Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([OH:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1>CC(C)=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:12]([CH:16]=1)[C:13]([O:15][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)=[O:14]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1cccc(F)c1)c1cc(Br)ccc1OCc1cccc(F)c1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
Solid potassium carbonate (2.76 g, 20 mmol) was added to a stirred solution of 5-bromo-2-hydroxybenzoic acid (1 g, 4.61 mmol) in acetone (20 ml) at 20° C. The reaction mixture was stirred at 20° C. for 10 min, and then 1-(bromomethyl)-3-fluorobenzene (1.92 g, 10.14 mmol) was added dropwise. The reaction mixture was stirred at 71° C. for 18 h. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated to give a colourless oil. The crude product was added to a silica gel column and was eluted with hexane/ethyl acetate (100:5 then 20:1) to yield the title compound as a white solid. 1.65 g.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5].[S:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:24]2[CH:25]=[CH:26][S:22][CH:23]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])=[O:5]
Reactant: O=C(NS(=O)(=O)c1ccc(I)cc1)c1ccc(Cl)cc1Cl
Reactant: OB(O)c1ccsc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(NS(=O)(=O)c1ccc(-c2ccsc2)cc1)c1ccc(Cl)cc1Cl
Temperature: 100 °C

Procedure:
To a solution of N-(2,4-dichlorobenzoyl)-4-iodo-phenylsulfonamide (0.10 mmol) in toluene/ethanol 20/1 (3 mL) is added 3-thiopheneboronic acid (0.18 mmol, 0.18 mL, 1.0M solution in DMF) and tetrakis-(triphenylphosphine) palladium (0) (10 mol %). Then 2M aqueous Na2CO3 is added (0.3 mL) and the stirred mixture is heated to 100° C. overnight (17 hr)(Buchi Syncore system). The reaction mixture is concentrated (Genevac apparatus), then water is added (2.5 mL) and ethyl acetate (5 mL). The phases are separated and the aqueous layer is extracted with ethyl acetate (3×5 mL). This process is automatically carried out using a Tecan system. The solvents are evaporated and the corresponding crude product is purified by HPLC to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[C:16](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(Br)cn1
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
Tert-butyl 5-bromopyridin-2-ylcarbamate (10 g) and cesium carbonate (20 g) were added to 50 mL of DMF. Methyl iodide (4 mL) was subsequently slowly added to the stirring reaction mixture. After 30 minutes tlc indicates that the reaction is complete. The majority of the DMF was removed under hi-vacuum and the reaction mixture was extracted with ethyl acetate and water. The organic layer was dried, filtered and concentrated. The crude product was purified by Isco 0-30% gradient (H/E) over 25 mins. The tubes were pooled and concentrated to get 9.85 g of tert-butyl 5-bromopyridin-2-yl(methyl)carbamate as a clear oil.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]([F:14])[C:8]([C:9](O)=[O:10])=[C:7]([CH:15](OC)OC)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:21][NH2:22]>C(O)C.C(O)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[C:12]([F:14])[CH:13]=1)[C:9](=[O:10])[NH:22][N:21]=[CH:15]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC(OC)c1cc(C(C)(C)C)cc(F)c1C(=O)O
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
4-tert-Butyl-2-dimethoxymethyl-6-fluoro-benzoic acid (220.3 g, 0.815 moles) was dissolved in ethanol (2 vol, 440 mL) and acetic acid (0.5 vol, 110 mL). Hydrazine hydrate (1.5 eq, 61 mL) was added and the solution stirred at 80° C. for 6 hours. The mixture was cooled to rt overnight, then in an ice bath and then filtered and washed with cold ethanol. The fine white crystals were dried at 100° C. in a vacuum oven with N2 sweep, to provide 154.7 g (86%) of 6-tert-butyl-8-fluoro-2H-phthalazin-1-one.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:20])[C:13]=2[N+:17]([O-])=O)[C:8]1=[O:21])(=[O:3])[CH3:2].C(O)C.[Cl-].[NH4+].O>[Fe].C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:20])[C:13]=2[NH2:17])[C:8]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCn1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CC(=O)OCCn1ccc2c(N)c(Cl)ccc2c1=O
Reaction time: 0.75 h

Procedure:
A round bottom flask was charged with 2-(6-chloro-5-nitro-1-oxoisoquinolin-2(1H)-yl)ethyl acetate (450.00 mg, 0.0014484 mol), ethanol (20 mL, 0.3 mol) and ammonium chloride (774.8 mg, 0.01448 mol) in water (10 mL, 0.6 mol) was added at 85° C. followed by iron (324 mg, 0.00579 mol) in two portions. The reaction was stirred at that temperature for 45 minutes and then poured into methylene chloride (200 mL) and extracted. The solvent was removed to give the pure product as a light yellow solid. MS m/z=281.3 (M+H)
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:10])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:11](O)[CH2:12][C:13]#[CH:14]>>[CH2:14]([N:2]1[C:3](=[O:10])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1)[CH2:13][C:12]#[CH:11]
Reactant: C#CCCO
Reactant: O=c1[nH]nc2ccccn12
Product: C#CCCn1nc2ccccn2c1=O
Yield: 26.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 109(D), from [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (405 mg, 3.00 mmol) and but-3-yn-1-ol (200 mg, 2.85 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 140 mg (0.75 mmol, 26%) of 2-(but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one.
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[CH:3]/[CH2:4]Cl.[C:7]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:16])[CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10]>>[CH:2]([CH:3]1[CH2:4][C:8]1([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])[C:7]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])=[CH2:1]
Reactant: ClC/C=C/CCl
Reactant: CCCCOC(=O)CC(=O)OCCCC
Product: C=CC1CC1(C(=O)OCCCC)C(=O)OCCCC
Yield: 69 %

Procedure:
Example 3 was repeated except the organic solvent was omitted and the mol ratio of trans 1,4-dichlorobutene-2 to di-n-butyl malonate was 2:1. Di-n-butyl 2-vinylcyclopropane-1,1-dicarboxylate was obtained in 69% yield.
Reaction SMILES: [CH3:1][Li].[CH2:3]([O:5][C:6](=[O:21])[C@@:7]([F:20])([CH3:19])[CH2:8]S(C1C=CC(C)=CC=1)(=O)=O)[CH3:4]>CCOCC.[Cu](I)I>[CH2:3]([O:5][C:6](=[O:21])[C@:7]([F:20])([CH3:19])[CH2:8][CH3:1])[CH3:4]
Reactant: [Li]C
Reactant: CCOC(=O)[C@](C)(F)CS(=O)(=O)c1ccc(C)cc1
Agent: I[Cu]I
Solvent: CCOCC
Product: CCOC(=O)[C@@](C)(F)CC
Reaction time: 10 h

Procedure:
4.8 g (0.025 mol) of copper iodide was added to 10 ml of dried ether, which was cooled to -25°~-30° C. under a nitrogen gas flow and thereafter 36 ml of methyl lithium was added dropwise thereto. Then, 3.8 g (0.01 mol) of (S)-(-)-3-(p-toluenesulfonyl)-2-fluoro-2-methylpropionic acid monoethyl ester dissolved in 10 ml of dried ether at -15°~-20° C. was added dropwise thereto, which was stirred at 0°~5° C. for 10 hours. After the completion of the reaction, the precipitate was removed by filtration and then the filtrate was washed with 1 normal hydrochloric acid and further with water and dried on anhydrous magnesium sulfate. After the removal of magnesium sulfate by filtration, the solvent was distilled off and the residue as it is was used for the following reaction.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[C:12][CH2:13][CH2:14][OH:15])[CH:6]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C#CCCO)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Oc1cccc(CCCCO)c1

Procedure:
A solution of 3-(4-hydroxybut-1-ynyl)phenyl acetate (4.47 g) was hydrogenated over 5% Pd on carbon in ethyl acetate (100 mL) and ethanol (100 mL) over 20 h. The reaction mixture was filtered through celite under nitrogen, and the filtrate was concentrated in vacua. The residue was purified by chromatography (SPE, gradient from cyclohexane to EtOAc) to give the title compound. LCMS RT=2.64 min
Reaction SMILES: O[N:2]=[CH:3][C@@H:4]([N:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[N:29]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:28]=[N:27][N:26]=2)=[CH:15][CH:14]=1)[C:7](=[O:11])[CH2:8][CH2:9][CH3:10])[CH3:5].C([BH3-])#N.[Na+].C([O-])(=O)C.[NH4+].[OH-].[NH4+]>[Cl-].[Ti+3].[Cl-].[Cl-].CO>[NH2:2][CH2:3][C@@H:4]([N:6]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[N:29]([C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:28]=[N:27][N:26]=2)=[CH:17][CH:18]=1)[C:7](=[O:11])[CH2:8][CH2:9][CH3:10])[CH3:5]
Reactant: CCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](C)C=NO
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: CCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](C)CN
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
A solution of intermediate (5d) (105 mg, 0.2 mmol), sodium cyanoborohydride (47 mg, 0.7 mmol), ammonium acetate (28 mg, 0.4 mmol), and MeOH (6.0 mL) was cooled to 0° C. After 15 minutes, titanium (III) chloride (83 mg, 0.5 mmol) was added. After 10 minutes, ammonium hydroxide (1 mL) was added and the mixture was stirred at room temperature for 5 minutes. The mixture was filtered through Celite®, rinsing with MeOH, and the filtrate was concentrated in vacuo to yield a white solid. The solid was extracted with DCM and water. The combined organic extracts were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo to afford intermediate (5e) (95 mg), which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br.C(OCC)(=O)C>CN(C=O)C>[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:6]1[C:2]([CH3:1])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3](=[O:20])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:5]1=[O:7]
Reactant: Clc1cccc(CBr)c1
Reactant: CC1(c2ccccc2)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine -2,4-dione (43 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 3-chlorobenzyl bromide (26 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 26 mg of white crystals.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].O.O.O.O.C([O-])(=[O:13])C.[Mn+2:15].C([O-])(=O)C>O>[OH2:3].[OH2:13].[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[Mn+2:15]
Reactant: O=C(O)C(=O)O
Reactant: CC(=O)[O-]
Agent: [Mn+2]
Solvent: O
Product: O=C([O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 10 l four-neck round-bottom flask with a stirrer, thermometer and reflux condenser was initially charged with 176.0 g (1.95 mol) of oxalic acid in 4200 ml of water, and the resulting solution was admixed dropwise at room temperature with a solution of 318.6 g (1.30 mol) of manganese(II) acetate tetrahydrate in 2100 ml of water, and stirred for a further 15 min after the addition had ended. Subsequently, the reaction mixture was heated to reflux and stirred for a further 30 min. After cooling to room temperature, the white precipitate was filtered off with suction, washed three times with 200 ml of water each time and dried in a vacuum drying cabinet at room temperature overnight.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[CH2:12]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26](C#N)=[C:25]([O:31][CH3:32])[CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([C:1]2[NH:2][C:3](=[O:4])[C:5]3[C:6]([CH:11]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[C:25]([O:31][CH3:32])[CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cc(OCCOCc2ccccc2)ccc1C#N
Reactant: CNC(=O)c1ccccc1C
Product: COc1cc(OCCOCc2ccccc2)ccc1-c1cc2ccccc2c(=O)[nH]1
Yield: 10.3 %

Procedure:
According to Example 36-1, N-methyl-o-toluamide (1.70 g) and 4-(2-benzyloxyethoxy)-2-methoxybenzonitrile (3.30 g) were reacted, to give 3-[4-(2-benzyloxyethoxy)-2-methoxyphenyl]isoquinolin-1-one (0.47 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]([C:7](=[O:19])[N:8]([CH2:16][CH:17]=C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=C>C(Cl)Cl.[Ru]>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[C:7](=[O:19])[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:16][CH:17]=1
Reactant: C=CCN(Cc1ccccc1)C(=O)C(=C)CC(=O)OC
Agent: [Ru]
Solvent: ClCCl
Product: COC(=O)CC1=CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.7 %

Procedure:
234 mg of 3-(allyl-benzyl-carbamoyl)-but-3-enoic acid methyl ester (o) (0.1 mM) prepared by the above Step 1 was added to the catalyst solution containing 36 mg of Grubb's (I) catalyst (0.04 mM) such as ruthenium dissolved in CH2Cl2 under Ar atmosphere. Then the mixture was stirred for 24 hrs at room temperature, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with EtOAc and hexanes (1:2) as an eluant to give 180 mg of (1-benzyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)-acetic acid methyl ester (p) (yield: 85%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[NH:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29]I>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH3:29])[S:22]([CH2:25][CH3:26])(=[O:23])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCS(=O)(=O)NC1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCS(=O)(=O)N(C)C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Analogously to Example 1f, 8.6 g (23 mmol) of 6-benzyloxy-4-(ethylsulfonyl)amino-2,2-dimethylchroman were introduced in portions into a suspension of 1 g (25 mmol) of sodium hydride (60% dispersion) in 75 ml of DMA at 10° C. After stirring at RT for 2 h, 1.6 ml (25 mmol) of methyl iodide were added dropwise, the temperature rising to 40° C. The mixture was then heated to 35-45° C. for 2 h, and concentrated in vacuo, the residue was treated with water, the resinous product was taken up with EA, the solution was dried and concentrated, and the residue was chromatographed using n-heptane/EA (1:1) on silica gel. 7.4 g of product were crystallized from appropriate fractions using petroleum ether/diisopropyl ether, m.p. 91-93° C.
Reaction SMILES: C(O)(=O)C.[C:5]1([CH:11]2[CH2:16][CH2:15][C:14](=[N:17]O)[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O1CCCC1>C(O)(C)(C)C>[C:5]1([C@H:11]2[CH2:12][CH2:13][C@H:14]([NH2:17])[CH2:15][CH2:16]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ON=C1CCC(c2ccccc2)CC1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
Into a solution of 8.58 g. of 4-phenylcyclohexanone oxime acetate (prepared in Example 79) in 90 ml. of tetrahydrofuran and 27 ml. of t-butanol, 350 ml. of ammonia is distilled from over sodium. To this there is added 1.9 g. of lithium in three portions at a rate that the blue color just persists. When the final blue color fades, 10 g. of solid ammonium chloride is added and the solvent is then evaporated with a stream of nitrogen. The residue is dissolved in ether and aqueous N-sodium hydroxide solution. The organic layer is separated, washed with water and brine and then taken to dryness to give a residue of trans 4-phenylcyclohexylamine. The residue is dissolved in a small amount of ether and treated with an excess of 4.9N hydrogen chloride in ether. The precipitate that forms is collected on a filter to yield 7.9 g. of trans 4-phenylcyclohexylamine hydrochloride. A sample of identical material previously prepared melts above 300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH:20]([C:22]2[CH:34]=[CH:33][CH:32]=[CH:31][C:23]=2[O:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])[CH3:21])[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:41][C:39]=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.CN.Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH:20]([C:22]2[CH:34]=[CH:33][CH:32]=[CH:31][C:23]=2[O:24][CH2:25][CH2:26][CH2:27][C:28]([NH:41][CH3:39])=[O:29])[CH3:21])[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(c1ccccc1OCCCC(=O)O)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)CCCOc1ccccc1C(C)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 97.4 %

Procedure:
A mixture of acid 4-[2-(1-([(4-chlorophenyl)sulfonyl]-2,5-difluoroanilino}ethyl)phenoxy]butanoic acid (107 mg, 0.21 mmol), HOBT (31 mg, 0.23 mmol), EDCI (44 mg, 0.23 mmol), Et3N (88 μL, 0.63 mmol) and CH3NH2.HCl (16 mg, 0.23 mmol) in CH2Cl2 (1.0 mL) was stirred at 25° C. for 13 h. The mixture was diluted with ethyl acetate. The organic solution was washed with H2O and sat. NaCl solution then dried over MgSO4. Concentration and chromatography afforded the amide (107 mg, 97%) as colorless gum: Rf 0.32 (10:20, hexane-ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 7.64 (d, 2H, J=6.9 Hz), 7.42 (d, 2H, J=7.8 Hz), 7.18 (t, 1H, J=8.7 Hz), 6.36-6.91 (m, 7H), 6.26 (q, 1H, 1=6.9 Hz), 4.13 (m, 1H), 4.05 (m, 1H), 2.78 (m, 4H), 2.57 (m, 1H), 2.23 (m, 2H), 1.55 (br s, 3H); LCMS m/z 524 (M+H+, C25H25ClF2N2O4S requires 522.99).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:14])[C:5]2[O:10][CH2:9][CH:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=1.[CH3:15][S:16]([O-:18])=[O:17].[Na+].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:14][C:4]1[C:5]2[O:10][CH2:9][C@H:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=[C:2]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:3]=1
Reactant: CS(=O)[O-]
Reactant: OCC1COc2c(Cl)cc(Br)cc2O1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cc(Cl)c2c(c1)O[C@@H](CO)CO2

Procedure:
Preparation according to Preparation 9 using (7-bromo-5-chloro-2,3-dihydro-1,4-benzodioxin-2-yl)methanol (1.07 g, 3.8 mmol), sodium methanesulfinate (85%) (0.6 g, 5.7 mmol), CuI (0.07 g, 0.4 mmol), L-proline (0.09 g, 0.8 mmol) and K2CO3 (0.04 g, 0.8 mmol) in DMSO (10 ml). Yield (0.33 g). MS m/z (rel. intensity, 70 eV) 280 (38), 278 (M+, bp), 247 (35), 207 (18), 57 (18).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH:14](OC)[O:13][N:12]=[C:11]2[CH3:17])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([CH3:17])=[N:12][O:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C2C(C)=NOC2OC)cc1Br
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2conc2C)cc1Br
Temperature: 25 °C
Yield: 67.7 %

Procedure:
A solution of 4-(3-bromo-4-methoxyphenyl)-5-methoxy-3-methyl-4,5-dihydroisoxazole (260 mg, 0.87 mmol) in 15 mL of a 5:1 mixture of ethanol and 12N aqueous HCl was heated at reflux overnight. After cooling to room temperature, the reaction was concentrated to a small volume in vacuo. Saturated aqueous sodium bicarbonate (50 mL) was added and the mixture was extracted with 3×50 mL of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of brine, dried over sodium sulfate, and evaporated. The crude residue was subjected to flash chromatography on 25 g of silica gel eluting with 500 mL of 20% of diethyl ether/hexane to give 4-(3-bromo-4-methoxyphenyl)-3-methylisoxazole (158 mg, 68% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.57 (d, 1H, J=2 Hz), 7.29 (dd, 1H, J=9, 2 Hz), 6.86 (d, 1H, J=9 Hz), 3.94 (s, 3H), 2.40 (s, 3H). Mass spectrum (ESI): m/e=268 (M+1).
Reaction SMILES: C([C:5]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:7]2[C:8]([NH:10][C:11](=[O:12])[C:6]=12)=[O:9])CCC.Cl[Si](Cl)(C)[Si:19]([CH3:22])(C)[CH3:20]>CC1C=CC=CC=1C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([N:10]1[C:11](=[O:12])[C:6]2=[C:5]([SiH:19]([CH3:22])[CH3:20])[C:15]([Cl:16])=[CH:14][CH:13]=[C:7]2[C:8]1=[O:9])[CH2:5][CH2:6][CH3:7]
Reactant: CCCCc1c(Cl)ccc2c1C(=O)NC2=O
Reactant: C[Si](C)(C)[Si](C)(Cl)Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CCCCN1C(=O)c2ccc(Cl)c([SiH](C)C)c2C1=O
Yield: 24 %

Procedure:
A reaction mixture containing 5 gm (0.021 moles) of n-butyl-4-chlorophthalimide and 3.95 gm (0.021 moles) of 1.2 dichlorotetramethyldisilane dissolved in 10 ml of o-xylene was heated to 150° C. in the presence of 5 mole % tetrakis(triphenylphosphine)palladium. After 24 hours reaction time, GC and GC/MS analysis showed a 24% yield of N-butyl-4-chlorodimethylsilyl-phthalimide. The product is readily isolatable by vacuum distillation.
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:11]>O>[Cl:11][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH3:9]
Reactant: Cl
Reactant: CCC(O)c1ccccc1
Solvent: O
Product: CCC(Cl)c1ccccc1

Procedure:
13.6 g (0.1 mole) of 1-phenylpropan-1-ol are taken up in petroleum ether and are reacted at -20° C. with hydrochloric acid until the precipitation of water is terminated. Subsequently, the organic phase is washed neutral with water, dried (sodium sulfate) and the petroleum ether removed in a vacuum. The bright yellow, thermolabile oil is used without further purification. The oil has an Rf of 0.8 (CH2Cl2) and is attained in a yield of 13.1 g (85%).