Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][S:8][CH:7]([C:11]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[C:17]3[C:23]([O:25]C)=[O:24])=[O:12])[CH2:6]1.[Li+].[OH-].Cl>C1COCC1>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][S:8][CH:7]([C:11]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[C:17]3[C:23]([OH:25])=[O:24])=[O:12])[CH2:6]1
Reactant: COC(=O)c1n[nH]c2ccc(NC(=O)C3CN(Cc4ccccc4F)CCS3)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1n[nH]c2ccc(NC(=O)C3CN(Cc4ccccc4F)CCS3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(2-fluorobenzyl)thiomorpholine-2-carboxamido)-1H-indazole-3-carboxylate (250 mg, 0.58 mmol) in THF (4 mL), was added LiOH (1.2 mL, 1M, 1.2 mmol). The resulted solution was stirred at RT for overnight. 1 N HCl was added to the reaction mixture until pH reached around 4. The solvent was removed and the residual was used directly for the next step. LC-MS: 415.1 [M+H]
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:42][O:43][CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:10]([NH:12][CH:13]2[C:40](=[O:41])[N:15]3[C:16]([C:37]([OH:39])=[O:38])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:52]>CO>[ClH:52].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:42][O:43][CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:10]([NH:12][CH:13]2[C:40](=[O:41])[N:15]3[C:16]([C:37]([OH:39])=[O:38])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=O)OC(C)(C)C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=O)OC(C)(C)C)CS[C@H]12)c1csc(N)n1
Yield: 93.8 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.5 g.) and conc. hydrochloric acid (1.9 g.) in methanol (35 ml.) was stirred at room temperature for 1.5 hours. After concentration, the residue was pulverized with diethyl ether to give 7-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 3.32 g.).
Reaction SMILES: [CH:1]([C:5]1[N:9]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12][C:11]2([CH3:22])[CH3:21])[CH:8]=[N:7][CH:6]=1)=[CH:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([C:5]1[N:9]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12][C:11]2([CH3:21])[CH3:22])[CH:8]=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC=Cc1cncn1C1c2ccccc2C(=O)OC1(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCc1cncn1C1c2ccccc2C(=O)OC1(C)C
Reaction time: 8 h

Procedure:
To a solution of 4-(5-but-1-enyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (0.110 g, 0.37 mmol) in methanol (2 mL) is added Pd/C (0.020 g). The reaction vessel is flushed with hydrogen gas and stirred under balloon pressure overnight. The mixture is filtered and the filtrate concentrated in vacuo to give a residue which is purified by semi-preparative reverse phase HPLC to give 4-(5-butyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one as a white solid; MS (ESI) m/z 299.1 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.02 (br. s, 3 H), 1.22 (s, 3 H), 1.53 (br. s, 5 H), 1.77 (br. s, 2 H), 2.81 (br. s, 2 H), 5.54 (br. s, 1 H), 6.82 (s, 1H), 7.19 (br. s, 1 H), 7.39 (d, J=7.3 Hz, 1 H), 7.60-7.67 (m, 1 H), 7.71-7.78 (m, 1 H), 8.21 (d, J=7.8 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[C:10]1[CH:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].N1C2C(=CC=CC=2)C=CC=1.Cl>O.N1C=CC=CC=1>[O:20]=[C:19]1[C:17]2[CH:18]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:15][C:16]=2[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1]1
Reactant: O=C(O)c1ccc(C(=O)O)c(Br)c1
Reactant: Nc1ccccc1S
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: c1ccc2ncccc2c1
Product: O=C(O)c1ccc2c(c1)Sc1ccccc1NC2=O
Temperature: 180 °C
Yield: 117 %

Procedure:
A mixture of 2-amino-benzenethiol (1.34 mL, 12.5 mmol), 2-bromo-terephthalic acid (1.54 g, 6.3 mmol), cuprous oxide (0.50 g, 3.5 mmol), quinoline (6.3 mL), and pyridine (0.63 mL) was heated in a 180° C. oil bath under nitrogen for 20 hours, then cooled to room temperature. Concentrated hydrochloric acid (20 mL) was added slowly while cooling in cold water, with stirring. The resulting precipitate was filtered, washed with water, and dried to give crude title compound (2 g). LC-MS: m/z 270 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1I>>[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: Brc1ccccc1I
Product: COC(=O)CCc1ccc(C#Cc2ccccc2Br)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (300 mg, 1.59 mmol) and 1-bromo-2-iodobenzene (0.3 mL, 2.34 mmol) according to the general procedure ID to give 340 mg (62%) of an yellow oily product after purification by flash chromatography (SiO2, EtOAc:PE, 1:5). Rf=0.27 (EtOAc:PE, 1:5); 1H NMR (CDCl3) δ 7.61 (dd, J=8.0, 1.1 Hz, 1H), 7.54 (dd, J=7.7, 1.7 Hz, 1H), 7.52-7.48 (m, 2H), 7.28 (td, J=7.6, 1.2 Hz, 1H), 7.22-7.14 (m, 3H), 3.67 (s, 3H), 2.97 (t, J=7.7 Hz, 2H), 2.64 (t, J=7.7 Hz, 2H); 13C NMR (CDCl3) δ 173.1, 141.3, 133.2, 132.4, 131.8, 129.3, 128.4, 127.0, 125.6, 125.5, 120.9, 93.9, 87.8, 51.7, 35.4, 30.9; ESI-MS m/z 365.0 (M+Na+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][OH:12])[C:4]=2[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[C:4]=2[CH2:3][CH2:2]1
Reactant: OCCc1cccc2c1CCO2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccc2c1CCO2

Procedure:
A solution of 2-(2,3-dihydrobenzofuran-4-yl)-ethanol (1.13 g) in dichloromethane (11 ml) was treated with triethylamine (1.25 ml), followed by methanesulfonyl chloride (0.64 ml). After 5 min the reaction mixture was poured into 2M hydrochloric acid (10 ml) and extracted with dichloromethane (2×10 ml). The combined extracts were washed with water (10 ml), dried (Na2SO4) and the solvent evaporated to give the title compound (1.76 g) as a yellow oil.
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[C:13](=[O:29])[N:12]([CH3:30])[C:11]=2[N:10]=[C:9]1[O:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=1)C1C=CC=CC=1.C(Cl)Cl.Cl>C(O)C.O.C(OCC)C>[F:38][C:35]1[CH:36]=[CH:37][C:32]([O:31][C:9]2[NH:8][C:16]3[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:29])[N:12]([CH3:30])[C:11]=3[N:10]=2)=[CH:33][C:34]=1[C:39]([F:40])([F:42])[F:41]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Oc1ccc(F)c(C(F)(F)F)c1)n2Cc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1c(=O)n(CCCO)c(=O)c2[nH]c(Oc3ccc(F)c(C(F)(F)F)c3)nc21
Temperature: 25 °C
Yield: 126.8 %

Procedure:
Step 2 7-Benzyl-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-8-(4-fluoro-3-(trifluoromethyl)phenoxy)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.44 g, 0.686 mmol) was dissolved in ethanol (15 mL) and DCM (1 mL) then 6 N aqueous HCl (2.0 mL) were added. The clear solution was stirred at room temperature. After 1 h reaction was diluted with water (100 mL) and extracted with DCM (3×75 ml). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to yield a white solid. Solid was slurried in diethyl ether (6 mL) and filtered to give 7-benzyl)-8-(4-fluoro-3-(trifluoromethyl)phenoxy)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.35 g, 79% yield) as a white solid. LCMS retention time=3.641 min and 99% purity, LCMS MH+=493. 1H NMR (CDCl3) δ 7.23-7.52 (m, 8H), 5.47 (s, 2H), 4.20 (t, 2H, J=8 Hz), 3.47-3.54 (m, 2H), 3.43 (s, 3H), 1.88-1.92 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([CH:17]([CH3:20])[CH:18]=O)[C:13]=3[CH:21]=2)[CH:5]=[C:4]([F:22])[C:3]=1[C:23]([F:26])([F:25])[F:24].[N+:27]([C:30]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=1[NH:39][NH2:40])([O-:29])=[O:28].OS(O)(=O)=O>C(O)C.O>[N+:27]([C:30]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=1[NH:39][N:40]=[CH:18][CH:17]([CH3:20])[N:14]1[C:13]2[CH:21]=[C:9]([O:8][C:6]3[CH:5]=[C:4]([F:22])[C:3]([C:23]([F:26])([F:25])[F:24])=[C:2]([Cl:1])[CH:7]=3)[CH:10]=[CH:11][C:12]=2[N:16]=[N:15]1)([O-:29])=[O:28]
Reactant: NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(C=O)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CC(C=NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21

Procedure:
A solution of 6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl) oxy]-α-methyl-1H-benzotriazol-1-acetaldehyde (0.0294 mole) in ethanol is added to a solution of 2,4-dinitrophenylhydrazine (7 g, 0.035 mole) and conc. H2SO4 (35 ml, 0.63 mole) in H2O at 50° C., allowed to come to room temperature and filtered. The solid filter cake is recrystallized from aqueous acetic acid and from ethanol to afford the title compound, mp 148°-149° C., identified by elemental and NMR analyses.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH3:9][O-].[Na+].IC.O>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Sc1ccc(Cl)nn1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CI
Product: CSc1ccc(Cl)nn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
6-Chloropyridazine-3-thiol (500 mg, 3.41 mmol) synthesized in Example (118a) was dissolved in methanol (20 mL), and sodium methoxide (203 mg, 3.75 mmol) and iodomethane (234 mL, 3.75 mmol) were added, followed by stirring at 60° C. for 30 minutes under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (50 mL) was added, and extraction was carried out twice with ethyl acetate (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-50%) to afford the desired compound (515 mg, yield 94%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:36][C@H:37]([C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1)[CH3:38]>ClCCl>[CH3:46][O:45][C:43]([C:42]1[CH:47]=[CH:48][C:39]([C@@H:37]([NH:36][C:18]([C@H:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:19])[CH3:38])=[CH:40][CH:41]=1)=[O:44]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.8 %

Procedure:
To a 0° C. mixture of (3R)-2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinoline-3-carboxylic acid (40.0 g, 141.4 mmol) and dichloromethane (784 mL), add triethylamine (21.7 mL, 155.5 mmol). Then add isobutyl chloroformate (20.3 mL, 155.5 mmol) in a dropwise fashion. After the end of the addition, stir the mixture at 0° C. for 20 minutes. Then, add methyl (S)-4-(1-aminoethyl)benzoate (27.9 g, 155.5 mmol), and stir the mixture at room temperature for 1 hour. Add water (400 mL), separate the layers, and wash the organic layer with 1 M aqueous KHSO4 (500 mL), followed by saturated aqueous NaHCO3 (500 mL). Dry the organic phase over MgSO4, filter to remove the solids, and concentrate the filtrate under reduced pressure to furnish the title compound as a white solid (60 g, 97% yield). Mass spectrum (m/z): 339 ([M+H−Boc]+), 383 ([M+H−t-Bu]+), 439 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:28]([CH3:29])=[C:27]([CH3:30])[C:5]([O:6][CH2:7][C:8]([N:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[CH3:11])=[O:9])=[C:4]([CH3:31])[C:3]=1[CH3:32].OO.[OH-].[Na+].C(=O)([O-])[OH:38].[Na+]>CO>[NH2:1][C:2]1[C:3]([CH3:32])=[C:4]([CH3:31])[C:5]([O:6][CH2:7][C:8]([N:10]([CH3:11])[CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH2:26])=[O:38])=[CH:23][CH:24]=3)[CH2:16][CH2:17]2)=[O:9])=[C:27]([CH3:30])[C:28]=1[CH3:29]
Reactant: O=C([O-])O
Reactant: Cc1c(C)c(OCC(=O)N(C)C2CCN(Cc3ccc(C#N)cc3)CC2)c(C)c(C)c1N
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C)c(OCC(=O)N(C)C2CCN(Cc3ccc(C(N)=O)cc3)CC2)c(C)c(C)c1N
Reaction time: 6 h
Yield: 77 %

Procedure:
To a mixture solution of 82 mg of the compound (18) obtained in the Example 18 in methanol were added 58 μl of 30% hydrogen peroxide aqueous solution and 150 μl of 3N-sodium hydroxide aqueous solution under ice-cooling, and the reaction mixture was stirred for 6 hours at the room the temperature. After the reaction, saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and extracted with dichloromethane. The organic layer was washed with saturated saline, dried and the solvent was removed under reduced pressure. The resulting residue was purified by amine coated silica gel (Fuji Silysia Chemical Ltd.) column chromatography (dichloromethane : methanol =10:1) to give 66 mg (77%) of the above-mentioned compound (19).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([Br:19])=[CH:17][CH:18]=2)[CH2:9]1)=O)(C)(C)C.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[C:20]([OH:26])=[O:21].[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[N:15][CH:14]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(Br)nc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(OC2CNC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 3-(6-Bromo-pyridin-3-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (1.08 g, 3.28 mmol) in DCM (30 mL), add TFA (10 mL). Let the mixture be stirred at room temperature for 2 hrs. LC-MS and TLC show reaction was complete. So evaporate all the solvent and excessive TFA. The residue brown solid 5-(Azetidin-3-yloxy)-2-bromo-pyridine trifluoro-acetic acid salt (1.06 g, 95% yield) was used directly for next step.
Reaction SMILES: [C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:12][C:10](=[O:11])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C[O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19]>>[C:1]([NH:7][C@H:8]([C:13]([NH:19][C@H:18]([C:17]([OH:27])=[O:16])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:14])[CH2:9][C:10](=[O:11])[OH:12])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Product: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
reacting the resulting N-acetoacetyl-L-aspartic acid anhydride with L-phenylalanine methyl ester to form N-acetoacetyl-α-L-aspartyl-L-phenylalanine and
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:25][N:26]1[CH:30]=[C:29]([CH:31]=O)[C:28]([CH3:33])=[N:27]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:29]3[C:28]([CH3:33])=[N:27][N:26]([CH3:25])[CH:30]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nn(C)cc1C=O
Reactant: Cc1nc(CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)no1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(CN2CCN(c3c(Cl)cnc4[nH]c(-c5cn(C)nc5C)nc34)CC2)no1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 5-chloro-4-(4-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (60.0 mg, 0.170 mmol) and 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (22.2 mg, 0.179 mmol) in EtOH (3.8 mL) was added 1M Na2S2O4 (0.678 mL, 0.678 mmol, freshly prepared) and the solution was heated to 80° C. and stirred for 16 h whilst being open to air. Once cooled, the reaction was evaporated in vacuo and the residue dry loaded onto silica. Purification was accomplished by flash chromatography on silica gel (3×14) eluting with MeOH/CH2Cl2 (5-7.5%) to yield the title compound as a pale yellow solid. Recrystallisation in EtOAc/Et2O gave the title compound (20 mg, 27%) as an off white solid. The filtrate was concentrated in vacuo, an additional amount of title compound (12 mg, 16%) as a pale yellow solid. 1H-NMR (500 MHz, CDCl3) 2.60 (s, 3H, CH3), 2.62 (s, 3H, CH3), 2.81 (app t, J=4.5 Hz, 4H, CH2), 3.76 (s, 2H, —CH2—), 3.87 (app s, 4H, CH2), 3.90 (s, 3H, NCH3), 7.77 (br s, 1H, CHar), 7.96 (br S, 1H, CHar), 12.18 (s, 1H, NH);
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:21]=[N:20][CH:19]=[CH:18][C:5]=1[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:7].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:8]2[CH2:2][CH2:3][C:4]3[C:5](=[CH:18][CH:19]=[N:20][CH:21]=3)[C:6]2=[O:7])=[CH:11][CH:12]=1
Reactant: COc1ccc(CNC(=O)c2ccncc2CCO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2CCc3cnccc3C2=O)cc1
Yield: 145.4 %

Procedure:
3-(2-Hydroxyethyl)-N-(4-methoxybenzyl)isonicotinamide (220 mg, 0.769 mmol) was reacted with PPh3 (403 mg, 1.538 mmol), DEAD (0.15 mL, 0.922 mmol) and THF (10 mL) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 300 mg of the product. LCMS: 66.95%, m/z=269.0 (M+1)
Reaction SMILES: CN(C)C(=O)C[NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl.Cl[CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>>[CH3:24][C@:21]12[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:37])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:26])([CH3:27])[C:15]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]1([NH:5][CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)[CH2:23][CH2:22]2
Reactant: ClCCCN1CCOCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 4-(3-chloropropyl)morpholine hydrochloride as the alkylating reagent in Step 1. The product was isolated as a white solid (60 mg, 48.1%). LCMS: m/e 657.55 (M+H)+, 2.24 min (method 13). 1H NMR (400 MHz, METHANOL-d4) δ 7.95 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 5.33 (d, J=4.5 Hz, 1H), 4.88 (s, 1H), 4.75 (s, 1H), 3.97 (m, 4H), 3.30-3.04 (m, 8H), 2.85-2.66 (m, 1H), 2.46-2.24 (m, 2H), 2.24-1.85 (m, 7H), 1.82-1.65 (m, 7H), 1.65-1.45 (m, 7H), 1.45-1.26 (m, 4H), 1.22 (s, 3H), 1.14 (s, 3H), 1.08 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:16]([N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[CH:14]1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Reactant: OB(O)c1ccccc1
Product: CC(C)Cn1cnc2c(N)nc3ccc(-c4ccccc4)cc3c21

Procedure:
8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by recrystallization from methanol afforded 1-isobutyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a beige solid, m.p. 203–204° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[N+:12]([O-])=O.CO>CCOC(C)=O.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[NH2:12]
Reactant: CCCOc1ccc([N+](=O)[O-])c(C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCOc1ccc(N)c(C)c1
Reaction time: 4 h
Yield: 84.9 %

Procedure:
Compound 404b (3.78 g, 19.4 mmol) was dissolved in EtOAc (20 mL) and MeOH (20 mL) and transferred to a 250 mL hydrogenation flask. 10% Pd/C (378 mg, 10% w/w) was added and the sample was hydrogenated for 4 h at 35 psi H2. Upon completion, the mixture was filtered over a bed of Celite and then concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with NaHCO3 (100 mL×3). The organic layer was separated and then dried over Na2SO4 to provide a crude brown oil which was further purified by chromatography (20% to 50% EtOAc/hexanes) to yield an amber oil (2.72 g, 85%): TLC Rf 0.27 (20% EtOAc/hexanes). 1NMR (600 MHz, CDCl3) δ 6.67 (s, 1H), 6.62 (m, 2H), 3.85-3.38 (t, 2H, J=6.66 Hz), 2.16 (s, 3H), 1.79-1.73 (sex, 2H, J=7.44 Hz), 1.02-1.00 (t, 3H, J=7.44 Hz). 13C NMR (150 MHz, CDCl3) δ 152.3, 137.8, 124.1, 117.2, 116.1, 112.9, 70.1, 22.7, 17.7, 10.5. Elemental analysis calculated for C10H15NO: C, 72.69; H, 9.15; N, 8.48. Found: C, 72.42; H, 9.14; N, 8.46.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:12]([O:19][C:20](=[O:29])[CH2:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]#[N:45])=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:12]([O:19][C:20](=[O:29])[CH2:21][N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]#[N:45])=[CH:36][CH:37]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: O=C(CNc1ccccc1)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1-c1ccc(CN(CC(=O)OCc2ccccc2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
24.8 g (60 mmol) of rac. phenylglycine benzyl ester tosylate and 8.2 g (30 mmol) of 4-bromomethyl-2'-cyanobiphenyl are kept at 80° with stirring for 2 hours together with 15.5 g of diisopropylethylamine (Hunig base) in 60 ml of DMF. The reaction mixture is then poured into ice-water and extracted with ethyl acetate. The ethyl acetate is separated off and stirred with 2N hydrochloric acid. The hydrochloride of the title compound which precipitates as an oil is separated off, converted into the base using sodium carbonate solution and further used in crude form (Rf 0.65 in system B7).