Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([NH:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:69])[C:58]2[CH:63]=[C:62]([C:64]([F:67])([F:66])[F:65])[CH:61]=[CH:60][C:59]=2[Cl:68])[CH2:53][CH2:52]1)=[O:50].Cl>CN(C=O)C.O>[Cl:68][C:59]1[CH:60]=[CH:61][C:62]([C:64]([F:67])([F:65])[F:66])=[CH:63][C:58]=1[C:57]([N:54]1[CH2:53][CH2:52][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:21](=[O:23])[C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:25][CH:24]=2)[CH2:56][CH2:55]1)=[O:69]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)ccc2Cl)CC1)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
DIPEA (74 mg, 0.1 mL, 0.63 mmol) was added drop wise to 4-(phenyl-amino)-benzoic acid (45 mg, 0.21 mmol) in DMF (5 mL). EDCI (100 mg, 0.52 mmol) and HOBT (34 mg, 0.25 mmol) were added consecutively and, after 10 minutes, 2-amino-1-[4-(2-chloro-5-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (97 mg, 0.25 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 70% EtOAc in Hexane as eluent) to afford 60 mg (52% yield) of N-{2-[4-(2-chloro-5-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenylamino-benzamide. LC-MS purity: 98.43%. 1H-NMR (DMSO-d6): δ 8.6 (s, 1H), 8.3 (t, 1H), 7.9 (d, 1H), 7.8 (m, 4H), 7.3 (t, 2H), 7.2 (d, 2H), 7.1 (d, 2H), 6.9 (t, 1H), 4.1 (dd, 2H), 3.6 (m, 6H), 3.2 (m, 2H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11].C(O)=O>>[CH:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:3]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC(C)[C@H](NC=O)C(=O)O
Temperature: 25 °C

Procedure:
Acetic anhydride (4 mL, 0.04 mol) was added dropwise to a solution of L-Valine (1 g, 8.35 mmol) in formic acid (12 mL, 0.32 mol) while stirring on ice. The mixture was then warmed up to RT and kept stirring for 24 hours before the solvent was removed by rotary evaporation under high vacuum. The formyl-valine was recrystallized from ethyl acetate and the desired product was obtained as a white solid. Yield: 0.78 g (64%) 1HNMR (500 MHz, [D6]Acetone, 25° C., TMS): δ=8.22 (s, 1H), 7.41 (b, 1H), 4.50 (m, 1H), 2.22 (m, 1H), 0.98 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13](Cl)=[O:14].[CH3:22][NH2:23].O>CCOCC>[CH3:22][NH:23][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:10]([S:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:11]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Reactant: CN
Solvent: O
Solvent: CCOCC
Product: CNC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(2,4-difluorophenylthio)-4-nitrobenzoyl chloride (1.2 g) in ether (8 ml) was added to a stirred mixture of 40% methylamine (2 ml), water (8 ml) and ether (5 ml) at 0° to 5° C. The mixture was stirred at the same temperature for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, dried and concentrated. The oily residue was crystallized from a mixture of ethyl acetate and hexane to give crystals of N-methyl-3-(2,4-difluorophenylthio)-4-nitrobenzamide (0.7 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f54) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[NH:12][N:11]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:18][N:19]([CH3:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(O)CCC.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[NH:12][N:11]=2)=[N:4][C:5]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([N:19]([CH3:28])[CH3:18])=[CH:21][CH:22]=2)=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(CN)cc1
Reactant: Clc1ncc(Br)c(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(CNc2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)cc1
Temperature: 170 °C
Yield: 28.9 %

Procedure:
A mixture of 5-bromo-2-chloropyrimidin-4-yl-(5-cyclopropyl-1H-pyrazol-3-yl)-amine (313 mg, 1.00 mmol) and 4-dimethylaminobenzylamine (225 mg, 1.5 mmol) in 1-butanol (20 mL) was heated to 170° C. in a 50 mL sealed tube for 3 h. The mixture was cooled and diluted with ethyl acetate. The organic layer was washed with 2 N sodium hydroxide, water and brine and dried over sodium sulfate. The solution was concentrated, redissolved in DMF and purified by preparative reverse phase HPLC to give the desired product (124 mg, 29%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17]([CH2:20]OS(C)(=O)=O)[C:16]2=[O:26])=[CH:11][CH:10]=1.[CH3:27][O:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(#N)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17]([CH2:20][N:34]3[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][O:28][CH3:27])[CH2:32][CH2:33]3)[C:16]2=[O:26])=[CH:11][CH:10]=1
Reactant: COCCN1CCNCC1
Reactant: CS(=O)(=O)OCC1CCN(c2ccc(Cl)cc2)C1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCN1CCN(CC2CCN(c3ccc(Cl)cc3)C2=O)CC1
Yield: 86.3 %

Procedure:
Triethylamine (8.0 g) was added to a solution of 18.5 g of 1-(4-chlorophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 17.6 g of 1-(2-methoxyethyl)piperazine in 50 mL of acetonitrile, and the mixture was heated under reflux for 4 hours. After concentrating, water was added to the reaction mixture to precipitate crystals, which were then collected by filtration and dried in vacuo to give 18.5 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([O:16]CC2C=CC=CC=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Cc1cc2ccc(F)cc2c(O)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A round-bottom flask was charged with (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (11.7 g, 34.58 mmol) in ethanol (350 mL). Some heating was required in order to dissolve all of the starting material in ethanol. A full spatula scoop of 10% palladium on carbon was added into the reaction flask. The reaction mixture was stirred under hydrogen gas at atmospheric pressure overnight at room temperature. After this time, it appeared that approximately 750 mL hydrogen gas had been consumed, and TLC (1:3 ethyl acetate, hexanes) indicated that the starting material had been consumed. The reaction mixture was filtered through a bed of celite. The filtrate was concentrated to afford 7.91 g (92%) of (6-fluoro-4-hydroxy-3-methyl-naphthalen-2-yl)-acetic acid methyl ester, which was used in the next step without further purification. MS (ES−) cald. for C14H13FO3 [(M−H)−] 247, obsd. 247.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([C:23](=O)[CH2:24][CH2:25][CH3:26])[C:18](OCC)=[O:19])=[CH:12][CH:11]=1)#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][C:42]([CH3:44])=[N:41][N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([N:38]3[C:18](=[O:19])[C:17]([CH2:16][C:13]4[CH:12]=[CH:11][C:10]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][C:7]([F:9])=[CH:6][CH:5]=5)=[CH:15][CH:14]=4)=[C:23]([CH2:24][CH2:25][CH3:26])[N:40]4[N:41]=[C:42]([CH3:44])[N:43]=[C:39]34)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1
Reactant: Cc1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccc(F)cc2C#N)cc1)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(Cc2ccc(-c3ccc(F)cc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Temperature: 180 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-4′-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (2.9 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-5-methyl-4H-1,2,4-triazol-3-amine (0.93 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) and N,N-diethylaniline (30 mL) was stirred at 180° C. for 16 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.1 g, 48%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[N:15]=[C:14]([I:20])[C:13]([CH:21]=[O:22])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[N:15]=[C:14]([I:20])[C:13]([CH2:21][OH:22])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc2cc(OCc3ccccc3)c(F)cc2nc1I
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc2cc(OCc3ccccc3)c(F)cc2nc1I

Procedure:
A suspension of 6-benzyloxy-7-fluoro-2-iodo-3-quinolinecarbaldehyde (obtained according to 1.e, 13 g, 32 mmol) in methanol (100 ml) is treated with sodium borohydride (1.85 g, 48 mmol). After 1 hour of reaction, the reaction medium is concentrated under reduced pressure then taken up with water, filtered, washed with water and ethanol in order to produce, after drying under reduced pressure, 10 g (76%) of a white solid, m.p. 188° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:14])[F:13])[C:3]=1[C:18]([OH:20])=O.S(Cl)(Cl)=O.C[N:26](C)C=O>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:14])[F:13])[C:3]=1[C:18]([NH2:26])=[O:20]
Reactant: CN(C)C=O
Reactant: COc1ccc2c(C(=O)O)c(Br)ccc2c1C(F)(F)F
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(C(N)=O)c(Br)ccc2c1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.58 h

Procedure:
A suspension of 2-bromo-6-methoxy-5-trifluoromethyl-1-naphthoic acid (2.0 g, 5.73 mmol, prepared by the process of Example 11, Step 2), thionyl chloride (11 mL) and dimethylformamide (40 μl, 0.095 eq) was heated with stirring at 60° C. under a dry N2 atmosphere for 35 minutes. The reaction mixture was cooled to room temperature and the thionyl chloride was removed. The solid residue was dissolved in THF (20 mL) and this solution was added dropwise to stirred, cold (0°-5° C.) ammonium hydroxide over a 5 minute period. After 15 minutes water (100 mL) was added and the suspension was filtered. The solid was washed with water and dried in vacuo to yield the title compound as a white solid in (1.80 g, 90%)
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([CH2:15][O:16]C(=O)C2C=CC=CC=2)[O:13][C@H:12]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:11]1)(=O)C1C=CC=CC=1>CO.O>[C@H:12]1([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[O:13][C@@H:14]([CH2:15][OH:16])[C@@H:10]([OH:9])[CH2:11]1
Reactant: O=C(OC[C@@H]1O[C@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: CO
Solvent: O
Product: O=c1[nH]c(=O)n([C@@H]2C[C@H](O)[C@H](CO)O2)cc1F
Yield: 85 %

Procedure:
A solution of 1-(3,5-di-O-benzoyl-2-deoxy-β-L-xylofuranosyl)-5-fluorouracil (6b) (0.25 g, 0.55 mmol) in ammoniacal methanol (25 ml) is stirred overnight at room temperature. The solution is evaporated under reduced pressure and the residue is evaporated several times with methanol. The crude material obtained is dissolved in water and the resulting solution is washed several times with chloroform. The aqueous phase is evaporated and the residue is directly crystallized from methanol to give 115 mg (yield 85%) of pure 7b: m.p.=198-200° C.; UV [EtOH 95] λmax 267 nm (ε, 8500), λmin 233 nm (ε, 2100); 1H NMR (DMSO-d6) δ ppm=11.79 (s, 1H, 3-NH), 8.16 (d, 1H, H-6; J=7.4 Hz), 6.05 (dd, 1H, H-1′; J=1.8 and 6.5 Hz), 5.38 (d, 1H, OH-3′; J=3.3 Hz), 4.73 (t, 1H, OH-5′; J=5.4 Hz), 4.30-4.20 (m, 1H, H-3′), 3.85-3.60 (m, 3H, H-4′,5′ and 5″), 2.60-2.50 (m, 1H, H-2′ partially obscured by DMSO-d5), 1.90 (dd, 1H H-2″; J=1.8 and 14.7 Hz); mass spectra (matrix: glycerol-thioglycerol, 50:50, v/v): FAB>0 339 [M+glycerol+H]+, 247 [M+H]+, 131 [BH2]+ and 115 [s]+; FAB<0 245 [M−H]− and 129 [B]−.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([Cl:12])[N:3]=1.CCN(C(C)C)C(C)C.[CH:22]([O:25][C:26]1[NH:30][N:29]=[C:28]([NH2:31])[CH:27]=1)([CH3:24])[CH3:23]>C1COCC1>[Cl:8][C:7]1[C:2]([NH:31][C:28]2[CH:27]=[C:26]([O:25][CH:22]([CH3:24])[CH3:23])[NH:30][N:29]=2)=[N:3][C:4]([Cl:12])=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)nc1Cl
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Nc2nc(Cl)c([N+](=O)[O-])cc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 120 h
Yield: 18.1 %

Procedure:
To a mixture of 2,3,6-trichloro-5-nitropyridine (2.61 g, 11.4 mmol) and DIEA (1.90 ml, 11.4 mmol) in THF (50 ml) was added 5-isopropoxy-1H-pyrazol-3-amine (1.20 g, 8.50 mmol) at 0° C. After addition, the reaction mixture was stirred at 25° C. for 5 days. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.51 g, 18%). 1H NMR (400 MHz) δ 12.22 & 11.35 (s, 1H), 10.12 & 9.80 (s, 1H), 8.64 & 8.54 (s, 1H), 5.95 & 5.84 (s, 1H), 4.70 & 4.46 (m, 1H), 1.27-1.32 (m, 6H). MS: Calcd.: 331. Found: [M+H]+ 332.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([O:22][CH3:23])=[N:16][N:17]([CH2:20][CH3:21])[C:18]=2[CH3:19])[CH2:10][CH2:9]1)=O)(C)(C)C.N1CCCCC1>>[CH2:20]([N:17]1[C:18]([CH3:19])=[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15]([O:22][CH3:23])=[N:16]1)[CH3:21]
Reactant: CCn1nc(OC)c(C2CCN(C(=O)OC(C)(C)C)CC2)c1C
Solvent: C1CCNCC1
Product: CCn1nc(OC)c(C2CCNCC2)c1C

Procedure:
The title compound was prepared from 1-tert-butoxycarbonyl-4-(1-ethyl-3-methoxy-5-methyl-(1H)-pyrazol-4-yl)piperidine (Step E) using a procedure analogous to that described for Piperidine 14, Step F. 1H-NMR (500 MHz) δ 1.33 (t, J=7.2, 3H), 1.61–1.64 (m, 2H), 1.89–1.98 (m, 2H), 2.17 (s, 3H), 2.42–2.49 (m, 1H), 2.68–2.73 (m, 2H), 2.90 (m, 1H),3.19–3.22 (m, 2H), 3.87 (s, 3H), 3.92 (q, J=7.2, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:32])[CH3:31])[CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[O:21])[C:15]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45](Cl)(=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:30]([CH3:31])[CH3:32])[CH:24]([O:29][C:45](=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47])[C:25]([F:26])([F:27])[F:28])=[O:21])[C:15]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)C(NC(=O)Cn1c(-c2cccs2)ncc(NC(=O)OCc2ccccc2)c1=O)C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)C(NC(=O)Cn1c(-c2cccs2)ncc(NC(=O)OCc2ccccc2)c1=O)C(OC(=O)C(C)(C)C)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 2-[5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide (1.95 g), triethylamine (1.4 mL), and 4-dimethylaminopyridine (10 mg) in dichloromethane (35 mL) was added pivaloyl chloride (0.53 mL); and the resulting solution allowed to stir for 2 h. The solution was diluted with ethyl acetate, washed (saturated aqueous sodium bicarbonate (twice), saturated aqueous ammonium chloride, and brine), dried, and evaporated. Purification by chromatography, eluting with ethyl acetate:dichloromethane (10:90), afforded the ester (1.80 g) as a white foam; TLC: Rf =0.34, ethyl acetate:dichloromethane (10:90); MS: m/z=623(M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12]C=CC=2)[N:5]=[C:4]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])C)[CH:3]=1.ClC1C=C(Cl)N=[C:23]([C:28]2C=CC=[CH:30][CH:29]=2)N=1.ClC1C=C(Cl)N=C(CCC)N=1.C(C(CCCC)CO)C>CC(C)CCO>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:13][CH3:12])[N:5]=[C:4]([O:14][CH2:15][CH:16]([CH2:17][CH3:19])[CH2:23][CH2:28][CH2:29][CH3:30])[CH:3]=1
Reactant: CC(C)CCOc1cc(Cl)nc(-c2ccccc2)n1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Agent: CCCc1nc(Cl)cc(Cl)n1
Solvent: CCCCC(CC)CO
Solvent: CC(C)CCO
Product: CCCCC(CC)COc1cc(Cl)nc(CCC)n1

Procedure:
The compound of Example 21 is prepared analogously to the compound of Example 3, with 4,6-dichloro-2-phenylpyrimidine being replaced by 4,6-dichloro-2-propylpyrimidine and 3-methylbutanol by 2-ethylhexanol.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[C@H:3]([NH:31][C:32](=[O:35])[O:33][CH3:34])[C:4](=[O:30])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1.Br[C:38]1[CH:39]=[C:40]2[C:63](=[CH:64][CH:65]=1)[C:44]1[NH:45][C:46]([C@@H:48]3[CH2:52][C@H:51]([CH2:53][O:54][CH3:55])[CH2:50][N:49]3[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[N:47][C:43]=1[CH:42]=[CH:41]2.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:34][O:33][C:32]([NH:31][C@@H:3]([CH:2]([CH3:36])[CH3:1])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:38]3[CH:39]=[C:40]4[C:63](=[CH:64][CH:65]=3)[C:44]3[NH:45][C:46]([C@@H:48]5[CH2:52][C@H:51]([CH2:53][O:54][CH3:55])[CH2:50][N:49]5[C:56]([O:58][C:59]([CH3:62])([CH3:60])[CH3:61])=[O:57])=[N:47][C:43]=3[CH:42]=[CH:41]4)=[CH:19][CH:20]=2)=[CH:13][N:14]=1)=[O:30])=[O:35]
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(Br)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc(-c6cnc([C@@H]7CCCN7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc5)ccc4c3[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 85 °C
Yield: 49.7 %

Procedure:
Methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (260 mg, 0.524 mmol), (2S,4S)-tert-butyl 2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (201 mg, 0.437 mmol), Pd(PPh3)4 (50 mg, 0.0437 mmol) and K2CO3 (2 M in H2O, 0.55 mL, 1.1 mmol) were combined in DME (4 mL). The reaction mixture was degassed with bubbling N2, then heated to 85° C. for 5 h. Upon completion, the reaction mixture was cooled to RT, diluted with 5 mL MeOH, filtered and concentrated. The crude residue was purified by silica column chromatography (0% to 45% MeOH/EtOAc) to afford (2S,4S)-tert-butyl 2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (163 mg, 50%).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1[O:10]C=[C:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2.[N+](C1C=C(C)[N+]([O-])=CC=1)([O-])=O.[K+].[Br-]>>[CH2:1]([S:8][C:15]1[CH:14]=[C:13]([CH3:12])[N+:9]([O-:10])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2nocc2c1
Reactant: SCc1ccccc1
Agent: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [Br-]
Agent: [K+]
Product: Cc1cc(SCc2ccccc2)cc[n+]1[O-]
Temperature: 0 °C
Yield: 30 %

Procedure:
Mineral oil was removed from potassium hydride (0.11M; 35 wt. % dispersion in mineral oil) by several washings with petroleum ether (5×50 ml). The remaining petroleum ether was removed under vacuum. To this dry solid, 350 ml of anhydrous THF was added cautiously. The well stirred suspension was cooled to 0° C. To this mixture, 14.1 ml (0.12 mol) of benzylmercaptan was added dropwise over a period of 30 minutes. The resultant milky white mixture was warmed to room temperature and allowed to stir for an additional 30 minutes. The mixture was then cooled to -30° C., and 15 41 g (0.1 mol) of 4-nitro 2-picoline-N-oxide was added portionwise. The mixture became dark orange-brown in color. Once warmed to room temperature, the mixture was refluxed for one hour. At this time, the reaction was cooled to 0° C. and quenched with 50 ml of water. The pH of the mixture was adjusted to approximately 6 with 2M HCl, and extracted with dichloromethane (3×300 ml). The combined organic layers were dried (anhydrous Na2SO4), and the solvent was removed under reduced pressure. The crude residue was chromatographed on flash silica gel with MeOH/CH2Cl2 (Gradient: 3:97, 4:96, 5:95). The pure product was isolated (6.94 g; 30% yield) as a tan solid: M.P. 98°-99° C.; IR (KBr) 3063, 3028, 1612, 1466, 1236, 831, 715, 675 cm-1 ; 1H NMR (CDCl3) δ 2.45 (s, 3H), 4.16 (s, 2H), 6.97 (dd, 1H, J=6.8, 2.7 Hz), 7.07 (d, 1H, J=2.7 Hz), 7.32 (m, 5H), 8.09 (d, 1H, J=6.8 Hz). Anal. Calcd. for C13H13NOS: C, 67.50; H, 5.66; N, 6.05; S, 13.86. Found: C, 67.51; H, 5.69; N, 6.08; S, 13.77.
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9](C(OC(C)(C)C)=O)[CH2:8][CH:7]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:28]>O1CCOCC1>[ClH:28].[ClH:28].[N:17]1([C@H:7]2[CH2:6][C@@H:5]([CH2:3][OH:2])[NH:9][CH2:8]2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)C1CC(N2CCCC2)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1COCCO1
Product: OC[C@@H]1C[C@H](N2CCCC2)CN1

Procedure:
The title compound was prepared in analogy to 193B, by reduction of 3′S,5′S)-[1,3′]Bipyrrolidinyl-1′,5′-dicarboxylic acid 1′-tert-butyl ester 5′-methyl ester with lithium aluminium hydride and subsequent deprotection with 4M hydrochloric acid in dioxane. MS: 171.3 (MH+).