Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CO.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>[CH3:27][O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]4[CH:17]=[C:16]([N:18]5[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]5)[N:15]=[C:14]([NH2:25])[N:13]=4)[CH2:9]3)=[CH:4][CH:3]=2)[CH:33]=[N:32]1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: COCCn1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cn1
Temperature: 90 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.1 mg, 0.036 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in 1,4-dioxane (0.2 mL) and water (0.1 mL) was stirred at 90° C. for 2 h. After cooling, it was diluted with methanol, and purified with RP-HPLC (pH=10). to afford the desired product (4.7 mg). LCMS (M+H)+: m/z=463.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15]C(=O)C)[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:21][CH:22]([CH3:24])[CH3:23].[OH-].[Na+].O.Cl>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NC(C)C)c3)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Nc1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
N-(6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (123.6 mg, 342.5 μmol) was suspended in MeOH (2.2 ml) and sodium hydroxide (89.90 mg, 2248 μmol) and water (0.44 ml) were added. The reaction flask was fit with a reflux condenser and placed in a preheated oil bath (80° C.), and the reaction was stirred for 1 hour. The reaction was cooled to room temperature, treated with 5 N HCl to neutralize the solution, and allowed to stand overnight. It was then extracted with 10:1 DCM/MeOH, and the organic extracts were combined, concentrated, and purified on a silica gel column (20:1 DCM/MeOH to 15:1 DCM/2 N ammonia in MeOH). Fractions with product collected, concentrated, and treated with Et2O and MeOH. The MeOH washings were decanted, and the solid was collected and dried under high vacuum to afford 6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (18.2 mg, 17% yield). MS (ESI pos. ion) m/z: 319. Calculated exact mass for C15H15ClN4S 318.
Reaction SMILES: ClC1N=C(N[C@H](C)CSC2SC3C=CC=CC=3N=2)C2N=CN(C=2N=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(C)=NC=2Cl)(=O)C.C([O:66][C@@H:67]1[C@H:71]([O:72]C(=O)C)[C@@H:70]([CH2:76][O:77]C(=O)C)[O:69][C@H:68]1[N:81]1[C:103]2[N:102]=[C:101]([CH3:104])[N:100]=[C:85]([NH:86][C@H:87]([CH3:99])[CH2:88][S:89][C:90]3[S:91][C:92]4[CH:98]=[CH:97][CH:96]=[CH:95][C:93]=4[N:94]=3)[C:84]=2[N:83]=[CH:82]1)(=O)C.C[O-].[Na+]>CO>[S:91]1[C:92]2[CH:98]=[CH:97][CH:96]=[CH:95][C:93]=2[N:94]=[C:90]1[S:89][CH2:88][C@H:87]([NH:86][C:85]1[C:84]2[N:83]=[CH:82][N:81]([C:103]=2[N:102]=[C:101]([CH3:104])[N:100]=1)[C@@H:68]1[O:69][C@H:70]([CH2:76][OH:77])[C@@H:71]([OH:72])[C@H:67]1[OH:66])[CH3:99]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CSc4nc5ccccc5s4)nc(C)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[C@H](CSc1nc2ccccc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: C[O-]
Solvent: CO
Product: Cc1nc(N[C@H](C)CSc2nc3ccccc3s2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Yield: 11 %

Procedure:
The title compound was prepared according to general method A as described above in Example 1 by reacting 2-[(R)-2-amino-1-propylthio]benzothiazole hydrochloride (prepared as described in Example 5) (0.89 g, 3.0 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-methyl-9H-purine (1.07 g, 2.5 mmol) [prepared from 2-methylinosine (Journal of Organic Chemistry, 1967, 32, 3258-3260) by standard acylation and chlorination steps]. Deacylation of the purified 2',3',5'-tri-O-acetyl-N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-methyladenosine using sodium methoxide in methanol to provide the desired N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-methyladenosine (0.28 g, 11%) (following column chromatography), 1H NMR (DMSO-d6) δ1.40 (3H, d, --CHCH3), 2.30 (3H, s, --CH3), 3.50-3.77 (4H, m, H-5'a and H-5'b and --CH2 --), 3.98 (1H, d, H-4'), 4.13 (1H, d, H-3'), 4.63 (1H, q, H-2'), 4.86 (1H, br, --CHCH3), 5.19, 5.42 (2H, 2d, 2'- and 3'-OH), 5.70 (1H, t, 5'-OH), 5.85 (1H, d, H-1'), 7.36, 7.47 (2H, 2t, Ar--H), 7.80-7.96 (2H, m, Ar--H), 8.0 (1H, s, N--H), 8.26 (1H, s, H-8), 8.52 (1H, s, N--H). HPLC retention time 22.4 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>C(Cl)Cl>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccccc2)ccc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.3 %

Procedure:
Trifluoroacetic acid (1 mL) was added to a methylene chloride (3 mL) solution of the obtained tert-butyl 2-(2-hydroxy-5-phenylbenzamido)-4-phenylbenzoate (0.085 g), followed by stirring at room temperature for 17 hours. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the residue. The solid substance was collected by filtration to obtain 0.072 g of 2-(2-hydroxy-5-phenylbenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][N:14]1[CH2:19][CH2:18][C:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)([OH:20])[CH2:16][CH2:15]1)[CH2:7][CH2:6]2.B(Br)(Br)Br.C(Cl)Cl.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][N:14]1[CH2:19][CH2:18][C:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)([OH:20])[CH2:16][CH2:15]1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(CN1CCC(O)(Cc3ccc(C)cc3)CC1)C2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1ccc(CC2(O)CCN(CC3CCc4cc(O)ccc4C3)CC2)cc1
Temperature: 25 °C
Yield: 616.2 %

Procedure:
To (RS)-1-(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (843 mg, 2.22 mmol) in CH2Cl2 (20 ml) was added 1M BBr3/CH2Cl2 (4.88 ml, 4.88 mmol, 2.2 eq.) over 15 min at −78° C., the mixture was then allowed to warm to RT over 40 min. MeOH (3 ml), H2O (20 ml) and NaHCO3 (20 ml) were added and the mixture extracted with CH2Cl2 (4×50 ml). The extracts were washed with satd. NaCl solution (30 ml), dried (Na2SO4), filtered and evaporated, to afford the crude product as a yellow foam. Chromatography over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2—MeOH (97:3) afforded (RS)-1-(6-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol as a white foam (500 mg, 13.68 mmol, 61%), MS m/e=366.2 (M+H+).
Reaction SMILES: [C:1]([CH:3]([CH:9]([CH3:21])[CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])C(OCC)=O)#[N:2].[OH-].[Na+].C(O)C(O)C.Cl>>[CH3:21][CH:9]([CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:3][C:1]#[N:2]
Reactant: CCOC(=O)C(C#N)C(C)CC/C=C(\C)CCC=C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(O)CO
Product: CC(C)=CCC/C(C)=C/CCC(C)CC#N

Procedure:
To the entirety of the product obtained in the above (a) step, there were added 39 g. of sodium hydroxide and 120 ml. of propylene glycol, and the mixture was stirred at room temperature for 10 min. The reaction mixture was then made acidic by addition of 6N hydrochloric acid, and was then extracted with benzene. The extract was then washed with water and dried. The solvent was then removed by evaporation. The residue was dissolved in 120 ml. of pyridine, and the resulting solution was refluxed for 2 hours after addition of 0.6 g. of copper powder. Subsequently, the copper powder was removed by filtration and the solvent was removed by evaporation. The residue was dissolved in n-hexane, washed with water and dried. The solvent was then removed by evaporation, and the residue was purified by silica gel column chromatography to obtain 45 g. of the desired oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:23][CH3:24])[C@@H:10]([CH3:22])[CH2:11][C:12](=[O:21])[CH2:13]4.[N:25]#CBr.C(=O)([O-])[O-].[K+].[K+]>>[C:20]([N:19]1[CH2:18][CH2:17][C@@:14]23[C:15]4[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@:9]2([O:23][CH3:24])[C@@H:10]([CH3:22])[CH2:11][C:12](=[O:21])[CH2:13]3)#[N:25]
Reactant: COc1ccc2c(c1)[C@]13CCN(C)[C@H](C2)[C@]1(OC)[C@@H](C)CC(=O)C3
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2c(c1)[C@]13CCN(C#N)[C@H](C2)[C@]1(OC)[C@@H](C)CC(=O)C3

Procedure:
A slurry of 3,14-dimethoxy-8β,17-dimethylmorphinan-6-one (35) (4.4 g, 0.0134 mol), cyanogen bromide (4.2 g, 0.04 mol), and anhydrous potassium carbonate (5.5 g, 0.04 mol) in 140 ml of methylene chlordie was heated at reflux temperature for 22 hours under a nitrogen atmosphere. The potassium carbonate was removed by suction filtration and the filter cake washed throughly with methylene chloride. The solvent was removed from the filtrate under reduced pressure to leave 4.1 g (90% theory) of the title compound which was used in the next reaction step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([CH2:14][S:15]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:39]>C(OCC)C>[ClH:39].[C:33]1([C:11]2([CH2:14][S:15]([CH2:18][C:19]3[CH:20]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:24]=3)(=[O:16])=[O:17])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CS(=O)(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Product: O=S(=O)(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC1(c2ccccc2)CCNCC1
Reaction time: 16 h

Procedure:
1t-Butoxycarbonyl-4-phenyl-4-[3,5-bis(trifluoromethyl) benzylsulphonyl methyl]piperidine was dissolved in diethyl ether (5 ml) and ethereal HCl (5 ml) was added. The solution was left standing for 16 h, solvent was removed and residue was recrystallised from isopropyl alcohol/isopropyl ether giving 4-phenyl-4-[3,5-bis(trifluoromethyl)benzylsulphonylmethyl]piperidine hydrochloride (196 mg) as a white solid, m.p. 249° C. (dec), m/z (CI+) 466 (M+ +1). Found: C, 49.90; H, 4.36; N, 2.89. C21H21NO2SF6. HCl requires C, 50.25; H, 4.42; N, 2.79.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:11])=[C:6]([F:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[C:12](C1NC=CN=1)(C1NC=CN=1)=[O:13]>O1CCCC1>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=2[NH:11][C:12]1=[O:13])[CH3:2]
Reactant: CCNc1cccc(F)c1N
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCn1c(=O)[nH]c2c(F)cccc21

Procedure:
To 2,6-difluoroaniline (8 g, 62 mmol) in dimethylformamide (100 mL) was added a 2 M solution in tetrahydrofuran of ethyl amine (93 mL, 186 mmol) and the reaction stirred at room temperature overnight. The reaction was partitioned between 1 N hydrochloric acid and ethyl acetate and dried over sodium sulfate. The product was purified by silica gel using the ISCO (0-100% ethyl acetate/hexane) to give an equal mixture of ethyl-(3-fluoro-2-nitro-phenyl)-amine and N,N′-Diethyl-2-nitro-benzene-1,3-diamine. This mixture was reduced using the parr shaker and a spatula tip of 5% Pd/C in MeOH (100 mL). Upon complete reduction, the reaction was filtered through a pad of celite and concentrated onto silica gel. The desired product was purified on silica gel using the ISCO (0-100% ethyl acetate/hexane) to give N1-Ethyl-3-fluoro-benzene-1,2-diamine (2.48 g, 52%). N1-Ethyl-3-fluoro-benzene-1,2-diamine (2.48 g, 16.1 mmol) and carbonyl diimidazole (4.38 g, 27 mmol) in tetrahydrofuran (50 mL) was stirred at room temperature overnight. Upon disappearance of the starting material, the reaction was partitioned between 1 N hydrochloric acid (100 mL) and ethyl acetate (100 mL). The organics were dried over sodium sulfate and concentrated to give 1-ethyl-4-fluoro-1,3-dihydro-2H-benzimidazol-2-one as a white solid in near quantitative yield. MS (ES) m/z 181.1;
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.Br[CH2:17][C:18]1[CH:48]=[CH:47][CH:46]=[CH:45][C:19]=1[CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[O:6]=[C:5]([CH2:7][CH2:17][C:18]1[CH:48]=[CH:47][CH:46]=[CH:45][C:19]=1[CH2:20][O:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:4][C:3]([O:9][CH3:10])=[O:8]
Reactant: BrCc1ccccc1COCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CCc1ccccc1COCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (448 mg/l 1.2 mmol) in THF (22 ml) was added a solution of methyl acetoacetate (1.30 g/11.2 mmol) in THF (4.5 ml) dropwise at 0° C. over 15 minutes. After 20 minutes at 0° C., n-butyl lithium (7,3 ml/11.2 mmol) was added dropwise at 0° C. over 15 minutes. After 20 minutes at 0° C., a solution of 3-{[2-(bromomethyl)benzyl]oxy}-N-trityl-1-propanamine in THF (6.6 ml) was added dropwise at 0° C., and the solution was stirred at 0° C. for 3 hours. The mixture was quenched with water, and the whole was extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in diethylether (100 ml) and hexane (100 ml). The solution was washed with water (50 ml×5), brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, 200-350 mesh/hexane:ethyl acetate=10:0-3:1) to afford a colorless oil (3.70 g/74%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:14]4[NH:15][C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[C:22](=[O:23])[C:13]=4[CH2:12][N:11]3[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:9][C:4]=2O[CH2:2]1.[CH:31]1C=C(Cl)C=C(C(OO)=O)C=1.CO.C(Cl)Cl>C(Cl)Cl.CN(C=O)C>[CH2:24]([N:11]1[CH:12]=[C:13]2[C:14]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]2=[O:23])=[C:10]1[C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:31][C:4]=2[CH:9]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(Cc1ccccc1)C2
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1c2ccccc2[nH]c2c(-c3ccc4c(c3)CCO4)n(Cc3ccccc3)cc12

Procedure:
3-Benzo[1,3]dioxol-5-yl-2-benzyl-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one, prepared as in WO 01/87882, Example 3, page 45, (39.6 mg, 0.1 mmol) in a mixture of CH2Cl2 (4 mL) and DMF (1 mL) was stirred with a solution of mCPBA (26 mg, 0.15 mmol) in CH2Cl2 (2 mL) at room temperature for 72 h. The product was isolated by preparative TLC (2.5% MeOH/CH2Cl2, Rf=0.72) to yield the title compound as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:25])[CH:11]=[C:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2.CO.[Li+].[OH-].Cl>O>[CH:14]1[C:13]2[C:12](=[CH:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2])=[O:25])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.8 %

Procedure:
6-(2-(9H-fluoren-9-ylidene)acetamido)hexanoic acid methyl ester (349 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture was neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (281 mg, 84% yield) as a white solid. 1H NMR (DMSO-d6) δ1.30 (m, 2H, CH2), 1.51 (m, 4H, 2×CH2), 2.18 (t, J=8.0 Hz, 2H, CH2CO), 3.23 (m, 2H, NCH2), 7.08 (s, 1H, ═CH—CO), 7.34 (m, 2H, Ar—H), 7.41 (t, J=8.0 Hz, 2H, Ar—H), 7.76 (d, J=8.0 Hz, 1H, Ar—H), 7.81 (m, 2H, Ar—H), 8.53 (t, J=4.0 Hz, 1H, CONH), 8.68 (d, J=8.0 Hz, 1H, Ar—H). LC-MS (m/z) 336 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[N:4](CC2C=CC(OC)=CC=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:3](=[O:25])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2c(c1)nc(Cl)c(=O)n2Cc1ccc(OC)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Temperature: 25 °C

Procedure:
Methyl 3-chloro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (13 g, 36.31 mmol) was added to sulfuric acid (conc, 15 ml) in several batches with stirring at room temperature and then stirred an additional 10 mins. The resulting solution was quenched with ice-water (100 ml), adjusted to PH=7 with aqueous sodium hydroxide (10 N), and extracted with 1-butanol (3×200 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (12.4 g, crude).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][C:10]([OH:15])([C:12]([OH:14])=[O:13])[CH2:9]2)C=CC=CC=1.[ClH:22].O1CCOCC1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[ClH:22].[OH:15][C:10]1([C:12]([OH:14])=[O:13])[CH2:11][NH:8][CH2:9]1
Reactant: [H][H]
Reactant: O=C(O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)C1(O)CNC1

Procedure:
1-(Diphenylmethyl)-3-hydroxyazetidine-3-carboxylic acid (assume 3.90 mmol) was suspended in methanol (40 mL) and 4 N hydrochloric acid in dioxane (1 mL, 4 mmol) was added. 20 wt % Palladium hydroxide on carbon (100 mg) was added to the solution and the mixture was treated with hydrogen at 40 psi for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford 3-hydroxyazetidine-3-carboxylic acid hydrochloride which was dissolved in tetrahydrofuran (5 mL) and water (5 mL) and treated with potassium carbonate (1.615 g, 11.7 mmol) and di-tert-butyl dicarbonate (935 mg, 4.29 mmol) were added. The mixture was stirred at ambient for 17 h and then the mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate and then was acidified to pH ˜3-4 and extracted twice more with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-hydroxyazetidine-3-carboxylic acid which was dissolved in DMF (3 mL). Benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (2.028 g, 3.90 mmol) and N,N-diisopropylethylamine (0.7 mL, 4.03 mmol) were added. The mixture was stirred at ambient for 5 minutes and then allylamine (0.6 mL, 8.03 mmol) was added and the mixture was stirred for 17 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, ethyl acetate) gave 1,1-dimethylethyl 3-hydroxy-3-[(prop-2-en-1-ylamino)carbonyl]azetidine-1-carboxylate (782 mg, 3.05 mmol, 78% yield from 1-(diphenylmethyl)-3-hydroxyazetidine-3-carboxamide). 1,1-Dimethylethyl 3-hydroxy-3-[(prop-2-en-1-ylamino)carbonyl]azetidine-1-carboxylate (782 mg, 3.05 mmol) was dissolved in methanol (10 mL) and 4 N hydrochloric acid in dioxane (2 mL, 8 mmol) was added. The mixture was refluxed for 15 minutes and then was concentrated in vacuo to afford 3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide hydrochloride (3.05 mmol).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:27][O:28][CH2:29][CH2:30][NH:31][CH3:32]>C(Cl)Cl>[CH3:27][O:28][CH2:29][CH2:30][N:31]([CH3:32])[S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: CNCCOC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(C)S(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 83 %

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (500 mg; 1.48 mmol; 1.00 eq) in DCM (30 ml). The solution is degassed with N2 and cooled down to 0° C. Triethylamine (1.0 ml; 7.42 mmol; 5.00 eq) followed by N-(2-methoxyethyl)methylamine (0.80 ml; 7.42 mmol; 5.00 eq) are added. After 45 minutes at 0° C., the reaction is complete. The reaction mixture is washed with NaHCO3 sat. (twice) and water (twice). The organic phase is dried over MgSO4, filtered and concentrated under vacuum, affording Compound (21) as a beige solid (478 mg; 83%).