Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)[CH:13]=2)[C:8]=1[Br:26])[CH3:2].[C:28]([CH2:32][C:33](Cl)=[O:34])([CH3:31])([CH3:30])[CH3:29].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:33](=[O:34])[CH2:32][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:13]=2)[C:8]=1[Br:26])[CH3:2]
Reactant: CCOC(=O)COc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Br
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc2cc(-c3sc4ccccc4c3C(=O)CC(C)(C)C)ccc2c1Br
Temperature: 25 °C
Yield: 6.5 %

Procedure:
To a 0° C. mixture of (6-benzo[b]thiophen-2-yl-1-bromo-naphthalen-2-yloxy)-acetic acid ethyl ester (5.18 g, 11.7 mmol) in chloroform (270 mL) was added t-butylacetyl chloride (2.0 mL, 14 mmol) and tin (IV) chloride (2.1 mL, 18 mmol). It was refluxed for 23 hours. During reflux, more t-butylacetyl chloride (9.0 mL, 66 mmol) in four portions and tin (IV) chloride (8.4 mL, 71 mmol) in four portions were added. It was then allowed to cool to ambient temperature and poured into ice water. It was diluted with additional chloroform and washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was purified by flash chromatography using (1) 100% chloroform, (2) 25–60% methylene chloride in hexane. It was then purified by HPLC using 90% acetonitrile (0.1% trifluoroacetic acid) in water as the mobile phase. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at ambient temperature for two hours yielded {1-bromo-6-[3-(3,3-dimethyl-butyryl)-benzo[b]thiophen-2-yl]-naphthalen-2-yloxy}-acetic acid ethyl ester as an amber semi-solid (0.412 g, 6.53%); mass spectrum (+EI, [M+H]+) m/z 539/541. 1H NMR (500 MHz, DMSO-d6): δ8.26 (d, 1H, J=8.81 Hz), 8.07–8.14(m, 3H), 7.91–7.93 (m, 1H), 7.76 (dd, 1H, J=8.81 Hz and 1.97 Hz), 7.45–7.53 (m, 3H), 5.12 (s, 2H), 4.19 (q, 2H, J=7.15 Hz), 2.33 (s, 2H), 1.20–1.25 (m, 3H), 0.76 ppm (s, 9H). Elemental Analysis for C28H27BrNO4S: Calcd: C, 62.34; H, 5.04; N, 0.00; Found: C, 57.16; H, 4.37; N, 0.00.
Reaction SMILES: [CH3:1][CH:2]([CH3:43])[CH2:3][S:4]([N:7](S(CC(C)C)(=O)=O)[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])[CH:15]=2)[N:10](C(OC(C)(C)C)=O)[N:9]=1)(=[O:6])=[O:5].FC(F)(F)C(O)=O>ClCCl>[C:23]([C:22]1[CH:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[NH:7][S:4]([CH2:3][CH:2]([CH3:43])[CH3:1])(=[O:6])=[O:5])[C:18]([C:27]#[N:28])=[C:19]([CH3:26])[NH:20][C:21]=1[CH3:25])#[N:24]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N(S(=O)(=O)CC(C)C)S(=O)(=O)CC(C)C)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1=C(C#N)C(c2ccc3[nH]nc(NS(=O)(=O)CC(C)C)c3c2)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
120 mg (0.19 mmol) tert-butyl 3-{bis[(2-methylpropyl)sulfonyl]amino}-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-1H-indazole-1-carboxylate (Example 18A) were dissolved in dichloromethane (4 ml) and treated with 0.161 ml (2.1 mmol) trifluoroacetic acid. The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (4 ml), treated with 1 M aqueous lithium hydroxide solution (0.75 ml) and stirred at room temperature for 4 h. The mixture was then concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC (acetonitrile/water gradient) to give 13 mg (16% of th.) of the title compound.
Reaction SMILES: [CH3:1][CH:2](O)[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.C1(P([N:25]=[N+:26]=[N-:27])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:25]([CH:2]([C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1)[CH3:1])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(N=[N+]=[N-])c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
To a solution of 10.0 g (49.7 mmol) of 4-bromo-a-methylbenzyl alcohol and 16.4 g (59.6 mmol) of diphenylphosphoryl azide in 70 mL of toluene was added 9.1 g of 1,8-diazabicyclo[5.4.0]undec-7-ene and the mixture was stirred at room temperature for 16 hours. The reaction mixture was washed once with 30 mL of 10% aqueous sodium bisulfate. The organic layer was separated and the aqueous layer was extracted three times with 10 mL each of ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo to afford 11.2 g (100%) of the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)COc1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
To a 1 L round bottomed flask with a stirring bar, addition funnel and an argon inlet was added ethyl 2-(4-hydroxymethylphenoxy)acetate 35-4 (7.47 g, 35.53 mmol), CBr4 (13.26 g, 39.97 mmol) and dry CH2Cl2 (300 mL). This solution was cooled in an ice bath and and a solution of triphenyl phosphine (10.48 g, 39.97 mmol) in CH2Cl2 (100 mL) was added dropwise over 1 h. The ice bath was allowed to expire and and the mixture was stirred at ambient temperature 18 h. The solvent was removed in vacuo and the residue was chromatographed directly on 200 g of silica gel useing 15% EtOAc-hexane as eluant. There was obtained ethyl 2-(4-bromomethylphenoxy)acetate 35-5 (7.2 g, 74%) as a low melting solid, mp.: 44°-45° C. 1H NMR (CDCl3): δ 1.29 (t, J=7 Hz, 3H), 4.26 (q, J=7 Hz, 2H), 4.48 (s, 2H), 4.61 (s, 2H), 6.86 (d, J=9 Hz, 2H), 7.32 (d, J=9HZ, 2H).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](OC)=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30].N1C=CN=C1>CO>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:30][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reactant: CN(C)CCN
Agent: c1c[nH]cn1
Solvent: CO
Product: CN(C)CCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A suspension of methyl 4-(4-biphenylylmethoxy)phenylacetate (1.00 g), N,N-dimethylethylenediamine (0.80 g), and imidazole (205 mg) in methanol (2.0 ml) was heated under reflux under nitrogen for 30 min and cooled until the temperature of the reaction mixture reached to 60±2° C. Methanol (4.0 ml) was added to the reaction mixture, which was heated under reflux for additional one hr and cooled to room temperature. The precipitate was collected by filtration and washed with methanol (2.0 ml) to obtain the titled compound (1.03 g).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:31][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:14]=[C:13]2[CH:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC(c3cc(CC(=O)O)cc4ccc(F)cc34)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.9 %

Procedure:
To a stirred solution of {6-fluoro-4-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (70 mg, 0.2 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (32 mg, 0.76 mmol) in water (1 mL) and the reaction mixture was stirred for 24 h at RT. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give [{6-fluoro-4-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid (52 mg, 77%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.37 (br s, 1H), 7.94 (dd, J=8.8, 6.4 Hz, 1H), 7.88 (d, J=10.3 Hz, 1H), 7.66-7.73 (m, 3H), 7.50 (d, J=8.3 Hz, 2H), 7.33-7.42 (m, 2H), 3.79 (d, J=12.2 Hz, 2H), 3.71 (s, 2H), 1.90 (d, J=11.7 Hz, 2H), 1.69-1.82 (m, 1H); MS cald. for C24H25FNO4S [(M−H)−]: 440, obsd. 440.4.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[CH2:13]([O:15][CH2:16][CH2:17]Br)[CH3:14]>C(O)C>[CH3:14][CH2:13][O:15][CH2:16][CH2:17][O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CCOCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOCCOc1ccc(C(=O)O)cc1
Yield: 29.6 %

Procedure:
Into a 1 l three-neck flask were introduced 400 ml of 90% ethanol, 25 g of potassium hydroxide, 40 g of p-hydroxybenzoic acid and 45 g of β-ethoxyethyl bromide, and the contents were heated under reflux for 10 hours. After removing ethanol by distillation, 100 ml of a 10% aqueous solution of potassium hydroxide was added and the contents were heated under reflux for additional two hours. After acidifying with hydrochloric acid, separated acid was collected and recrystallized from benzene and then ethanol to obtain 18 g of p-(β-ethoxy)ethoxybenzoic acid. The melting point of the resulting product was 130° C.-132° C. and the elemental analysis values thereof were as follows, which accorded with the calculated values very well.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[C:27](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([N:8]([CH3:27])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1
Reactant: COC(=O)c1cc(Cl)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 80 °C
Yield: 61 %

Procedure:
To a stirred solution of tert-butyl 4-((5-chloro-3-(methoxycarbonyl)-2-methylphenyl)amino)piperidine-1-carboxylate (4 g, 9.09 mmol) in acetonitrile (50 mL), cesium carbonate (5.9 g, 18.09 mmol) and methyl iodide (6.95 g, 48.94 mmol) were added; resulting reaction mass was heated at 80° C. for 12 h. On completion, reaction mass was cooled to room temperature and filtered, residue was washed with ethyl acetate and filtrate was concentrated and then purified by column chromatography to afford the desired compound (2.2 g, 53%).
Reaction SMILES: ClN1[C:6](=[O:7])[CH2:5]CC1=O.Br[C:10]1[C:24]2=[C:25]3[C:13]([N:14]([Si](C(C)(C)C)(C)C)[CH:15]=[C:16]3[CH2:17][C@@H:18]3[C@@H:23]2[CH2:22][C@H:21]([NH:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:20][N:19]3[CH3:34])=[CH:12][CH:11]=1>>[C:6]([C:11]1[CH:12]=[C:13]2[C:25]3[C:16]([CH2:17][C@@H:18]4[C@@H:23]([C:24]=3[CH:10]=1)[CH2:22][C@H:21]([NH:26][C:27](=[O:33])[N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])[CH2:20][N:19]4[CH3:34])=[CH:15][NH:14]2)(=[O:7])[CH3:5]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(Br)ccc4c3c(cn4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Reactant: O=C1CCC(=O)N1Cl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(C(C)=O)cc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
With N-chlorosuccinimide and 3-(12-bromo-1-tert-butyldimethylsilyl-6-methyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:18]>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccccc1OCc1ccccc1
Solvent: CCOCC
Product: BrCc1ccccc1OCc1ccccc1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
To a solution of 2-benzyloxybenzyl alcohol (4.83 g) in diethyl ether (40 ml) was added dropwise, at 0° C., a solution of phosphorus tribromide (6.27 g) in diethyl ether (10 ml). The mixture was warmed to ambient temperature, diluted with diethyl ether (100 ml) and filtered through a pad of silica gel washing with 1 litre of diethyl ether. The combined organic solution was washed with saturated aqueous sodium hydrogen carbonate (100 ml) and brine (100 ml), dried (sodium sulphate), filtered and evaporated to give 2-benzyloxybenzyl bromide (5.88 g) as an oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5](=[O:17])[CH2:4]1.CCN(CC)CC>C(Cl)Cl>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:6]2[C:5](=[O:17])[CH2:4][CH:3]([CH:2]=[O:1])[CH2:7]2)=[CH:14][CH:13]=1
Reactant: COc1ccc(CN2CC(CO)CC2=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CC(C=O)CC2=O)cc1
Temperature: 1 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
In a three necked flask, under argon, a solution 4-hydroxymethyl-1-(4-methoxy-benzyl)-pyrrolidin-2-one a2 (4.3 g, 0.018 mol) and Et3N (8.9 ml) in CH2Cl2 (25 ml) cooled down to −10° C. Pyridine-SO3 (10.1 g, 0.064 mol, 3.5 eq) is added by portions and the temperature raised up to 1° C. After 3 h at −10° C., the reaction is quenched with water (100 ml) and extracted with CH2Cl2 (3 times). The organic phase is washed with successively a 1M solution of KHSO4, water, brine, dried over MgSO4, filtered and evaporated in vacuo to give the crude aldehyde a3 (3.2 g, 87%). It is dried several times by azeotropic distillation with toluene and used as such in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH:28]([C:29]([O:21][CH2:20][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:4]=1[O:3][CH2:1][CH3:2])[CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1CO
Product: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1COC(=O)Nc1ccccc1

Procedure:
Using dimethyl 2-[4-ethoxy-3-(hydroxymethyl)benzyl]-malonate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH3:1][C@H:2]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[C:14]2[N:13]([CH3:17])[CH:12]=[N:11][C:10]=2[N:9]([CH3:18])[C:7]1=[O:8].C[N+]1([O-])CCOCC1.[OH2:33].S([O-])([O-])=O.[Na+].[Na+].CC(C)=O.[OH2:44]>>[CH3:1][C@@H:2]([CH2:19][CH2:20][CH:21]([OH:44])[C:22]([OH:33])([CH3:23])[CH3:24])[CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[C:14]2[N:13]([CH3:17])[CH:12]=[N:11][C:10]=2[N:9]([CH3:18])[C:7]1=[O:8]
Reactant: O
Reactant: CC(C)=CCC[C@@H](C)CCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: C[N+]1([O-])CCOCC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C[C@H](CCCn1c(=O)c2c(ncn2C)n(C)c1=O)CCC(O)C(C)(C)O
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of 1-(4-(R)-Methyl-8-methylnon-7-enyl)-3,7-dimethylxanthine (0.48 g, 1.44 mmol), 4-methylmorpholine-N-oxide (0.51 g, 4.38 mmol) and potassium osmate dihydrate (5 mg, 0.015 mmol) in acetone/water 1:2 (9 mL) was stirred for 16 hours. Water (10 mL) and sodium sulfite (1 g) were added and the reaction mixture stirred for 1 hour. The reaction mixture was extracted with dichloromethane (3×30 ml) using dried magnesium sulfate and the solvent evaporated to yield 0.51 g (97% yield) 1-(4-(R)-Methyl-7,8-dihydroxy-8-methylnonyl)-3,7-dimethylxanthine (inventive compound no. 2537R) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]([CH3:11])[CH2:9][O:10][C:6]=2[C:5]([CH:12]2[C@H:17]([O:18]CC3C=CC=CC=3)[C@@H:16]([O:26]CC3C=CC=CC=3)[C@H:15]([O:34]CC3C=CC=CC=3)[C@@H:14]([CH2:42][O:43]CC3C=CC=CC=3)[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH3:60])=[CH:54][CH:53]=1>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:7]2[CH:8]([CH3:11])[CH2:9][O:10][C:6]=2[C:5]([C@H:12]2[C@H:17]([OH:18])[C@@H:16]([OH:26])[C@H:15]([OH:34])[C@@H:14]([CH2:42][OH:43])[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:53]=[CH:54][C:55]([O:58][CH2:59][CH3:60])=[CH:56][CH:57]=1
Reactant: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)C(C)CO3)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)C(C)CO3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.6 %

Procedure:
To a solution of 4-chloro-5-(4-ethoxybenzyl)-3-methyl-7-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran (102 mg, 0.124 mmol) in THF/MeOH (4 mL/2 mL) was added 10% Pd/C (50 mg) at rt. The reaction mixture was stirred at r.t. for 15 hours under hydrogen and filtered off. The filtrate was concentrated in vacuo and the residue was purified using reverse phase preparative HPLC to provide the title compound (24 mg, 42%) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH2:8]([O:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)CCO)=[O:14])[CH2:9][CH2:10][CH3:11].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:8]([O:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:26][CH2:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:5]([O:4][C:1]([CH3:2])=[O:3])[CH:6]=1)=[O:14])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOC(=O)Nc1ccccc1C(CCO)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)Nc1ccccc1CCCc1cccc(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Acetic anhydride (0.42 ml, 0.42 mmol) was added to a solution of N-butyloxycarbonyl-2-(3-hydroxy-1-phenylpropyl)aniline (1.21 g, 3.7 mmol), triethylamine (0.77 ml, 5.56 mmol) and DMAP (5 mg) in DCM (25 ml). After stirring at room temperature for 90 minutes the reaction mixture was diluted with DCM (25 ml), washed with 10% aqueous citric acid solution (40 ml), saturated aqueous sodium bicarbonate solution (40 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the product. (1.39 g, 100%).
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[C:27]([CH3:33])=[N:28][CH:29]=[C:30]([CH3:32])[N:31]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:29]3[C:30]([CH3:32])=[N:31][CH:26]=[C:27]([CH3:33])[N:28]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: Cc1cnc(C)c(Cl)n1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1cnc(C)c(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 3-chloro-2,5-dimethyl-pyrazine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.44 min; Mass spectrum (ESI+): m/z=418 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].C(N(CC)CC)C.[CH3:35][O:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:35][O:36][C:37]1[CH:43]=[CH:42][C:40]([NH:41][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:2])=[CH:39][CH:38]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Reactant: COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2cccc([C@H](C)Nc3nccc(-n4cnc5ccccc54)n3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.7 %

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (28.9 mg) was dissolved in CH2Cl2 (2 mL), then triethylamine (55 μL) was added followed by 4-methoxyaniline (62 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53.4 mg) and 4-dimethylaminopyridine (˜1 mg). The mixture was stirred at room temperature for 18 h then directly eluted on silica gel column (1-4% MeOH:CH2Cl2) to yield 19.7 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.45 (br s, 1H); 8.37 (d, J=5.5 Hz, 1H); 7.99 (s, 1H); 7.88 (s, 1H); 7.80 (d, J=6.2 Hz, 1H); 7.75 (d, J=7.5 Hz, 1H); 7.62 (d, J=7.8 Hz, 1H); 7.49 (m, 3H); 7.33 (m, 2H); 6.90 (d, J=8.9 Hz, 2H); 6.77 (d, J=5.5 Hz, 1H); 5.87 (br s, 1H); 5.26 (br s, 1H); 3.81 (s, 3H); 1.65 (d, J=6.8 Hz, 3H). Mass Spectrum (ESI): m/e 465.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1>>[NH2:1][C:2]1[CH:9]=[C:8]([O:17][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: OC1CCOCC1
Product: N#Cc1cnc(N)cc1OC1CCOCC1

Procedure:
From intermediate 21 and tetrahydro-2H-pyran-4-ol, reacted in an analogous manner to the preparation of intermediate 45. (UPLC-MS 3) tR 0.53 min; ESI-MS 220.1 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: c1coc(C2CCCN2)c1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccco1

Procedure:
The title compound, yellow oil, MS: m/e=311 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-furan-2-yl-pyrrolidine and 4-chloro-benzenesulfonyl chloride.