Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:8]([O:10][C:11](=[O:33])[CH:12]([O:30][CH2:31][CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:16][CH:15]=1)[CH3:9].CCCCCCC>C1(C)C=CC=CC=1>[CH2:8]([O:10][C:11](=[O:33])[CH:12]([O:30][CH2:31][CH3:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:27][CH:28]=2)=[CH:16][CH:15]=1)[CH3:9]
Reactant: CC(C)(C)N=C=O
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(O)cc2)cc1)OCC
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OC(=O)NC(C)(C)C)cc2)cc1)OCC
Yield: 20.3 %

Procedure:
tert-Butyl isocyanate (0.14 g; 1.4 mmole) was slowly added to a solution of 2-ethoxy-3-{4-[2-(4-hydroxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 26b) (0.5 g; 1.4 mmole) in toluene (5 ml) and thereafter the reaction mixture was stirred over night. The crude mixture was purified by chromatography on silica gel using ethyl acetate:heptane (gradient 1.25-80% ethyl acetate) as eluant to give 0.13 g (yield 20%) of 3-{4-[2-(4-tert-butylcarbamoyloxyphenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:27]=[CH:26][NH:25][N:24]=2)=[CH:19][CH:18]=1>>[CH2:9]([N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]1[CH2:2][N:25]1[CH:26]=[CH:27][C:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[N:24]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Fc1ccc(-c2cc[nH]n2)cc1
Reactant: BrCC1CCCCN1Cc1ccccc1
Product: Fc1ccc(-c2ccn(CC3CCCCN3Cc3ccccc3)n2)cc1
Yield: 22.9 %

Procedure:
The title compound (0.8 g) was prepared from 2-bromomethyl-N-benzylpiperidine (2.68 g) and 3-(4-fluoro-phenyl)-1H-pyrazole (1.62 g) according to the method of example 93.
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:23][O:24]C1C(N)=CC=CC=1>C(O)C>[ClH:1].[CH3:23][O:24][C:4]1[C:3]([NH:2][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccccc1N
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CCO
Product: COc1ccccc1Nc1cc(C)nc2ccc3nc[nH]c3c12

Procedure:
A mixture of 30 g. (0.138 m.) of the compound of Example I, C. 17 g. (15.6 ml. 0.138 m.) of o-anisidine and 200 ml. of ethanol was stirred and heated at reflux overnight. The solution was concentrated in vacuo to give 45 g. m.p. 271°-275°. The crude product was recrystallized from 350 ml. of MeOH. The yield after oven-drying (100°) was 29 g. m.p. 300°-301°.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17])=[O:10])=[CH:7][N:8]=1)[CH3:2].[OH:18]O>C(O)(=O)C>[CH2:1]([S:3]([C:4]1[S:5][C:6]([C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17])=[O:10])=[CH:7][N:8]=1)=[O:18])[CH3:2]
Reactant: OO
Reactant: C#CCCCCNC(=O)c1cnc(SCC)s1
Solvent: CC(=O)O
Product: C#CCCCCNC(=O)c1cnc(S(=O)CC)s1

Procedure:
In this preparation a mixture of 0.064 mole of 2-ethylthio-5-(hex-5-ynylaminocarbonyl) thiazole; 40 ml. of 30% aqueous hydrogen peroxide and 200 ml. of acetic acid is stirred at a temperature of from 40° to 50° C for 4 hours. The mixture is concentrated by evaporation of a large portion of the acetic acid, under vacuum, at room temperature (about 20° C) and the resulting residue poured into 500 ml. of ethyl acetate and then washed with aqueous sodium bicarbonate solution until no acetic acid is present in the organic layer. The ethyl acetate layer is then separated, dried with anhydrous magnesium sulfate, filtered, and the resulting filtrate evaporated to dryness, under vacuum, affording 2-ethylsulfinyl-5-(hex-5-ynylaminocarbonyl)thiazole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:28](=[O:30])[CH3:29].P([O-])(O)(O)=O.[K+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH:28]([OH:30])[CH3:29])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2)on1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.8 g) was dissolved in tetrahydrofuran (16 ml), and butyllithium (1.6M hexane solution, 3.7 ml) was added dropwise thereto at -70° C. under a nitrogen atmosphere, and the mixture was stirred for 10 minutes. After acetaldehyde (0.22 ml) was added dropwise to the reaction mixture, the resulting mixture was stirred for 10 minutes and the temperature of the mixture was raised to 0° C. The mixture was then poured into ice-cold water and the pH of the mixture was adjusted to a value of 6 with an aqueous potassium dihydrogenphosphate solution. After the reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous NaCl solution, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain the title compound (0.90 g, 98%) as a colorless oil.
Reaction SMILES: N[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[C:18]([F:21])[CH:17]=[C:16]([C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.N([O-])=[O:29].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH:25]1([NH:24][C:22]([C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[O:7][C:3]([CH2:2][OH:29])=[N:4][N:5]=4)=[CH:9][CH:10]=3)[C:19]([CH3:20])=[C:18]([F:21])[CH:17]=2)=[O:23])[CH2:26][CH2:27]1
Reactant: O=N[O-]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CO)o2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4′-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide (Example 45) (96 mg) in acetic acid/water (1:1 v/v, 7 ml) was cooled to 0° C. Sodium nitrite (206 mg) was added and the solution stirred for 30 minutes at 0° C. and then for a further 16 hours at room temperature. Concentrated sodium hydroxide solution (10 ml) was added to the reaction and the mixture extracted with ether (3×40 ml) and then chloroform (40 ml). The organic phases were combined, dried and reduced to dryness under vacuum. The residue was dissolved in 5% potassium hydroxide in methanol and stirred at room temperature for 90 minutes. The methanol was removed in vacuo, the residue partitioned between ethyl acetate/chloroform (1:1)/water and the organic phase dried and reduced to dryness under vacuum. This material was purified by chromatography on a bond-elut (silica, 2 g), eluting with an ethyl acetate/cyclohexane gradient to give after evaporation of the solvent N-cyclopropyl-5-fluoro-4′-[5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl]-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[NH2:20])=[CH:14][CH:15]=2)[CH:10]=[N:9]1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[NH:20][C:1](=[O:3])[CH3:2])=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1Oc1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Acetic anhydride (0.04 ml) was added to a solution of the 2-(1H-indazol-5-yloxy)aniline (34 mg, 0.151 mmol) obtained in Example 476 in pyridine (1 ml) at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was cooled to 0° C. and a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was dissolved in a mixed solution of tetrahydrofuran (1 ml) and methanol (1 ml), followed by adding thereto 1N aqueous sodium hydroxide solution (1 ml). The resulting mixture was stirred at room temperature for 1 hour. The reaction solution was added to a saturated aqueous sodium chloride solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (chloroform/methanol) to obtain N-[2-(1H-indazol-5-yloxy)phenyl]acetamide (32 mg, 79%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)OC1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:29][N:28]1[C:24]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)=[CH:25][CH:26]=[N:27]1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: COC(=O)c1cc(Br)cs1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)cs1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-bromo-2-thiophenecarboxylate (1 g, 4.52 mmol) in dioxane/H2O (5:1, 16 mL) was added K2CO3 (2.7 g, 19 mmol), bis(tri-t-butylphosphine)palladium(0) (116 mg, 0.226 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (1.2 g, 5.88 mmol). The reaction mixture was heated to 80° C. in a sealed tube. After 1 h, the reaction was partitioned between H2O-DCM and the aqueous phase was extracted several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly: LCMS (ES) m/z 223 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([Cl:12])[CH:3]=1.[NH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(N(CC)CC)C>C(O)CCC>[C:24]([O:23][C:21]([N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][NH:13][C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([Cl:12])[CH:3]=2)[CH2:16][CH2:17]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(Cl)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 84 %

Procedure:
A solution of methyl 4,6-dichloronicotinate (1.20 g, 5.8 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (1.24 g, 5.8 mmol) and triethylamine (4.09 mL, 29.1 mmol) in n-butanol (13 mL) was heated at 120° C. for 90 minutes by microwave irradiation. The solvent was evaporated and the mixture was purified by flash chromatography on silica, eluting with ethyl acetate-hexane (1:4), to give methyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6-chloronicotinate as a colourless solid (1.87 g, 84%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[NH:3]1.C([Li])CCC.[Br:16][CH:17]([CH3:21])[C:18](Br)=[O:19].P([O-])([O-])([O-])=O>O1CCCC1.CCCCCC>[Br:16][CH:17]([CH3:21])[C:18]([N:3]1[C:2]([CH3:10])([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5][C:4]1=[O:9])=[O:19]
Reactant: CC1(C)NC(=O)OC1(C)C
Reactant: CC(Br)C(=O)Br
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(Br)C(=O)N1C(=O)OC(C)(C)C1(C)C
Reaction time: 0.08 h

Procedure:
To a solution of 4,4,5,5-tetramethyloxazolidin -2-one (0.30 g; 2.01 mmol) in tetrahydrofuran (2.5 ml), a hexane solution of 1.57 N n-butyl lithium (1.50 ml; 2.3 mmol) was added at 0° C., and after 5 minutes, 2-bromopropionyl bromide (0.54 g; 2.5 mmol) was added thereto and followed by stirring at the same temperature for 10 minutes. A phosphate buffer (pH 7) (1.1 ml) was added thereto to decompose the excess reaction agent, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous solution of sodium bicarbonate and then brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give a residue, which was purified by silica gel column chromatography (benzene→benzene:ethyl acetate=95:5) to give 3-(2'-bromopropionyl)-4,4,5,5-tetramethyloxazolidin-2-one as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1(Cl)[Cl:8].[CH3:10][O:11][P:12]([O-:16])([O:14][CH3:15])=[O:13].[Na+].C(#N)C>O>[CH3:10][O:11][P:12]([O-:16])([O:14][CH3:15])=[O:13].[CH3:1][NH+:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH:3]1[Cl:8]
Reactant: CN1CCN(C)C1(Cl)Cl
Agent: COP(=O)([O-])OC
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN1CC[NH+](C)C1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.9 %

Procedure:
3.00 g (17.75 mmol) of 1,3-dimethyl-2,2-dichloroimidazolidine and 2.63 g (17.77 mmol) of sodium dimethylphosphate are mixed with 20 ml of acetonitrile and 2 ml of water. The reaction mixture is stirred for 12 hours at room temperature, and the precipitate NaCl is subsequently filtered off. The solvent is distilled off, and the residue is dried for 6 hours under a reduced pressure of 7 Pa and at an oil-bath temperature of 70-80° C., giving 4.39 g of 1,3-dimethyl-2-chloroimidazolidinium dimethylphosphate, corresponding to a yield of 95.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[SH:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([S:18][C:14]2[N:13]([CH3:12])[CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1Sc1ccc([N+](=O)[O-])c(N)c1

Procedure:
A mixture of 2.5 G. of 2-amino-4-chloro-1-nitrobenzene, 3.4 g. of 1-methyl-2-mercapto-imidazole and 4.2 g. potassium carbonate in 20 ml. dimethylformamide is heated overnight at 110°-120° C., then cooled, and poured into water. The product is filtered off and recrystallized from aqueous methanol to give 2-amino-4-(1-methylimidazol-2-ylthio)-1-nitrobenzene.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1.[OH-].[K+].O>C(O)C>[F:13][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:3]2[CH2:2][O:22]2)[CH:11]=[C:10]([F:12])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reaction time: 1 h

Procedure:
To a 250 mL 3-neck round bottom flask equipped with magnetic stir bar, nitrogen inlet and thermocouple, is added tert-butyl (1S,2S)-3-chloro-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (IV, EXAMPLE 3, 3.5 g, 0.010 moles, 1 equivalent) followed by absolute ethanol (60 mL) and cooled to 0°. To this mixture is added potassium hydroxide (0.73 g, 0.013 moles, 1.25 equivalents) dissolved in absolute ethanol (10 mL) over 1 hr and the resulting suspension is warmed to 15-20° and stirred for 1 hr. At this time, water (100 mL) is added and the reaction contents are cooled to −5° and stirred for 30 min. The solids are collected by filtration and washed with cold water (2×25 mL) then dried under reduced pressure at 45° to give the title compound, mp=133°; NMR (DMSO-d6) δ 7.03, 3.61, 2.68-2.98 and 1.33; CMR (DMSO-d6) δ 163.72, 161.29, 155.55, 143.35, 112.65, 101.80, 78.17, 53.42, 52.71, 44.90, 36.98 and 28.36.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])=[CH:11][CH:10]=1.S(Cl)([Cl:24])=O>O>[CH3:7][O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([Cl:24])=[O:18])=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(OCCCC(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(OCCCC(=O)Cl)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Benzene (70.0 cc) and 14 0 grams of γ-(p-methoxyphenoxy)butyric acid were agitated with water cooling and 5.74 cc of thionyl chloride was added dropwise. Subsequently, the mixture was agitated for 10 minutes at an internal temperature of 60° C. After the reaction had been completed, the reaction mixture was cooled and transferred to a separate flask and the solvent and excess thionyl chloride were removed in a rotary evaporator. γ-(p-Methoxyphenoxy)butyric acid chloride was obtained as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6](Cl)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:3]=1.O.[NH3:22]>>[Cl:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:5]=[C:6]([NH2:22])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(Cl)nc(-c2ccc(Cl)c(OC)c2F)nc1Cl
Reactant: N
Solvent: O
Product: COc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1Cl
Temperature: 125 °C
Yield: 88 %

Procedure:
4,6-Dichloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-methoxy-pyrimidine (500 mg, 1.5 mmol) was suspended in ammonia saturated ethanol (10 mL) and heated in a CEM microwave at 125° C. for 30 min The mixture was poured into 15 mL water and extracted with ethyl acetate thrice. The combined organic phases were washed once with brine, dried and evaporated to give the title compound (420 mg, 88% yield: 1H NMR (DMSO-d6) δ 7.59 (dd, 1H), 7.45 (br s, 2H), 7.39 (dd, 1H), 3.91 (s, 3H), 3.76 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][S:11]([CH3:10])(=[O:13])=[O:12])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: Cc1cc(N)cc(Br)c1
Reactant: CS(=O)(=O)Cl
Product: Cc1cc(Br)cc(NS(C)(=O)=O)c1
Yield: 99.3 %

Procedure:
3-Bromo-5-(methyl)aniline (2 g, 10.75 mmol) was treated with methanesulfonyl chloride (915 μl, 11.82 mmol) according to the method described in Preparation 15b to give 2.82 g (96% yield) of the title compound. Purity 95%.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH:14]=[CH:13][C:12]=2[CH:16]=1.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>C1COCC1>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([B:21]([OH:22])[OH:20])=[CH:13][C:12]=2[CH:16]=1
Reactant: COc1ccc2occc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2oc(B(O)O)cc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
n-Butyllithium 2.5M in hexanes (5.6 mL) was added slowly to a solution of 5-methoxybenzofuran (13.5 mmol) in dry THF (30 mL) at −78° C. After 1 h stirring at −78° C., triisopropylborate (27.0 mmol) was added dropwise and the mixture was stirred for another 20 min at −78° C. The dry ice bath was removed and HCl 2N (aq. 40 mL) was added and the mixture allowed to warm to r.t. and then poured in water (50 mL). The resulting aqueous solution was extracted with ether, the organic layer was washed with brine, dried over MgSO4, filtered and concentrated under vacuum to afford the title compound as a beige powder (2.40 g). 1H NMR δ ppm 8.49 (s, 2 H) 7.45 (d, 1 H) 7.38 (s, 1 H) 7.18 (d, 1 H) 6.93 (dd, 1 H) 3.78 (s, 3 H).
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH:15]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:16][O:17]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>C(Cl)(Cl)Cl>[CH2:1]([O:13][CH2:14][CH:15]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:16][OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCCCCCCCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCCCCCOCC(CO)OCCCCCCCCCC
Yield: 63 %

Procedure:
Detritylation of 3-dodecyloxy-2-decyloxy-1 -triphenylmethoxypropane was accomplished using p-toluenesulfonic acid (0.9 g) in CHCl3 :MeOH (72 mL:36 mL) (stirred at room temperature for 48 h, added 10% sodium bicarbonate, extracted with CHCl3, dried over magnesium sulfate, and concentrated). The residue was purified by column chromatography using a gradient of hexanes:ethyl acetate (20:1 to 5:1) to give 3.5 g (63%) of pure 3-dodecyloxy-2-decyloxy-1-propanol.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18]>N1C=CC=CC=1>[C:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: c1ccncc1
Product: C=C(C)C(=O)Oc1ccc(C(=O)c2ccccc2)cc1

Procedure:
Prepared from 6.0 g of 4-hydroxybenzophenone and 4.4 ml of methacryloyl chloride in 70 ml of pyridine. Recrystallized from ethyl acetate-ethanol-water; M.P.~69.5°-70.5° C.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=O)[CH3:8])[CH3:3].[CH3:12][O:13][C:14](=[O:27])/[C:15](/[CH3:26])=[C:16](\P(OCC)(OCC)=O)/[CH3:17].[Na]>C1C=CC=CC=1.CO>[CH3:12][O:13][C:14](=[O:27])[C:15]([CH3:26])=[CH:16][CH:17]=[CH:10][CH2:9][CH:7]([CH3:8])[CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1]
Reactant: CC(C)=CCCC(C)CC=O
Reactant: CCOP(=O)(OCC)/C(C)=C(/C)C(=O)OC
Agent: [Na]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(C)=CC=CCC(C)CCC=C(C)C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
24 g of citronellal and 40 g of diethylphosphono-α-methylcrotonic acid methyl ester are dissolved in 100 ml of absolute benzene. To this solution there is added dropwise 4 g of sodium in 50 ml of absolute methanol. The mixture is stirred for 5 hours at 60°C., poured on to ice-water and extracted with diethyl ether. The ethereal solution is washed with water, then with aqueous sodium bicarbonate solution and once again with water, dried over sodium sulphate, filtered and concentrated on a rotary evaporator. After chromatography on a 30-fold amount of Kieselgel, using hexane/diethyl ether (9:1 parts by volume) as the eluant, there is obtained 2,7,11-trimethyl-2,4,10-dodecatrienoic acid methyl ester; boiling point 95°C/0.001 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[N:47][C:46]([CH:49]3[CH2:51][CH2:50]3)=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:52].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:52])=[CH:38][C:39]([C:43]6[CH:48]=[N:47][C:46]([CH:49]7[CH2:50][CH2:51]7)=[CH:45][N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2cnc(C3CC3)cn2)cc(C)c1Cl
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cnc(C7CC7)cn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-chloro-3,5-dimethyl-phenyl)-5-cyclopropyl-pyrazine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.31 min; Mass spectrum (ESI+): m/z=565 [M+H]+.