Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:7]=1[C:8]#[N:9].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:3]1[C:2]([Cl:1])=[C:7]([C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:5][N:4]=1)[C:8]#[N:9]
Reactant: COc1cccc(-c2c[n+]([O-])cc(Cl)c2C#N)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cccc(-c2cnc(Cl)c(Cl)c2C#N)c1
Reaction time: 1 h

Procedure:
A mixture of crude 3-chloro-4-cyano-5-(3-methoxyphenyl)pyridine 1-oxide from Step 2 and phosphorus oxychloride (15 mL) in a sealed tube was placed in a 100° C. bath. After 1 h at 100° C., HPLC analysis indicated that a 2:1 mixture of products was formed. The mixture was concentrated. Recrystallization from ethyl acetate/hexanes (10 mL/10 mL) gave 2,3-dichloro-5-(3-methoxyphenyl)isonicotinonitrile as white solid (200 mg). The mother liquor was purified by reverse phase HPLC, using Sunfire S10 30×250 mm column and eluting with 80-100% solvent B (90% methanol-10% water-0.1% TFA) in solvent A (10% methanol-90% water-0.1% TFA), to give additional 2,3-dichloro-5-(3-methoxyphenyl)isonicotinonitrile (400 mg). 1H NMR (500 MHz, methanol-d4) δ ppm 8.54 (1H, s), 7.45 (1H, t, J=7.97 Hz), 6.77-7.28 (3H, m), 3.86 (3H, s); MS (ES+) m/z: 279 (M+H); LC retention time: 3.768 min (analytical HPLC Method A). No attempt was made to isolate the undesired 2,5-dichloro-3-(3-methoxyphenyl)isonicotinonitrile isomer.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(SCC(CCC(=O)O)C(=O)O)cc1C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CCC(CSc1ccc(C)c(C)c1)C(=O)O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 1423.5 %

Procedure:
A mixture of 2-(3,4-dimethylphenylthiomethyl)glutaric acid (1.16 g), methanol (20 ml), and p-toluenesulfonic acid (0.04 g) was stirred at 40° C. for 1.5 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica by eluting with chloroform/ethanol (10:1) to give 0.98 g of 3-(3,4-dimethylphenylthio)-2-(2-methoxycarbonylethyl)propionic acid as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=O)[CH2:7][C:6]2([CH3:16])[CH3:15].[CH3:17][CH2:18][O:19][C:20]([CH2:22][C:23]#[N:24])=[O:21].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:18]([O:19][C:20](=[O:21])[C:22]([C:23]#[N:24])=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2)[C:6]([CH3:16])([CH3:15])[CH2:7]1)[CH3:17]
Reactant: COc1cc2c(cc1OC)C(C)(C)CC2=O
Reactant: CCOC(=O)CC#N
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=C1CC(C)(C)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Yield: 71.4 %

Procedure:
122 g (0.55 mol) of 2,3-Dihydro-5,6-dimethoxy-3,3-dimethyl-1H-inden-1-one (CAS N.[4136-26-9] for preparation see F. Camps, Z. Naturforsch., B : Anorg. Chem., Org. Chem. (1984), 39B (12), 1801-5), 63,3 g (0.56 mol) of ethyl cyano acetate, 12 g (0.14 mol of piperidine, 12 g (0.1 mol) of benzoic acid and 1000 ml toluene were mixed together and heated under reflux for 48 hours. The reaction mixture was cooled to room temperature, washed with diluted HCl, aqueous Na2CO3, and water and then dried (MgSO4). Removal of the solvent and crystallization from EtOH gave 123.8 g of a yellow solid (m.p.: 148-149° C). Yield: 71%; E1%cm: 790 (1 max.: 367 nm) in EtOH. Solubility: 0.35% in CÉTIOL LC
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1C=C2OCOC2=C[C:20]=1[C:28](=O)C)=[O:17])(=[O:10])=[O:9].[NH2:32][C:33]1[CH:38]=[CH:37]C(C)=CN=1.NC1C=C2OCOC2=CC=1C(=O)C>>[Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[N:32]=[CH:33][C:38]([CH3:37])=[CH:28][CH:20]=1)=[O:17])(=[O:9])=[O:10]
Reactant: CC(=O)c1cc2c(cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl)OCO2
Reactant: Cc1ccc(N)nc1
Agent: CC(=O)c1cc2c(cc1N)OCO2
Product: Cc1ccc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)nc1

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6-pyridyl)aminocarbonyl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148), except that 2-amino-5-picoline was used in stead of 2′-amino-4′,5′-(methylenedioxy)acetophenone, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6-pyridyl)aminocarbonyl]thiophene-3-sulfonamide was obtained, via HPLC purification of the crude reaction mixture, as a bright yellow powder (17% yield, m.p. 158-160° C.).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1.CCN(CC)CC.ClC(OCC)=O.[BH4-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(-n2ccccc2=O)cc1
Agent: CCOC(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-n2ccccc2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a stirred solution of 4-(2-oxo-2H-pyridin-1-yl)-benzoic acid (0.31 g, 1.4 mmol) in THF (12 mL) was added Et3N (0.30 mL, 2.15 mmol, 1.5 eq) followed by dropwise addition of ClCOOEt (0.16 mL, 1.2 eq) at 0° C. under N2. The mixture was stirred for 1 h at 0° C., filtered, and rinsed with THF. The THF solution was stirred at 0° C., MeOH (3 mL) was added followed by portionwise addition of NaBH4 (0.26 g, 6.8 mmol). The mixture was stirred at 0° C. for 20 min, sat'd Na2SO4 added, extracted with CH2Cl2, dried (MgSO4), filtered, and concentrated to dryness to give 4-(2-oxo-2H-pyridin-1-yl)-benzaldehyde (0.17 g) as a tan solid.
Reaction SMILES: Cl.[CH:2]1([C:8](=[NH:12])[O:9][CH2:10][CH3:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.N1C(C)=CC(C)=CC=1C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23]([N:12]=[C:8]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[O:9][CH2:10][CH3:11])=[O:24])[CH3:27]
Reactant: CCOC(=N)C1CCCCC1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)N=C(OCC)C1CCCCC1
Temperature: 0 °C
Reaction time: 12 h
Yield: 95.6 %

Procedure:
Ethyl cyclohexanecarbimidate hydrochloride (1.8 g, 9.2 mmol) was suspended in hexanes (22.9 mL) and cooled to 0° C. 2,4,6-Collidine (4.1 mL, 30.9 mmol) and ethyl chloroformate (1.9 g, 17.8 mmol) were sequentially added and the mixture was allowed to warm to RT and stirred for 12 h. The solvent was removed in vacuo. The residue was suspended in EtOAc (50 mL) and the solids were removed by filtration through diatomaceous earth. The filter cake was washed with EtOAc (3×10 mL) and the combined filtrates were concentrated in vacuo to afford ethyl N-ethoxycarbonylcyclohexanecarbimidate (2.0 g, 96%) as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 4.09 (q, J=7.1 Hz, 2H), 4.02 (q, J=7.1 Hz, 2H), 2.41-2.31 (m, 1H), 1.70-1.65 (m, 4H), 1.40-1.36 (m, 2H), 1.26-1.09 (m, 4H), 1.19 (t, J=7.1 Hz, 6H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[NH2:13][C:14]1[CH:15]=[C:16]([C@@H:20]([NH:22][C:23]2[CH:28]=[N:27][CH:26]=[C:25]([Cl:29])[N:24]=2)[CH3:21])[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:29][C:25]1[N:24]=[C:23]([NH:22][C@H:20]([C:16]2[CH:15]=[C:14]([NH:13][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[N:1]=[CH:2][NH:3][C:4]=4[CH:9]=3)=[O:11])[CH:19]=[CH:18][CH:17]=2)[CH3:21])[CH:28]=[N:27][CH:26]=1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1cccc(N)c1
Reactant: O=C(Cl)c1ccc2nc[nH]c2c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cncc(Cl)n1)c1cccc(NC(=O)c2ccc3nc[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5-benzimidazole carbonyl chloride (108 mg, 0.5 mmol), (S)—N-(1-(3-aminophenyl)ethyl)-6-chloropyrazin-2-amine (144 mg, 0.5 mmol) and triethylamine (0.7 mL, 5 mmol) was stirred at room temperature for 72 hours. After this time the mixture was allowed to cool to room temperature and was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium hydrogen carbonate (2×15 mL), brine (15 mL), dried (MgSO4) and concentrated under reduced pressure to give a yellow oil which was purified by flash chromatography (silica, ethyl acetate/methanol) to give (S)—N-(3-(1-(6-chloropyrazin-2-ylamino)ethyl)phenyl)-1H-benzo[d]imidazole-6-carboxamide as a yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:16])=[C:12]([OH:15])[CH:13]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].Cl[C:34]1[CH:44]=[CH:43][C:37]([C:38]([N:40]([CH3:42])[CH3:41])=[O:39])=[CH:36][N:35]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:16])=[C:12]([O:15][C:34]3[CH:44]=[CH:43][C:37]([C:38](=[O:39])[N:40]([CH3:41])[CH3:42])=[CH:36][N:35]=3)[CH:13]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:19][CH:18]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)c(Cl)cc2n1-c1ccc(C(C)(C)C)cc1
Reactant: CN(C)C(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(=O)N(C)C)cn3)c(Cl)cc2n1-c1ccc(C(C)(C)C)cc1

Procedure:
1-(4-tert-Butylphenyl)-6-chloro-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (120 mg, 0.26 mmol, see step (b) above), 6-chloro-N,N-dimethylnicotinamide (72 mg, 0.39 mmol), K2CO3 (181 mg, 1.31 mmol) and DMF (3 mL) was heated at 115° C. for 96 h and filtered through Celite®. The solids were washed with EtOAc and the combined filtrates concentrated and purified by chromatography to give the sub-title compound. Yield 48 mg (78%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:6](=[O:23])[C:7]([C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[CH:8][C:9](=[N:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[CH:10]=1)([CH3:4])[CH3:3]>C(OCC)(=O)C.[C].[Pd]>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[C:7]([C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[C:6]=1[OH:23])([CH3:1])[CH3:3]
Reactant: CC(C)(C)C1=CC(=Nc2cnccn2)C=C(C(C)(C)CO)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(Nc2cnccn2)cc(C(C)(C)CO)c1O
Temperature: 25 °C
Yield: 91.4 %

Procedure:
In 450 ml of ethyl acetate was dissolved 2.5 g of Compound 1a followed by addition of 0.30 g of 10% palladium-carbon as a catalyst. After purging the atmosphere in the reaction vessel with hydrogen gas, the reaction mixture was stirred at ambient temperature. After 180 ml of hydrogen had been consumed, the reaction mixture was filtered through Celite to remove the catalyst and the filtrate was washed with ethyl acetate and concentrated under reduced pressure. The crude product thus obtained was washed with diethyl ether to give 2.3 g of the desired compound as a colorless solid. The structure and physical properties of the product compound are shown in Table 2.
Reaction SMILES: [CH2:1]([O:3][N:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH3:2].C([BH3-])#N.[Na+]>>[CH2:1]([O:3][NH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCON=Cc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCONCc1ccc(F)cc1
Yield: 74 %

Procedure:
Reduction of 4-fluorobenzaldehyde O-ethyloxime with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a clear oil after chromatography (74% yield). 1HNMR 400 MHz (C6D6) δ (ppm): 1.13 (3H, t, J=7.1 Hz, CH3), 3.70 (2H, q, J=7.1 Hz, OCH2), 3.78 (2H, d, J=5.4 Hz, NCH2), 5.20 (2H, broad t, NH), 6.89 (2H, m, aromatics), 7.09 (2H, m, aromatics). Anal. calcd for C9H12FNO: C, 63.88; H, 7.14; N, 8.27. Found: C, 63.68; H, 7.08; N, 8.46.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:19])=[C:8]([C:12]([O:14]C(C)(C)C)=[O:13])[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].FC(F)(F)C(O)=O>O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:19])=[C:8]([C:12]([OH:14])=[O:13])[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c(C(=O)OC(C)(C)C)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)c1c(C)[nH]c(C(=O)O)c1C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 6b (5.34 g, 20 mmol) was dissolved in trifluoroacetic acid (7.4 mL, 100 mmol) and the mixture was stirred for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. Then 40 mL of water was added. The mixture was filtered and the filter cake was washed with dichloromethane and dried to obtain the title compound 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid 4-ethyl ester 6c (3.65 g, yield 86.5%) as a pink solid.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[CH2:25][C@H:24]2[CH2:26][C@H:22]([C:23]2([CH3:28])[CH3:27])[C@@H:21]1[NH:29][C:30]1[C:35]([F:36])=[CH:34][N:33]=[C:32]([C:37]2[C:45]3[C:40](=[N:41][CH:42]=[C:43]([Cl:46])[CH:44]=3)[N:39](S(C3C=CC(C)=CC=3)(=O)=O)[CH:38]=2)[N:31]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C(#N)C.O1CCOCC1>[Cl:46][C:43]1[CH:44]=[C:45]2[C:37]([C:32]3[N:31]=[C:30]([NH:29][C@@H:21]4[C@@H:20]([CH2:19][OH:18])[CH2:25][C@H:24]5[CH2:26][C@@H:22]4[C:23]5([CH3:27])[CH3:28])[C:35]([F:36])=[CH:34][N:33]=3)=[CH:38][NH:39][C:40]2=[N:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4[C@@H](CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)C[C@H]5C[C@@H]4C5(C)C)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: CC1(C)[C@H]2C[C@H](CO)[C@@H](Nc3nc(-c4c[nH]c5ncc(Cl)cc45)ncc3F)[C@@H]1C2
Temperature: 70 °C

Procedure:
To a solution of N-((1R,2S,3S,5R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine, 77f, (0.037 g, 0.046 mmol) in acetonitrile (1.1 mL) was added HCl (0.221 mL of a 4 M solution in dioxane, 0.883 mmol). The mixture was heated to 70° C. for 18 h, during which a precipitate formed. The reaction was concentrated in vacuo and triturated three times with CH3CN to afford 4 mg of the desired product as a white solid: 1H NMR (300.0 MHz, MeOD) δ 8.72-8.64 (m, 1H), 8.39 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 8.21 (d, J=5.2 Hz, 1H), 4.71 (d, J=6.3 Hz, 1H), 3.67-3.57 (m, 2H), 2.33-2.26 (m, 1H), 2.10 (m, 1H), 1.78-1.70 (m, 1H), 1.28-1.25 (m, 7H) and 1.19 (s, 3H) ppm; LCMS RT=3.13 (M+H) 416.42.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]C(=O)N(C)C)=[C:6]([CH2:16][CH2:17][CH3:18])[C:5]=1[OH:19])(=[O:3])[CH3:2].[OH-].[K+].C(O)C.Cl>O>[OH:19][C:5]1[C:6]([CH2:16][CH2:17][CH3:18])=[C:7]([SH:10])[CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CCCc1c(SC(=O)N(C)C)ccc(C(C)=O)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1c(S)ccc(C(C)=O)c1O
Yield: 94.1 %

Procedure:
Reflux a stirred mixture of dimethyl-thiocarbamic acid S-(4-acetyl-3-hydroxy-2-propyl-phenyl)ester (1.08 g, 3.84 mmol), potassium hydroxide (1.1 g, 19.2 mmol), ethanol (25 mL), and water (10 mL) for 2 hours. Cool the reaction in an ice/water bath and adjust the pH to 2 with aqueous 5N hydrochloric acid. Extract the mixture with ethyl acetate (3×50 mL). Combine the extracts and wash with water (50 mL) and brine (50 mL) and dry over magnesium sulfate, filter, and concentrate to afford the title compound (0.76 g, 94%) as a brown oil which solidifies on standing. LCMS (m/z) 211 M−1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17]C=C[CH:14]=2)[C@@H:10]([CH2:19][OH:20])[CH2:9]1)[C:2]1C=CC=C[CH:3]=1.C1C(/C=C/C(O)=O)=C[S:23]C=1.C(O)(=O)/C=C/C1C=CC=CC=1.COCN(CC=C)C[Si](C)(C)C.COCN(CC1C=CC=CC=1)C[Si](C)(C)C>>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][S:23][CH:14]=2)[C@@H:10]([CH2:19][OH:20])[CH2:9]1)[CH:2]=[CH2:3]
Reactant: OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Reactant: O=C(O)/C=C/c1ccsc1
Agent: C=CCN(COC)C[Si](C)(C)C
Agent: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C(O)/C=C/c1ccccc1
Product: C=CCN1C[C@H](CO)[C@@H](c2ccsc2)C1

Procedure:
The title compound was prepared using procedures analogous to those used to prepare 1-benzyl-3-(R)-(hydroxymethyl)-4-(S)-phenylpyrroldine (Pyrrolidine 1, Step C), except that trans-3-(3-thienyl)acrylic was substituted for trans-cinnamic acid in Step A and N-methoxymethyl-N-trimethylsilylmethyl(prop-2-enyl)amine was substituted for N-methoxymethyl-N-trimethylsilylmethyl benzyl amine in Step B. For the title compound: 1H NMR (500 MHz) δ 2.30-2.34 (m, 1H), 2.44 (t, J=8.5, 1H), 2.67 (t, J=9.0, 1H), 2.77 (dd, J=5.0, 9.0, 1H), 3.02-3.15 (4H), 3.53 (dd, J=7.5, 10.0, 1H), 3.64 (dd, J=5.0, 10.0, 1H), 5.07 (d, J=10.0, 1H), 5.17 (d, J=17.5, 1H), 5.83-5.91 (m, 1H), 6.97-6.99 (2H), 7.20-7.22 (m, 1H); ESI-MS 224 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C:15]4([C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.I[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[C:30]1([CH2:29][CH2:28][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C:15]5([C:25]6[CH:24]=[CH:23][N:22]=[CH:21][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1OC2(CCN(C(=O)C3(c4ccc(O)cc4)CC3)C2)c2ccncc21
Reactant: ICCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C1OC2(CCN(C(=O)C3(c4ccc(OCCc5ccccc5)cc4)CC3)C2)c2ccncc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1′-{[1-(4-hydroxyphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (15 mg, purity: 80%, 0.034 mmol), (2-iodoethyl)-benzene (12 mg, 0.051 mmol), and tetra-n-butylammonium iodide (1 mg, 0.003 mmol), and Cesium Carbonate (28 mg, 0.086 mmol) in Dimethyl sulfoxide (0.3 ml) was stirred at r.t. overnight. Then the desired product was obtained from the mixture by prep-HPLC (0.24 mg). LCMS: m/z 455.1 (M+H)+; 477.0 (M+Na)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[C:26]1[CH3:37]>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]([CH3:24])[C:26]=2[CH3:37])=[O:35])=[O:10])[N:12]=1
Reactant: Cc1c(C(=O)O)c2ccccc2n1C
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)n(C)c3ccccc23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 1,2-Dimethyl-1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.92 min; [M+H]+=499.4.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl.C(N(CC)CC)C.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41](=O)[NH:40][N:39]=2)=[CH:33][CH:32]=1.CN(C)C(=O)N(C)C.N>CCOCC.O>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:41]2[C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:38]([CH2:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)=[N:39][N:40]=2)=[CH:26][CH:25]=1
Reactant: O=c1[nH]nc(Cc2ccncc2)c2ccccc12
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Agent: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CN(C)C(=O)N(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: Clc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 200 °C
Reaction time: 0.17 h

Procedure:
A mixture of 17.03 g (0.12 mol) phosphorus pentoxide, 11.56 g (0.084 mol) triethylamine hydrochloride and 15.31 g (0.12 mol) 4-chloroaniline is heated and stirred under argon atmosphere at 200° C. (oil bath temperature) until a homogeneous melt has formed (about 45 min). To the melt (internal temperature about 160° C.) 7.12 g (0.03 mol) of 4-(4-pyridylmethyl)-1 (2H)-phthalazinone (for preparation see German Auslegeschriftno. 1 061 788 [published Jul. 23, 1959]) is added and the reaction mixture stirred for 4 h at an internal temperature of 160-170° C. After cooling to about 120° C. (internal temperature) 28 ml tetramethylurea is added dropwise, the temperature rising temporarily to 150° C. For about 10 min at 120° C., 100 ml water is then added to the reaction mixture, which is stirred for 0.5 h at 100-103° C. (internal temperature), then cooled to 60° C., before a mixture of 40 ml water and 37 ml concentrated ammonia solution is added dropwise to the brown solution, whereupon a suspension forms. While cooling to an ultimate temperature of 15° C., the suspension is stirred for 0.5 h, then mixed with 80 ml ether and stirred for a further 10 min. The mixture is filtered, the filter residue is washed with water, then ether, and dried in air. After recrystallization from methanol/ether (under treatment with activated carbon) and drying under HV for 8 h at 120° C., the title compound is obtained with a water content of 0.31%; m.p. 207-209° C.; 1H NMR (DMSO-d6) 9.29 (s, 1H), 8.58-8.63 (m, 1H), 8.44-8.47 (m, 2H), 8.10-8.15 (m, 1H), 7.89-8.05 (m, 4H), 7.37-7.45 (m, 2H), 7.31-7.34 (m, 2H), 4.59 (s, 2H). A further portion of title compound can be obtained from the mother liquor.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([O:8][OH:9])([CH:6]=[CH2:7])[CH3:5].[C:10](Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>O>[C:10]([O:9][O:8][C:4]([CH3:5])([CH:6]=[CH2:7])[CH3:3])(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: C=CC(C)(C)OO
Reactant: CC(C)(C)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=CC(C)(C)OOC(=O)C(C)(C)C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a stirred mixture cooled at 10° C. of 10 g of demineralized water, 17.3 g of a 45% by weight-potassium hydroxide solution in water (0.139 moles) and 12.9 g of 2-methyl-3-buten-2-yl hydroperoxide (0.120 moles) there were added over a period of 25 minutes 14.5 g of pivaloyl chloride (0.120 moles); the temperature of the reaction mixture was kept at 10°-12° C. Stirring was continued for 1 hour, after which the organic layer was isolated. It was washed successively with an aqueous solution of 10% by weight-KOH (15 min, 10° C.), an aqueous bisulphite/acetate buffer (20 min., 10° C.) and a dilute solution of sodium bicarbonate in water (2x). Finally, the organic layer was dried with MgSO4 and the product was isolated by filtration. There were obtained 17.3 g of colourless oil containing 97.7% of peroxy ester, which corresponds to a yield of 75.6 %. The identity of the product was confirmed by IR and NMR spectroscopy (1H and 13C).