Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=O.[N:9]1([C:20](=[O:21])[C:19]2[NH:18][CH:17]=[N:16][C:15]=2[N:13]([CH3:14])[C:11]1=[O:12])[CH3:10].CN(C)C=[O:25]>C(=O)([O-])[O-].[Na+].[Na+]>[C:6]([CH2:5][CH2:4][CH2:3][C:17]1[NH:18][C:19]2[C:20](=[O:21])[N:9]([CH3:10])[C:11](=[O:12])[N:13]([CH3:14])[C:15]=2[N:16]=1)([OH:7])=[O:25]
Reactant: CN(C)C=O
Reactant: O=C1CCC(=O)N1O
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1c(=O)c2[nH]c(CCCC(=O)O)nc2n(C)c1=O
Temperature: 4 °C
Reaction time: 18 h

Procedure:
8-(3-carboxypropyl)-theophylline was synthesized as described in copending patent application Ser. No. 315,922, filed Oct. 28, 1981. 15 mg of this compound was reacted with 7 mg of N-hydroxysuccinimide in 2.0 ml of dimethylformamide at 4° C. for 18 hours. At the end of this time, 200 mg of KLH, dissolved in 15 mL of 0.1 M sodium carbonate, pH 8.5, was added. The reaction mixture was stirred for 18 hours at 4° C. Unreacted theophylline was removed by dialysis.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=O)(=[O:3])[CH3:2].S(Cl)([Cl:20])=O>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[Cl:20])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A suspension of 7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate (2.00 g), DMF (0.20 mL) and thionyl chloride (30 mL) was stirred at 70° C. for 3 h. The mixture was concentrated in vacuo, and the residue was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([C:21]1[N:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].Cl[C:29]1[N:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1.CC(C1C=CC(OCC2C=CC=CN=2)=CN=1)(C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)C(C)C.ClC1N=NC(Cl)=CC=1>>[CH3:1][C:2]([C:21]1[N:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([C:6]1[CH:7]=[CH:8][C:9]([C:29]2[N:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=2)=[CH:10][CH:11]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: CC(C)C(C)(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(O)cn1
Agent: CC(C)C(C)(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(OCc2ccccn2)cn1
Agent: Clc1ccc(Cl)nn1
Product: CC(C)C(C)(c1ccc(-c2ccc(C(F)(F)F)nn2)cc1)c1ccc(O)cn1

Procedure:
Compound 8b was prepared from 8a following procedures similar to those described for preparing compound 5, substituting compound 8a and 3-chloro-6-trifluoromethylpyridazine for compound 5a and 3,6-dichloropyridazine, respectively. m/z (ES) 402 (MH)+)
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C:7]#N)=[CH:4][CH:3]=1.[OH-:9].[Na+].[OH2:11]>>[F:1][C:2]1[S:6][C:5]([C:7]([OH:11])=[O:9])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)s1
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)c1ccc(F)s1
Yield: 82 %

Procedure:
A mixture of the title product of Example 1 (1.5 g, 11.8 mmol) and 1.0 N NaOH (25 mL, 25 mmol) was refluxed for 3 hours. The mixture was poured into water (200 mL) and washed two times with 200 mL diethyl ether. The aqueous extract was acidified with 1N hydrochloric acid to pH 1, then extracted two times with 200 mL methylene chloride. The organic extracts were combined, washed with water (80 mL), dried (MgSO4) and concentrated in vacuo to give a solid. Trituration with hexanes afforded 1.2 g (82%) of the title product as a white solid, mp 140-2° C. 1H-NMR (d6 -DMSO): δ 7.47 (m, 1H), 6.84 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5](C(N=[N+]=[N-])=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][N:24]3[CH:29]([CH3:30])[CH2:28][NH:27][CH:26]([CH2:31][CH2:32][CH3:33])[C:25]3=[O:34])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1.C[N:36]([CH:38]=[O:39])C>>[Cl:1][C:2]1[S:6][C:5]([NH:36][C:38]([N:27]2[CH2:28][C@H:29]([CH3:30])[N:24]([CH2:23][C:19]3[CH:18]=[C:17]4[C:22]([C:13]([NH2:12])=[N:14][CH:15]=[N:16]4)=[CH:21][CH:20]=3)[C:25](=[O:34])[C@@H:26]2[CH2:31][CH2:32][CH3:33])=[O:39])=[CH:4][CH:3]=1
Reactant: CCCC1NCC(C)N(Cc2ccc3c(N)ncnc3c2)C1=O
Reactant: CN(C)C=O
Reactant: [N-]=[N+]=NC(=O)c1ccc(Cl)s1
Product: CCC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)[C@@H](C)CN1C(=O)Nc1ccc(Cl)s1
Temperature: 100 °C

Procedure:
A mixture of 5-chloro-thiophene-2-carbonyl azide (28 mg, 0.15 mmol, EXAMPLE 38) and 4-[4-Amino-quinazolin-7-ylmethyl]-5-methyl-3-oxo-2-propyl-piperazine, EXAMPLE 888, (26 mg, 0.08 mmol) in 3 mL of dry DMF is heated at 100° C. for 1 h. The resulting mixture is concentrated in vacuo. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 70% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are combined and lyophilized to provide the title compound (18 mg, 0.03 mmol) as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ9.96 (bs, 1H), 9.70 (bs, 2H), 8.72 (s, 1H), 8.22 (d, 1H), 7.55 (d, 1H), 7.50 (s, 1H), 6.68 (d, 1H), 6.37 (d, 1H), 4.99-4.38 (m, 3H, rotamers), 4.15 (m, 1H, rotamers), 3.58 (m, 1H, rotamers), 3.10 (m, 1H), 1.85 (m, 2H), 1.32 (m, 2H), 1.07 (m, 3H, rotamers), 0.88 (t, 3H). ISP MS, [M+H]+=473, 475 (Cl pattern).
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]3[NH:19][C:18]4[C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH3:23])[C:15](=[O:24])[N:14]([CH2:25][CH2:26][CH3:27])[C:13]=4[N:12]=3)([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.C(N(CC)CC)C.C(OCC)(=O)C.Cl>CS(C)=O>[O:24]=[C:15]1[N:14]([CH2:25][CH2:26][CH3:27])[C:13]2[N:12]=[C:11]([C:6]34[CH2:7][CH2:8][C:3]([CH:2]=[O:1])([CH2:10][CH2:9]3)[CH2:4][CH2:5]4)[NH:19][C:18]=2[C:17](=[O:20])[N:16]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CO)(CC3)CC4)nc2n(CCC)c1=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCn1c(=O)c2[nH]c(C34CCC(C=O)(CC3)CC4)nc2n(CCC)c1=O

Procedure:
8-(4-Hydroxymethylbicyclo[2.2.2]oct-1-yl)-1,3-dipropyl-3,7-dihydropurine-2,6-dione (X, Example 86a, 1 wt) and dimethyl sulphoxide (4 vol) are mixed and stirred under nitrogen; the mixture is stirred for 5 to 15 mins and triethylamine (2.42 vol) is added. A mixture of sulphur trioxide pyridine complex (1.275 wt) in dimethyl sulphoxide (6 vol) is added, maintaining the internal temperature below 30°. The temperature is adjusted to 14 to 20° and the reaction mixture is then stirred at 14 to 20° for 16 to 20 hours until complete by NMR. If there is any starting alcohol remaining sulphur trioxide pyridine complex (0.15 wt) is added and the reaction stirred for a further 2 to 3 hours at 14 to 20°. Ethyl acetate (20 vol) and hydrochloric acid (1 M, 10 vol) are added to the reaction mixture and stirred vigorously for 5 to 15 mins. The phases are separated and the organic phase is washed with hydrochloric acid (1 M, 10 vol). The phases are separated and the organic phase is again washed with hydrochloric acid (1 M, 10 vol). The phases are separated and the organic phase is washed with saline (5 vol), dried over magnesium sulphate (0.5 wt) for 5 to 10 mins and filtered. The filter cake is washed with ethyl acetate (1 vol). The solvent is removed under reduced pressure at 40 to 45° to give the title compound.
Reaction SMILES: C[Si](C)(C)[C:3](=[O:5])[CH3:4].C1CCN2C(=NCCC2)CC1.[C:19]1([CH:25]=[CH:26][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(O)C>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.C1COCC1>[C:29]1([C:27](=[O:28])[CH2:26][CH:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:3](=[O:5])[CH3:4])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)[Si](C)(C)C
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(=O)C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
1-Trimethylsilanyl-ethanone (1.15 mL; 8.02 mmol) followed by DBU (0.18 mL; 1.2 mmol) were added to a suspension of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (304 mg; 1.21 mmol) in dry THF (5 mL). The mixture was heated at 70° C. for 4 min, cooled near rt, then chalcone (833 mg; 4.00 mmol) and 2-propanol (1.22 mL; 15.9 mmol) were added. The reaction was degassed and reacted under nitrogen at 70° C. After 24 h, the reaction was concentrated on a rotary evaporator. Ethyl acetate (25 mL) was added and this washed with H2O (3×3 mL) and satd NaCl (2×3 mL). The organic portion was dried (MgSO4) and filtered through silica with an EtOAc wash. Crude product was adsorbed onto silica (2 g) then purified by MPLC (40 g of silica using a 0→20% EtOAc in hexanes gradient). Pure product was obtained as a clear, colorless viscous liquid (980 mg; 97%). 1H NMR (CDCl3) δ 7.98-7.94 (m, 2H), 7.56 (m, 1H), 7.47-7.42 (m, 2H), 7.39-7.27 (m, 5H), 4.44 (dd, J=3.6, 10.0 Hz, 1H), 4.02 (dd, J=10.0, 18.0 Hz, 1H), 3.14 (dd, J=3.6, 18.0 Hz, 1H); GC-MS 252 ([M]+).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:38][OH:39])=[O:6])[CH:2]=[CH2:3].[CH3:40][I:41]>CC(C)=O>[I-:41].[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][N+:33]1[CH:37]=[CH:36][N:35]([CH3:40])[C:34]=1[CH2:38][OH:39])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CCn3ccnc3CO)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: CI
Solvent: CC(C)=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC[n+]3ccn(C)c3CO)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Reaction time: 6 h

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(2-hydroxymethylimidazol-1-yl)ethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (3.02 g) in acetone (15 ml) was added methyl iodide (3.36 ml) at room temperature and the solution was allowed to stand for 6 hours. The solvent was evaporated to give allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(2-hydroxymethyl-3-methyl-1-imidazolio)ethyl}-pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate iodide (3.75 g) as a yellow solid. This compound was immediately used as the starting compound for the next step.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.ClC1S[C:15]2[CH:21]=CC=C(Cl)[C:16]=2N=1.[OH-:23].[Na+].O>C(O)CC>[CH2:21]([O:23][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1)[CH2:15][CH3:16]
Reactant: Clc1cccc2sc(Br)nc12
Reactant: [OH-]
Reactant: Clc1nc2c(Cl)cccc2s1
Agent: [Na+]
Solvent: CCCO
Solvent: O
Product: CCCOc1nc2c(Cl)cccc2s1
Yield: 97.7 %

Procedure:
A mixture (11.30 g, 0.05 mole) of 2-bromo-4-chlorobenzothiazole and 2,4-dichlorobenzothiazole and 94% sodium hydroxide (2.34 g, 0.055 mole) in n-propanol (100 c.c.) was heated under reflux for 1 hour. Water was added and the alcohol was distilled azeotropically together with water. The resulting oily substance was extracted with chloroform, and the chloroform layer was washed with water. The solvent was removed under reduced pressure to obtain 11.12 g of 2-n-propoxy-4-chlorobenzothiazole as a yellow viscous liquid. Yield 97.7%, purity 98.9%, b.p. 106°-108° C./0.12 mmHg.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2C(O)=O)[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.[CH2:58]([O:60][C:61](=[O:66])[CH:62]([OH:65])[CH2:63][NH2:64])[CH3:59].C(N(C(C)C)CC)(C)C.CN([CH:79]=[O:80])C>C(Cl)Cl>[CH2:58]([O:60][C:61](=[O:66])[CH:62]([OH:65])[CH2:63][NH:64][C:79](=[O:80])[C:33]1[CH:32]=[CH:28][C:27]([CH:11]([NH:12][C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=2)=[O:14])[C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=2)=[CH:35][CH:34]=1)[CH3:59]
Reactant: CCOC(=O)C(O)CN
Reactant: CC(C)(C)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccccc2C(=O)O)cc1
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(O)CNC(=O)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [1-(4-tert-butylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoic acid (1.0 g, 2.06 mmol) in DMF (1 mL) and DCM (10 mL) was added 1-hydroxy-7-azabenzotriazole (0.33 g, 2.47 mmol). After stirring for 1 hour at room temperature, EDAC (0.47 g, 2.47 mmol), (RS)-isoserine ethyl ester hydrochloride (0.52 g, 3.09 mmol) and diisopropylethylamine (1.1 mL, 6.18 mmol) were added, successively. After stirring for 17 hours at ambient temperature the reaction mixture was partitioned between water, brine and ethyl acetate. The aqueous phase was further extracted with ethyl acetate. The combined organic phases were washed with water and brine. After drying (magnesium sulphate) and filtration, the organic phase was evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (6:4). This afforded 1.2 g (97%) of (RS)-3-{4-[1-(4-tert-butylphenyl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid ethyl ester as an oil.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:22]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[CH2:12]2
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(CN2Cc3cc(Br)cc(Cl)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (1.06 g, 3.00 mmol), 4-methoxy-benzylamine (0.521 mL, 4.0 mmol), and K2CO3 (0.967 g, 7.0 mmol) in toluene (7 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-chloro-2-(4-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.365 g, 33%). GC-MS: m/z 367 (M)+, 336 (M−31)+. 1H NMR (300 MHz, CDCl3): δ (ppm) 3.79 (S, 3H), 4.20 (s, 2H), 4.70 (s, 2H), 6.85 (d, 2H) 7.27 (d, 2H), 7.42 (s, 1H), 7.57 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:50])[CH2:3][CH2:4][CH2:5][NH:6][CH2:7][C@:8]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:43])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:42]=[CH:41][C:33]([C:34]([O:36]C(C)(C)C)=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:50][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][CH2:7][C@:8]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:43])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:41][CH:42]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(CNCCCN(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
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.1 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(dimethylamino)propylamino)methyl)-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)benzoate (114 mg, 0.167 mmol) in DCM (1 ml) was added TFA (0.4 ml, 5.19 mmol). The mixture was stirred at rt for 5 h and was concentrated under reduced pressure. The residue was purified by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to afford the title compound as a white solid (77 mg, 0.122 mmol, 73.3% yield). LCMS: m/e 629.6 (M−H)−, 2.22 min (method 6). 1H NMR (500 MHz, Acetic acid) δ ppm 8.03 (d, J=8.24 Hz, 2H) 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.58 Hz, 1H), 4.79 (s, 1H), 4.68 (s, 1H), 3.32-3.44 (m, 3H), 3.25-3.32 (m, 2H), 2.96 (d, J=13.12 Hz, 1H), 2.89-2.94 (m, 6H), 2.49-2.58 (m, 1H), 2.30-2.38 (m, J=8.09, 7.86, 7.74, 7.74 Hz, 2H), 1.75 (s, 3H), 1.19 (s, 3H), 1.13-2.23 (m, 22H), 1.09 (s, 3H), 1.08 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C:3]([O:5][CH:6]([O:9][C:10](CC)=S)[CH2:7][CH3:8])=[O:4].[OH:15][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].C(OO)(=[O:25])C>ClCCl>[CH3:14][CH:2]([CH3:1])[C:3]([O:5][CH:6]([O:9][C:10]([O:15][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22])=[O:25])[CH2:7][CH3:8])=[O:4]
Reactant: CCC(=S)OC(CC)OC(=O)C(C)C
Reactant: CC(=O)OO
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: CCC(OC(=O)ON1C(=O)CCC1=O)OC(=O)C(C)C
Yield: 61 %

Procedure:
Following the above general procedure, 1-(ethylthiocarbonyloxy)-propyl 2-methylpropanoate (2.3 g, 9.82 mmol) and N-hydroxysuccinimide (4.6 g, 40 mmol) were reacted in dichloromethane (20 mL) with peracetic acid (32 wt. %, 6.13 mL). After aqueous workup, isolation and removal of residual solvents in vacuo, the crude product 2 (1.76 g, 61%) was obtained as a yellow oil. The material was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=1.02 (t, J=7.6 Hz, 3H), 1.20 (d, J=6.8 Hz, 3H), 1.21 (d, J=7.2 Hz, 3H), 1.88-2.00 (m, 2H), 2.61 (hept., J=7.2 Hz, 1H), 2.84 (s, 4H), 6.71 (t, J=5.2 Hz, 1H).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.O.[OH-].[Li+].O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[C:13]=2[C:29]2[CH:30]=[CH:31][C:32]([O:35][C:36]([F:38])([F:39])[F:37])=[CH:33][CH:34]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(R)-4-[6-(4-tert-Butyl-cyclohexyloxy)-5-(4-trifluoromethoxy-phenyl)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.2041 g, 0.0003768 mol) was dissolved in ethanol (4.00 mL, 0.0685 mol) in a capped 40 mL EPA vial equipped with a magnetic stir bar. 4.2 M lithium hydroxide, monohydrate in water (2.00 mL, 0.00840 mol) was added and the mixture was stirred overnight at 80° C. HPLC analysis showed that the reaction was complete. The reaction mixture was concentrated to dryness under reduced pressure. The product was partitioned between water and methylene chloride. The combined organic phase was dried over MgSO4, filtered, concentrated and purified by flash chromatography [0-50% of 2M NH3 solution in MeOH (10% in methylene chloride) and methylene chloride to give the title compound in 69% yield. MS: m/z=499.23 [M−NH2]+. 1H NMR (MeOD) δ: 7.93-7.96 (m, 1H), 7.91 (d, J=9.3 Hz, 1H), 7.47-7.52 (m, 1H), 7.38-7.45 (m, 6H), 4.06-4.16 (m, 1H), 3.72 (d, J=10.8 Hz, 1H), 3.67 (d, J=10.8 Hz, 1H), 1.99-2.07 (m, 2H), 1.76-1.84 (m, 2H), 1.51 (s, 3H), 0.91-1.24 (m, 5H), 0.86 (s, 9H)
Reaction SMILES: [O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:3]([OH:5])=O.[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2>>[O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:3]([NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2)=[O:5]
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: O=C(O)C(=O)N1CCC(Oc2ccccc2)CC1
Product: O=C1Cc2cc(NC(=O)C(=O)N3CCC(Oc4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from oxo-(4-phenoxy-piperidin-1-yl)-acetic acid and 5-amino-1,3-dihydro-indol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 78-81° C. (diethyl ether)
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.C1(N2C3[C:46]([O:62][C@@H:63]([C@H]4CNC(=O)C4)C)=NC(C4C=CC(N5CCNCC5)=CC=4)=CC=3N=C2)CC1.O1CC(S(Cl)(=O)=O)C1>>[CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([S:25]([CH:28]6[CH2:63][O:62][CH2:46]6)(=[O:26])=[O:27])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCN(S(C)(=O)=O)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: O=S(=O)(Cl)C1COC1
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(S(=O)(=O)C4COC4)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1

Procedure:
Following the procedure described for intermediate 3.45, starting from (R)-4-((R)-1-((3-cyclopropyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (90 mg, 0.2 mmol) and oxetane-3-sulfonyl chloride (0.12 ml, 0.89 mmol) to provide 42.4 mg of (R)-4-((R)-1-((3-cyclopropyl-6-(4-(4-(oxetan-3-ylsulfonyl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1.O1CCCC1>CCOCC>[OH:9][C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[C@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1
Reactant: Br[Mg]c1ccccc1
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)[C@@H]1CC(O)(c2ccccc2)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
Phenylmagnesium bromide in ether (3.00M, 0.400 mL) was added to a solution of 1-tert-butyl 2-methyl (2S)-4-oxopyrrolidine-1,2-dicarboxylate (243.0 mg, 0.0009989 mol) in tetrahydrofuran (5.00 mL, 0.0616 mol) at −40° C. The reaction mixture was stirred at between −40° C. and −10° C. for 2 h and then was quenched with ammonium chloride solution (5 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without further purification.