Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(CC)CC)[CH:14]=1.[OH-].[K+]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH:14]=1
Reactant: CCB(CC)c1cccnc1
Reactant: O=C1CCc2cc(Br)ccc2N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C1CCc2cc(-c3cccnc3)ccc2N1

Procedure:
To a solution of 1.0 g of 6-bromo-3,4-dihydrocarbostyril, 520 mg of 3-pyridyldiethylborane and 205 mg. of tetrakis(triphenylphosphine)palladium in 20 ml of tetrahydrofuran was added 600 mg of powdered potassium hydroxide and 114 mg of tetrabutylammonium bromide. The mixture was refluxed for 48 hours under an inert atmosphere and the solvent then removed under reduced pressure. The residue was extracted with a mixture of 10% of methanol in methylene chloride and the organic solution washed with water and dried over anhydrous sodium sulfate. The solvent was removed from the dried solution under reduced pressure, and the residue chromatographed on silica gel, eluting with 5% methanol in methylene chloride to give 6-(3-pyridyl)-3,4-dihydrocarbostyril, m.p. 180°-182° C.
Reaction SMILES: [Cl:1]C1(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl.ClCl.[Cl:14][C:15]1[C:19]([F:21])([F:20])[C:18]([Cl:23])(F)[C:17]([F:25])([F:24])[C:16]=1[Cl:26]>>[Cl:14][C:15]1[C:19]([F:21])([F:20])[C:18]([Cl:1])([Cl:23])[C:17]([F:25])([F:24])[C:16]=1[Cl:26]
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Reactant: FC1(F)C(Cl)=C(Cl)C(F)(F)C1(F)Cl
Agent: ClCl
Product: FC1(F)C(Cl)=C(Cl)C(F)(F)C1(Cl)Cl
Temperature: 0 °C
Yield: 9.7 %

Procedure:
200 g of HF were passed over 140 ml of this catalyst at 360° C. in the course of 6 hours. 102 g of hexachlorocyclopentadiene, 170 g of HF and 23 g of chlorine were then passed over at 350° C. in the course of 5 hours. The reaction gases were condensed in ice-water. 85.4 g of an organic phase which contained 60.5% of 1,2-dichloro-3,3,4,4,5,5-pentafluorocyclopent-1-ene, 23.5% of 1,2,4-trichloro-3,3,4,5,5-pentafluorocyclopent-1-ene (and isomers as in Example 1) and 9.7% of 1,2,4,4-tetrachloro-3,3,5,5-tetrafluorocyclopent-1-ene (and isomers as in Example 1) were formed. The hexachlorocyclopentadiene content in the reaction product was 0.1%.
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[O:7])=[CH:4][C:3]=1[Br:22].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][C:39]([O-:41])=[O:40].[Na+]>>[NH2:1][C:2]1[C:15]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:41][C:39](=[O:40])[CH2:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[NH:31][C:25]2[C:24]([Cl:23])=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:30])=[O:7])=[CH:4][C:3]=1[Br:22]
Reactant: Nc1c(Br)cc(C(=O)OCCCCCl)cc1CN1CCCC1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Product: Nc1c(Br)cc(C(=O)OCCCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc1CN1CCCC1

Procedure:
This compound was prepared from 4-(4-amino-3-bromo-5-pyrrolidinomethyl-benzoyloxy)-n-butyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][C:9]#[N:10])=[O:7].C(N(CC)CC)C.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>COCCOC>[O:7]=[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[CH:8]([C:25](=[O:26])[NH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]#[N:10]
Reactant: O=C=Nc1ccccc1
Reactant: N#CCC(=O)c1ccc[nH]1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1ccc[nH]1
Reaction time: 8 h

Procedure:
A solution of 3.1 g of 2-pyrroloylacetonitrile in 25 ml of glyme (ethylene glycol dimethyl ether) and 2.7 g of anhydrous triethylamine is treated with 3.0 g of phenyl isocyanate. After the moderately exothermic reaction, the mixture is let stand overnight. Most of the solvent is evaporated and the residue is treated with water and 12 ml of 10% NaOH solution. The aqueous, alkaline solution is washed with ethyl acetate and acidified with 6N HCl. The product is collected, washed with water, dried and recrystallized from ethanol, to give β-oxo-α-(phenylcarbamoyl)-β-(2-pyrrolyl)-propionitrile, m.p. 207°-209°, the compound of formula II, wherein R1 to R4 are hydrogen.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:27]3[CH2:30][CH:29]([OH:31])[CH2:28]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: OC1CNC1
Agent: Cl
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)N3CC(O)C3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and azetidin-3-ol monohydrochloride and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][Cl:9].[OH2:10]>>[ClH:9].[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][OH:10]
Reactant: Cc1nc[nH]c1CCl
Reactant: O
Agent: Cl
Product: Cc1nc[nH]c1CO
Reaction time: 4.5 h
Yield: 73 %

Procedure:
67 parts of 4-methyl-5-chloromethyl-imidazole hydrochloride are dissolved in 200 parts of water and the mixture is stirred for 4.5 hours at 50°-60° C. The water is then substantially distilled off under reduced pressure from a waterpump and the crystal slurry is recrystallized from ethanol, the solution being cooled in ice. 43.4 parts (73%) of 4-methyl-5-hydroxymethyl-imidazole hydrochloride of melting point 238°-240° C. are obtained (the melting point given in the literature is 240°-242° C., cf. A. J. Ewins, J. Chem. Soc. 99 (1911), 2052.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:29]=[O:30])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[C:20]([CH3:28])=[N:21][C:22]([O:26][CH3:27])=[N:23][C:24]=3[CH3:25])[CH2:16][CH2:17][CH2:18][N:11]21>O1CCCC1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:20]([CH3:28])=[N:21][C:22]([O:26][CH3:27])=[N:23][C:24]=4[CH3:25])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:29]([OH:30])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: CC[Mg]Br
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)n1
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.25 mL, 0.75 mmol) was added to a stirred solution of 9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (256 mg, 0.689 mmol) in tetrahydrofuran (3.5 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. The reaction was quenched by water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with ethyl acetate/diisopropyl ether to give the title compound as a colorless powder (224 mg, 0.557 mmol, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[C:5]([CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1>P(=O)(O)(O)O.O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:10][CH2:11][O:12][CH2:8]2)=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Cl)cc1CO
Agent: O=P(O)(O)O
Solvent: O
Product: Clc1ccc2c(c1)COCC2

Procedure:
2-(4-Chloro-6-hydroxymethylphenyl)ethanol (45 g) was dissolved in orthophosphoric acid (200 ml) and the solution was heated at 100° for 2 hr. The cooled reaction mixture was diluted with water (1 liter), extracted with ether (4×200 ml) and the combined ether extract was washed with sodium hydrogen carbonate solution (10% w/v 2×200 ml) and water (200 ml) and then dried (magnesium sulphate) and decolourised with activated carbon and evaporated in vacuo to afford 7-chloroisochroman as an oil, (30 g), characterised by its nmr spectrum.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[S:17][C:16]([NH:18]C(OC(C)(C)C)=O)=[N:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[S:17][C:16]([NH2:18])=[N:15][CH:14]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(Cc2cnc(NC(=O)OC(C)(C)C)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCN(Cc2cnc(N)s2)CC1
Reaction time: 12 h
Yield: 84 %

Procedure:
To a stirred solution of 1-(2-tert-Butoxycarbonylamino-thiazol-5-ylmethyl)-piperidine-4-carboxylic acid ethyl ester (0.98 g) in 2 ml of DCM, 10 ml TFA was added at room temperature and reaction mixture was stirred for 12 hrs. After completion of reaction TFA was removed under reduced pressure. The residue was taken in ethyl acetate (25 ml), and neutralized by aqueous saturated sodium bicarbonate. Organic layer was separated and aqueous layer was further extracted with ethyl acetate (25 ml). Combined organic layer was washed with water (25 ml) followed by brine (25 ml). Organic layer was dried over anhydrous sodium sulfate, sodium sulfate was filtered and washed with ethyl acetate (10 ml) and solvent was evaporated using rotavapour to get required product as solid which was dried under vacuum (2 mbar) for 2 hours. The crude yellow solid material was used for the next step with out any further purification, (0.6 g, and 84% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8].ClC1C=C2C(N=CC=C2)=C2C=1C=CC=N2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:36]1[CH:37]=[CH:38][C:39]([C:42]([F:45])([F:44])[F:43])=[N:40][CH:41]=1.[OH-].[NH4+].O>CN1CCCC1=O>[F:43][C:42]([F:45])([F:44])[C:39]1[N:40]=[CH:41][C:36]([N:3]2[CH:4]=[CH:5][S:1]/[C:2]/2=[N:6]\[C:7]([N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:8])=[CH:37][CH:38]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: O=C(Nc1nccs1)N1CCCC1
Agent: Clc1cc2cccnc2c2ncccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(/N=c1\sccn1-c1ccc(C(F)(F)F)nc1)N1CCCC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
In a 4 mL vial charged with a stir bar, N-1,3-thiazol-2-ylpyrrolidine-1-carboxamide (46 mg, 0.23 mmol, Example 32A) was added, followed by copper(I) trifluoromethanesulfonate benzene complex (30 mg, 0.05 mmol), 5-chloro-1,10-phenanthroline (23 mg, 0.09 mmol) and cesium carbonate (100 mg, 0.3 mmol). A loose cap with septum was placed on the vial and the vial was placed under vacuum in a vacuum oven for 30 minutes. The solid mixture was purged with nitrogen gas a couple of times. Then 5-bromo-2-(trifluoromethyl)pyridine (68 mg, 0.3 mmol) dissolved in 1-methyl-2-pyrrolidinone (1.0 mL) was added to the solid mixture. The vial was capped and placed on a heater/stirrer and heated to 120° C. overnight. Then a 1 mL solution of concentrated ammonium hydroxide/water (1:2) was added. The reaction was filtered and concentrated to dryness. The residue was purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:22][C:20]([F:21])([F:23])[C:17]1[CH:18]=[CH:19][C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)=[N:15][CH:16]=1
Reactant: N#Cc1ccc(C(F)(F)F)cn1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccc(C(F)(F)F)cn2)sc2ccccc12
Yield: 22.5 %

Procedure:
A mixture of methyl thiosalicylate (0.43 g, 2.6 mmol), 2-cyano-5-trifluoromethylpyridine (0.44 g, 2.6 mmol), triethylamine (0.60 ml, 3.8 mmol) and toluene (30 ml) was refluxed for 48 hrs as described in Example 1. The solvent was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the titled compound (0.18 g, 23%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>C(Cl)Cl>[CH3:21][S:22]([O:13][CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:11][CH3:12])(=[O:24])=[O:23]
Reactant: CCC(O)Cc1cccc(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(Cc1cccc(OC)c1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
1-[3-(Methyloxy)phenyl]-2-butanol (51) (3.50 g, 19.4 mmol) was dissolved in CH2Cl2 (90 mL). To this solution was added Et3N (5.4 mL, 38.8 mmol) followed by catalytic amount of N,N-dimethylaminopyridine (DMAP). The mixture was cooled in an ice bath, methanesulfonyl chloride (2.3 mL, 29.1 mmol) was added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature overnight. Water was added to the mixture, CH2Cl2 layer was separated. The aqueous layer was further extracted with CH2Cl2 (50 mL). The extracts were combined and washed with brine, (Na2SO4), filtered, and the filtrate was concentrated to give the crude product as a brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (4:1) to give 4.66 g (94%) of the title compound (52) as a yellow oil, which solidified upon freezing. 1H NMR (400 MHz, CDCl3): δ 1.03 (t, J=7.5 Hz, 3H), 1.70-1.85 (m, 2H), 2.53 (s, 3H), 2.94 (d, J=6.7 Hz, 2H), 3.80 (s, 3H), 4.70-4.80 (m, 1H), 6.75-6.85 (m, 3H), 7.20-7.25 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[CH:5]=[CH:6][N:7]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5-bromo-7-azaindole (67, 1.5 g, 7.6 mmol) in N,N-dimethylformamide (20 mL) were added sodium hydride (60% in mineral oil, 0.27 g, 11.0 mmol) and triisopropylsilyl chloride (2.6 mL, 12.0 mmol), under an atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give the compound (68, 1.6 g, 59%). MS (ESI) [M+H+]+=352.3.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](OC)=[O:18])=[CH:11][N:10]=1>C1COCC1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][N:10]=1
Reactant: COC(=O)CCc1ccc(OC)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CCCO)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a suspension of 0.56 g (1.1 eq) of LAH in 50 ml of dry THF at 5° C. under nitrogen was added a solution of 2.7 g (13.5 mmol) of methyl 3-(2-methoxy-pyridin-5-yl)-propionate in THF and the reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with 0.6 ml of water, 0.6 ml of 10% NaOH, and 1.8 ml of water successively. The mixture was filtered and the filtrate was concentrated in vacuo to yield 2.0 g (87%) of 2-methoxy-5-(3-hydroxypropyl)-pyridine as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=[C:17]([OH:30])[CH:16]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2].[N:33]1([CH2:39][CH2:40][CH2:41]O)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:18]=[C:17]([O:30][CH2:41][CH2:40][CH2:39][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:16]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2]
Reactant: OCCCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(SCc2cc(O)cc(C#CCc3ccccc3)c2)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(SCc2cc(C#CCc3ccccc3)cc(OCCCN3CCOCC3)c2)cc1C
Reaction time: 1 h

Procedure:
{4-[3-Hydroxy-5-(3-phenyl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.45 mmol), 3-morpholin-4-yl-propan-1-ol (97.6 mg; 0.67 mmol), tributylphosphine (0.27 mg; 1.34 mmol) and 1,1′-(Azodicarbonyl)dipiperidine (0.34 g; 1.34 mmol) were dissolved in THF (20 mL) in a dried reaction flask under an atmosphere of nitrogen. The reaction mixture was stirred for 1 h and purified by prep. HPLC (method A). Yield: 200 mg. HPLC-MS: m/z: 574.3 (M+H); Rt: 2.07 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=4)[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[F:33][C:30]1[CH:31]=[C:32]2[C:27]([CH2:26][CH2:25][N:24]2[CH:21]2[CH2:22][CH2:23][N:18]([C:15]3[N:16]=[N:17][C:12]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[CH:13][CH:14]=3)[CH2:19][CH2:20]2)=[CH:28][CH:29]=1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cc1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, STEP 4, reacting 4-methylphenylboronic acid and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)CCCC1.[C:28]([CH:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29].C(OC(=O)CSC1SC(N)=NC=1)C>>[C:28]([C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)C1CCC(NC2CCCC2)CC1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via (4-tert-butyl-cyclohexyl)-cyclopentyl-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][N:5]=[C:4]([NH2:17])[N:3]=1.Br[C:19]1[CH:20]=[CH:21][C:22]([Cl:35])=[C:23]([NH:25][S:26]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)(=[O:28])=[O:27])[CH:24]=1>>[NH2:17][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([C:19]2[CH:20]=[CH:21][C:22]([Cl:35])=[C:23]([NH:25][S:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)(=[O:28])=[O:27])[CH:24]=2)=[CH:6][N:5]=1
Reactant: O=S(=O)(Nc1cc(Br)ccc1Cl)c1cccnc1
Reactant: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Product: Cc1nc(N)ncc1-c1ccc(Cl)c(NS(=O)(=O)c2cccnc2)c1

Procedure:
This compound is prepared as described for Example 3-25 (step 2) from 4-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-pyrimidin-2-ylamine (Intermediate G) and pyridine-3-sulfonic acid [5-bromo-2-chloro-phenyl]-amide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:15][C@H:14]([O:16][CH3:17])[C@@H:13]2[C@@H:11]1[O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-:18].[Na+].O>C(O)CO>[CH2:1]([O:8][CH2:9][C@H:10]1[O:15][C@H:14]([O:16][CH3:17])[C@@H:13]([OH:12])[C@@H:11]1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@H]2O[C@H]12
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](F)[C@@H]1O
Temperature: 200 °C
Reaction time: 4 h
Yield: 32.9 %

Procedure:
Compound 35.7 (2.2 g, 9.32 mmol) was dissolved in 10 mL ethyleneglycol, and then treated with NaF (2.2 g), KHF2 (2.2 g). The mixture was stirred at 200° C. for 4 h, cooled to r.t. and then treated with water (150 mL). The aqueous mixture was extracted twice with 200 mL EtOAc. The organic extracts were combined, dried over MgSO4, filtered and concentrated down under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 20-100% EtOAc in hexane to give compound 35.8 (786 mg, 33% yield).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:10](=[O:12])[CH:11]=1.[Cl:28]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>ClC(Cl)C>[Cl:28][C:11]1[C:10](=[O:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[CH:8]=[N:7][C:6]=1[O:5][CH2:4][C:3]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)cc1=O
Agent: O=C(O)C(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Temperature: 65 °C
Yield: 47.9 %

Procedure:
3-[4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 2) (6.62 g, 17.8 mmol), N-chlorosuccinimide (2.85 g, 21.3 mmol), and dichloroacetic acid (4 mL) are combined in dichloroethane (50 mL) and heated at 65° C. for 65 h. The reaction mixture is cooled to 0° C. and the precipitate is filtered, washed with cold dichloroethane, and dried in vacuo. Product obtained as a white solid (3.47 g, 48%). Used without further purification. 1H NMR (CD3OD/300 MHz) δ8.32 (s, 1H), 8.09 (m, 1H), 7.94 (s, 1H), 7.62 (q, 1H, J=8.4 Hz), 7.54 (d, 1H, J=7.8 Hz), 7.03 (m, 2H), 5.61 (s, 2H), 2.21 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:28][OH:29].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[N:28][OH:29])=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Reactant: NO
Agent: Cl
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=NO
Yield: 91 %

Procedure:
A solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde (i.e. the product of Step 1, 5.00 g), hydroxylamine hydrochloride (1.30 g) and concentrated hydrochloric acid (1 mL, 1.05 g) in MeOH (methanol) (37.5 mL) was stirred at 70° C. for 4 h. After cooling, the mixture was freed from all volatiles by evaporation and partitioned between MTBE and water. The organic layer was separated and dried. Chromatography over silica gel yielded the title compound (4.70 g, 91%).