Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH3:22].[CH3:23][S-:24].[Na+]>CN(C)C=O>[CH3:22][C:9]1[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:24][CH3:23])[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCCCCl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCCCCCn1c(C)nc2c(N)nc3ccccc3c21
Temperature: 160 °C
Yield: 57.1 %

Procedure:
1-(6-Chlorohexyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.5 g, 8 mmol), sodium thiomethoxide (1.13 g, 15.5 mmol) and N,N-dimethylformamide (15 mL) were combined and heated at 160° C. for 3 hours. The reaction was quenched with water and the precipitate isolated to provide 1.5 g of 2methyl-1-[6-(methylthio)hexyl]-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28](C)[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][O:33][C@H]1CC[C@H](N)CC1.C1(CCC(O)=O)C=CC=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:11]([CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:26][CH2:27]1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: CO[C@H]1CC[C@H](N)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: O=C(O)CCc1ccccc1
Product: CO[C@H]1CC[C@H](N(CCCc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using trans-4-methoxy-cyclohexylamine, 3-phenyl propionic acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][C:22]([F:31])([F:30])[CH:23]([F:29])[O:24][C:25]([F:28])([F:27])[F:26])=[N:4][N:5]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[CH:6]=1.ClC1C=CC=C(C(OO)=[O:40])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:21][C:22]([F:31])([F:30])[CH:23]([F:29])[O:24][C:25]([F:26])([F:27])[F:28])=[N:4][N:5]([C:7]2[CH:12]=[C:11]([S:13]([CH2:14][C:15]([F:18])([F:17])[F:16])=[O:40])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(F)c(-n2cc(Cl)c(OC(F)(F)C(F)OC(F)(F)F)n2)cc1SCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2cc(Cl)c(OC(F)(F)C(F)OC(F)(F)F)n2)cc1S(=O)CC(F)(F)F
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
0.24 g of 4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 0.11 g of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.21 g of 4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C@H:20]([OH:22])[CH2:19][C@@H:18]3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[N:13][C:12]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[C:1]([NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C:20](=[O:22])[CH2:19][C@@H:18]3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[N:13][C:12]=12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cnn2ccc(N3CC(=O)C[C@@H]3c3cccc(F)c3)nc12
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
N-tert-butyl-5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 42, 10 mg, 0.025 mmol) and the Dess-Martin reagent (16 mg, 0.038 mmol) in DCM (2.0 mL) were stirred at ambient temperature overnight. 1N NaOH (2.5 mL) was added and the reaction stirred for 30 minutes. Brine (2.5 mL) was added and the reaction was filtered through a phase separator frit, washing with several portions of DCM. The DCM solution was concentrated and the residue purified by reverse phase chromatography (20-70% acetonitrile/water) to provide the title compound (2.7 mg, 27% yield) as a clear oil. MS (apci) m/z=396.0 (M+H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][C@@H:10](O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C[I:50]>C1COCC1>[CH3:16][O:15][C:13]([C@@H:12]1[CH2:11][C@H:10]([I:50])[CH2:9][N:8]1[C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])=[O:14]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CI
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](I)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 91 %

Procedure:
To a round-bottom flask equipped with a magnetic stir bar and an addition funnel under N2 was added N-Boc-L-trans-4-hydroxy-proline methyl ester (60 mmol, 1 equiv), P(Ph)3 (72 mmol, 1.2 equiv) and anhydrous THF (275 ml). The solution was cooled to 0 centigrade, DEAD (1.2 equiv) in dry THF was added dropwise; followed by the addition of MeI (1.2 equiv). Upon addition of MeI, the solution turned from dark brown to bright yellow. The reaction mixture was allowed to warm to ambient temperature and stirred for 10 hours. The solvent was removed under reduced pressure and the crude oil was purified by chromatography on silica gel to afford title product (19.44 g) as colorless oil in 91% yield. MS m/e=356.4 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].O.[NH2:18][C:19]1[N:28]=[C:27]([C:29]([N:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32]2)=[O:30])[C:26]2[C:21](=[CH:22][CH:23]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[N:20]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:18][C:19]1[N:28]=[C:27]([C:29]([N:31]2[CH2:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:39]2)=[O:30])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:2]3[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=3[CH:4]=[O:5])[CH:25]=2)[N:20]=1
Reactant: O=Cc1cc(F)ccc1Br
Reactant: CC1(C)OB(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccc(F)cc3C=O)ccc2n1
Temperature: 120 °C

Procedure:
244 mg of 2-bromo-5-fluorobenzaldehyde, 1.7 g of potassium carbonate, 87 μl of water and 196 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are added to a solution of 2 g of [2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 200 ml of ethanol under argon. The mixture is heated at 120° C. for 30 min; the hot mixture is filtered through kieselguhr, and the filtrate is evaporated. The residue obtained is triturated with 2 ml of acetonitrile, and the precipitate formed is filtered off with suction.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[C:30]([CH2:31][CH2:32]O)=[C:29]([F:34])[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>C(Cl)Cl.CCCCCC>[Br:20][CH2:32][CH2:31][C:30]1[C:23]([Cl:22])=[C:24]([CH:27]=[CH:28][C:29]=1[F:34])[C:25]#[N:26]
Reactant: N#Cc1ccc(F)c(CCO)c1Cl
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: N#Cc1ccc(F)c(CCBr)c1Cl
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a 25 mL round bottomed flask equipped with a magnetic stirrer was added triphenylphosphine (1.57 g, 6 mmol) and methylene chloride (8 mL). Upon cooling the mixture to −10° C., bromine (0.28 mL, 5.5 mmol) was added dropwise. After 10 min, 2-chloro-4-fluoro-3-(2-hydroxyethyl)benzonitrile (1 g, 5 mmol) in methylene chloride (6 mL) was added and stirring was continued for 20 min while the internal reaction temperature was allowed to warm to 15° C. The mixture was then diluted with hexane (30 mL) and purified via a silica plug [hexane-Et2O (20:1) as eluent]. The combined filtrates were concentrated to furnish the title compound (1.26 g, 96%): 1H NMR (400 MHz, Acetone-d6, δ in ppm) 7.92 (dd, J=6 and 9 Hz, 1H), 7.42 (t, J=9 Hz, 1H), 3.70 (t, J=7 Hz, 2H), 3.13 (dt, J=2 and 7 Hz, 2H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:44])([CH3:43])[C@@H:14]([O:35]CC1C=CC=CC=1)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:34])[C:22]([CH3:33])([CH3:32])[CH2:23][O:24]CC1C=CC=CC=1)=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]>[Pd].CO>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:44])([CH3:43])[C@@H:14]([OH:35])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:34])[C:22]([CH3:32])([CH3:33])[CH2:23][OH:24])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)C(C)(C)COCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCOC(=O)C(C)(C)CO
Reaction time: 8 h
Yield: 25.1 %

Procedure:
Following the general procedure of hydrogenolysis of benzyl ethers of Description 18, a mixture of [2,2-dimethyl-3-(phenylmethoxy)propanoyloxy]ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate (46c) (0.13 g, 0.21 mmol) and 75 mg of 10 wt.-% of palladium on activated carbon in 6 mL of methanol (MeOH) was stirred overnight under a hydrogen atmosphere. After work-up and further purification by mass-guided preparative HPLC, 24 mg (25% yield) of the title compound (46) was obtained as a colorless, viscous oil. 1H NMR (400 MHz, CDCl3, both diastereomers): δ=0.96-0.99 (2s, 3H), 1.10-1.11 (2s, 3H), 1.18 (s, 3H), 1.20-1.21 (2s, 3H), 1.55-1.57 (2d, J=5.2, 5.6 Hz, 3H), 1.98-1.99 (2s, 3H), 2.03-2.12 (m, 2H), 2.54-2.68 (br. m, 1H), 3.11-3.29 (m, 2H), 3.30-3.51 (m, 3H), 3.51-3.63 (m, 2H), 3.93-3.96 (2d, J=8.8, 9.2 Hz, 1H), 4.05-4.07 (m, 1H), 4.14-4.17 (2d, J=9.6, 9.6 Hz, 1H), 5.92-5.98 (br. m, 1H), 6.91-6.98 (m, 1H) ppm. MS (ESI) m/z: 456.07 (M+H)+, 478.02 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14].Cl[CH2:17][S:18]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].CC(C)([O-])C.[K+].Cl>C1COCC1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([N+:13]([O-:15])=[O:14])=[C:7]([CH2:17][S:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:20])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Reactant: COc1ccc([N+](=O)[O-])c(OCCCl)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(CS(=O)(=O)c2cccc3ccccc23)c([N+](=O)[O-])c(OCCCl)c1
Reaction time: 4 h
Yield: 76.7 %

Procedure:
A mixture of 2-(2-chloro-ethoxy)-4-methoxy-1-nitrobenzene (1.4 g, 6 mmoles) and 1-chloromethane-sulfonyl-naphthalene (1.4 g, 6 mmoles) was stirred in THF (50 mL) at −78° C., in a round bottom flask under nitrogen. A solution of 1M potassium t-butoxide was added dropwise (18 mL, 18 mmoles) over a half an hour period. Temperature was allowed to rise to −40° C., and the reaction mixture was stirred at this temperature for 4 hours. The reaction mixture was poured into cold 2N HCl, extracted with EtOAc, dried over Na2SO4, and concentrated under vacuum. Compound was recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid (2 g, 4.6 mmoles).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]2[NH:30][CH2:29][CH:26]1[CH2:27][CH2:28][O:23][CH2:24][CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1Cl
Reactant: NCC1CCOCC1
Product: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1NCC1CCOCC1

Procedure:
The method described in Part E of Example 1 can be used to treat 7-benzyloxy-4-chloro-3-nitroquinoline with tetrahydro-2H-pyran-4-ylmethylamine to provide (7-benzyloxy-3-nitroquinolin-4-yl)(tetrahydro-2H-pyran-4-ylmethyl)amine. The same method can be used to treat 6-benzyloxy-4-chloro-3-nitroquinoline with tetrahydro-2H-pyran-4-ylmethylamine to provide (6-benzyloxy-3-nitroquinolin-4-yl)(tetrahydro-2H-pyran-4-ylmethyl)amine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[N:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:5]2[N:11]=[C:10]([C:12](/[N:14]=[CH:23]/[N:24]([CH3:26])[CH3:25])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Solvent: Cc1ccccc1
Product: CN(C)/C=N/C(=O)c1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Temperature: 95 °C

Procedure:
2-Chloro-4-morpholinopyrido[3,2-d]pyrimidine-6-carboxamide (90 mg) was suspended in toluene (5 mL) and treated with 1,1-dimethoxy-N,N-dimethylmethanamine (11 eq). The reaction was heated at 95° C. overnight then concentrated to dryness to afford crude (E)-2-chloro-N-((dimethylamino)methylene)-4-morpholinopyrido[3,2-d]pyrimidine-6-carboxamide. This intermediate was subsequently brought up in acetic acid (1.4 mL), isopropyl hydrazine hydrochloride was added and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated to dryness then extracted with DCM and a saturated bicarbonate solution. The organic layer was dried (Mg2SO4), filtered and concentrated to give 0.11 g crude 4-(2-chloro-6-(1-isopropyl-1H-1,2,4-triazol-5-yl)pyrido[3,2-d]pyrimidin-4-yl)morpholine.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44]N)=[CH:40][CH:39]=1>>[CH3:36][O:37][C:38]1[CH:39]=[C:40]2[C:41](=[CH:42][CH:43]=1)[NH:44][C:22]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=1)=[C:21]2[CH2:20][CH2:19][CH2:18][N:15]1[CH2:14][CH2:13][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:34])[CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH2:17][CH2:16]1
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Agent: Cl
Product: COc1ccc2[nH]c(-c3ccc(C(F)(F)F)cc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl)phenyl]pentyl}-4-piperidinyl)phenyl]propanamide and 4-methoxyphenylhydrazine hydrochloride: ESMS m/e: 578.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]1[CH:14]([CH3:16])[S:15][C:7]1=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22].Cl.[F:24][C:25]([F:35])([F:34])[C:26]([NH:28][C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=[O:27].C1CCN2C(=NCCC2)CC1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:31]1[CH2:32][CH2:33][C@H:29]([NH:28][C:26](=[O:27])[C:25]([F:35])([F:34])[F:24])[CH2:30]1)[N:8]1[CH:14]([CH3:16])[S:15][C:7]1=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: O=C(N[C@H]1CCNC1)C(F)(F)F
Reactant: CCOC(=O)c1c2n(c3c(F)c(F)c(F)cc3c1=O)C(C)S2
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c2n(c3c(F)c(N4CC[C@H](NC(=O)C(F)(F)F)C4)c(F)cc3c1=O)C(C)S2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1.34 g of ethyl 6,7,8-trifluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate, 2.66 g of (S)-3-trifluoroacetylaminopyrrolidine hydrochloride [[α]D20 -28.6° (c=1, MeOH)], 1.80 g of 1.8-diazabicyclo[5,4,0]-7-undecene and 30 ml of N,N-dimethylformamide was stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo, and water was added to the residue. The precipitate was collected by filtration and was chromatographed on silica gel using chloroform-methanol (8:2) to give the desired compound, which was recrystallized from methanol to give 0.80 g of pale yellow needles, m.p. 219°-224° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15](=[O:17])[CH3:16]>[Au].ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:8]=[C:9]1[CH2:10][CH2:11][CH2:12][C:13]1=[C:14]2[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)C#CCCCC=Cc1ccccc1Cl
Agent: [Au]
Solvent: Clc1ccccc1Cl
Product: CC(=O)c1c2c(cc3c(Cl)cccc13)CCC2
Temperature: 180 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A microwave irradiation vial (10-20 mL) was equipped with a sir bar (1.5 cm) and was charged with compound 5c (0.20 g, 0.81 mmol) and 1,2-dichlorobenzene (13.5 mL). The reaction was irradiated with stirring at 180° C. for 3 h, turning gold in color. The solution was directly added to a silica gel column, which was eluted with n-hexane to separate the 1,2-dichlorobenzene and then AcOEt/n-hexane 1:9 to collect the pure product. The title compound was isolated as a yellow solid in a 86% yield (0.17 g).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C:7]([O:11][CH3:12])(=[O:10])[CH2:8][SH:9].N1CCCCC1>>[CH3:6][O:5][C:1](=[O:4])[CH2:2][CH2:3][S:9][CH2:8][C:7]([O:11][CH3:12])=[O:10]
Reactant: C=CC(=O)OC
Reactant: COC(=O)CS
Solvent: C1CCNCC1
Product: COC(=O)CCSCC(=O)OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Methyl acrylate (99.16 mL, 1.1 mol) was added slowly to a solution of methyl thioglycolate (91 mL, 1 mol) and piperidine (2 mL) while maintaining the temperature of reaction mixture at 50° C. The reaction mixture was stirred at 50° C. for 2 h. Excess methyl acrylate and piperidine were distilled off under high vacuum to yield 192 g (99%) of 3-methoxycarbonylmethylsulfanyl-propionic acid methyl ester as a colorless viscous oil. 1H NMR (400 MHz, CDCl3) δ 2.63 (d, J=7.2 Hz, 2H), 2.89 (d, J=7.2 Hz, 2H), 3.24 (s, 2H), 3.68 (s, 3H), 3.72 (s, 3H) ppm.
Reaction SMILES: [N:1]1[N:2]=[C:3]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[N:20]=[C:19]([NH2:21])[C:18]([N+:22]([O-])=O)=[CH:17][CH:16]=3)[CH2:10]2)[N:4]2[CH2:8][CH2:7][CH2:6][C:5]=12.[CH:25]1([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=O)[N:29]=2)[CH2:27][CH2:26]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)C>O>[CH:25]1([C:28]2[N:29]=[C:30]([C:34]3[NH:21][C:19]4=[N:20][C:15]([N:11]5[CH2:12][CH2:13][CH2:14][CH:9]([C:3]6[N:4]7[CH2:8][CH2:7][CH2:6][C:5]7=[N:1][N:2]=6)[CH2:10]5)=[CH:16][CH:17]=[C:18]4[N:22]=3)[CH:31]=[CH:32][CH:33]=2)[CH2:27][CH2:26]1
Reactant: O=Cc1cccc(C2CC2)n1
Reactant: Nc1nc(N2CCCC(c3nnc4n3CCC4)C2)ccc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1cc(-c2nc3ccc(N4CCCC(c5nnc6n5CCC6)C4)nc3[nH]2)nc(C2CC2)c1
Temperature: 110 °C
Yield: 20.6 %

Procedure:
A mixture of 6-(3-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)piperidin-1-yl)-3-nitropyridin-2-amine (Intermediate 45) (300 mg, 0.91 mmol), 2-cyclopropylpyridine-6-aldehyde (187.5 mg, 1.27 mmol), sodium dithionite (602.6 mg, 4.46 mmol), ethanol (15 mL) and water (2.4 mL) in a sealed tube was heated to 110° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was and purified via preparative TLC to afford the title compound (80 mg, 21%) as a racemic mixture. MS (ES+) (M+H) 427.3; LCMS retention time 2.687 min (Method J). 1H NMR (400 MHz, CDCl3) δ 1.02-1.15 (m, 4H), 1.73-1.82 (m, 1H), 1.89-2.13 (m, 3H), 2.21 (d, 1H), 2.74-2.85 (m, 2H), 2.94-3.01 (m, 2H), 3.02-3.12 (m, 2H), 3.21-3.32 (m, 1H), 3.91-4.10 (m, 2H), 4.33 (d, 1H), 4.65 (d, 1H), 6.75 (d, 1H), 7.20 (d, 1H), 7.66 (t, 2H), 7.88 (d, 1H), 8.05 (d, 1H), 10.20 (br s, 1H).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]([O:20][CH:21]([O:28][C:29]([NH:31][CH2:32][C:33]1([CH2:39][C:40]([O:42]CCC#N)=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:12]([O:20][CH:21]([O:28][C:29]([NH:31][CH2:32][C:33]1([CH2:39][C:40]([OH:42])=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#CCCOC(=O)CC1(CNC(=O)OC(OC(=O)c2ccccc2)c2ccccc2)CCCCC1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)CC1(CNC(=O)OC(OC(=O)c2ccccc2)c2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.7 %

Procedure:
DBU (79.2 mg, 78 μL, 0.520 mmol) was added to a solution of 2-cyanoethyl 1-{[α-benzoyloxybenzyloxy)carbonyl]aminomethyl}-1-cyclohexane acetate (11) (166 mg, 0.347 mmol) in 10 mL of CH2C1 at −10° C. The reaction mixture was stirred at 0° C. for 1 hour, then allowed to warm to room temperature, stirred for two hours and cooled to 0° C. Another 78 μL of DBU was added, the reaction mixture was stirred for 3 hours at 0° C. and then allowed to warm to room temperature. The reaction mixture was diluted with CH2Cl2, washed with citric acid and brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by reversed phase HPLC to afford 7 mg (4.7%) of the title compound. M.p. 75.5-76.0° C. 1H NMR (CDCl3): δ 8.08 (2H, dd, J=8.8, 1.2 Hz); 7.89 (1H, s); 7.63-7.55 (3H, m); 7.46-7.26 (5H, m); 5.38 (1H, t, J=6.8 Hz); 3.26 (2H, dd, J=6.8, 0.8 Hz); 2.34 (2H, s); 1.58-1.35 (10H, m). MS (ESI) m/z 424 (M−H−).
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20]CC)=[O:19])=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[CH2:23]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)=[O:10])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1ccc(NC(=O)N(Cc2ccccc2)Cc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NC(=O)N(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
A solution of 5.61 g. of 1,1-dibenzyl-3-(4-carboethoxyphenyl)urea in 100 ml of ethanol is treated with 25 ml of 1 N aqueous sodium hydroxide solution, stirred under reflux for 16 hours, allowed to cool, acidified with 1 N hydrochloric acid, and filtered. The solid is recrystallized from ethanol to yield 1,1-dibenzyl-3-(4-carboxyphenyl)urea as a white solid, mp 210°-214°.