9]
Reactant: CC(C)(C)OCl
Reactant: CN1CC(C)(CCl)NC1=O
Solvent: CO
Product: CN1CC(C)(CCl)N(Cl)C1=O
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A solution of 4-(chloromethyl)-1,4-dimethylimidazolidin-2-one (204 mg, 1.25 mmol) in MeOH (2.5 ml) was cooled to 0° C. tert-Butylhypochlorite (177 ul, 1.57 mmol) was added. The resulting solution was stirred for 60 min, during which time a white precipitate formed. The reaction mixture was concentrated under reduced pressure to half its initial volume and the solid was collected on a glass fritted filter and washed with water to give 168 mg of desired product (69% yield). 1H NMR (400 MHz, CDCl3) δ1.48 (s, 3H), 2.90 (s, 3H), 3.21-3.23 (d, J=8.8 Hz, 1H), 3.52-3.54 (d, J=8.9 Hz, 1H), 3.59-3.67 (q, J=11.1 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 19.9, 31.7, 47.6, 54.5, 63.1, 158.7. LRMS (ESI/APCI): 197 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5].O=[C:18]([CH3:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20]([C:19]1[C:18]([CH3:25])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:7]=[CH:8][CH:9]=2)=[O:21])[CH3:24]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1Oc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(Oc3ccccc3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-phenoxybenzonitrile and ethyl 3-oxobutanoate as a yellow oil (72%). 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, J=8.0 Hz, 3H), 2.59 (s, 3H), 4.33 (q, J=8.0 Hz, 2H), 6.61 (dd, J=8.0 Hz, 1H), 7.16 (d, J=4.0 Hz, 2H), 7.25 (t, J=8.0 Hz, 1H), 7.39-7.52 (m, 4H), 7.93 (brs, 2H). MS 323 (MH+).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[C@H:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: C1CCNC1
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N2CCCC2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@]4(C)[C@@H](O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
To a solution of 50 mg (0.116 mmol) 17-hydroxywortmannin in 1 mL methylene chloride (CH2Cl2) is added 12.1 mL (0.145 mmol) pyrrolidine. The reaction mixture is stirred at room temperature for 2 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give 40 mg (68.7%) product as a yellow solid. HRMS (ESI) m/z calcd for C27 H35NO8 501.2364, found: 502.24250 (M+H)+1.
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:4][CH:3]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>C(O)C.C(OCC)(=O)C>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][CH:2]([F:1])[CH:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccncc2[N+](=O)[O-])CCC1F
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CN(c2ccncc2N)CCC1F
Yield: 99 %

Procedure:
Following Method 2 of Example 49, (+/−)-tert-butyl 4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate in ethanol and ethyl acetate (1:1, 0.1 M solution) was reduced yielding (+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-4-fluoropiperidin-3-ylcarbamate, (>99%). LCMS (m/z): 311.2 (MH+); LC Rt=2.14 min.
Reaction SMILES: CS([CH2-])=O.[Na+].[H-].[Na+].[NH2:8][C:9]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:10]=1[NH:11][C:12]1[C:16]([C:17](OCC)=[O:18])=[CH:15][N:14]([CH3:22])[N:13]=1>CS(C)=O>[F:27][C:25]1[CH:24]=[CH:23][C:10]2[NH:11][C:12]3=[N:13][N:14]([CH3:22])[CH:15]=[C:16]3[C:17](=[O:18])[NH:8][C:9]=2[CH:26]=1
Reactant: CCOC(=O)c1cn(C)nc1Nc1ccc(F)cc1N
Agent: [CH2-]S(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1cc2c(n1)Nc1ccc(F)cc1NC2=O
Temperature: 65 °C
Reaction time: 0.33 h

Procedure:
A solution of sodium methyl sulphinyl methanide was generated by stirring sodium hydride (50% oil dispersion, 1.5 g) in dry dimethylsulphoxide (15 ml) at 65° C. until gas evolution ceased. A solution of ethyl 3-(2-amino-4-fluoroanilino)-1-methylpyrazole-4-carboxylate (2.7 g) dissolved in dry dimethyl sulphoxide (5 ml) was added dropwise and the mixture stirred at 65° C. for 20 minutes. The mixture was poured on to excess ice-water, filtered and dried to give the title compound which was crystallised from chloroform-hexane m.p. 264° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:33])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)C2CCCCC2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.4 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.46 mmol) and triethylamine (92 μL, 0.66 mmol) in methylene chloride (20 mL) was added dropwise cyclohexanecarbonyl chloride (67 μL, 0.46 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 10 min and then washed with dilute aqueous sodium hydrogen carbonate. The organic phase was separated, dried (Na2SO4), filtered and evaporated in vacuo and the residue was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. This gave 71 mg (45% yield) of the title compound as white crystals: mp 183-184° C.; [α]21D +12° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 355 (56, M+).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:29][CH:28]([N:30]=[C:31]=[O:32])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:33]([NH2:35])[CH3:34]>C1COCC1.CCOC(C)=O>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:27][CH:28]([NH:30][C:31]([NH:35][CH2:33][CH3:34])=[O:32])[CH2:29]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N=C=O)C3)ccc2n1CC1CCC(F)(F)CC1
Reactant: CCN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNC(=O)NC1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
A solution of 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-5-[(3-isocyanatoazetidin-1-yl)sulfonyl]-1H-benzimidazole in THF (4.0 mL, 0.095 mmol) (see following step B for preparation) was added to a solution of ethylamine (100 uL, 2.0 M in THF, 0.2 mmol) in THF (2.0 mL). The reaction mixture was stirred for 4 h at room temperature, diluted with EtOAc (50 mL), washed with NaHCO3 (2×5 mL) and dried over Na2SO4. The crude product was purified by MPLC using EtOAc/MeOH (20:1) on silica gel to give 21 mg (44%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.02 (t, J=7.13 Hz, 3 H), 1.51-1.64 (m, 2 H), 1.66 (s, 9 H), 1.69-1.87 (m, 4 H), 2.01-2.15 (m, 2 H), 2.21-2.37 (m, 1 H), 3.04 (q, J=7.16 Hz, 2 H), 3.62 (dd, J=8.11, 6.74 Hz, 2 H), 3.99 (t, J=8.10 Hz, 2 H), 4.16-4.29 (m, 1 H), 4.54 (d, J=7.62 Hz, 2 H), 7.90 (dd, J=8.59, 1.56 Hz, 1 H), 8.03 (d, J=8.59 Hz, 1 H), 8.17 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=512.3; Anal. Calcd for C24H35F2N5O3S+1.40 TFA+0.50H2O (680.28): C, 47.32; H, 5.54; N, 10.29. Found: C, 47.36; H, 5.57; N, 10.32.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([NH:33][NH2:34])=[O:32])[CH2:26]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:34][NH:33][C:31]([CH:27]3[CH2:28][CH2:29][CH2:30][NH:25][CH2:26]3)=[O:32])=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:23])([F:24])[F:1])[CH:8]=1
Reactant: NNC(=O)C1CCCNC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC(=O)C1CCCNC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (Example 1, Step 4; 0.25 g, 1.0 eq.) was dissolved in THF:EtOAc (15 mL, 2:1) and cooled to −60° C. where piperidine-3-carbohydrazide (0.113 g, 1.1 eq.) was introduced dropwise. T3P (50% in EtOAc) (1.69 mL, 4 eq.) was added dropwise followed by DIPEA (0.25 mL, 2 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)—N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)piperidine-3-carbohydrazide (0.01 g, yield: 2.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([NH2:16])([C:13]([OH:15])=[O:14])[CH2:8]2.C(N(CC)CC)C.[C:24](=O)([O:40]N1C(=O)CCC1=O)[O:25][CH2:26][CH:27]1[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2>C(#N)C.O>[C:24]([CH:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1([NH2:16])[C:13]([OH:15])=[O:14])([O:25][CH2:26][CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[C:39]1=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:40]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: COc1cccc2c1CCC(N)(C(=O)O)C2
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cccc2c1CCC(N)(C(=O)O)C2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 30 h
Yield: 71 %

Procedure:
A mixture of racemic 5-methoxy-2-aminotetraline-2-carboxylic acid (prepared according to Obrecht, D. et. al. Helv. Chim Acta. 1992, 75, 1666) (802 mg, 3.62 mmole), triethylamine (0.62 ml, 4.45 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 1.47 g, 4.36 mmole) in acetonitrile (25 ml) and water (25 ml) was stirred at room temperature for 30 hours. TLC analysis of the reaction indicated the presence of starting material amino acid. 9-fluorenylmethyl succinimidyl carbonate (370 mg) and triethylamine (0.6 ml) were added and the mixture was stirred at room temperature for another 24 hours. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH 3 with 10% aqueous citric acid solution, and the white emulsion was extracted three times with ethyl acetate. The combined organic layers were washed with water, brine and dried over magnesium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 1→3→5→10% methanol/methylene chloride) to give racemic Fmoc-5-methoxy-2-aminotetraline-2-carboxylic acid (1.14 g, 71% yield) as an off-white solid. HRMS (FAB): C27H26NO5 (M+H) calc. 444.1812; observed: 444.1814.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[C:12]([O:16][C:17](=[O:30])[CH2:18][CH2:19][N:20]([CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[C:21]([NH2:23])=[S:22])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:30])[CH2:18][CH2:19][N:20]([C:21]1[S:22][C:2]2[CH2:10][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[N:23]=1)[CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C1c2ccccc2CC1Br
Reactant: CC(C)(C)OC(=O)CCN(Cc1cccs1)C(N)=S
Product: CC(C)(C)OC(=O)CCN(Cc1cccs1)c1nc2c(s1)Cc1ccccc1-2

Procedure:
3-[(8H-Indeno[1,2-d]thiazol-2-yl)-thiophen-2-ylmethyl-amino]-propionic acid tert-butyl ester was prepared (35 mg) following general procedure B using 2-bromo-indan-1-one (22 mg, 0.1 mmol), and 3-(1-thiophen-2-ylmethyl-thioureido)-propionic acid tert-butyl ester (30 mg, 0.1 mmol). LCMS m/z: 414 (M+1)+.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.C(N(CC)CC)C.[NH:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[Cl:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:14])=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(CCCl)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc(CCCl)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Add thionylchloride (6 mL) to 4-(2-chloroethyl)benzoic acid (1.00 g, 5.4 mmol) and stir at 50° C. for 30 min. Remove the excess thionylchloride in vacuo and dissolve the reside to dichloromethane (2 mL). Add this acid chloride solution to the mixture of triethylamine (656 mg, 6.5 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (1.00 g, 6.5 mmol) in dichloromethane (30 mL) at 0° C. and stir it at room temperature for 2 h. Dilute the reaction mixture and wash with brine, dry over sodium sulfate and remove the solvent. Purify the crude product by a silica-gel column chromatography (dichloromethane:2M ammonia in methanol=40:1) to give the title compound. 1.35 g (80%). Observed Mass 321.