Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])(CC)C.[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]2[C:31]([C:32]#[N:33])=[C:30]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[S:29][C:28]=2[CH:42]=1>O1CCCC1>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]2[C:31]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)([CH:32]=[NH:33])[CH:30]([C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)[S:29][C:28]=2[CH:42]=1
Reactant: Brc1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C#N)cc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1ccc(C2Sc3cc(OC)ccc3C2(C=N)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4-[2-(1-piperidinyl)ethoxy]bromobenzene (114.5 mg, 0.357 mmol) in tetrahydrofuran (2 ml) at -78° C. is added secbutyl lithium (0.275 ml of a 1.3 M solution, 0.358 mmol). The resulting solution is stirred at that temperature for 30 minutes, then a solution of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonitrile (98.5 mg, 0.333 mmol) in tetrahydrofuran (1 ml) is added. The resulting mixture is stirred and allowed to warm to room temperature overnight. The reaction is then quenched by addition of saturated aqueous ammonium chloride (2 ml) and partitioned between methylene chloride and water. The layers are separated, and the aqueous layer extracted again with methylene chloride. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated to an oil, which is chromatographed on silica gel (95:5:0.2 dichloromethane:methanol:triethylamine) to afford a fraction containing desired product. This fraction is concentrated and further chromatographed on silica gel (10:5:1 hexanes:dichloromethane:triethylamine) to afford, after drying in vacuo, 78.6 mg (47%) of title compound as an oil. IR (KBr) 2933, 1607, 1501, 1249, 1032 cm-1 ; 1H NMR (CDCl3): δ7.71 (d, 2 H, J=8.4 Hz), 7.42 (d, 2 H, J=8.7 Hz), 7.26 (m, 2 H), 6.90 (dd, 1 H, J=8.9, 2.2 Hz), 6.80 (m, 4 H), 4.10 (t, 2 H, J=6.0 Hz), 3.87 (s, 3 H), 3.76 (s, 3 H), 22.76 (t, 2 H, J=6.0 Hz), 2.50 (m, 4 H), 1.58 (m, 4 H), 1.44 (m, 2 H); 13C NMR (CDCl3): d 173.4, 161.4, 159.6, 157.7, 139.9, 138.5, 134.0, 131.1, 130.5, 129.9, 129.7, 125.9, 123.8, 114.7, 114.5, 114.2, 104.8, 66.2, 57.9, 55.7, 55.3, 55.1, 26.0, 24.3. Anal. Calcd. for C30H32N2O3S: C, 71.97; H, 6.44; N, 5.60; S, 6.40. Found: C, 71.73; H, 6.36; N, 5.41; S, 6.27.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[N+:18]([CH2:20]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:19]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][CH:20]=[N:18][CH:19]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ncc(-c2ccc3c(c2)OCO3)o1
Temperature: 70 °C
Yield: 81.6 %

Procedure:
To a stirred solution of benzo[1,3]dioxole-5-carbaldehyde (657 mg, 4.83 mmol) in methanol (15 mL) was added potassium carbonate (786 mg, 5.69 mmol, 1.3 equiv) and 1-isocyanomethanesulfonyl-4-methyl-benzene (863 mg, 4.38 mmol, 1 equiv). The resulting solution was heated to 70° C. under a nitrogen atmosphere for 3 hours, cooled to ambient temperature, and concentrated in vacuo. The residue was partitioned between methylene chloride and water, and the aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Silica gel chromatography (30% ethyl acetate in hexanes) provided 5-benzo[1,3]dioxol-5-yl-oxazole (676 mg, 82%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:13]=[C:12]([I:14])[CH:11]=[C:6]([C:7](OC)=[O:8])[CH:5]=1.[BH4-].[Na+].Cl>C1COCC1.O>[OH:8][CH2:7][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:13]=[C:12]([I:14])[CH:11]=1
Reactant: COC(=O)c1cc(I)cc(C(=O)OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(I)cc(CO)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of dimethyl-5-iodisophthalate in 800 ml of THF was treated with with 22.2 g of CaCI2. Then, 15.2 g of NaBH4 were added portionwise. The mixture was stirred for one day at room temperature. Then, the mixture was acidified with 250 ml of 3N HCl and diluted with 2 l of H2O. The crude product was isolated by extraction and purified by crystallization from THF/hexane. There were obtained 11.2 g of (3-hydroxymethyl-5-iodo-phenyl)-methanol as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)([O:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH2:18](Br)[C:19]#[CH:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)([O:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1)[C:19]#[CH:18]
Reactant: CCC(OC)(c1cccc(O)c1)c1nccs1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cccc(C(CC)(OC)c2nccs2)c1
Yield: 94 %

Procedure:
A mixture of 2-[1-(3-hydroxyphenyl)-1-methoxypropyl]thiazole (31 g), 2-propynyl bromide (80% solution in toluene, 48.1 ml), potassium carbonate (48 g) and acetone (375 ml) was stirred and heated to reflux for 17 hours. The mixture was filtered and the filtrate was evaporated. The residue was partitioned between diethyl ether and water and the organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by chromatography eluting with hexane/ethyl acetate (1:1 v/v) to give 2-[1-(3-(2-propynyloxy)phenyl)-1-methoxypropyl]thiazole as an oil (34 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=O)[CH3:9])[CH:3]=1.O.[NH2:12][NH2:13]>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](/[C:8](=[N:12]\[NH2:13])/[CH3:9])[CH:3]=1
Reactant: CC(=O)c1cc(Br)ccn1
Reactant: NN
Solvent: CO
Solvent: O
Product: C/C(=N/N)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 1-(4-bromopyridin-2-yl)ethanone (2.4 g, 12 mmol) in MeOH (40 mL) was added hydrazine monohydrate (2.9 mL, 60 mmol) in one portion. After stirring at room temperature for 2 hours, the mixture was concentrated to afford the product. 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=5.3 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 7.33 (dd, J=5.3, 1.8 Hz, 1H), 5.66 (br s, 2H), 2.23 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[CH2:18]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:32])[CH:26]([NH2:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH3:19].C(N(C(C)C)CC)(C)C>CS(C)=O>[CH2:18]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:32])[CH:26]([NH:31][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:5]=[C:4]([S:16][CH3:17])[N:3]=1)[CH2:27][CH:28]([CH3:29])[CH3:30])[CH3:19]
Reactant: CSc1nc(Cl)cc(COC2CCCCC2)n1
Reactant: CCOCCCNC(=O)C(N)CC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOCCCNC(=O)C(CC(C)C)Nc1cc(COC2CCCCC2)nc(SC)n1

Procedure:
A mixture of 4-chloro-6-cyclohexyloxymethyl-2-methylsulfanyl-pyrimidine, the hydrochloride salt of 2-amino-4-methylpentanoic acid (3-ethoxypropyl)amide (60 mg), and diisopropylethylamine (61 mg) in dimethylsulfoxide (0.5 mL) was heated at 95° C. for 16 h. The mixture was partitioned in water and ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (30% ethyl acetate in hexanes) to give 2-(6-cyclohexyloxymethyl-2-methylsulfanyl-pyrimidin-4-ylamino)-4-methyl-pentanoic acid (3-ethoxy-propyl)-amide (12 mg).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.C(=O)([O-])O.[Na+].[CH2:21](O)[CH3:22]>O>[N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH2:21][CH3:22])=[O:10])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc([N+](=O)[O-])[nH]n1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 5-nitropyrazol-3-carboxylic acid (19.9 g) in ethanol (200 mL) was added dropwise thionyl chloride (9.7 mL) over a period of 5 minutes and the mixture was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water (25 mL) and ethanol (50 mL) and to the mixture was neutralized with sodium hydrogencarbonate (54 g). The mixture was filtered and the residue was washed with ethanol. The filtrate and the washings were combined and concentrated in vacuo. The residue was azeotropically distilled with ethanol and the residue was dissolved in ethyl acetate, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and to the residue was added isopropylether. The precipitates were collected by filtration and washed with ethyl acetate/diisopropylether (1/2) to give ethyl 5-nitropyrazol-3-carboxylate (20 g, yield: 85%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:6][CH:7]=1.Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([OH:35])=[O:34])[CH:28]=1.C(N(CC)CC)C>C(O)C>[C:33]([C:29]1[CH:28]=[C:27]([N:22]2[CH2:21][CH2:20][CH:19]([CH2:18][NH:17][C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:25])[CH2:24][CH2:23]2)[CH:32]=[CH:31][N:30]=1)([OH:35])=[O:34]
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1NCC1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(N2CCC(CNc3ccc(F)cc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Yield: 45.1 %

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-5-fluoro-2-(piperidin-4-ylmethyl)aminobenzamide (200 mg, 0.55 mmol), 4-chloropicolinic acid (130 mg, 0.83 mmol), triethylamine (111 mg, 1.10 mmol), and ethanol (4 mL) yielded 120 mg (45%) of the title compound.
Reaction SMILES: Cl.CO.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:9]=[C:10]([CH3:16])[C:11]=1[O:12]COC>O>[OH:12][C:11]1[C:10]([CH3:16])=[CH:9][C:8]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])=[CH:7][C:6]=1[O:5][CH3:4]
Reactant: COCOc1c(C)cc(N2CCOC2=O)cc1OC
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1cc(N2CCOC2=O)cc(C)c1O
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 108.6 %

Procedure:
10% hydrochloric acid (5 ml) was added to a methanol solution (5 ml) of 3-(3-methoxy-4-methoxymethoxy-5-methylphenyl)oxazolidin-2-one (0.48 g, 1.79 mmol) and the mixture was stirred at 50° C. for 10 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The extracted material was dried over magnesium sulfate, and thereafter concentrated to dryness under reduced pressure to obtain 3-(4-hydroxy-3-methoxy-5-methylphenyl)oxazolidin-2-one (434 mg) as a light yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:6]=1)[CH3:2].Cl.[Cl:18][C:19]1[CH:20]=[C:21]([NH:25]N)[CH:22]=[CH:23][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:22]3[C:21](=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=3)[NH:25][C:13]=2[CH3:14])[CH:6]=1)[CH3:2]
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)c1cccc(SCC(C)=O)c1
Agent: Cl
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 2, using the following starting materials: 3-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:19])[CH2:14][O:15][CH:16]([CH3:18])[CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1F.CCO>CN(C=O)C.Cl>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[O:19][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][O:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)OC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)OC[C@H](Oc1ccc(Cl)cc1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-1-Hydroxy-2-isopropoxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (25.0 mg, 91.4 μmol) was dissolved in DMF (190 μL). NaH (2.6 mg, 109.7 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 2,4-Dichloro-1-fluorobenzene (21.4 μL, 182.9 mmol) was added and the mixture was stirred at 70° C. for 3 hours. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (949 μL, 1.1 mmol) and stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt oil (29.5 mg, 97% purity). MS m/z: [M+H]+ calcd for C15H21Cl2NO2, 318.10. found 318.0.
Reaction SMILES: COC([C:5]1([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH2:9][CH:8]=[C:7]([OH:10])[C:6]1=[O:11])=O.O1CCOCC1.Cl>O>[OH:11][C:6]1[C:7](=[O:10])[CH2:8][CH2:9][C:5]=1[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1
Reactant: COC(=O)C1(Cc2ccc3ccccc3c2)CC=C(O)C1=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCC(Cc2ccc3ccccc3c2)=C1O
Temperature: 100 °C
Reaction time: 5 h
Yield: 68.6 %

Procedure:
A mixture of 3-hydroxy-1-naphthalen-2-ylmethyl-2-oxo-cyclopent-3-enecarboxylic acid methyl ester (3.0 g, 10.71 mmol), dioxane (50 ml), and HCl (10N, 50 ml) was stirred at 100° C. for 5 hours. The mixture was cooled to room temperature, poured into H2O and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from acetone/ether gave a brown solid (1.75 g, 69%): m.p. 120°-122° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)=CC2CCNCC2)C=CC=CC=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)(O)[CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1.FC(F)(F)C(O)=O>CC1C=CC=CC=1>[F:43][C:40]1[CH:41]=[CH:42][C:37]([C:28]([C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=2)=[CH:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:38][CH:39]=1
Reactant: OC(CC1CCNCC1)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: C(=C(c1ccccc1)c1ccccc1)C1CCNCC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(C(=CC2CCNCC2)c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared in the same manner as the compound of example 6, starting with 25 g of alpha,alpha-bis(4-fluorophenyl)-4-piperidineethanol, 0.25 molar methylbenzene solvate and 50 mL of trifluoroacetic acid. Crystallization from hexane gave 19.6 g (83%) of the hexane solvate of 4-[2,2-bis(4-fluorophenyl)ethenyl]-piperidine, mp 84°-86° C. Analysis Calculated for C19H19F2N.O.15C6H14 : C, 76.54; H, 6.81; N, 4.49; F, 12.17. Found: C, 76.87; H, 6.72; 4.65; F, 12.12.
Reaction SMILES: [CH2:1]([C:3]([OH:35])([CH2:33][CH3:34])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:30][CH3:31])([C:15]2[CH:20]=[CH:19][C:18]([B:21]3[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]3)=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:32])[CH3:2].[H][H]>CO.[C].[Pd]>[CH2:1]([C:3]([OH:35])([CH2:33][CH3:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:30][CH3:31])([C:15]2[CH:20]=[CH:19][C:18]([B:21]3[O:25][C:24]([CH3:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22]3)=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:32])[CH3:2]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C)CC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C
Yield: 96.2 %

Procedure:
10% palladium carbon (20 mg) was added to a solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5); 50.5 mg, 0.106 mmol) in methanol (4 mL), and the mixture was stirred in a hydrogen atmosphere at room temperature for four hours. Then, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the target compound (48.8 mg, 96%).
Reaction SMILES: [Mg].Br[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.[CH2:15]([O:22][CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH:25]([CH2:30][N:31]([CH3:33])[CH3:32])[CH2:24]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1>[CH2:15]([O:22][CH:23]1[CH2:28][CH2:27][C:26]([C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=3)[CH:4]=2)([OH:29])[CH:25]([CH2:30][N:31]([CH3:33])[CH3:32])[CH2:24]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(C)CC1CC(OCc2ccccc2)CCC1=O
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2cc(C3(O)CCC(OCc4ccccc4)CC3CN(C)C)ccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
The corresponding Grignard reagent was produced in 11 ml THF p.a. from 0.28 g magnesium and 2.72 g 2-bromo-6-methoxynaphthalene, a solution of 2.00 g 4-benzyloxy-2-dimethylaminomethylcyclohexanone in 8 ml THF p.a. added dropwise with ice cooling, and the mixture stirred for 1 hour. For working up, 4 ml 4 M ammonium chloride solution were added to the ice bath, the organic phase separated off, the aqueous phase extracted twice with diethyl ether, the combined organic phases dried by sodium sulphate, filtered and concentrated. The crude product obtained (3.20 g) was chromatographed with ethyl acetate/methanol/hexane (V/V/V=1:1:1) on silica gel. 1.52 g 4-benzyloxy-2-dimethylaminomethyl-1-(6-methoxynaphthalen-2-yl)cyclohexanol were obtained and converted into the corresponding hydrochloride (1.32 g) in the same way as in AAV 1.
Reaction SMILES: [CH:1]1([C:4]2[NH:9][C:8](=O)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:23])=O>ClCCl>[Cl:23][C:8]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][N:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(C2CC2)ncc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc(C2CC2)nc1Cl
Reaction time: 2 h

Procedure:
To a suspension of the 2-cyclopropyl-5-nitro-3H-pyrimidin-4-one (900 mg, 4.9 mmol) in dichloromethane (15 ml) was added triethylamine (505 mg, 5 mmol). To the clear solution obtained, phosphorous oxychloride (1.5 g, 10 mmol) was slowly added and the reaction mixture kept at room temperature for 2 hours. TLC showed a single spot. The reaction mixture was diluted with dichloromethane, washed with water and dried over MgSO4, filtered and evaporated to dryness to give brown oil. This material was used as such for the next step.
Reaction SMILES: [C:1](O[C@@H](C(N)(C)[C@H](O)C)C)(=[O:3])[CH3:2].[CH:13]([C:16]([N+:21]([O-])=O)([CH2:19][OH:20])[CH2:17][OH:18])([CH3:15])[CH3:14]>>[C:1]([O:18][CH2:17][C:16]([NH2:21])([CH:13]([CH3:15])[CH3:14])[CH2:19][OH:20])(=[O:3])[CH3:2]
Reactant: CC(C)C(CO)(CO)[N+](=O)[O-]
Reactant: CC(=O)O[C@H](C)C(C)(N)[C@@H](C)O
Product: CC(=O)OCC(N)(CO)C(C)C
Yield: 98 %

Procedure:
Using the procedure in 5D, 2-isopropyl-2-nitro-1,3-propanediol (11A) gave 98% yield of 2-amino-2-isopropyl-1,3-propanediol acetate mp 155°-155.5°. H. S. Broadbent et al., J. Heterocyclic Chem., 13, 337 (1975) report the synthesis of this compound as the free base (mp 70°-72°)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19]C)=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:24])[C:6]=2[CH:25]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1.[Li+].[OH-]>C(Cl)Cl>[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:24])[C:6]=2[CH:25]=1)(=[O:28])[CH3:27]
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(N)cc3c2C)c1
Reactant: CC(=O)OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2sc(S(=O)(=O)Nc3cccc(C(=O)O)c3)c(C)c2c1
Reaction time: 4 h
Yield: 56 %

Procedure:
A solution of methyl 3-{[(5-amino-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate (7 mg, 0.019 mmol) in CH2Cl2 (200 uL), acetic anhydride (5 mg, 0.022 mmol) and pyridine (11 uL) was stirred at room temperature over night. The mixture was concentrated and dissolved in THF/water (1 mL) and LiOH (1 mg, 0.024 mmol) was added. The diacetylated intermediate was hydrolyzed at room temperature for 4 h. The crude product was purified by preparative HPLC (ACE C8, 5 μm, 21×50 mm, flow 25 ml/min, 50 mM NH4OAc in water/MeCN) to give 4.3 mg (56%) of the title compound. MS (ESI+) calcd for C18H16N2O5S2 404.050063, found 404.050323.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:27]=1)[CH:23]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][C:29]([F:30])([F:31])[F:32])[CH:27]=1)/[CH:23]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: O=Cc1cc(Br)cc(OC(F)(F)F)c1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(Br)cc(OC(F)(F)F)c1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of compound 13 (150 mg, 0.607 mmol) in toluene 15 mL was added 3-bromo-5-(trifluoromethoxy)benzaldehyde 29 (115.4 mg, 0.607 mmol). PTSA (230.9 mg, 1.214 mmol) was added to the reaction mixture, then stirred at 120° C. for 6 h. The reaction mixture was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound (E)-2-(3-bromo-5-(trifluoromethoxy)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 30, which was purified through flash chromatography by using 100-200 mesh silica gel. Compound 30 was eluted at 25% ethyl acetate in hexane to afford a yellow coloured solid. To 30 (45 mg, 0.107 mmol), dissolved in methanol 20 mL, was added Pd/C 20 mg and stirred under hydrogen balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude des-brominated compound 31. The crude 31 was purified by flash chromatography using 100-200 mesh silica gel. Compound 31 was eluted as des-brominated compound at 25% ethyl acetate in hexane as half white coloured solid compound 6-methoxy-5-morpholino-2-(3-(trifluoromethoxy)benzyl)-2,3-dihydro-1H-inden-1-one 31. 1HNMR (400 MHz, CDCl3) δ ppm 7.43 (m, 4H), 7.18 (s, 1H), 6.81 (s, 1H), 3.89 (m, 3H), 3.87 (m, 4H), 3.43 (m, 1H), 3.17 (m, 4H), 3.06 (m, 1H), 2.97 (m, 1H), 2.69 (m, 2H); MS (ESI) m/z 422.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1.[O-]CC.[Na+].CS(C)=O.Br[CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[CH2:1]([C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Cc1ccc2c(c1)=NC(=O)N=2
Reactant: CCCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: CCCCCc1ccc2c(c1)=NC(=O)N=2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-methylbenzimidazol-2-one (50 mg, 3.378×10−4 mol) in dry ethanol (5 ml), the freshly made sodium ethoxide in ethanol (1M, 1.01×10−3 mol equivalents) was added dropwise under a nitrogen atmosphere. At room temperature the mixture was stirred for 3 hrs under an atmosphere of nitrogen and the ethanol was then removed under reduced pressure. To this a solution of dry DMSO (3 ml) and 1-bromobutane (54 μl, 5.1×10−4 mol) was added and stirred at room temperature under an atmosphere of nitrogen overnight. The reaction mixture was then quenched with ice and neutralised using 1M hydrochloric acid solution, forming a white solid product. The solid was collected by filtration and purified using preparative thin liquid chromatography with 10% MeOH/CHCl3.