Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1c(C)ccc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)ccc2ccccc12
Temperature: 25 °C

Procedure:
A solution of methyl 2-methyl-1-naphthoate (1.277 g, 6.377 mmol), N-bromosuccinimide (1.14 g, 6.38 mmol) and 2,2′-azobis(isobutyronitrile) (10 mg) in carbon tetrachloride (10 ml) was heated under reflux for 0.5 hr. After cooling the reaction solution to room temperature, the white precipitate was removed by filtration, and the precipitate was washed with diethyl ether. The solvent of the collected filtrate was evaporated under reduced pressure to give a crude product of methyl 2-bromomethyl-1-naphthoate as a pale-yellow liquid. The obtained liquid, thiophenol (0.84 g, 7.65 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (1.14 ml, 7.65 mmol) were stirred in acetonitrile (20 ml) overnight at room temperature. The solvent of the reaction solution was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=20/1-9/1) to give the objective substance.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][CH2:7][C:6]1=[O:12])C.[C:13]1([NH:19]N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[C:13]1([N:19]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6](=[O:12])[C:5]=3[CH:4]=[N:2]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: O=C1CCCc2c1cnn2-c1ccccc1
Yield: 26.1 %

Procedure:
To a stirred solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (14 g, 83 mmol) in methanol (150 mL) was added phenyl hydrazine (8.92 g, 83 mmol). The reaction mixture was refluxed for 6 hours. The reaction was then concentrated under reduced pressure followed by the addition of n-butanol (130 mL) and glacial acetic acid (2 mL). The reaction mixture was refluxed for 3 hours. On the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was triturated with ether (100 mL) to give a precipitate, which was filtered and dried under reduced pressure to give the desired product (4.6 g, 30%) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 9.06 (s, 1H), 7.59-7.51 (m, 4H), 7.45-7.40 (m, 1H), 3.00 (t, J=6.4 Hz, 2H), 2.58 (t, J=6.4 Hz, 2H), 2.21 (quintet, J=6.4 Hz, 2H). LCMS [M+H]: 213.
Reaction SMILES: C([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:23])[CH:13]([C:19]([F:22])([F:21])[F:20])[CH2:14][S:15][C:16](=[O:18])[CH3:17])(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:16]([S:15][CH2:14][CH:13]([C:19]([F:20])([F:21])[F:22])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:24])=[O:5])=[O:23])(=[O:18])[CH3:17]
Reactant: CC(=O)SCC(C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCC(C(=O)N1CCC[C@H]1C(=O)O)C(F)(F)F

Procedure:
1-(3-Acetylthio-2-trifluoromethylpropanoyl)-L-proline tert-butyl ester (8 g.) is dissolved in a mixture of anisole (55 ml.) and trifluoroacetic acid (110 ml.). After one hour storage at room temperature the solvent is removed in vacuo and the residue is precipitated several times from ether-hexane to give 1-(3-acetylthio-2-trifluoromethylpropanoyl)-L-proline.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[C:6]([O:15]C)=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:2].[Cl-].[NH+]1C=CC=CC=1.C1COCC1>CN(C=O)C>[C:1]([CH2:3][CH2:4][C:5]1[C:6]([OH:15])=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:2]
Reactant: COC(=O)c1cnc(OC)c(CCC#N)c1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(O)c(CCC#N)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 5-(2-cyanoethyl)-6-methoxynicotinate (589 mg) in DMF (10 mL) was added pyridinium chloride (3.01 g), and the mixture was stirred at 100° C. for 4 hr. To the reaction mixture was added THF at 0° C., and the resulting precipitate was removed by filtration. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (479 mg) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][C@@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH2:15])=[CH:11][CH:10]=1)[CH3:2].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[S:36])=[C:30]([N+:37]([O-])=O)[CH:29]=1>C1COCC1>[NH2:37][C:30]1[CH:29]=[C:28]([O:27][CH3:26])[CH:33]=[CH:32][C:31]=1[NH:34][C:35](=[S:36])[NH:15][C@H:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:25])=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Reactant: COc1ccc(N=C=S)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1ccc(C[C@H](NC(=S)Nc2ccc(OC)cc2N)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
The aminoester 4-2 (350 mg, 1 mmole) in 20 ml of THF is mixed with 4-methoxy-2-nitrophenyl isothiocyanate (210 mg, 1 mmole), followed by agitating for 1 hour at ambient temperature, evaporating under reduced pressure, then adding SnCl2 (380 mg then 190 mg, 3 mmoles) in 10 ml of DMF and agitating for 4 hours at ambient temperature. After evaporating under reduced pressure and taking up in a water/NaHCO3/AcOEt mixture, decanting, drying the organic phase and evaporating under reduced pressure, 530 mg of crude product is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([F:14])[CH:3]=1.[CH2:15]([NH:22][C:23](=[O:41])[N:24]([CH3:40])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CN(C)C=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:14][C:4]1[CH:3]=[C:2]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([N:24]([CH3:40])[C:23]([NH:22][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:41])[CH:30]=2)[CH:7]=[CH:6][C:5]=1[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C=Cc1ccc(Br)cc1F
Reactant: CCCCCCCNC(=O)N(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C=CC(=O)OC)c(F)c2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
44 mg (5 mol %) of tetrakis(triphenylphosphine)palladium are added to a solution of 200 mg (0.77 mmol, 1.0 eq) of methyl 3-(4-bromo-2-fluorophenyl)acrylate and 430 mg (1.15 mmol, 1.5 eq) of 3-heptyl-1-methyl-1-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]urea (prepared as in 1e) in a mixture of dimethylformamide and 2M potassium phosphate solution (8/2). The reaction mixture is stirred for 2 hours at 90° C. The reaction is stopped by addition of 10 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 138 mg of methyl 3-[3-fluoro-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate are obtained. Yield=42%
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:14]([N:5]1[CH:6]=[C:2]([CH3:1])[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1n[nH]cc1C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(Cc2ccccc2)cc1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
Into a 100-mL 3-neck round-bottom flask, was placed a solution of ethyl 4-methyl-1H-pyrazole-3-carboxylate (1.0 g, 6.5 mmol) in tetrahydrofuran (20 mL). The solution was cooled to 0° C., then sodium hydride (360 mg, 9.00 mmol, 60% dispersion in mineral oil) was added in portions and the mixture was stirred for 20 min. Benzyl bromide (904 μL, 7.60 mmol) was added at 0° C., then the resulting mixture was stirred for 1.5 h at room temperature. The reaction was carefully quenched with by drop-wise addition of water (35 mL) and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with of brine (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (1:20-1:2) as eluent to obtain the title compound as a yellow solid (1.0 g, 63%).
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[S:11])[N:4]2[CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=2[C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([C:22]2[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=2[C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([N:7]3[C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[C:10](=[S:11])[N:4]4[CH2:3][CH2:2][CH2:1][C@H:5]4[CH2:6]3)=[O:32])=[CH:34][CH:35]=2)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Reactant: S=C1c2ccccc2NC[C@@H]2CCCN12
Product: O=C(Nc1ccc(C(=O)N2C[C@@H]3CCCN3C(=S)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Yield: 81.9 %

Procedure:
The same procedures used in Example 25 were repeated using (11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-thione prepared in Reference Example 32 and 4-[(2-phenylbenzoyl)amino]benzoic acid to give the title compound. Yield 81.9%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=1[CH:17]([CH3:19])[CH3:18])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=1.C([O-])([O-])=O.[K+].[K+]>>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=2)[C:11]=1[CH:17]([CH3:18])[CH3:19])([CH3:3])([CH3:4])[CH3:2]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)c1c(O)cccc1CCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)c1c(CCNC(=O)OC(C)(C)C)cccc1Oc1ccc(C#N)cn1
Yield: 74.8 %

Procedure:
Using a method similar to Example 221, Step 1, using [2-(3-hydroxy-2-isopropyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (4.02 g, 14.4 mmol), 6-chloronicotino-nitrile (1.99 g, 14.4 mmol) and K2CO3 (2.98 g, 21.5 mmol) gives {2-[3-(5-cyano-pyridin-2-yloxy)-2-isopropyl-phenyl]-ethyl}-carbamic acid tert-butyl ester (4.11 g) as a yellow foam. 1H NMR (CDCl3): 8.50 (s, 1H), 7.92 (d, 1H), 7.17 (t, 1H), 7.06 (d, 1H), 7.01 (d, 1H), 6.86 (d, 1H), 4.63 (br. s, 1H), 3.34 (m, 2H), 3.27 (m, 1H), 2.91 (t, 2H), 1.44 (s, 9H), 1.24 (d, 6H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][OH:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:13]1[CH2:17][CH2:16][O:15][C:14]1=[O:18]>CC(C)=O>[OH:5][CH2:4][CH2:3][CH2:2][S:1][CH:13]1[CH2:17][CH2:16][O:15][C:14]1=[O:18]
Reactant: O=C1OCCC1Br
Reactant: OCCCS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: O=C1OCCC1SCCCO
Reaction time: 40 h

Procedure:
3-Mercaptopropan-1-ol (1.61 g, 17.4 mmol) was dissolved in acetone (40 mL) followed by addition of cesium carbonate (5.67 g, 17.4 mmol) and 3-bromo-dihydrofuran-2(3H)-one (1.63 ml, 17.4 mmol). The suspension was stirred vigorously for 40 hours. The reaction was filtered through silica gel, rinsed with acetone and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 70-80% ethyl acetate/hexanes. Recovered the desired product as an oil (2.1 g, 71%).
Reaction SMILES: Br[C:2]1[C:7]([CH2:8]Cl)=[CH:6][C:5]2[O:10][CH2:11][O:12][C:4]=2[CH:3]=1.C([Li])(C)(C)C.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:30]=[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27]>>[C:37]([C:31]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:8][C:7]2[C:2](=[CH:3][C:4]3[O:12][CH2:11][O:10][C:5]=3[CH:6]=2)[CH:30]1[C:22]1[CH:21]=[C:20]([O:19][CH3:18])[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=1)([O:39][CH2:40][CH3:41])=[O:38]
Reactant: ClCc1cc2c(cc1Br)OCO2
Reactant: CCOC(=O)C(=Cc1cc(OC)c(OC)c(OC)c1)C(=O)OCC
Agent: [Li]C(C)(C)C
Product: CCOC(=O)C1(C(=O)OCC)Cc2cc3c(cc2C1c1cc(OC)c(OC)c(OC)c1)OCO3
Yield: 80.4 %

Procedure:
6-bromo-3,4-methylenedioxybenzyl chloride (364 mg, 1.45 mmol) is reacted as in Example 2 with t-butyllithium (0.98 ml, 1.5 mmol, 1.55 M in pentane) and diethyl (3,4,5-trimethoxyphenyl)methylenemalonate (490 mg, 1.45 mmol) to provide the title compound (551 mg, 81% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[CH:8][NH:7][CH:6]=1)=[O:4].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:22])[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH3:10])=[CH:8][N:7]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[CH:13]=2)[CH:6]=1)=[O:4]
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: COC(=O)c1c[nH]cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2cc(C)nc3ccccc23)cc1C
Temperature: 80 °C
Reaction time: 60 h

Procedure:
1 mmol (139 mg) of 4-methylpyrrole-3-carboxylic acid methyl ester, 1.1 mmol (195 mg) 4-chloro-2-methyl-quinoline and 1.2 mmol (390 mg) of Cs2CO3 are suspended in 3 mL of dry DMF. The mixture is stirred for 60 h at 80° C. under Argon, allowed to cool to room temperature, and diluted with water (20 mL). Part of the product precipitates and is filtered off. The filtrate is extracted twice with ethyl acetate (20 mL portions). The combined extracts are dried over anhydrous Na2SO4 and evaporated. The residue is combined with the precipitate and purified by prep. HPLC to yield 4-methyl-1-(2-methyl-quinolin-4-yl)-1H-pyrrole-3-carboxylic acid methyl ester (MS molpeak 281 (M+) H, electrospray ionisation)) as an off-white foam after freeze-drying.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:40]=[CH:39][C:25]([C:26]([NH:28][CH:29]5[CH2:32][N:31]([CH:33]6[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]6)[CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:41][CH3:42])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O.[CH:47]1([CH:50]=O)[CH2:49][CH2:48]1>CO>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:40]=[CH:39][C:25]([C:26]([NH:28][CH:29]5[CH2:30][N:31]([CH:33]6[CH2:38][CH2:37][N:36]([CH2:50][CH:47]7[CH2:49][CH2:48]7)[CH2:35][CH2:34]6)[CH2:32]5)=[O:27])=[CH:24][C:23]=4[O:41][CH3:42])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)NC2CN(C3CCNCC3)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: O=CC1CC1
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(C(=O)NC2CN(C3CCN(CC4CC4)CC3)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a solution of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-(piperidin-4-yl)azetidin-3-yl)benzamide (13 mg, 0.023 mmol) in MeOH (2.5 mL) was added AcOH (0.03 mL), cyclopropane aldehyde (3 μL, 0.034 mmol), borane-pyridine complex (10 μL, 0.08 mmol), and left to stir overnight. The solvent was then removed and the product purified by reverse phase HPLC, free based, and lyophilized to yield a white solid (6.4 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm −0.03-0.14 (m, 3H) 0.34-0.51 (m, 2H) 0.80 (s, 1H) 1.17 (d, J=2.53 Hz, 2H) 1.60 (br. s., 6H) 1.71 (br. s., 2H) 1.94 (br. s., 5H) 2.13 (d, J=6.32 Hz, 2H) 2.82 (br. s., 2H) 2.96 (t, J=7.20 Hz, 2H) 3.52 (t, J=7.20 Hz, 2H) 3.92 (s, 1H) 4.05 (t, J=14.02 Hz, 2H) 4.38-4.50 (m, 1H) 4.70-4.82 (m, 1H) 7.41-7.58 (m, 2H) 7.98 (s, 1H) 8.22-8.33 (m, 2H) 8.61 (d, J=6.57 Hz, 1H). [M+H] calc'd for C33H44F2N8O3, 638. found 638.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([O:18]/[N:19]=[C:20](/[C:22]3[CH:39]=[CH:38][C:25]([CH2:26][N:27]4[CH2:30][CH:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]4)=[CH:24][CH:23]=3)\[NH2:21])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O1CCCC1>C(#N)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:18][N:19]=[C:20]([C:22]4[CH:39]=[CH:38][C:25]([CH2:26][N:27]5[CH2:28][CH:29]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:30]5)=[CH:24][CH:23]=4)[N:21]=3)[S:10][C:11]=2[C:12]([F:13])([F:15])[F:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/OC(=O)c3cc(-c4ccccc4)c(C(F)(F)F)s3)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.3 %

Procedure:
To a solution of (Z)-tert-butyl 1-(4-(N′-(4-phenyl-5-(trifluoromethyl)thiophene-2-carbonyloxy)carbamimidoyl)benzyl)azetidine-3-carboxylate (744 mg, 1.33 mmol) in acetonitrile (30 mL) was added a 1M solution of TBAF in tetrahydrofuran (3.99 mL, 3.99 mmol), and the reaction mixture was allowed to stir at room temperature for 3 days. The volatiles were removed under reduced pressure, and the residue was chromatographed on a 5×12 cm silica gel column, eluting with a 0-50% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford tert-butyl 1-(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (521 mg, 0.962 mmol, 72.4% yield) as a colorless solid. HPLC ret. time=3.63 min. (YMC Combi S-5 4.6×50 mm ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=542.22. 1H NMR (500 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.25-3.31 (m, 3H), 3.52-3.58 (m, 2H), 3.69 (s, 2H), 7.43 (d, J=8.25 Hz, 2H), 7.47 (m, 5H), 7.91 (s, d, J=1.65 Hz, 1H), and 8.09 (d, J=8.25 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([O:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:27][CH2:26][C:21]4(OCC[O:22]4)[CH2:20][CH2:19]3)[C:13](=[O:28])[C@@H:12]2[CH2:29][O:30][CH3:31])=[O:10])=[CH:4][CH:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[S:6][C:5]([O:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:27][CH2:26][C:21](=[O:22])[CH2:20][CH2:19]3)[C:13](=[O:28])[C@@H:12]2[CH2:29][O:30][CH3:31])=[O:10])=[CH:4][CH:3]=1
Reactant: COC[C@H]1C(=O)N(CC2CCC3(CC2)OCCO3)CCN1C(=O)COc1ccc(Cl)s1
Solvent: O
Solvent: CC(=O)O
Product: COC[C@H]1C(=O)N(CC2CCC(=O)CC2)CCN1C(=O)COc1ccc(Cl)s1
Temperature: 65 °C
Yield: 94.8 %

Procedure:
4-[(5-Chloro-thiophen-2-yloxy)-acetyl]-1-(1,4-dioxa-spiro[4.5]dec-8-ylmethyl)-3-(S)-methoxymethyl-piperazin-2-one (2.8 g, 5.9 mmol) is placed in 80:20 acetic acid/water and heated at 65° C. for 0.2 h. The mixture is evaporated and is diluted with ethyl acetate (200 mL). The organic phase is washed with 1 N NaOH, is dried (MgSO4) and is evaporated to provide the intermediate title compound as a clear colorless oil (2.4 g, 95%). MS (ES), 429 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:16]=[C:17]([CH3:19])[CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C@H:3]1[O:20][CH3:21].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:16]=[C:17]([CH3:19])[CH:18]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C@H:3]2[O:20][CH3:21])=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1cc(C)cc(N2CC[C@H](N)[C@H](OC)C2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(C)cc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)c1
Yield: 76.4 %

Procedure:
The same operation as in Example (1g) was performed using ethyl cis(±)-3-(4-amino-3-methoxypiperidin-1-yl)-5-methylbenzoate obtained in Example (259g) (about 0.24 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (37 mg, 0.21 mmol), WSC hydrochloride (134 mg, 0.70 mmol), HOBT (47 mg, 0.35 mmol), dichloromethane (1.5 mL) and DMA (1.5 mL), to obtain 72 mg of the title compound as a colorless oily substance (75%).
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=O)[CH2:11][C@H:10]2[C:15]([NH:17][CH2:18][CH:19]([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])=[O:8])=[CH:3][CH:2]=1.O.[NH2:34][NH2:35]>>[C:1]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:34][NH2:35])[CH2:11][C@H:10]2[C:15]([NH:17][CH2:18][CH:19]([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])=[O:8])=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Solvent: O
Product: NN=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 63 %

Procedure:
Following the general method as outlined in Example 17, starting from (2S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-4-oxo-2-pyrrolidinecarboxamide and hydrazine hydrate (4% in EtOH), the resultant crude reaction mixture was purified by column chromatography using DCM/MeOH (30:1) to collect the desired product, e.g. (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-hydrazono-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide as a mixture of two isomers as a colorless solid in 63% yield (95.3% purity by HPLC).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[C:3]=1[NH2:23].[N:24]([O-])=O.[Na+]>>[Cl:1][C:2]1[C:3]2[N:23]=[N:24][N:9]([CH2:10][C:11]3[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1cc(CNc2nc(N)nc(Cl)c2N)cc(OC)c1OC
Reactant: O=N[O-]
Agent: [Na+]
Product: COc1cc(Cn2nnc3c(Cl)nc(N)nc32)cc(OC)c1OC

Procedure:
A solution of 6-chloro-N4-(3,4,5-trimethoxy-benzyl)-pyrimidine-2,4,5-triamine was treated with a cold aqueous solution of NaNO2, following the general procedure 2. HPLC RT was 5.755 min. 1HNMR (CDCl3): δ 6.66 (s, 2H), 5.55 (s, 2H), 5.42 (s, 2H), 3.83 (s, 3H), 3.80 (s, 6H).