Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:28])[CH:3]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH2:9]/[C:10](=[N:30]\[OH:31])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([CH3:28])[CH:3]=1
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(C(=O)O)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@@H](c2ccc(C(=O)O)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 4-[(S)-1-(4-chloro-2-methyl-phenyl)-3-(2-methyl-pyridin-4-yl)-3-oxo-propyl]-benzoic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow solid, MS (ESI+): m/z=409.3 ([M+H]+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[CH2:11]1.Cl[CH2:19][C:20](=O)[CH3:21]>C(O)C>[CH3:21][C:20]1[C:13]2[C:14](=[O:16])[CH2:15][CH:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH3:3])[CH2:11][C:12]=2[O:17][CH:19]=1
Reactant: Cc1ccccc1C1CC(=O)CC(=O)C1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1C1CC(=O)c2c(C)coc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.4 %

Procedure:
To 60% sodium hydride (0.21 g, washed with hexane thrice) was added ethanol (30 ml), and to the mixture was added 5-(2-methylphenyl)cyclohexane-1,3-dione (1.0 g) and then was added chloroacetone (0.45 g) at 0° C. The mixture was stirred at room temperature for 20 minutes and was refluxed for 24 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give oil of 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.18 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]([C@@H:11]3[O:33][C@H:32]([CH2:34][O:35]C(=O)C4C=CC=CC=4)[C@@H:22]([O:23]C(=O)C4C=CC=CC=4)[C@H:12]3[O:13]C(=O)C3C=CC=CC=3)[CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1>N>[NH2:1][C:2]1[C:3]2[N:10]([C@@H:11]3[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([OH:23])[C@H:12]3[OH:13])[CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2pcn([C@@H]3O[C@H](COC(=O)c4ccccc4)[C@@H](OC(=O)c4ccccc4)[C@H]3OC(=O)c3ccccc3)c12
Agent: N
Product: Nc1ncnc2pcn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.4 %

Procedure:
A mixture of 7-Amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-1,3-azaphospholo[4,5-d]pyrimidine (compound 21 , R=2,3,5-tri-O-benzoyl-β-ribofuranose, 0.45 g, 0.75 mmol) and methanolic ammonia (100 mL, saturated at 0° C.) was stirred at room temperature for 20 h and the methanolic ammonia was evaporated under reduced pressure. The residue was triturated with methanol (10 mL) and the product was collected by filtration. The filtrate was evaporated and the residue was purified by chromatography over a silica gel column. The column was flash eluted with dichloromethane containing 0-20% methanol. The appropriate fractions containing the pure product were collected and evaporated to give a total yield of 0.18 g (84%) of the title compound, mp 220-222° C. Ir (KBr): ν700 (=P-C), 1205 (-P=CH), and 2930-3470 (NH2, OH) cm-1. Uv (pH 1): λmax254 nm (ε23,400), 284 (15,600), and 314 (5600); (MeOH): λmax266 nm (ε32,900), and 340 (2100); (pH 11): 266 nm (ε36,050), and 338 (3250). 31 p nmr (DMSO-d6): δ 62.50; 1H nmr (DMSO-d6): δ3.73(dd,2H, C5'H2), 3.98 (m, 1 H, C4'H), 4.10 (br s, 1 H, C3'H), 4.28 (m, 1 H, C2'H), 5.24 (br s, 2 H, 2OH), 5.63 (br s, 1 H, OH), 5.70 (d, 1 H, C1'H), 8.24 (s, 2 H, NH2), 8.86 (d, 1 H, C5H), and 8.83 (d, 1 H, J =58.8 Hz, C2H). Anal. Calcd. for C10H13N4O4P.0.25 CH2Cl2 :C, 40.30; H, 4.45; N, 18.35. Found: C, 40.40; H, 4.15; N, 18.54.
Reaction SMILES: [NH2:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[C:28](O)(=O)[CH3:29]>>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][N:13]1[C:12]2[C:2](=[N:3][CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:11]=2)[N:1]=[C:28]1[CH3:29]
Reactant: CCOC(=O)c1cnc(N)c(NCc2ccc(Cl)cc2Cl)c1
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cnc2nc(C)n(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 100 °C
Yield: 89.7 %

Procedure:
A suspension of ethyl 6-amino5-(2,4-dichlorobenzylamino)nicotinate (300 mg) and acetic acid (132 mg) in polyphosphoric acid (6 g) was heated to 100° C. Two hours later, the reaction mixture was cooled and ice (5 g) was added. The mixture was neutralized with a saturated aqueous sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sulfate and filtrated. The filtrate was concentrated and the residue was crystallized from isopropyl ether to give the objective compound (288 mg) as pale-brown crystals.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([OH:19])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[C:22]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][CH3:22])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2oc(C(=O)OC(C)(C)C)c(C)c2c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To 80 mg of 4-hydroxy-3,5-dimethyl-benzofuran-2-carboxylic acid tert-butyl ester was added 1 mL of iodomethane, 80 mg of K2CO3 and 1 mL of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Removal of the solvent gave 82 mg of 4-methoxy-3,5-dimethyl-benzofuran-2-carboxylic acid tert-butyl ester as a pale yellow solid.
Reaction SMILES: C(Cl)Cl.[C:4]([O:8][C:9]([N:11]1[CH2:14][CH:13]([O:15][C:16]2[CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH:19]=[CH:20][C:21]=2[CH:22]=[O:23])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].C1C=C(Cl)C=C(C(OO)=[O:42])C=1>CCOC(C)=O>[C:4]([O:8][C:9]([N:11]1[CH2:12][CH:13]([O:15][C:16]2[CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:31])[F:32])[CH:19]=[CH:20][C:21]=2[C:22]([OH:42])=[O:23])[CH2:14]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(-c3ccccc3C(F)(F)F)ccc2C=O)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(-c3ccccc3C(F)(F)F)ccc2C(=O)O)C1
Reaction time: 15 h
Yield: 37.2 %

Procedure:
To a CH2Cl2 (6 mL) solution of the title compound of Step A (0.236 g, 0.560 mmol) was added m-CPBA (77 wt %, 0.189 g, 0.840 mmol). After 15 h, 10% Na2S2O5 was added and the solution allowed to stir until the aqueous was Kl paper negative and extracted with CH2Cl2 (2×). The combined organic layers were dried and treated with MeOH (10 mL) and 1N NaOH (10 mL). After 15 h, the reaction was partially concentrated to remove the MeOH and acidified with 1M HCl (220 mL) then extracted with EtOAc (2×). The combined organic layers were dried and concentrated. Silica gel chromatography (0-30% EtOAc in hexanes) gave 0.091 g (37% yield) of the title compound. (MS (ESI): mass calcd. for C22H22F3NO5, 437.15. m/z found, 382.1 [M-56]+, 460.1 [M+Na]+. 1H NMR (CDCl3): 7.73 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.87 (dd, J=8.2, 1.9 Hz, 1H), 6.52 (d, J=1.0 Hz, 1H), 4.97-4.88 (m, 1H), 4.30 (dd, J=9.8, 6.4 Hz, 2H), 4.05 (dd, J=9.9, 3.7 Hz, 2H), 1.45 (s, 9H)) and 0.091 g (39% yield) of 3-(4-Hydroxy-2′-trifluoromethyl-biphenyl-3-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (MS (ESI): mass calcd. for C21H22F3NO4, 409.15. m/z found, 354.1 [M-56]+, 432.1 [M+Na]+. 1H NMR (CDCl3): 8.19 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.12 (dd, J=8.0, 1.3 Hz, 1H), 6.63 (s, 1H), 5.11-5.00 (m, 1H), 4.36 (dd, J=10.1, 6.4 Hz, 2H), 4.12 (dd, J=10.6, 3.6 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: NCc1ccccc1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4)cc3)c2)o1

Procedure:
N-Benzyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and benzylamine using method N. NMR; δH [2H6]—DMSO 9.14,(1H, t), 8.00,(2H, d), 7.90,(1H, dd), 7.77,(1H, d), 7.56-7.51,(3H, m), 7.34,(4H, m), 7.25,(1H, m), 4.51,(2H, d), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.35 min, MH+ 384.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:17][C:10]3[C:11](=[O:16])[NH:12][CH2:13][CH2:14][S:15][C:9]=3[C:7]=2[CH:8]=1.CC(O)=[O:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:17][C:10]3[C:11](=[O:16])[NH:12][CH2:13][CH2:14][S:15](=[O:20])[C:9]=3[C:7]=2[CH:8]=1
Reactant: CC(=O)O
Reactant: COc1ccc2sc3c(c2c1)SCCNC3=O
Product: COc1ccc2sc3c(c2c1)S(=O)CCNC3=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A mixture of 2,3-dihydro-9-methoxy-[1]benzothieno[2,3-f]-1,4-thiazepin-5(4H)-one (200 mg, 0.75 mmol) and NaBO3 -4H2O (116 mg, 0.75 mmol) in 18 mL of AcOH is stirred at room temperature overnight. The reaction mixture is filtered and 60 mL of water is added to the filtrate. Filtration provides 2,3-dihydro-9-methoxy-[1]benzothieno[2,3-f]-1,4-thiazepin-5(4H)-one-1-oxide in 69% yield; mp 215°-216° C. (dec).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)#[CH:2].[N:25]([C@@H:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]1)=[N+:26]=[N-:27].[Na+].[Cl-]>CC(O)(C)C.O>[C:37]([O:36][C:34]([N:30]1[CH2:31][CH2:32][CH2:33][C@@H:28]([N:25]2[CH:2]=[C:1]([C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][CH:11]=3)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:7]=[C:6]4[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)[N:27]=[N:26]2)[CH2:29]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N=[N+]=[N-])C1
Reactant: C#Cc1ccc2c(c1)c(-c1ccncc1)nn2C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(-c3ccc4c(c3)c(-c3ccncc3)nn4C(=O)OC(C)(C)C)nn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.7 %

Procedure:
Tert-butyl 5-ethynyl-3-(pyridin-4-yl)-1H-indazole-1-carboxylate (0.385 g, 1.2 mmol) and (R)-tert-butyl 3-azidopiperidine-1-carboxylate (0.273 g, 1.2 mmol) were suspended in t-BuOH:H2O (1:1, 15 mL:15 mL) and then CuSO4.5H2O (0.060 g, 0.24 mmol) and Na-Ascorbic acid (0.096 g, 0.48 mmol) were added sequentially. Reaction mixture was stirred vigorously at room temperature overnight. After the completion of reaction, added sat. NaCl (30 mL), extracted with EtOAc (3×50 mL), evaporated the organic solvent to give (R)-tert-butyl 5-(1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-1H-1,2,3-triazol-4-yl)-3-(pyridin-4-yl)-1H-indazole-1-carboxylate (0.81 g) which was used for next step without purification.
Reaction SMILES: [C:1]([N:6]1[CH:12]([CH3:13])[C:11]2[CH:14]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[S:16][C:10]=2[S:9](=[O:22])(=[O:21])[CH2:8][CH2:7]1)(=O)[CH:2]([CH3:4])[CH3:3].B.C1COCC1.Cl.O>O1CCCC1>[CH2:1]([N:6]1[CH:12]([CH3:13])[C:11]2[CH:14]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[S:16][C:10]=2[S:9](=[O:21])(=[O:22])[CH2:8][CH2:7]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)N1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc2C1C
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CN1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc2C1C
Yield: 65.7 %

Procedure:
To a solution of 4-isobutyryl-5(R,S)-methyl-7-sulfamoyl-2,3,4,5-tetrahydrothieno[3.2-f]-1,4-thiazepine-1,1-dioxide (1.009 g, 2.75 mmol) in dry tetrahydrofuran (30 mL), under an inert atmosphere was added 1M borane·THF (9 mL, 9.0 mmol) and the reaction mixture was refluxed for three hours. Concentrated HCl and water were then added to the cooled reaction mixture. After refluxing this mixture for 0.5 hours, the solvent was removed, the residue was made basic with NaHCO3 and the product was extracted into ethyl acetate. The extract was dried (Na2SO4), filtered and the solvent evaporated. Trituration of the residue with diethyl ether and n-butyl chloride gave 637 mg (65%) of crystalline product. Recrystallization of the solid from diethyl ether twice afforded analytically pure title compound (446 mg), mp 125°-127° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[CH2:19]([N:22]=[C:23](SC)[O:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH3:21]>C(O)CC>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:23]([O:24][CH2:25][CH2:26][CH3:27])[N:22]([CH2:19][CH2:20][CH3:21])[C:4]2=[O:6]
Reactant: CCCN=C(OCCC)SC
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: CCCO
Solvent: CCN(CC)CC
Product: CCCOc1nc2ccc(I)cc2c(=O)n1CCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.4 %

Procedure:
To a solution of 0.38 g (1.44 mmoles) of 2-amino-5-iodobenzoic acid and 0.14 g (1.38 mmol) of triethylamine in 7.15 mL of n-propanol was added 0.25 g (1.143 mmol) of S-methyl O-propyl propylcarbonimidothioate. The reaction mixture was stirred at room temperature for 18 h, heated to 60° C. for 24 h, and then heated to reflux for 6 h. The reaction was then concentrated under reduced pressure to give about 0.6 g of crude material, which was purified by flash chromatography on silica (93:7 hexanes:ethyl acetate) to give 0.21 g of the title compound, 1H NMR (400 MHz, CDCl3): δ0.96 (t,3H); 1.06 (t,3H); 1.64-1.79 (m,2H); 1.81-1.92 (m,2H); 4.05 (t,2H); 4.43 (t,2H), 7.19 (d,1H); 7.85 (dd,1H); 8.49 (d,1H). In addition, 0.11 g of propyl-5-iodoanthranilate was obtained from the flash chromatography, 1H NMR (400 MHz, CDCl3): δ1.02 (t,3H); 1.76-1.86 (m,2H); 4.23 (t,2H); 5.8 (br s,2H); 6.45 (d,1H); 7.45 (dd, 1H); 8.13 (d,1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].[C:12]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[C:9]2[O:10][CH2:12][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1cc(O)c(O)c(F)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(F)c2c(c1)OCO2
Temperature: 60 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of 3-fluoro-4,5-dihydroxy-benzaldehyde (1.5 g, 9.6 mmol) and BrClCH2 (4.9 g, 38.5 mmol) in dry DMF (50 mL) was added Cs2CO3 (12.6 g, 39 mmol). The mixture was stirred at 60° C. overnight and was then poured into water. The resulting mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/E.A.=10/1) to afford 7-fluoro-benzo[1,3]dioxole-5-carbaldehyde (0.80 g, 49%). 1H NMR (300 MHz, CDCl3) δ 9.78 (d, J=0.9 Hz, 1H), 7.26 (dd, J=1.5, 9.3 Hz, 1H), 7.19 (d, J=1.2 Hz, 1H), 6.16 (s, 2H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:23]O.[OH-].[Na+]>C(O)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][C:18]([C:21]([NH2:22])=[O:23])=[N:19][CH:20]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2cnc(C#N)nc2)cc1OC1CCCC1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cnc(C(N)=O)nc2)cc1OC1CCCC1
Reaction time: 0.25 h

Procedure:
To a stirred mixture of the compound of Example 14 (1.3 g) in ethanol (8 ml) was added hydrogen peroxide (40 vols, 15 ml) and 6M aqueous NaOH (6 ml). After 15 min, the reaction mixture was diluted with water (75 ml) and the white solid filtered off. Recrystallisation from acetonitrile furnished the title compound (200 g) as small white plates (mp 235-238° C.). Found C, 65.06; H, 6.09; N, 13.44. C17H19N3O3 requires C, 65.16; H, 6.1 1; N, 13.41%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15]O)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:18][CH2:15][C:13]1[CH:12]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1cc(CO)cc(C(C)(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(CBr)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 98.6 %

Procedure:
To a solution of methyl 3-tert-butyl-5-hydroxymethylbenzoate VII (9.50 g, 42.7 mmol) and carbon tetrabromide (17.25 g, 52.0 mmol) in dichloromethane (50 mL) was slowly added triphenylphosphine (13.6 g, 52.0 mmol) over the period of 20 minutes, and the mixture was stirred at room temperature for 25 minutes. The reaction mixture was concentrated under reduced pressure and the residue was suspended in ethyl acetate. The precipitate was removed by filtration and the filtrate was concentrated. The crude material was purified by a silica gel chromatography (hexanes/ethyl acetate, 4:1), and the product was re-crystallized form ethyl acetate/hexanes to afford methyl 3-bromomethyl-5-tert-butylbenzoate VIII (12.0 g, 42.1 mmol, 99%) as a white solid: 1H NMR (CDCl3) δ 1.45 (s, 9H), 3.7 (s, 3H), 4.4 (s, 2H), 7.6 (s, 1H), 7.8 (s, 1H), 8.0 (s, 1H); 13C NMR (CDCl3) δ 31.3 (3C), 33.2, 36.0, 52.3, 126.9, 127.5, 130.6, 130.7, 137.9, 152.4, 167.0.
Reaction SMILES: [O:1]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:16]([N:13]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][N:7]([C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:1][CH2:15][CH2:14]1)=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: C1COCCNCCOCCOCCN1
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)N1CCOCCOCCN(C(=O)C(C)(C)C)CCOCC1

Procedure:
Analogously to Example 2 from 1,4,10-trioxa-7,13-diazacyclopentadecane and pivalyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8]([N+:13]([O-])=O)=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[H][H].O>[Ni].C(O)C>[NH2:13][C:8]1[C:9]([F:12])=[C:10]([F:11])[C:2]([Cl:1])=[C:3]([F:16])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Nc1c(F)c(F)c(Cl)c(F)c1C(=O)O

Procedure:
63.9 g (0.25 mol) of 3-chloro-2,4,5-trifluoro-6-nitrobenzoic acid and 15 g of Raney nickel are suspended in 450 ml of ethanol. Hydrogenation is carried out at 10°-15° C. under a hydrogen pressure of 5-10 bar until the uptake of hydrogen has ended. The crude reaction mixture is poured onto 1 l of water. The carboxylic acid which has precipitated is dissolved by addition of 10% strength sodium hydroxide solution. When the catalyst has been filtered off with suction, a pH of 2-3 is established by addition of half-concentrated hydrochloric acid. The precipitate is filtered off with suction, washed with water and dried over KOH in a desiccator.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:30])[CH2:23][C:22]([CH3:25])([CH3:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:26][C:27]([OH:29])=[O:28])[CH:20]=2)[O:15]1.[CH2:31](I)[CH2:32][CH2:33][CH2:34][CH3:35]>C1COCC1>[CH3:13][C:14]1([CH3:30])[CH2:23][C:22]([CH3:24])([CH3:25])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH:26]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:27]([OH:29])=[O:28])[CH:20]=2)[O:15]1
Reactant: CCCCCI
Reactant: CC1(C)CC(C)(C)c2cc(CC(=O)O)ccc2O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCC(C(=O)O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.55 ml of diisopropylamine were dissolved in 60 ml THF and treated dropwise, at 0° C., with 7.2 ml of butyl lithium (2.5M). After 30 min. at 0° C., a solution of 1.8 g of (2,2,4,4-tetramethyl-chroman-6-yl)-acetic acid in 8 ml of THF was dropped in. The reaction mixture was stirred at 0° C. for one hour then at room temperature for 30 min. After cooling back to 0° C., a solution of 1.42 ml of pentyl iodide in 4 ml THF was added dropwise. The mixture was kept at 0° C. for one hour then at room temperature for two hours. The mixture was quenched with the addition of 50 ml of water and the pH was adjusted to 2 with HCl 1N. The mixture was extracted with three portions of 50 ml of ether. The combined organic extracts were washed with two portions of 50 ml of water and one portion of 50 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes), yielding 1.2 g of a pale yellow oil. 1H NMR (CDCl3): 7.17 (d, J=2.2 Hz, 1H), 7.03 (dd, J=8.4, 2.2 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 3.45 (t, J=7.7 Hz, 1H), 2.10-1.90 (m, 1H), 1.81 (s, 2H), 1.80-1.65 (m, 1H), 1.33 (s, 6H), 1.32 (s, 6H), 1.40-1.20 (m, 6H), 0.85 (t, J=6.9 Hz, 3H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]>C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCCc1nccc2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCCC(=O)O)nccc34)no2)cc1Cl
Temperature: 70 °C
Yield: 15.9 %

Procedure:
Sodium hydroxide (16 mg) was added to a suspension of ethyl 4-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]butanoate (D41; 0.1 g) in isopropanol (10 ml) and water (10 ml). The reaction mixture was heated to 70° C. for 2 hours. After cooling, isopropanol was evaporated in vacuo and the remaining aqueous solution was acidified with aq. HCl (0.5 N) to pH=1. The aqueous solution was extracted with DCM (2×20 ml). The organic fractions were combined and dried over anhydrous sodium sulphate. The dried solution was filtered and the filtrate was concentrated. The residue was washed with THF (3×10 ml) to afford the title compound (15 mg). δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 2.04 (2H, m), 2.40 (2H, m), 3.34 (2H, m), 4.89 (1H, m), 7.47 (1H, d), 7.88 (1H, dd), 8.17 (1H, dd), 8.24 (1H, d), 8.57 (4H, m), 12.11 (1H, s).