Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:9]([O:11][C:12]([N:14]1[C:23]2[C:18](=[N:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[C@@H:17]([NH:26][C:27]2[N:32]=[C:31]([CH2:33][C:34]3[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=3)[C:30]([CH2:48]Br)=[CH:29][N:28]=2)[CH2:16][C@H:15]1[CH2:50][CH3:51])=[O:13])[CH3:10].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:9]([O:11][C:12]([N:14]1[C:23]2[C:18](=[N:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[C@@H:17]([NH:26][C:27]2[N:32]=[C:31]([CH2:33][C:34]3[CH:39]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:37]=[C:36]([C:44]([F:45])([F:46])[F:47])[CH:35]=3)[C:30]([CH2:48][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:29][N:28]=2)[CH2:16][C@H:15]1[CH2:50][CH3:51])=[O:13])[CH3:10]
Reactant: C1COCCN1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CBr)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CN3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reaction time: 0.5 h

Procedure:
Morpholine (0.02 ml) is dissolved in N,N-dimethylformamide (2 ml), then thereto is added sodium hydride (9 mg) under ice-cooling, and the mixture is stirred for 30 minutes. (2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(bromomethyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (112 mg) is added to the reaction solution under ice-cooling, and the mixture is stirred at room temperature for 1 hour and 30 minutes. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=3:1→1:1) to give (2R*,4S*)-4-([3,5-bis(trifluoromethyl)benzyl]-{5-[(morpholin-4-yl)methyl]pyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (33 mg). MS (m/z): 683 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)c1ccccc1N
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccccc2C(N)=O)cc1

Procedure:
prepared by reaction of 2-amino-benzamide with 4-tert-butyl-benzenesulfonyl chloride
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH:11]2[C:15]([OH:17])=[O:16])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:20]1(C)C=CC(S(O)(=O)=O)=C[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([N:8]1[C:9](=[O:18])[CH:10]2[CH:12]([CH:11]2[C:15]([O:17][CH2:20][CH3:21])=[O:16])[C:13]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1C2C(=O)N(Cc3ccccc3)C(=O)C12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1C2C(=O)N(Cc3ccccc3)C(=O)C12
Yield: 726.3 %

Procedure:
3-Benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (1.50 g, 6.13 mmol) was suspended in ethanol (30 ml), followed by adding p-toluenesulfonic acid monohydrate (145 mg, 0.76 mmol), heating the mixture under reflux for 8 hours, adding sodium carbonate to the reaction solution for neutralization, concentrating the mixture under reduced pressure, adding a saturated aqueous sodium bicarbonate to the reaction residue, extracting it with ethyl acetate, washing the extraction solution successively with water and saturated aqueous NaCl solution, drying it over anhydrous magnesium sulfate, concentrating the resulting solution to obtain ethyl 3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate (1.51 g, 5.52 mmol, 90%), and recrystallizing it from ethanol to obtain a pure product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([O:11][CH3:12])(OC)OC)[CH3:2].C(O)(=O)C.[N+:18]([C:21]1[C:22]([CH3:31])=[C:23]([NH:29][NH2:30])[C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27])([O-:20])=[O:19]>CO>[CH2:1]([O:3][C:4](=[O:13])[CH:5]=[C:6]([O:11][CH3:12])[NH:30][NH:29][C:23]1[C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]([N+:18]([O-:20])=[O:19])[C:22]=1[CH3:31])[CH3:2]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)c1NN
Reactant: CCOC(=O)CC(OC)(OC)OC
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C=C(NNc1c(C)cc(C)c([N+](=O)[O-])c1C)OC
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
26.9 g (0.14 mol) of trimethoxypropionic acid ethyl ester (prepared according to DT-OS 2,042,920 ) are dissolved in 100 ml of absolute methanol, 7 ml of glacial acetic acid are added and the mixture is heated to the boil. 23.4 g (0.12 mol) of 3-nitro-2,4,6-trimethylphenylhydrazine (prepared according to DT-OS 2,156,913) are introduced in portions into the mixture over the course of 10 minutes. The mixture is stirred for a further 10 minutes at the boil and is allowed to cool whilst stirring. The orange crystals which have precipitated are filtered off, washed with a little methanol and dried (18 hours in vacuo at 50° C.). 14.4 g of β-methoxy-β-(3-nitro-2,4,6-trimethylphenylhydrazino)-acrylic acid ethyl ester of melting point 82° - 83° C. are obtained.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][C:16]([C:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)=[O:8])=[CH:17][C:12]=1[CH3:11]
Reactant: COc1ccccc1C
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)c2ccc(C)cc2)cc1C

Procedure:
p-Toluoyl chloride (15.5g, 0.10 mole) is added dropwise at room temperature over a 1 hour period to a mixture of o-methylanisole (15.3 g, 0.125 mole) and aluminum chloride (AlCl3, 37.3g, 0.28 mole) in carbon disulfide (CS2, 50 ml) in a flask fitted with a stirrer, addition funnel, drying tube and reflux condenser. The reaction mixture is then refluxed for 1 hour, cooled and the carbon disulfide removed in vacuo. The residue is then slurried in methylene chloride and poured into 400 g of cracked ice containing 20 ml of concentrated hydrochloric acid. This mixture is then transferred to a separatory funnel and extracted with additional methylene chloride (3 × 15 ml) and the methylene chloride extract dried (anhydrous MgSO4) prior to concentrating in vacuo. The residue was then triturated with benzene. The benzene extract is then diluted with hexane which results in precipitation of 2.5 g. of product (10%), m.p. 73°-5°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[CH2:25]([N:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]1=[O:18])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1[nH]cc(-c2cccc(Cl)c2)c2ncccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cccnc2c(-c2cccc(Cl)c2)cn1Cc1ccccc1
Temperature: 21 °C
Reaction time: 8 h
Yield: 55820.2 %

Procedure:
To a suspension of 8-(3-chlorophenyl)-1,6-naphthyridin-5-one (200 mg, 0.78 mmoles) and potassium carbonate (130 mg, 0.93 mmoles) in 10 ml DMF was added dropwise benzyl bromide (0.14 ml, 1.2 mmoles) under an atmosphere of nitrogen and stirred overnight at 21° C. The reaction mixture was poured into 100 ml water and after stirring for one hour the white precipitate was collected and dried. Crystallization from methanol gave 151 grams (56% yield) of the desired 6-benzyl-8-(3-chlorophenyl)-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 148.8°-150° C.; TLC in 1:4 EtOAc/Hex; 1H NMR (CDCl3, 300 MHz) δ5.28 (s, 2H), 7.30-7.55 (m, 10H), 8.78 (dd, 1H, J=8.1, 1.9), 8.94 (dd, 1H, J=4.5, 1.9); 13C NMR (75 MHz, CDCl3 ) δ154.31, 151.66, 136.97, 136.84, 136.17, 134.30, 134.13, 130.02, 129.51, 129.05, 128.23, 128.07, 127.77, 122.10, 122.01,119.86, 52.04; IR (KBr) vmax 1645, 1612, 1589, 1552, 1483, 1460, 1439, 1417, 1369, 1304, 1294, 1197, 1170, 790, 744, 729, 713, 702, 692, 599 cm-1 ; mass spectrum (EI), m/e 346. Anal. (C21H15ClN2O) Calcd.: C, 72.73; H, 4.36; N, 8.08. Found: C, 72.61; H, 4.35; N, 8.14.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[S:20][C:21]([CH3:24])=[CH:22][CH:23]=4)=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:25]1[C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]2[C:34]([O:36][C:37](=O)[C:27]=2[CH:26]=1)=[O:35]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[S:20][C:21]([CH3:24])=[CH:22][CH:23]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:34](=[O:35])[C:28]2[C:27](=[CH:26][CH:25]=[C:30]([C:31]([OH:33])=[O:32])[CH:29]=2)[C:37]1=[O:36]
Reactant: COc1ccc(-c2nc3cc(-c4ccc(C)s4)ccc3o2)cc1N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(-c2nc3cc(-c4ccc(C)s4)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-4-methoxyphenyl-5-[(5-methyl)thiophen-2-yl]benzoxazole (64 mg, 0.19 mmol) and 1,2,4-benzenetricarboxylic anhydride (40 mg, 0.20 mmol) the title compound was obtained (62 mg, 64%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.36–8.30(m, 3H), 8.11(d, 1H), 7.94(d, 1H), 7.77(d, 1H), 7.61(dd, 1H), 7.49(d, 1H), 7.36(d, 1H), 6.84(dd, 1H), 3.89(s, 3H), 2.50(s, 3H). MS m/z 511.1 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[P:18]([O:25]CC)([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>>[CH2:20]([O:19][P:18]([CH2:2][C:3]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)c1cc(CBr)nc2ccccc12
Product: CCOC(=O)c1cc(CP(=O)(OCC)OCC)nc2ccccc12
Temperature: 100 °C

Procedure:
Ethyl 2-(bromomethyl)quinoline-4-carboxylate (1.0 g, 3.4 mmol, as prepared above) was treated with triethyl phosphite (11.3 g, 68.0 mmol) and the resultant slurry was heated to 100° C. overnight. The reaction was concentrated under reduced pressure, diluted with DCM (50 mL), washed with sodium bicarbonate, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0:100-1:1 EtOAc/heptane) to afford compound 45a. Mass spectrum (LCMS, ESI pos.) Calcd. For C17H22NO5P: 352.1 (M+H). found 352.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Br)[CH3:21].CN1CCOCC1>CN(C=O)C>[CH2:20]([O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][NH:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])=[CH:17][CH:16]=1)[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(N)cc1
Reactant: CCOC(=O)CCCBr
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Yield: 18.1 %

Procedure:
A solution of [4-(4-aminophenyl)butyl]carbamic acid tert-butyl ester (1.7 g, 6.43 mmol), 4-bromo-n-butyric acid ethyl ester (1.88 g, 9.64 mmol), 4-methylmorpholine (1.0 mL, 9.64 mmol), and DMF (10 mL) was stirred at 85° C. for 3 hours under a nitrogen atmosphere. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 4:1, hexanes/ethyl acetate, v/v) to provide 27 (0.44 g, 18%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.23 (t, 3H), 1.47 (s, 9H), 1.55 (m, 4H), 1.96 (m, 2H), 2.43 (t, 2H), 2.51 (t, 2H), 3.19 (m, 4H), 4.14 (q, 2H), 6.54 (d, 2H), 7.00 (d, 2H). m/z (ESI) 379.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.Br[CH2:18][CH2:19][C:20](C)=[CH2:21]>>[CH2:14]([O:13][C:11](=[O:12])[CH:10]([S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=1)(=[O:9])=[O:8])[CH2:18][CH:19]=[CH:20][CH3:21])[CH3:15]
Reactant: C=C(C)CCBr
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(C)cc1
Product: CC=CCC(C(=O)OCC)S(=O)(=O)c1ccc(C)cc1

Procedure:
5-Methyl-2-(3-methyl-but-2-enyl)-2-(toluene-4-sulfonyl-hex-4-enoic acid ethyl ester was prepared according to general method as outlined in example 9. Starting from ethyl α-(p-tolylsulfonyl)acetate (2.9 g, 10.9 mmol and 4-bromo2-methyl butene (3.42 g, 23 mmol). Yield 4.6 g; tan oil; MS 379.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][C:13](=NO)[CH2:12][C:11]=2[C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C1C[O:30]CC1>>[CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][C:13](=[O:30])[CH2:12][C:11]=2[C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C1CCc2c(c(-c3ccc(Cl)cc3)nn2Cc2ccccc2)C1
Reactant: C1CCOC1
Agent: Cl
Product: O=C1CCc2c(c(-c3ccc(Cl)cc3)nn2Cc2ccccc2)C1

Procedure:
1-Benzyl-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-indazol-5-one oxime. A solution of 3.87 g of the compound from step G in 80 mL of THF with 5 mL of 1 M HCl was heated at reflux for 16 h. The volatiles were removed in vacuo and water was added (300 mL). The mixture was adjusted to pH 9 by the addition of 1 M NaOH and then was extracted with CH2Cl2. The combined extracts were washed with brine and the solvent was removed in vacuo to provide 1-benzyl-3-(4-chloro-phenyl)-1,4,6,7-tetrahydro-indazol-5-one. This product (3.13 g) was treated with hydroxylamine hydrochloride (3.0 g) in 20 mL of pyridine. The reaction mixture was stirred at RT for 14 h then was diluted with water (300 mL), and stirred an additional hour. The mixture was filtered on paper and the solids were washed with EtOAc and dried in vacuo to afford 2.48 g of the desired compound. 1H NMR (500 MHz, acetone-d6): 10.24 (s, 1H), 7.30-7.26 (m, 2H), 7.06-7.02 (m, 2H), 6.91-9.87 (m, 2H), 6.85-6.81 (m, 1H), 6.77-6.73 (m, 2H), 4.87 (s, 2H), 3.21 (s, 2H), 2.31 (t, J=6.6 Hz, 2H), 2.09 (t, J=6.6 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:9]([OH:11])=[O:10].[C:13]([CH:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)#[CH:14]>>[CH3:1][C:2]1([CH3:12])[C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:9]([O:11][CH:15]([C:13]#[CH:14])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:10]
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C(=O)O)C12CCCC2
Product: C#CC(OC(=O)C1C(C)(C)C12CCCC2)c1cccc(Oc2ccccc2)c1

Procedure:
The procedure of Example 1 is followed using 2,2-dimethylspiro[2,4]heptane-1-carboxylic acid in place of 2,2-dimethyl-4,5-benzospiro[2,4]hepta-4,6-diene-1-carboxylic acid and α-ethynyl-m-phenoxybenzyl alcohol in place of m-phenoxybenzyl alcohol to give the product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16](OC)=[O:17])[CH:5]=[CH:6][C:7]=1[F:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)CCc1cnoc1-c1ccc(F)c(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of methyl 3-[5-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propionate (1.43 g) in tetrahydrofuran (20 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(3-bromo-4-fluorophenyl)-4-isoxazolyl]propan-1-ol (1.11 g, yield 85%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 57–58° C.
Reaction SMILES: [OH-].[Na+].[F:3][CH:4]([F:20])[O:5][C:6]1[C:7]([F:19])=[C:8]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:9]([O:11]CC)=[O:10].Cl>C(O)C>[F:20][CH:4]([F:3])[O:5][C:6]1[C:7]([F:19])=[C:8]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1cc(F)c(F)c(OC(F)F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Reaction time: 8 h
Yield: 102.7 %

Procedure:
20 ml of a 6% w/v aqueous solution of sodium hydroxide were added to a solution of 5.79 g (0.021 moles) of ethyl 3-difluoromethoxy-2,4,5-trifluorobenzoate [(XXVI), X=X'=F, R16 =C2H5O] [prepared as described in step (b) above] in 40 ml of ethanol, and the mixture was left at room temperature overnight. The reaction mixture was then acidified by the addition of 3.5 ml of concentrated aqueous hydrochloric acid, and, after concentration by evaporation under reduced pressure, it was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure, to give 5.22 g of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid as a colorless powder, melting at 68°-70° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH:22]=[CH:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+:35]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH2:27][CH2:28][C:29]([O-:31])=[O:30])[CH:22]=[CH:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[Na+:35]
Reactant: CCOC(=O)CCn1ccc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(ccn4CCC(=O)[O-])c3)no2)cc1C#N
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]propanoate (D53) (150 mg, 0.38 mmol) was dissolved in ethanol (25 ml) by warming to 60° C. Allowed solution to cool to RT then added 2N sodium hydroxide (3 ml, 6 mmol). The solution was stirred at RT for 30 minutes. LC/MS showed a single product. Evaporated off the ethanol and filtered off the solid which precipitated out of solution. Mass of title compound as a light tan solid obtained on drying was 50 mg. δH (400 MHz, d6-DMSO) 1.45 (6H, d), 2.67 (2H, t), 4.48 (2H, t), 4.92-4.98 (1H, m), 6.54-6.55 (1H, m), 7.34 (1H, d), 7.38 (1H, d), 7.60 (1H, d), 7.91 (1H, dd), 8.35 (1H, d), 8.41-8.46 (2H, m). MS (ES) C23H20N4O4 requires 416; found 417 (MH+).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)[CH:2]=1.C([O:34][C:35](=[O:56])[C:36]([O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([CH3:48])[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1)C>C(O)C>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14][C:41]3[C:42]4[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:38]([CH2:37][C:36]([CH3:48])([O:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:35]([OH:56])=[O:34])=[CH:39][CH:40]=3)[N:11]=2)[CH:2]=1
Reactant: CCOC(=O)C(C)(Cc1cccc2ccccc12)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)c2ccccc12
Temperature: 55 °C
Yield: 24 %

Procedure:
Toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) (see Ex. 2, Part F) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 2-phenoxy-3-(naphthalen-1-yl)-2-methylpropionic acid ethyl ester (see Ex. 12, Part B) (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by mass-directed HPLC to produce a white solid (24%). MS [EI+] 584 (M+H)+, [EI−] 582 (M−H)+
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH3:10])[CH:5]=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[OH-].[K+]>C(O)C>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH3:10])[CH:5]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: C1CCNC1
Reactant: CNc1cc(Cl)nc(N)[n+]1[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CNc1cc(N2CCCC2)nc(N)[n+]1[O-]
Reaction time: 1 h
Yield: 58.9 %

Procedure:
3.4 g of 2-amino-4-methylamino-6-chloropyrimidine 3-oxide are suspended in 70 ml of ethanol. 4.15 g of pyrrolidine are added. The reaction mixture is refluxed for 7 hours. After it has returned to room temperature, 1.30 g of potassium hydroxide are added as an 85% solution in 15 ml of ethanol. After 1 hour's stirring the mixture is filtered on paper. The filtrates are evaporated to dryness. The residue obtained is recrystallized from 50 ml of a 9/1 acetonitrile-water mixture. 2.40 g of 2-amino-4-methylamino-6-pyrrolidinopyrimidine 3-oxide are obtained.
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][O:6][C:7]([N:9]([CH3:24])[C:10](=[O:23])[O:11][C:12]1[C:20]2[O:19][C:18]([CH3:22])([CH3:21])[CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:8])[CH3:2].[OH2:25]>C(O)(=O)C>[CH2:1]([S:3]([CH2:4][CH2:5][O:6][C:7]([N:9]([CH3:24])[C:10](=[O:23])[O:11][C:12]1[C:20]2[O:19][C:18]([CH3:21])([CH3:22])[CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:25])[CH3:2]
Reactant: O
Reactant: CCSCCOC(=O)N(C)C(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: CC(=O)O
Product: CCS(=O)CCOC(=O)N(C)C(=O)Oc1cccc2c1OC(C)(C)C2

Procedure:
2.7 ml of 40% strength hydrogen superoxide were added dropwise to 10.6 g (0.03 mol) of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl N-(2-ethylthioethoxycarbonyl)-N-methyl-carbamate in 40 ml of glacial acetic acid at 0° C. The next day, the mixture was poured into 300 ml of water and extracted with methylene chloride. The solution was neutralized with sodium bicarbonate. After filtration, the organic phase was worked up as described in Example 1. Yield: 11 g of a colorless oil (98% of theory) of nD20 =1.5320.