Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:14][C@@H:13](/[CH:15]=[CH:16]/[C:17]2[N:18]([CH:35]([CH3:37])[CH3:36])[C:19](=[O:34])[C:20]3[C:25]([C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:12][C@H:11]([O:38]C)[CH2:10]1)(C(C)(C)C)(C)C.C(O)(=O)C.O1CCCC1.O>C(OCC)C>[OH:38][CH:11]1[CH2:10][C@H:9]([OH:8])[CH2:14][C@@H:13](/[CH:15]=[CH:16]/[C:17]2[N:18]([CH:35]([CH3:37])[CH3:36])[C:19](=[O:34])[C:20]3[C:25]([C:26]=2[C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:12]1
Reactant: CO[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H](/C=C/c2c(-c3ccc(F)cc3)c3ccccc3c(=O)n2C(C)C)O1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)n1c(/C=C/[C@@H]2C[C@@H](O)CC(O)O2)c(-c2ccc(F)cc2)c2ccccc2c1=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
A solution of (2S,4R,6S)-(E)-4-(t-butyldimethylsilyloxy)-6-[2-{4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl}ethen-1-yl]-2-methoxy-3,4,5,6-tetrahydro-2H-pyran [149 mg; prepared as described in Example 8(a)] in a mixture of glacial acetic acid, tetrahydrofuran and water (3:2:2 by volume; 5 ml) was stirred at 70° C. under argon and under a reflux condenser for 3 hours. The resulting clear solution was diluted with diethyl ether (50 ml), washed with water (20 ml) and then with saturated aqueous sodium bicarbonate solution (2×20 ml), dried over magnesium sulphate and evaporated. The resulting residue was subjected to flash chromatography on silica gel, using as eluant ethyl acetate containing from 0 to 50% hexane by volume, to give (2RS,4R,6S)-(E)-2,4-dihydroxy-6-[2-{4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinolin-3-yl}-ethen-1-yl]-3,4,5,6-tetrahydro-2H-pyran (78 mg) in the form of a white foam.
Reaction SMILES: [I:1][C:2]1[S:3][C:4]([CH:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)O)=[CH:5][CH:6]=1.O.O.[Sn](Cl)Cl.Cl.[OH-].[Na+]>C(O)(=O)C.O>[I:1][C:2]1[S:3][C:4]([CH2:7][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:6]=1
Reactant: OC(c1ccncc1)c1ccc(I)s1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Ic1ccc(Cc2ccncc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
A suspension of 2-iodo-5-(4-pyridylhydroxymethyl)thiophene (0.65 g, 2.05 mmol) and tin(II) chloride dihydrate (1.01 g, 4.51 mmol) in acetic acid (5 mL) was treated with HCl gas for 10 rain and stirred for 2 hours at ambient temperature. The reaction mixture was poured into H2O, neutralized with 10% aqueous NaOH, and extracted twice with ethyl acetate. The combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel provided 2-iodo-5-(4-pyridylmethyl)thiophene (0.22 g, 36% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([C:26]([N+:29]([O-])=O)=[CH:27][N:28]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:14][C@H:13]1[O:32][CH3:33])=[O:10]>Cl.C(O)(=O)C>[NH2:29][C:26]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][C:18]([N:15]2[CH2:16][CH2:17][C@H:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[C@H:13]([O:32][CH3:33])[CH2:14]2)=[N:28][CH:27]=1
Reactant: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)ncc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
A solution of SnCl2 dihydrate (870 mg, 3.8 mmol) in 5 ml concentrated HCl was added to a solution of 436 mg (0.87 mmol) of Cis(±)-ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-nitroisonicotinate (Example 308) in 30 ml acetic acid. The mixture was stirred at room temperature overnight. Solvent was removed and the residue was partitioned between water and EtOAc. The EtOAc was separated and washed with brine. Drying (MgSO4), removal of solvent and chromatography on silica gel (100% CH2Cl2 followed by gradient elution to 100% EtOAc and then to 10% MeOH in EtOAc) gave 230 mg of product. MS (ES)(MH+): 470 for C20H25Cl2N5O4; NMR (CDCl3): 1.5 (t, 3H), 2.1 (m, 2H) 2.4 (s, 3H), 3.2 (m, 2H), 3.6 (s, 3H), 3.65 (m, 1H), 4.0 (m, 1H), 4.4 (m, 1H), 4.5 (q, 2H), 7.3 (s, 1H), 8.0 (s, 1H), 9.5 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH2:36][O:37][CH3:38])=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)=[CH:12][CH:11]=[C:10]([C:26]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][N:27]=1)[N:9]=2)=[O:4].O[Li].O.Cl>CO.O>[CH3:38][O:37][CH2:36][C:6]1[C:5]([C:3]([OH:4])=[O:2])=[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)[C:13]2[C:8](=[N:9][C:10]([C:26]3[C:31]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:11][CH:12]=2)[N:7]=1
Reactant: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(Nc2ccc(C(F)(F)F)cc2)c1C(=O)OC
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(Nc2ccc(C(F)(F)F)cc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 2-methoxymethyl-4-(4-trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-[1,8]napthyridine-3-carboxylic acid methyl ester (150 mg, 0.279 mmol) in a solution of MeOH (6 mL), H2O (2 mL), and LiOH.H2O (58.6 mg, 1.40 mmol). Stir the mixture overnight at room temperature. Add water (30 mL) and acidify the mixture with 3 N HCl. Extract with CH2Cl2 (2×40 mL). Dry the combined organic extracts over Na2SO4. Remove the solvent under reduced pressure and chromatograph the crude product on silica gel eluting with CH2Cl2/MeOH/AcOH (95:5:1) to yield the title compound. MS 523.18 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:21](Cl)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C.CS(C)=O>O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3nc2Cl)C1
Reactant: C1CCNCC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3nc2N2CCCCC2)C1
Temperature: 160 °C
Yield: 180 %

Procedure:
To a mixture of 3-(3-chloro-quinoxalin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (91) (0.16 g, 0.50 mmol) and piperidine (0.085 g, 1.0 mmol) was added triethylamine (0.10 g, 1.0 mmol) and DMSO (3 mL). The solution was heated to 160° C. in microwave for 2 h. Then the mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 50% EtOAc in petroleum ether) to give 3-(3-piperidin-1-yl-quinoxalin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (92) (0.16 g, 0.90 mmol, 90% yield) as a white solid. ESI-MS (M+1): 369 calc. for C21H28N4O2 368.
Reaction SMILES: [O:1]([C@@H:9]([CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32])[C@@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[Si](C(C)(C)C)(C)C.F.C(=O)(O)[O-].[Na+]>C(#N)C>[CH:12]1([CH2:11][C@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C@@H:9]([OH:1])[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][C:28]2=[O:32])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](CN1CCCC1=O)O[Si](C)(C)C(C)(C)C
Agent: *CC(*)C
Agent: F
Agent: O=C([O-])O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CN1CCCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
0.62 g (1.28 mmol) of t-butyl [(1S,2S)-2-(t-butyldimethylsiloxy)-1-(cyclohexylmethyl)-3-(2-oxo-1-pyrrolidinyl)propyl]carbamate was dissolved in 9 ml of acetonitrile in a polypropylene reaction vessel and treated at room temperature with 1.2 ml of 40% aqueous hydrofluoric acid. The reaction mixture was subsequently stirred at room temperature for 3 hours, thereafter poured into 2N sodium bicarbonate solution and extracted with methylene chloride. The methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure, whereby there were obtained 434 mg of t-butyl [(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-3-(2-oxo-1-pyrrolidinyl)propyl]carbamate as an oil which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[C:13]([CH:21]([CH3:23])[CH3:22])[CH:12]=2)=[C:8]([CH3:24])[CH:7]=[C:6]([OH:25])[C:3]=1[CH2:4]O>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH3:20][O:19][CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:9]2[C:8]([CH3:24])=[CH:7][C:6]([OH:25])=[C:3]([CH3:4])[C:2]=2[CH3:1])=[CH:12][C:13]=1[CH:21]([CH3:23])[CH3:22]
Reactant: COCOc1ccc(Cc2c(C)cc(O)c(CO)c2C)cc1C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCOc1ccc(Cc2c(C)cc(O)c(C)c2C)cc1C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A mixture of 2,4-dimethyl-6-hydroxy-3-(4′-methoxymethoxy-3′-iso-propylbenzyl)benzyl alcohol ((0.20 g, 0.58 mmol) and Pd—C (0.08 g, 10%) in ethyl acetate-acetic acid (3.5 mL, 95:5) was stirred at room temperature under a H2 atmosphere for 6 h. The reaction mixture was filtered through a Celite plug and the solvent was removed under reduced pressure to afford 4-(4′-methoxymethoxy-3′-iso-propylbenzyl)-2,3,5-trimethylphenol (0.19 g, 100%) as colorless oil: 1H NMR (300 MHz, CD3OD): δ 6.94 (m, 1 H), 6.91 (d, J=13.2 Hz, 1 H), 6.68 (dd, J=13.2, 2.4 Hz, 1 H), 6.55 (s, 1 H), 5.17 (s, 2 H), 3.95 (s, 2 H), 3.47 (s, 3 H), 3.30 (m, 1 H), 2.19 (s, 3 H), 2.16 (s, 3 H), 2.11 (s, 3 H), 1.17 (d, J=10.8 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=acetone-hexanes (3:7); Rf=0.60.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12](COC(=O)C(C)(C)C)[C:11]=2[N:10]=[C:9]1[N:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.[H-].[Na+].Cl>CO.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[NH:12][C:11]=2[N:10]=[C:9]1[N:28]1[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]1
Reactant: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2Cl)n(COC(=O)C(C)(C)C)c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2nc(N3CCN(C(=O)OC(C)(C)C)CC3)n(-c3ccccc3Cl)c2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl 4-[7-(2-chlorophenyl)-3-(2,2-dimethylpropionyloxy methyl)-1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in a mixture of 10 ml of methanol and 20 ml of tetrahydrofuran, and 200 mg of sodium hydride was added thereto. The resulting mixture was stirred at room temperature overnight. 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated. The residue was suspended in ether and the mixture was filtered. Thus, 450 mg of the title compound was obtained.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:19][CH2:20][C:21]([CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=O)=[O:22])[CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16]>C(Cl)(Cl)Cl>[Cl:4][C:24]1[CH2:25][CH2:26][CH2:27][C:23]=1[C:21](=[O:22])[CH2:20][CH2:19][C:11]1[CH:10]=[C:9]([O:8][CH3:7])[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=1
Reactant: COc1cc(CCC(=O)C2CCCC2=O)cc(OC)c1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(CCC(=O)C2=C(Cl)CCC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
13 ml of oxalyl chloride were added at ambient temperature to a solution of 23 g of the product of Stage C and 230 ml of chloroform and the mixture was stirred for three hours at ambient temperature, and concentrated under reduced pressure by proceeding with two entrainments with cyclohexane to obtain 28 g of crude product which was crystallized from a mixture of 50 ml of cyclohexane and 50 ml of diisopropyl ether after partial concentration. Separation was carried out, followed by washing with diisopropyl ether and drying under reduced pressure to obtain 16.24 g of the expected product melting at 93° C.
Reaction SMILES: [F:1][C:2]([F:8])([S:5]([O-:7])=[O:6])[CH2:3][OH:4].[CH2:9]([NH+:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH3:10].[OH:16]O>O>[F:1][C:2]([F:8])([S:5]([O-:16])(=[O:7])=[O:6])[CH2:3][OH:4].[CH2:9]([NH+:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH3:10]
Reactant: O=S([O-])C(F)(F)CO
Reactant: OO
Agent: CC[NH+](CC)CC
Solvent: O
Product: O=S(=O)([O-])C(F)(F)CO
Temperature: 40 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
A 100 mL reactor was charged with 11.5 g (26% purity, 0.012 mole/1.0 equivalent) of triethylammonium 1,1-difluoro-2-hydroxy-ethane-1-sulfinate, 20 g of water and 4.2 g (0.036 mole/3.0 equivalents) of 30% hydrogen peroxide at room temperature, followed by one day of stirring at 40° C. Upon confirming the termination of the reaction, the reaction liquid underwent cooling. Thereafter, the reaction liquid was subjected to distillation of the solvent and brought into dryness, thereby obtaining 10.5 g of a target triethylammonium 1,1-difluoro-2-hydroxy-ethane-1-sulfonate. It exhibited a purity of 26% and a yield of 85% at this time.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([N:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH3:16])[S:13][CH:14]=2)=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C>[Br:1][C:14]1[S:13][C:12]([N:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH3:16])=[N:11][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([Br:3])=[CH:9][CH:8]=1
Reactant: COC(=O)CN(C)c1nc(-c2ccc(Br)cc2)cs1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CN(C)c1nc(-c2ccc(Br)cc2)c(Br)s1
Yield: 98.9 %

Procedure:
A solution of 2.34 g (0.015 mol) of bromine in 5 ml of glacial acetic acid is added dropwise with stirring in the course of 45 minutes at room temperature to a mixture of 4.5 g (0.013 mol) of methyl N-[4-(4-bromophenyl)-thiazol-2-yl]-N-methylaminoacetate and 2.5 g (0.03 mol) of sodium acetate in 30 ml of glacial acetic acid, the mixture is subsequently stirred with an excess of aqueous saturated sodium hydrogen carbonate solution, and the precipitate which has separated out is filtered off with suction. After drying, 5.4 g (97% of theory) of methyl N-[5-bromo-4-(4-bromophenyl)-thiazol-2-yl]-N-methylaminoacetate are obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:14]CN(CC)CC.ClC(OC)=O>C(Cl)Cl.CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:14])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a solution of 10 g (49.6 mmol) of 5-chloro-2-nitrobenzoic acid and 9 mL (64.5 mmol) Et3N in 300 ml CH2Cl2 at 0° C. was added 4.6 mL (59.5 mmol) methyl chloroformate. The cold bath was removed and after 10 minutes, 0.200 mL methanol was added. Bubbles of CO2 could be seen rising from the solution. After 2 hours, the mixture was diluted with Et2O, was washed with 5% HCl, was washed with saturated NaHCO3 solution, was washed with brine, was dried over MgSO4 and decolorized with charcoal, then was stripped of solvent in vacuo to give the product. Rf 0.35 in 15% EtOAc/hexane, visualized by UV; 1H-NMR (400 MHz, CDCl3): δ7.92 (d, J=8.6 Hz, 1H), 7.69 (d, J=2.3 Hz, 1H), 7.59 (dd, J1 =2.2 Hz, J2 =8.8 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([C:25]([OH:27])=O)=[C:16]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:17][C:11]=2[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:9]1=[O:32].[CH3:33][N:34](C)[CH:35]=O>ClCCl>[CH3:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([C:25]([N:34]([CH3:35])[CH3:33])=[O:27])=[C:16]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:17][C:11]=2[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:9]1=[O:32]
Reactant: CN(C)C=O
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3ccccc3)sc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)N(C)C)c(Cc3ccccc3)sc21
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.087 ml) was added to a stirred solution of 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-phenylmethyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid (0.37 g) and dimethylformamide (0.01 ml) in anhydrous dichloromethane (20 ml). After 1 hour, the solution was evaporated. The residue was dissolved in anhydrous tetrahydrofuran (7 ml) and 1 ml of this solution was added to a stirred mixture of 40% aqueous dimethylamine solution (1 ml) and saturated sodium hydrogen carbonate solution (2 ml). After 30 minutes water (10 ml) was added and the mixture was extracted with ethyl acetate (10 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was recrystallised from ethyl acetate/isohexane to give the title compound (0.025 g).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([C:25]2[N:26]([CH3:34])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:19][C:16]=1[CH:17]=O>>[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([C:25]2[N:26]([CH3:34])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:19][C:16]=1/[CH:17]=[CH:2]/[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Product: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 87 %

Procedure:
The title compound was prepared by condensing 4-acetylbenzoic acid and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)-benzaldehyde (Ex-116A) in a similar manner as described in Ex-3. Yellow solid, 87% yield, mp 157–160° C. 1H-NMR (DMSO-d6) δ 8.17 (d, J=8 Hz, 2H), 8.08 (d, J=15 Hz, 1H), 7.99–9.02 (m 3H), 7.83 (d, J=15 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.10–7.15 (m, 1H), 6.99–7.04 (m, 1H), 6.85 (s, 1H), 6.42 (s, 1H), 4.01 (s, 3H), 3.88 (s, 3H), 3.50 (s, 3H). MS m/z=442 ([M+H]+, 100%). HRMS (ES+) Calcd. for C27H23NO5: 442.1654. Found: 442.1633.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[CH:12]([CH2:13][C:14]3[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=3)[O:11]C(=O)[NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Li+].[OH-].CO.O.O>[CH:1]1([CH2:7][C@H:8]([NH2:9])[CH:12]([OH:11])[CH2:13][C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ccnc1CC1OC(=O)N[C@H]1CC1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ccnc1CC(O)[C@@H](N)CC1CCCCC1

Procedure:
790 mg of 4(S)-cyclohexylmethyl-5(R,S)-(1-methylimidazol-2-yl-methyl)-1,3-oxazolidin-2-one are dissolved in 33 ml of 2N LiOH in MeOH/H2O 1:1; and the solution is heated under reflux for 3 h, then diluted with 150 ml of water and extracted 3 times with 50 ml of CH2Cl2. Drying with Na2SO4 and concentration in vacuo results in the title compound as colorless oil which is used further without purification.
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5].[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([O:6][C@@H:21]1[CH:22]2[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]2)[CH2:20]1)=[O:5]
Reactant: CN(c1ccccc1)C(C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN(c1ccccc1)C(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.8 %

Procedure:
2-(Methyl(phenyl)amino)-2-phenylacetic acid (I35) (2.20 g, 9.12 mmol) was dissolved in THF (25 ml), and (R)-quinuclidin-3-ol (1.28 g, 10.0 mmol) was added. To the resulting solution, HOBt (1.23 g, 9.12 mmol) and DCC (1.88 g, 9.12 mmol) were added, and the mixture was stirred at room temperature for three days. THF was removed under vacuum and the residue was portioned between H2O and EtOAc. The organic phase was washed with a saturated aqueous Na2CO3 solution, dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography (EtOAc to EtOAc/MeOH=75/25) to afford (R)-quinuclidin-3-yl 2-(methyl(phenyl)amino)-2-phenylacetate (2.2 g, 68.8% yield, mixture of diastereomers).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5](N(OC)C)=[O:6].[CH2:14]([Mg]Cl)[CH2:15][CH3:16].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH2:14][CH2:15][CH3:16])[CH:11]=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)c1cccc(F)c1
Reactant: CCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(=O)c1cccc(F)c1
Temperature: -10 °C
Reaction time: 1.25 h

Procedure:
To a solution of 3-fluoro-N-methoxy-N-methylbenzamide (130 mg, 0.71 mmol) in dry THF (2 mL) cooled to −10° C. was added propyl magnesium chloride (532 μl, 2M solution in ether, 1.1 mmol) under nitrogen. The solution was stirred at −10° C. for 1 h and at room temperature for 75 min. The solution was the poured into saturated aqueous ammonium chloride and the product extracted into ethyl acetate (3×25 mL). The organic layers were combined, washed with brine, dried (MgSO4) and concentrated to give a pale yellow oil, which was purified by chromatography using ethyl acetate-hexane (1:9) to separate the pure product (78 mg, 66%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=2)(=[O:20])=[O:19])[N:7]([CH3:28])[N:6]=1.[H-].[Na+].[Cl:31][C:32]1[CH:33]=[N:34][C:35](S(C)(=O)=O)=[N:36][CH:37]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Cl:31][C:32]1[CH:33]=[N:34][C:35]([O:1][CH2:2][CH2:3][O:4][C:5]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:8]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=3)(=[O:19])=[O:20])[N:7]([CH3:28])[N:6]=2)=[N:36][CH:37]=1
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C)cn2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(OCCOc3ncc(Cl)cn3)nn(C)c2NS(=O)(=O)c2ccc(C)cn2)cc1
Reaction time: 0.33 h
Yield: 78.9 %

Procedure:
To N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-2-pyridine sulphonamide (Example 50) (100 mg) in dry tetrahydrofuran (5 ml) at room temperature was added sodium hydride (80% dispersion in oil, 20 mg) the mixture was stirred for 20 minutes. A solution of 5-chloro-2-methylsulphonylpyrimidine (72 mg) in dry tetrahydrofuran (2.5 ml) was then added and the mixture was stirred for a further 16 hours. The mixture was then treated with further sodium hydride (80% dispersion in oil, 20 mg) and after 15 minutes stirring further 5-chloro-2-methylsulphonylpyrimidine (84 mg) was also added. The mixture was stirred for 4 hours. The reaction was treated with citric acid (10% aq.) and extracted with ethyl acetate (50 ml). The organic fraction was washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with a solvent gradient of pentane:ethyl acetate (8:2 to 0:1) to yield the tile compound as a yellow solid (101 mg).