Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH:8](O)[C:9]([OH:11])=O)[CH2:4][CH2:3]1.[Si](Cl)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CN=C1>CN(C)C=O.O>[CH2:4]1[C:5]2[N:6]([C:9](=[O:11])[CH2:8][CH:7]=2)[C:2](=[O:1])[CH2:3]1
Reactant: O=C1CCC(CC(O)C(=O)O)N1
Agent: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC=C2CCC(=O)N12
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A solution of 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid (1.73 g), t-butyl-diphenylsilyl chloride (11 g), and imidazole (5.4 g) is allowed to stir in dimethylformamide (50 ml) for six hours at room temperature. The solution is diluted with water (100 mL) and extracted with diethyl ether (4×100 mL). The combined extracts are concentrated and the oil is dissolved in methanol (50 mL) and a 10% aqueous solution of potassium carbonate (50 mL) is added and the solution is stirred 18 hours. The solution is concentrated and washed with saturated brine (50 mL) and extracted with diethyl ether (4×75 mL). The combined extracts are dried and concentrated to an oil. The oil is dissolved in acetic anhydride (50 mL) and the solution is heated at 90° C. for two hours. The solution is filtered hot, concentrated, and the residue purified by chromatography on SiO2 (elution with chloroform:methanol; 99:1) to yield cis- and trans-2-t-butyl-diphenyllsilyloxy-dihydro-1H)-pyrrolizine-3,5(2H,6H )-dione as a white solid with mp 155°-156° C. NMR (CDCl3) and 7.60 (m, 10H), 4.66 (m, 1/2H), 4.40 (dd, 1H), 3.86 (m, 1/2H), 2.77-1.55 (m, 6H), 1.08 (s, 9H). IR (KBr) 3074, 2933, 1858, 1791, 1705, 1591, 1474, 1430, 1380, 1313, 1279.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH2:14][CH3:15])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:29][CH2:30][C@H:31]([OH:33])[CH3:32]>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:29]([CH2:30][C@H:31]([OH:33])[CH3:32])[C:5]=32)=[CH:10][CH:9]=1)[CH3:15]
Reactant: CCOc1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Reaction time: 0.75 h
Yield: 54.6 %

Procedure:
A solution of 1.6 g of (RS)-2-(2-oxoethyl)-6-ethoxy-1-indanone and 70 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.2 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 4:1). 1.03 g (52%) of (R)-1-(7-ethoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.Cl.CN(C)[CH2:14][CH2:15]CN=C=NCC.C(O)C.CN(C1C=CC=CN=1)C>ClCCl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][N:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(I)nc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc(I)nc1
Temperature: 50 °C

Procedure:
To a suspension of 6-iodonicotinic acid (23.38 g, 94.20 mmol) in dichloromethane (100 ml) was added a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.86 g, 103.6 mmol) in dichloromethane (250 ml). To this mixture was added ethanol (12.40 g, 269.27 mmol) followed by dimethylaminopyridine (1.15 g, 9.41 mmol). The mixture was heated at 50° C. for 24.5 hours, concentrated in vacuo, and diluted with water (200 ml) then extracted with ethyl ether (550 ml). The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO4) and concentrated to a yellow solid. Purification by flash chromatography (silica, 10% EtOAc-hexane) afforded the title compound as white needles: mp 48°-49° C.; 1H NMR (CDCl3): δ 8.94 (1H, d, J=2.1 Hz), 7.91 (1H, dd, J=2.1, 8.2 Hz), 7.85 (1H, d, J=8.2 Hz), 4.41 (2H, q, J=7.1 Hz), 1.41 (3H, t, J=7.1 Hz).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.[C:40]([O:44][C:45]([N:47]1C=C(C2C=CC=C(N)C=2)N=[CH:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>>[C:40]([O:44][C:45](=[O:46])[N:47]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:48])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)n1cnc(-c2cccc(N)c2)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that 4-(3-amino-phenyl)-imidazole-1-carboxylic acid tert-butyl ester (prepared in three steps from 2-bromo-3′-nitroacetophenone) was used in place of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 8.35 (1H, s), 7.82 (1H, s), 7.68 (1H, s), 7.51-7.46 (3H, m), 7.33-7.19 (5H, m), 7.04 (1H, d, 8.1), 4.78 (1H, d, 17.1), 4.66 (1H, d, 17.1), 4.35 (1H, d, 16.5), 4.22 (1H, d, 16.5), 2.80 (1H, m), 2.05-1.62 (5H, m), 1.31-1.18 (14H, m). Found C, 62.46; H, 7.01; N, 14.35%; C31H36N6O3.3.0H2O requires C, 62.61; H, 7.12; N, 14.13%.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH3:26])=[O:4].[F:29][C:30]([F:35])([F:34])[CH2:31][NH:32][NH2:33]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:21])[F:22])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:32]([CH2:31][C:30]([F:35])([F:34])[F:29])[N:33]=[C:25]([CH3:26])[CH:24]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Reactant: NNCC(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1CC(F)(F)F

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with 2,2,2-trifluoroethylhydrazine (CAS Reg. No. 5042-30-8) to give the title compound as yellow solid. MS (ESI): m/z=500.2 [M+H]+.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10](=[O:31])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:8].CI.CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[CH2:7]([O:9][C:10](=[O:31])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:1])=[CH:26][N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:8]
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(O)cn1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(OC)cn1
Temperature: 50 °C
Yield: 56.2 %

Procedure:
K2CO3 (12 mg, 0.087 mmol) was added to compound II (20 mg, 0.058 mmol) in DMF (2 mL) at it under Ar(g). After 15 min CH3I (0.004 mL, 0.058 mmol) was added and the reaction was stirred at 50° C. for 3 h30. Brine (15 mL) and EtOAc (15 mL) were added, then the phases were separated, and the aqueous phase was extracted with EtOAc (2×5 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (80:20 then 70:30) to furnish III as a colourless oil (11.65 mg, 56%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([O:15]C)=[O:14])[CH2:10][CH2:9][N:8]2[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1.[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10][CH2:9][N:8]2[C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(F)cc2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(F)cc1
Yield: 80.1 %

Procedure:
Dimethyl 2-(4-fluorobenzyl)piperidine-1,4-dicarboxylate (5.797 g, 18.74 mmol) was dissolved in acetonitrile (60 mL) and water (1.2 mL), then lithium bromide (13.02 g, 149.92 mmol) was added. Triethylamine (10.39 mL, 74.96 mmol) was added and the resulting yellow suspension was heated at reflux for 1.5 h. water (60 mL) and MTBE (120 mL) were added. The organic phase was extracted with water (×2). The pooled aqueous layer was acidified to pH 1 with 3.8 M HCl and then extracted with MTBE (×2). The combined organic layer was washed with water and evaporated. Traces of water were azeotropically removed by MeCN. 2-(4-Fluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.43 g, 80%) was isolated as a beige solid. MS m/z 296 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][OH:8])[C:5](=[O:9])[CH:4]([CH3:10])[N:3]1[CH2:11][CH2:12][CH3:13].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH:22]([CH:26]([CH3:28])[CH3:27])[C:23](O)=[O:24])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][CH:22]([CH:26]([CH3:28])[CH3:27])[C:23]([O:8][CH2:7][N:6]2[C:5](=[O:9])[CH:4]([CH3:10])[N:3]([CH2:11][CH2:12][CH3:13])[C:2]2=[O:1])=[O:24])=[CH:19][CH:20]=1
Reactant: CCCN1C(=O)N(CO)C(=O)C1C
Reactant: CC(C)C(Nc1ccc(Cl)cc1)C(=O)O
Product: CCCN1C(=O)N(COC(=O)C(Nc2ccc(Cl)cc2)C(C)C)C(=O)C1C

Procedure:
Using the procedure of Example 1, (2,4-dioxo-5-methyl-1-n-propyl-3-imidazolidinyl)methanol is reacted with the acid chloride of 2-(4-chlorophenylamino)-3-methylbutanoic acid to give (2,4-dioxo-5-methyl-1-n-propyl-3-imidazolidinyl)methyl 2-(4-chlorophenylamino)-3-methylbutanoate (A'; R is carbonyl, R' is ethylidene, R1 =R4 =R5 is hydrogen, R2 is p-chlorophenyl, R3 is isopropyl, R6 is n-propyl).
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:5])C.[NH:17]([C:19]1[N:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[NH2:18].O>ClCCl.CO>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:17]([C:19]3[N:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[N:18]=[C:4]([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: CCOC(C)=NC(=O)c1ccc(OC)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1ccc(-c2nc(C)nn2-c2ccc(S(N)(=O)=O)cn2)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
N-(1-ethoxy-ethylidene)-4-methoxy-benzamide 462 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-[5-(4-methoxy-phenyl)-3-mehtyl-[1,2,4]triazole-1-yl]-pyridine-3-sulfonic acid amide (397 mg, yield: 55%) was obtained as a solid phase.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.[Cl:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]2)=[CH:14][C:13]=1[O:26][CH2:27][CH3:28]>CN(C=O)C>[Cl:10][C:4]1[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=[C:2]([NH:23][CH:20]2[CH2:21][CH2:22][N:17]([CH2:16][C:15]3[CH:24]=[CH:25][C:12]([Cl:11])=[C:13]([O:26][CH2:27][CH3:28])[CH:14]=3)[CH2:18][CH2:19]2)[N:3]=1
Reactant: OCc1cc(Cl)nc(Cl)c1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3cc(CO)cc(Cl)n3)CC2)ccc1Cl
Yield: 4 %

Procedure:
A solution of (2,6-dichloro-pyridin-4-yl)-methanol (44.5 mg, 0.25 mmol, 1.25 equiv; commercially available) and 1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (53.8 mg, 0.20 mmol, 1.2 equiv; intermediate A2) in DMF (2.0 mL) was heated by microwave irradiation to 220° C. for 1 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 3.2 mg (4%) of the title compound. MS (ISP): 410.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C(=O)(O)[O-].[Na+].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:32][CH2:31]1>C(#N)C>[CH2:1]([N:3]([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:32][CH2:31]1)[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reactant: BrCCCCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCCC1CC1)CCCC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
According to Procedure B (Example 17, Step IV), a stirred mixture of N-[4-[4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide Example 7, Step II) and sodium bicarbonate in acetonitrile was allowed to react with 1-bromo-4-cyclopropylbutane (Step IV) to give the titled product, a compound of Formula I'. The high resolution mass spectrum had M+ at m/z 382. Theory for C20H34N2O3S: 382.2290; measured: 382.2298.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[CH:4]=[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[CH:9][CH:8]=1)[CH3:6]>CO.[Pt]>[F:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:5]([CH3:6])[CH2:4][C:3]([NH:2][CH3:1])=[O:22])=[CH:12][CH:11]=1
Reactant: CNC(=O)C=C(C)c1ccc(OCc2cccc(F)c2)cc1
Agent: [Pt]
Solvent: CO
Product: CNC(=O)CC(C)c1ccc(OCc2cccc(F)c2)cc1
Yield: 81.5 %

Procedure:
100 mg (0.33 mmol) of 3-[4-(3-fluoro-benzyloxy)-phenyl]-but-2-enoic acid methylamide is dissolved in 7 ml methanol. 25 mg of platinum 5% on charcoal is added and the mixture is hydrogenated at RT and normal pressure. The catalyst is filtered off and the filtrate evaporated to dryness, leaving 81 mg of a colorless solid. MS: m/e=302.3 (M++H).
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:7]=1)=[CH2:2].[H][H]>CO.[Pd]>[CH2:1]([C:3]1[O:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:7]=1)[CH3:2]
Reactant: C=Cc1ncc(C(=O)OCC)o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cnc(CC)o1
Yield: 98.9 %

Procedure:
To a solution of ethyl 2-vinyloxazole-5-carboxylate (470 mg, 2.81 mmol) in MeOH (7 mL) is added 10% wt. Pd/C (100 mg, 0.094 mmol) at room temperature. After stirring at room temperature under a balloon of hydrogen for 1 hour, the crude is filtered to remove Pd/C. The filtrate is collected and concentrated to give ethyl 2-ethyloxazole-5-carboxylate (470 mg). HPLC retention time=1.09 minutes (condition A); MS (m+1)=170.3; 1H NMR (400 MHz, CD3OD) δ ppm 1.35 (t, J=7.6 Hz, 3H) 1.36 (t, J=7.2 Hz, 3H) 2.87 (q, J=7.7 Hz, 2H) 4.35 (q, J=7.2 Hz, 2H) 7.71 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]([F:16])([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:5]2.[CH3:17][Mg]Br>O1CCCC1.C(OCC)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH3:17])([OH:11])[C:6]([F:16])([S:12]([CH3:15])(=[O:13])=[O:14])[CH2:5]2
Reactant: CS(=O)(=O)C1(F)Cc2cc(Cl)ccc2C1=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1(O)c2ccc(Cl)cc2CC1(F)S(C)(=O)=O

Procedure:
At room temperature, 260 mg (1 mmol) of 5-chloro-2-fluoro-2-methanesulfonylindan-1-one are dissolved in 10 ml of dry tetrahydrofuran, and 0.33 ml of a 3M solution of methylmagnesium bromide in diethyl ether is added dropwise with stirring. The reaction mixture is stirred at 50° C. for 3 h. A further 0.33 ml of the methylmagnesium bromide solution is then added, and the mixture is stirred at room temperature for another hour. After the reaction has ended, the reaction mixture is diluted with ethyl acetate and extracted successively with sat. ammonium chloride solution, sat. sodium bisulfite solution, sat. sodium bicarbonate solution and sat. sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure Chromatographic purification on silica gel (n-heptane/ethyl acetate 60/40) gives 5-chloro-2-fluoro-2-methanesulfonyl-1-methylindan-1-ol of melting point 148° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[CH:5]=2)[CH2:3][CH2:2]1.CN(CCN(C)C)C.C([Li])CCC.[B:27](OC)([O:30]C)[O:28]C.[Cl-].[NH4+]>O1CCCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([O:12][CH3:13])[C:7]([B:27]([OH:30])[OH:28])=[C:8]([O:10][CH3:11])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: COB(OC)OC
Reactant: COc1cc(OC)cc(C2CC2)c1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C2CC2)cc(OC)c1B(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
To a tetrahydrofuran (45 ml) solution of 1-cyclopropyl-3,5-dimethoxybenzene (1.59 g, 8.92 mmol) was added N,N,N,N-tetramethylethylenediamine (2.01 ml, 13.4 mmol) at room temperature and 2.77M n-butyllithium (4.83 ml, 13.4 mmol) was added dropwise at −78° C., and the mixture was stirred at room temperature for two hours. The temperature was returned to −78° C. again, trimethyl borate (1.49 ml, 13.4 mmol) was added dropwise and warmed to room temperature, and the mixture was stirred for 13 hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added to the reaction mixture while cooling on ice, which was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane/ethyl acetate: 3/1) to obtain the title compound (1.36 g, 6.12 mmol).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(Cl)c23)cc1OC
Reactant: c1nc[nH]n1
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(C)c(Cl)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,5-dichloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-chloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[CH2:12]([NH2:18])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:18][CH2:12][CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1
Reactant: NCC1CCCO1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Solvent: O
Product: O=[N+]([O-])c1ccc(NCC2CCCO2)c(Cl)c1
Temperature: 150 °C

Procedure:
A mixture of 0.3 mol (57.6 g) of 3,4-dichloronitrobenzene and 1 mol (101 g) of tetrahydrofurfurylamine is heated in an oil bath. When the temperature of the reaction medium reaches 110° C., the reaction starts and the temperature rises rapidly to 160° C. and is maintained for a certain time without external heating. When the temperature falls, the reaction medium is heated for 30 minutes in an oil bath at 150° C. and is then poured into 500 ml of ice-cooled water. The expected product initially precipitates in the form of an oil which rapidly crystallises. After it has been filtered off, washed with water, recrystallised and dried in vacuo, the product melts at 70° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[N:9]=[CH:10][C:11]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:12][C:13]=1[C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])=[N:17][N:18]=1.Br[CH2:38][CH3:39].O>CN(C=O)C>[NH2:7][C:8]1[N:9]=[CH:10][C:11]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:12][C:13]=1[C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:38][CH3:39])=[N:17][N:18]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4O)o3)n2)cc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccccc1-c1nnc(-c2nc(-c3ccc(C(=O)N(C)C)cc3)cnc2N)o1
Temperature: 62.5 °C
Reaction time: 0.33 h
Yield: 72.5 %

Procedure:
Potassium carbonate (25.46 mg, 0.1842 mmol) was added to a mixture of 4-[5-amino-6-[5-(2-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (50 mg, 0.1228 mmol) in DMF (1 mL) at room temperature. Colour change observed from yellow to orange. The resulting suspension was heated at 60-65° C. and bromoethane (14.72 mg, 10.01 μL, 0.1351 mmol) was added slowly. After the addition is complete the reaction heated at 60-65° C. for 30 min. The reaction mixture was cooled to room temperature. Water (2 mL) was added slowly at and the mixture stirred at room temperature for 20 min. A precipitate formed and was filtered and washed with water. The solid was re-dissolved in DCM and dried over MgSO4, filtered and evaporated to dryness. The solid was triturated with acetonitrile to give the product as a yellow solid (38.3 mg, 73% yield); 1H NMR (400.0 MHz, DMSO) d 1.49 (t, 3H), 2.97-3.02 (m, 6H), 4.24-4.29 (m, 2H), 7.17-7.18 (m, 1H), 7.20 (d, 1H), 7.32-7.35 (m, 2H), 7.53 (d, 1H), 7.65 (br s, 2H), 8.05 (d, 1H), 8.17 (d, 2H) and 8.99 (s, 1H) ppm; MS (ES+) 431.24
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si](C(C)(C)C)(C)C)[CH2:37]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([OH:43])[CH2:37]2)=[CH:10]1
Reactant: CCC(Oc1ccccc1OC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1ccccc1OC)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 27.8 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.30 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2-methoxyphenoxy]butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 91, above] and 36.0 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.25 g of the title compound as white crystals, melting at between 116° and 117° C.