Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:44])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:20](COCC[Si](C)(C)C)[C:17]3=[N:18][CH:19]=2)=[CH:10][C:9]=1[C:39](=[O:43])[N:40]([CH3:42])[CH3:41].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:44])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][NH:20][C:17]3=[N:18][CH:19]=2)=[CH:10][C:9]=1[C:39](=[O:43])[N:40]([CH3:42])[CH3:41]
Reactant: COCCOC(=O)Nc1ccc(-c2cnc3c(c2)c(-c2ccccc2OC)nn3COCC[Si](C)(C)C)cc1C(=O)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: COCCOC(=O)Nc1ccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)cc1C(=O)N(C)C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxy-methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-carbamic acid 2-methoxy-ethyl ester (53 mg, 0.084 mmol) was added 5% v/v 70% perchloric acid in acetic acid (0.5 mL) and the resulting solution was agitated for 60 min. Saturated sodium bicarbonate (2 mL) was added and the resulting mixture was extracted with ethyl acetate (3×2 mL,). The combined organic layers were concentrated and the residue was purified by mass-triggered reverse-phase HPLC to give {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-carbamic acid 2-methoxy-ethyl ester as a white solid (23 mg, 55%). MS: m/z 490 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 3.00 (s, 6H), 3.33 (s, 3H), 3.60 (t, 2H), 3.86 (s, 3H), 4.23 (t, 3H), 7.11 (t, 1H), 7.22 (d, 1H), 7.46 (t, 1H), 7.62 (s, 1H), 7.69 (d, 1H), 7.75 (d, 1H), 7.85 (d, 1H), 8.31 (s, 1H), 8.82 (s, 1H), 13.42 (br, 1H).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:13](=[N:3]/[NH:2][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1ccccc1C(=O)O
Reactant: O=Cc1ccccc1
Agent: Cl
Product: O=C(O)c1ccccc1N/N=C/c1ccccc1

Procedure:
The title compound was prepared from 2-hydrazinobenzoic acid hydrochloride (1.89 g, 10.0 mmol) and benzaldehyde (1.06 g, 10.0 mmol) according to the procedure of Fischer, E. and co-workers described in Chem. Ber., 35, 1902, 2318 (2.4 g, quantitative yield). MS (DCI) m/z 241 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([NH:15][CH2:16][CH:17]([OH:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH3:14])=[CH:7][CH:6]=1)(OC)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[OH:2][CH2:1][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH:13]([NH:15][CH2:16][CH:17]([OH:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=2)[CH3:14])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(CCC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(CCc1ccc(CO)cc1)NCC(O)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
A solution of N-[3-(4-carbomethoxyphenyl)-1-methylpropyl]-2-hydroxy-2-(3-trifluoromethylphenyl) ethanamine (2.5 g) in dry ether (50 ml) was added to a suspension of lithium aluminium hydride (0.88 g) in dry ether (100 ml) under an atmosphere of nitrogen and the resulting mixture was boiled for 1 hour before being cooled and treated with water (0.9 ml); 2 N NaOH (1.8 ml) then water (2.7 ml) and stirred for a further hour.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[F:14])[CH3:2].O.[C:16](OC(=O)C)(=[O:18])[CH3:17]>S(=O)(=O)(O)O>[CH2:1]([N:3]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[F:14])[C:16](=[O:18])[CH3:17])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCNc1cc(F)c([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Solvent: O
Product: CCN(C(C)=O)c1cc(F)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 5.4 g (0.027 mole) of N-ethyl-2,5-difluoro-4-nitroaniline in 100 ml of acetic anhydride was added three drops of concentrated sulfuric acid. This mixture was stirred at room temperature for 30 minutes, and was poured into 200 ml of ice and water. The aqueous mixture was extracted with three portions of ethyl acetate. The extracts were combined and washed in succession with an aqueous, saturated sodium chloride solution and water. The washed organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure to yield 6.1 g of N-ethyl-N-(2,5-difluoro-4-nitrophenyl)acetamide as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:34][C:35]1[CH:42]=[C:41]([OH:43])[CH:40]=[CH:39][C:36]=1[C:37]#[N:38].[S:44]1[CH:48]=[CH:47][C:46]([CH2:49]O)=[CH:45]1>O1CCCC1.ClCCl>[F:34][C:35]1[CH:42]=[C:41]([O:43][CH2:49][C:46]2[CH:47]=[CH:48][S:44][CH:45]=2)[CH:40]=[CH:39][C:36]=1[C:37]#[N:38]
Reactant: N#Cc1ccc(O)cc1F
Reactant: OCc1ccsc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1ccc(OCc2ccsc2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
A solution of triphenylphosphine (20 g) in tetrahydrofuran (300 mL) cooled at 0° C. is treated dropwise during 5 minutes with diisopropyl azodicarboxylate (15 mL) and stirred for 15 minutes at 0° C. It is then treated, dropwise, with a solution of 2-fluoro-4-hydroxybenzonitrile (7 g) and 3-thienylmethanol (7 g) in tetrahydrofuran (200 mL) during 2 hours, and stirring is continued at ambient temperature for 18 hours. The mixture is concentrated in vacuo and the residue is dissolved in ethyl acetate (500 mL). This solution is washed with water (200 mL) and aqueous sodium hydroxide solution (1 N), dried over magnesium sulphate and concentrated in vacuo, to give an oil, which is passed through a pad of silica gel (thickness 5 cm) with the aid of dichloromethane. The resulting filtrate is concentrated in vacuo, to give an oil which crystallizes on standing. Recrystallization from isopropyl ether gives 2-fluoro-4-(3-thienyl-methoxy)benzonitrile (6 g), in the form of a white solid, m.p. 63-65° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:10]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH-].[Na+].C1COCC1>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:11]2[CH:10]=[C:9]([CH:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:32])=[O:2])[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=3)[N:12]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)C(CC(C)C)c1cc(-c2ccc(F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
A solution of 2-[2-(4-fluoro-phenyl)-6-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-4-methyl-pentanoic acid methyl ester (80 mg, 0.18 mmol) in NaOH (1N, 1 mL) and THF (4 mL) was stirred at 40° C. overnight. The mixture was cooled to room temperature, acidified with 10% citric acid, and extracted with CH2Cl2 (3×). The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by chromatography (5-25% ethyl acetate in CH2Cl2) to give the product as a white foam (60 mg, 77%). 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J=8.29 Hz, 2H), 8.05-8.15 (m, 2H), 7.73 (d, J=8.29 Hz, 2H), 7.65 (d, J=1.51 Hz, 2H), 7.11-7.23 (m, 2H), 3.80 (t, J=7.72 Hz, 1H), 2.08-2.16 (m, 1H), 1.77 (dt, J=7.06, 13.75 Hz, 1H), 1.48-1.64 (m, 1H), 0.96 (d, J=6.40 Hz, 6H). MS m/e 432.3 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13]([NH:15]C(=O)C3C=CC=CC=3)=[S:14])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>CO.[OH-].[Na+]>[C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13]([NH2:15])=[S:14])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NC(=S)Nc1nc(-c2ccccc2)cs1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=S)Nc1nc(-c2ccccc2)cs1
Yield: 3.6 %

Procedure:
4.20 g N-{[(4-phenyl-1,3-thiazole-2-yl)amino]carbonothioyl}benzamide (339 mmol) were suspended in 40 ml methanol, were dissolved in aqueous sodium hydroxide (550 mg NaOH dissolved in 3 ml H2O) and were heated for 3 hours at reflux. The reaction mixture was evaporation-concentrated, the residue obtained was stirred with water and the precipitated solid was suction-isolated. After drying, 2.90 g of a light yellow solid were obtained.
Reaction SMILES: [C:1]([CH:4]1[CH2:6][CH:5]1[C:7]1[C:17]([F:18])=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([F:19])[C:8]=1[F:20])([OH:3])=[O:2].Cl(O)(=O)(=O)=O.C(OCC)(=O)C.O.C(O[C:37]([CH3:40])([CH3:39])[CH3:38])(=O)C>>[C:37]([O:2][C:1]([CH:4]1[CH2:6][CH:5]1[C:7]1[C:17]([F:18])=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([F:19])[C:8]=1[F:20])=[O:3])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc(F)c(C2CC2C(=O)O)c(F)c1F
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(F)c(C2CC2C(=O)OC(C)(C)C)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
In 10 ml of tert-butyl acetate was dissolved 1.00 g of ethyl 4-(2-carboxycyclopropyl)-2,3,5-trifluorobenzoate. To the resulting solution was added 0.2 ml of a 70% aqueous perchloric acid solution. The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture were added 40 ml of ethyl acetate and 20 ml of water in this order. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: n-hexane/toluene=1/1) to obtain 0.81 g (yield: 68.1%) of ethyl 4-(2-tert-butoxycarbonylcyclopropyl)-2,3,5trifluorobenzoate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=4)=[O:33])[CH:26]=3)=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C>O1CCOCC1.C(OCC)(=O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)[C:16]([C:25]3[CH:26]=[C:27]([NH:31][C:32]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:39][CH:40]=4)=[O:33])[CH:28]=[CH:29][CH:30]=3)=[N:15]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccncc3)c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)n2)CC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cccc(-c2nn(C3CCNCC3)cc2-c2ccncc2)c1

Procedure:
To 4-(4-pyridin-4-yl-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol) in dioxane (2 mL) HCl 4M in dioxane (1 mL, 3.30 mmol) was added. After one hour the reaction was diluted with ethyl acetate (50 mL) and washed with saturated NaHCO3 solution (3×50 mL) and brine (1×50 mL). The organic phase was dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The deprotected urea was isolated by reverse phase chromatography.
Reaction SMILES: [CH2:1]([SH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]2>>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:1][S:7][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]2
Reactant: SCc1ccco1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCSCc3ccco3)ccc2N1

Procedure:
Prepared analogous to Example 1 from furfuryl-mercaptan and 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.).
Reaction SMILES: ClCC([O:5][CH:6]([CH2:41][O:42]C(=O)CCl)[CH2:7][NH:8][C:9](=[O:40])[C:10]1[C:31]([I:32])=[C:30]([NH:33][C:34](=[O:37])[CH2:35][Cl:36])[C:29]([I:38])=[C:12]([C:13]([NH:15][CH2:16][CH:17]([O:24]C(=O)CCl)[CH2:18][O:19]C(=O)CCl)=[O:14])[C:11]=1[I:39])=O.[OH-].[Na+].O.Cl>CN(C)C(=O)C>[OH:5][CH:6]([CH2:41][OH:42])[CH2:7][NH:8][C:9](=[O:40])[C:10]1[C:31]([I:32])=[C:30]([NH:33][C:34](=[O:37])[CH2:35][Cl:36])[C:29]([I:38])=[C:12]([C:13]([NH:15][CH2:16][CH:17]([OH:24])[CH2:18][OH:19])=[O:14])[C:11]=1[I:39]
Reactant: O=C(CCl)Nc1c(I)c(C(=O)NCC(COC(=O)CCl)OC(=O)CCl)c(I)c(C(=O)NCC(COC(=O)CCl)OC(=O)CCl)c1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(CCl)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Yield: 88.4 %

Procedure:
N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide in N,N-dimethylacetamide, from Example 1, was hydrolyzed by adding 156 mL of 10N sodium hydroxide solution (1.56 moles). Water (100 mL) was then added to the mixture to give a homogeneous solution. 1N Hydrochloric acid (59 mL, 0.59 moles) was added to precipitate the N,N'-bis (2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide. The precipitate was collected and washed with water. The wet product was dried at 60° C. in a vacuum oven to give 81.69 g of product, 88.4% yield. The material was 100 % pure by HPLC analysis.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([CH2:31][OH:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=O)C1C=CC=CC=1.C(O)C.C1COCC1.[C:41]1([S:51](Cl)(=[O:53])=[O:52])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1>CN(C)C=O.CN(C1C=CN=CC=1)C.[C].[Pd]>[C:41]1([S:51]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([CH2:31][OH:32])[CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:53])=[O:52])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCO
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A mixture of N-benzyloxycarbonyl-(L)-isoleucyl-(L)-tryptophanol (55 g), palladium-carbon (5%, 50% wet, 30 g) and ethanol (50 ml)-THF (300 ml) was subjected to catalytic hydrogenation at room temperature and atmospheric pressure. After the catalyst was filtered off, the filterate was concentrated under reduced pressure to yield an oily substance. The oil was dissolved in N,N-dimethylformamide (300 ml), and 1-naphthalenesulfonyl chloride (30 g) and 4-(N,N-dimethylamino)pyridine (DMAP) (17 g) were added to the ice-cooling mixture. After stirring at 0° C. for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was suspended in ethyl acetate and the mixture was successively washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and brine, and dried (MgSO4). The organic solvent was evaporated off and the residual oil was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (3:2,v/v) gave N-(1-naphthylsulfonyl)-(L)-isoleucyl-(L)-tryptophanol (51 g, 82%) as crystals.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8]3[C:14]([C:15]4[C:16]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:17][O:18][C:19]=4[CH3:20])=[N:13][N:12]=[C:9]32)=[CH:5][CH:4]=1.[B].C(OCC)C.O>ClCCl>[CH3:20][C:19]1[O:18][N:17]=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]=1[C:14]1[N:8]2[CH2:7][C:6]3[C:10]([C:9]2=[N:12][N:13]=1)=[CH:11][C:3]([OH:2])=[CH:4][CH:5]=3
Reactant: COc1ccc2c(c1)-c1nnc(-c3c(-c4ccccc4)noc3C)n1C2
Agent: [B]
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(O)cc1-2
Temperature: -78 °C

Procedure:
8-Methoxy-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (4.6 g, 13 mmol) in dichloromethane (70 ml) was stirred with boron tribronide (25 g) for five days. The reaction was cooled to −78° C. and diethyl ether was added dropwise followed by water. The reaction was warmed to room temperature and the organic layer was washed with water and dried, filtered and evaporated. The residue was purified by column chromatography on silica using methanol/dichloromethane to yield the title compound.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)([CH3:14])[CH3:13])=[CH:6][CH:5]=1.I([O-])(=O)(=O)=[O:25].[Na+].Cl>CO.CCOCC>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:11][C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)([CH3:13])[CH3:14])=[O:25])=[CH:6][CH:5]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)(CSc1ccc(Cl)cc1)NCCCn1ccnc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(CS(=O)c1ccc(Cl)cc1)NCCCn1ccnc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-[2-(4-Chlorophenylthio)-1,1-dimethylethyl]-3-(imidazol-1-yl)propylamine dihydrochloride (1.0 g) was added in one portion to a stirred solution of sodium periodate (0.54 g) in aqueous methanol (15 ml of a 1:1 mixture) at 5-10° C. The mixture was stirred at ambient temperature for 24 hours and then evaporated to dryness. 5M Sodium hydroxide solution was added to the residue and the mixture extracted with dichloromethane to give an oil which was dissolved in ether containing a small amount of absolute alcohol and treated with ethereal hydrogen chloride. The mixture was filtered to give N-[2-(4-chlorophenylsulphinyl)-1,1-dimethylethyl]-3-(imidazol-1-yl)propylamine dihydrochloride, m.p. 208-211°C.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][CH:21]=1>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:26]=[C:24]([C:23]3[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=3)[O:25][CH:15]=2)[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Reactant: NC(=O)c1ccc(Cl)cc1
Product: O=C(O)COc1ccc(Br)cc1-c1coc(-c2ccc(Cl)cc2)n1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 4-chlorobenzamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.90 min, m/z 407.7 [M+H]+; 1H NMR (CDCl3): δ 4.89 (s, 2H), 7.09 (d, 1H), 7.48 (d, 1H), 7.64 (d, 2H), 8.08 (d, 2H), 8.20 (s, 1H), 8.89 (s, 1H), 13.2 (br s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]#[C:13][Si](C)(C)C)[C:5]([O:7]C)=[O:6].C.CO.[OH-].[Na+]>CCO.CCN(CC)CC.[Cu]I>[O:1]1[C:2]2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:9]=[CH:10][C:11]=2[CH:12]=[CH:13]1
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)c(O)c1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)c1ccc2ccoc2c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
Methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (3.0 g, 12.1 mmol) is dissolved in 1:1 EtOH/Et3N (30 mL), is treated with CuI (114 mg, 0.6 mmol), and the reaction is warmed to 75° C. for 3 h. The mixture is treated with DARCO and MeOH (15 mL) and heated to reflux for 1 h. The reaction is filtered through a fine fritted-glass funnel, the filtrate is treated with 3N NaOH (24.2 ml, 72.5 mmol), and the mixture is stirred overnight at RT. The mixture is concentrated to dryness, the residue is dissolved in H2O (20 mL), and the pH of the mixture is adjusted to 2 with 12N HCl. The resulting yellow precipitate is collected, washed with water, and is dried to give 1.83 g (93%) of benzofuran-6-carboxylic acid as a tan solid. HRMS (FAB) calcd for C9H6O3+H: 163.0395, found 163.0389 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH:11]=1)[C:6]([O-:8])=[O:7])#[N:2].[OH-].[Li+]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: N#Cc1cc(Cn2ccnc2)cc(C(=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1cc(Cn2ccnc2)cc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
A solution of 3-cyano-5-(1H-imidazol-1-yl-methyl)benzoate (150 mg, 0.62 mmol) in tetrahydrofuran (2 mL) was treated with 0.5 N lithium hydroxide (1.5 mL, 0.75 mmol). The reaction was stirred at 70° C. for 10 minutes and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH˜4) by the addition of 2N hydrogen chloride. The precipitate was collected and dried to afford 140 mg (quantitative) of 3-cyano-5-(1H-imidazol-1-yl-methyl)benzoic acid.
Reaction SMILES: [C:1]([CH:5]1[CH2:16][CH2:15][CH2:14][CH2:13][C:6]21[O:10][CH:9]([CH2:11][CH3:12])[CH2:8][O:7]2)([CH3:4])([CH3:3])[CH3:2].C(C1CCCCC1=O)(C)(C)C.C(O)C(O)CC>[Pd].[Ru]>[C:1]([CH:5]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:6]1[O:7][CH2:8][CH:9]([OH:10])[CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1COC2(CCCCC2C(C)(C)C)O1
Agent: [Pd]
Agent: [Ru]
Agent: CC(C)(C)C1CCCCC1=O
Product: CCC(O)COC1CCCCC1C(C)(C)C
Yield: 86.7 %

Procedure:
A 500 ml capacity autoclave was charged with 150 g (0.68 mol) of 6-t-butyl-2-ethyl-1,4-dioxaspiro[4.5]decane which has been prepared from 2-t-butylcyclohexanone and 1,2-butanediol, 1.47 g of a catalyst of 5% palladium supported on active carbon and 0.03 g of a catalyst of 5% ruthenium supported on active carbon. The reaction was carried out under ahydrogen pressure of 70 kg/cm2 and at a temperature of 190° C. for 10 hours until completion of the absorption of hydrogen. In this way, 134.7 g of 1-(2-t-butylcyclohexyloxy)-2-butanol was obtained (yield=89%; cis:trans=66:34).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][C:30]1[C:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:32][O:33][C:34]=1[CH3:35]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:29][C:30]5[C:31]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)=[N:32][O:33][C:34]=5[CH3:35])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: Cc1onc(-c2ccccc2)c1CBr
Agent: [H-]
Agent: [Na+]
Product: Cc1onc(-c2ccccc2)c1CN1C[C@@H](C)n2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 71 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and 4-(bromomethyl)-5-methyl-3-phenylisoxazol, to give the desired product as a brown oil (71%).