Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].B(F)(F)F.CCOCC.[CH3:15][CH:16]([CH3:22])[CH2:17][C:18](=[CH2:21])[CH:19]=[CH2:20].[OH-].[Na+]>C(Cl)Cl>[CH2:17]([C:18]1[CH2:21][CH:3]([CH3:4])[CH:2]([CH:1]=[O:5])[CH2:20][CH:19]=1)[CH:16]([CH3:22])[CH3:15]
Reactant: C/C=C/C=O
Reactant: C=CC(=C)CC(C)C
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)CC1=CCC(C=O)C(C)C1
Temperature: -30 °C
Yield: 94 %

Procedure:
Crotonaldehyde cis/trans (16 g, 230 mmol) was dissolved in methylene chloride and cooled to −30° C. With stirring, and under nitrogen, BF3.OEt2 (3.6 ml, 29 mmol) was added gradually. A solution of 5-methyl-3-methylenehex-1-ene 2 (21 g, 191 mmol) in methylene chloride (50 ml) was then added at −30° C. over 1 h and the pot allowed to warm to −20° C. The solution was stirred at this temperature for a further 1.5 h before being poured onto 2M NaOH (100 ml). After brief agitation the phases were separated and the lower organic phase washed with water (100 ml) and brine (2×100 ml). The combined aqueous phases were extracted with MTBE (150 ml), phase separated and the upper organic part washed to neutral with brine. The organic phases were combined, dried (Na2SO4) and concentrated in vacuo to afford 3b as a pale yellow oil (33 g, 94% yield; 98% pure). The product was used in the next steps without further purification.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:13][CH:14]([C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:22][CH:23]=1)[C:15]([O:17][CH3:18])=[O:16])([CH3:12])([CH3:11])[CH3:10].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:23]1[S:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:20][C:19]=1[CH:14]([O:13][C:9]([CH3:12])([CH3:10])[CH3:11])[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C(OC(C)(C)C)c1csc(-c2ccccc2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(OC(C)(C)C)c1nc(-c2ccccc2)sc1Br
Temperature: 70 °C
Yield: 78 %

Procedure:
Under a nitrogen atmosphere, N-bromosuccinimide (108 mg, 0.6 mmol) was added to a solution of methyl 2-(tert-butoxy)-2-(2-phenyl-1,3-thiazol-4-yl)acetate (6b) (30 mg, 0.1 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was warmed at 70° C. for 3 hours and ethyl acetate (20 mL) was then added. The organic layer was washed with water (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to afford the desired product (6c) as a yellow oil (30 mg, 0.078 mmol, 78%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1([CH2:17][CH:18]2[O:22][CH2:21][CH2:20][O:19]2)[CH2:14][CH:13]2[CH2:15][CH2:16][CH:10]1[CH2:11][CH2:12]2)#[N:8].O.[OH-].[Na+]>CCOCC>[NH2:8][CH2:7][C:9]1([CH2:17][CH:18]2[O:19][CH2:20][CH2:21][O:22]2)[CH2:14][CH:13]2[CH2:12][CH2:11][CH:10]1[CH2:16][CH2:15]2
Reactant: N#CC1(CC2OCCO2)CC2CCC1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NCC1(CC2OCCO2)CC2CCC1CC2
Yield: 73 %

Procedure:
3.7 g of lithium aluminum hydride are suspended in 60 ml of dry ether; 7.4 g of 2-cyano-2-(1,3-dioxolan-2-yl)methylbicyclo[2.2.2]octane, dissolved in 80 ml of dry ether, are added dropwise so that gentle boiling is maintained. The mixture is then boiled under reflux for 2 hours, then cooled in ice and, in sequence, 2.1 ml of water, 2.1 ml of 1N sodium hydroxide solution and 15 ml of water are added dropwise. The aluminum hydroxide is filtered off with suction and thoroughly washed with ether. 5.5 g of the title compound are obtained as a colorless oil.
Reaction SMILES: [CH2:1]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[N:39]=[C:40]=[O:41]>CCCCCC>[CH2:21]([N:20]([CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:40]([NH:39][C:33]2[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=2[F:31])=[O:41])[CH:14]=1)[C:40]([NH:39][C:33]1[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=1[F:31])=[O:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCCCCNCc1cccc(CNCCCCCCCCCC)c1
Solvent: CCCCCC
Product: CCCCCCCCCCN(Cc1cccc(CN(CCCCCCCCCC)C(=O)Nc2ccc(F)cc2F)c1)C(=O)Nc1ccc(F)cc1F
Reaction time: 2 h
Yield: 51.6 %

Procedure:
To a solution of 833 mg N,N'-didecyl-m-xylylenediamine in 20 ml n-hexane, was added dropwise with stirring 5 ml of a n-hexane solution containing 620 mg 2,4-difluorophenyl isocyanate under ice cooling. Stirring was continued at room temperature for two hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography, giving 750 mg of 1,3-bis[[1-decyl-3-(2,4-difluorophenyl)ureido]methyl]benzene.
Reaction SMILES: [CH2:1]([O:3]C(=O)CC1C=CC(N)=CC=1)C.C1(C#N)CCCC1.[CH2:21]([O:23][C:24](=[O:40])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([C:33]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])[CH:27]=1)[CH3:22].[NH2:41][C:42]1[S:43][CH:44]=[CH:45][N:46]=1>>[CH2:21]([O:23][C:24](=[O:40])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([C:33]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])[CH:27]=1)[CH3:22].[CH2:21]([O:23][C:24](=[O:40])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:1]([NH:41][C:42]2[S:43][CH:44]=[CH:45][N:46]=2)=[O:3])=[C:28]([C:33]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])[CH:27]=1)[CH3:22]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Nc1nccs1
Agent: CCOC(=O)Cc1ccc(N)c(C(=O)C2CCCC2)c1
Agent: N#CC1CCCC1
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2nccs2)c(C(=O)C2CCCC2)c1

Procedure:
(4-Amino-3-cyclopentanecarbonylphenyl)acetic acid ethyl ester (2.7 g) is prepared from (4-aminophenyl)acetic acid ethyl ester (18.0 g, 0.1 mol) and cyclopentanecarbonitrile (9.5 g, 0.1 mol) following the general procedure I. [3-Cyclopentanecarbonyl-4-(3-thiazol-2-yl-ureido)phenyl]acetic acid ethyl ester (140 mg) is prepared from (4-amino-3-cyclopentanecarbonylphenyl)acetic acid ethyl ester (138 mg, 0.5 mmol) and 2-aminothiazole (0.060 g, 0.6 mmol) following the general procedure D.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)C>CO.[OH-].[Na+]>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C:5]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)(=[O:17])=[O:16])([CH3:14])[C:4]([OH:26])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(Br)cc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C(C)(Cc2ccc(Br)cc2)C(=O)O)cc1

Procedure:
3-(4-Bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid was prepared starting from 3-(4-bromo-phenyl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-propionic acid ethyl ester (4.0 g, 9.0 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 3.0 g, 78%. Low melting solid. MS: 413 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10]([S:12][CH3:13])[C:9]([C:14]#[N:15])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:16].[Na+].OO.O>CS(C)=O>[C:1]([NH:5][C:6]1[N:11]=[C:10]([S:12][CH3:13])[C:9]([C:14]([NH2:15])=[O:16])=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: CSc1nc(NC(C)(C)C)ncc1C#N
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1nc(NC(C)(C)C)ncc1C(N)=O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
To a stirring solution of 2-(tert-butylamino)-4-(methylthio)pyrimidine-5-carbonitrile (0.6 g, 2.70 mmol) in DMSO (7 mL) was added 6M aqueous sodium hydroxide solution (2.249 mL, 13.49 mmol) and 30% aqueous hydrogen peroxide (1.530 mL, 13.49 mmol) solution at 0° C. Then the mixture was stirred at 50° C. for 15 min. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate under reduced pressure gave the crude product, which was purified by silica gel column chromatography (5% methanol in DCM) to afford 2-(tert-butylamino)-4-(methylthio)pyrimidine-5-carboxamide (0.462 g, 1.922 mmol, 71.2% yield) as a white solid. MS (ESI) m/z 241.0 [M+1]+.
Reaction SMILES: CC1(C)COB([C:8]2[CH:29]=[CH:28][C:11]3[C:12]4[N:13]=[C:14]([C:20]5[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=5)[S:15][C:16]=4[CH2:17][CH2:18][O:19][C:10]=3[CH:9]=2)OC1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41](=[O:44])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].[Cl-].C(C1C=CC=C(C(C)C)C=1[N+]1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C=1)(C)C.[F-].[Cs+]>C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni]>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]([OH:44])([C:8]2[CH:29]=[CH:28][C:11]3[C:12]4[N:13]=[C:14]([C:20]5[N:21]([CH:25]([CH3:26])[CH3:27])[N:22]=[CH:23][N:24]=5)[S:15][C:16]=4[CH2:17][CH2:18][O:19][C:10]=3[CH:9]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(B3OCC(C)(C)CO3)ccc1-2
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Agent: CC(C)c1cccc(C(C)C)c1-n1cc[n+](-c2c(C(C)C)cccc2C(C)C)c1
Solvent: C1=CCCC=CCC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)ccc1-2
Temperature: 80 °C
Yield: 63 %

Procedure:
8-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (200 mg, 0.47 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (63 mg, 0.31 mmol), bis(1,5-cyclooctadiene)nickel(0) (17 mg, 0.063 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (27 mg, 0.063 mmol) and cesium fluoride (81 mg, 0.53 mmol) were loaded into a reaction vial, which was then flushed with nitrogen. Dry toluene (3 mL) was then added and nitrogen was bubbled through the mixture for 15 min. before heating at 80° C. for 30 min. The reaction mixture was combined with a mixture from a similar reaction (same quantities of boronate ester and oxo-piperidine, half-quantities of nickel and imidazolium catalysts, heated for 19.5 h) and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium bicarbonate followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 20-70% ethyl acetate in cyclohexane) to give 4-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (100 mg). LCMS RT=4.73, [M+H]+=512.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:26][C@H:25]([C@@H:27]([CH2:36][O:37]C(=O)C)[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:7]1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)C.[O-]CC.[Na+].C(O)(=O)C>C(O)C>[C:10]1([CH2:9][O:8][C@H:7]2[C@H:16]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:25]([C@@H:27]([CH2:36][OH:37])[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:26][C@@H:6]2[CH2:5][OH:4])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)OC[C@@H](OCc1ccccc1)[C@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: OC[C@@H](OCc1ccccc1)[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A solution of 485 mg of 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-glycero-D-manno-heptitol 1,7-diacetate in 2 ml of ethanol was treated with 183 μl of an ethanolic solution of sodium ethoxide (2.4N). After 1 hour, 150 μl of glacial acetic acid was added and the mixture evaporated. The residue was taken up in ether, washed with saturated aqueous sodium bicarbonate and brine, dried and evaporated. Flash chromatography, eluting with hexane:ethyl acetate (1:1), gave 290 mg of the desired compound.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH2:19]([NH:26][C:27](=[O:33])[CH:28]([CH3:32])[C:29](O)=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][C:27](=[O:33])[CH:28]([CH3:32])[C:29]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C(=O)O)C(=O)NCc1ccccc1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: CC(C(=O)NCc1ccccc1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=428.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-benzyl-2-methyl-malonamic acid.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:6][C:5]([CH:24]=[CH2:25])=[CH:4][N:3]=1.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[N:31][CH:32]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>C1COCC1>[CH3:34][O:33][C:30]1[N:31]=[CH:32][C:27]([NH:26][C:2]2[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][N:12]4[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:6][C:5]([CH:24]=[CH2:25])=[CH:4][N:3]=2)=[CH:28][CH:29]=1
Reactant: C=Cc1cnc(F)c(-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Reaction time: 0.58 h
Yield: 31.2 %

Procedure:
6-(2-Fluoro-5-vinylpyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1.007 g, 2.967 mmol) and 5-amino-2-methoxypyridine (0.369 g, 2.97 mmol) were dissolved in THF (25 mL) and the reaction flask was cooled in an ice water bath. Then, LiHMDS (Aldrich, St. Louis, Mo., 1.0 M in THF, 9.0 mL, 9.0 mmol) was added via syringe, and the reaction was stirred under nitrogen for 35 minutes. Then, it was poured into water (50 mL), and the layers were separated. The aqueous phase was extracted with DCM, and the organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (40:1 DCM/2N ammonia in MeOH to 30:1 DCM/2N ammonia in MeOH) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-vinylpyridin-2-amine (410.3 mg, 85% purity, 20% yield over 2 steps). MS (ESI pos. ion) m/z 444 (M+H)+.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:25]CC)=[O:24])[CH:13]=[C:14]([Cl:21])[C:15]=3[O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:7]=[CH:6][C:5]=12.CO.O.O[Li].O>C1COCC1>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([OH:25])=[O:24])[CH:13]=[C:14]([Cl:21])[C:15]=3[O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC2CC2)c(-c2ccc3nsnc3c2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(OCC2CC2)c(-c2ccc3nsnc3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a stirred solution of ethyl 2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.22 g, 0.479 mmol) in a mixture of THF (5 mL), methanol (5 mL) and water (2 mL) was added LiOH.H2O (60.3 mg, 1.438 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography to afford 2-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methyl pentanoic acid (105 mg, 50.0%) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 8.18 (s, 1H), 8.03 (d, 1H), 7.96 (d, 1H), 7.42 (s, 1H), 7.18 (s, 1H), 3.68 (t, 1H), 3.43 (d, 2H), 2.00 (m, 1H), 1.70 (m, 1H), 1.58 (m, 1H), 0.98 (d, 6H), 0.88 (m, 1H), 0.38 (d, 2H), 0.0 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([C:27](=[O:29])[CH3:28])[CH2:25][CH3:26])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2].[CH3:31][Si](C)(C)[N-][Si](C)(C)C.[Na+].IC.CCOC(C)=O>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:27](=[O:29])[CH3:28])[CH2:25][CH3:26])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:31])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)c1cc(Cl)cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)c1
Reaction time: 0.08 h

Procedure:
To a solution of {2′-[(acetyl-ethyl-amino)-methyl]-5-chloro-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester (0.070 g, 0.17 mmol) in THF at −78° C. under N2 was added sodium hexamethyldisilazide (1 M in THF; 0.20 mL, 0.20 mmol), and the mixture was stirred for 5 minutes. Iodomethane (0.01 mL, 0.20 mmol) was then added, and the reaction was stirred at −78° C. for 30 minutes. Once no starting material was seen by analytical LCMS, the mixture was worked-up with EtOAc and H2O, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[O:24])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14](C)(C)C)=[O:12])[CH2:7][CH2:6]1.Cl.CCN(CC)CC.ClC(OC)=O>CO.C(Cl)Cl>[F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[O:24])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1
Reactant: Cc1cc(NC(=O)Nc2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2F)ccn1
Agent: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)N1CCN(Cc2cccc(NC(=O)Nc3ccnc(C)c3)c2F)CC1
Reaction time: 1 h
Yield: 37.1 %

Procedure:
To a solution of tert-butyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)piperazine-1-carboxylate (600 mg, 1.35 mmol, 1.0 equiv) in MeOH (3 mL) was added HCl (4N in dioxane, 3 mL, 12 mmol, 8.9 equiv). After 1 h, the solvent was removed in vacuo. To this residue was added DCM (10 mL) and Et3N (875 μL, 6.28 mmol, 4.65 equiv), and the resulting solution was divided into two equal parts. To the resulting solution was added methyl chloroformate (75 μL, 0.95 mmol, equiv) dropwise by syringe. After 30 min, the reaction was quenched by the addition of aq. satd. NaHCO3. The reaction was diluted with EtOAc, and washed twice with aq. satd. NaHCO3 and once with brine. The solution was then dried over sodium sulfate, filtered and concentrated in vacuo. Purification by reverse phase preparative HPLC provided methyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)piperazine-1-carboxylate (201.3 mg, 77%). LCMS m/z (APCI)=402.2 (M+H). LCMS m/z (APCI)=402.2 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1.[CH2:14](SSCC=C)[CH:15]=C.IC1C(C2C=NC=CC=2)=NNC=1>C(OCC)(=O)C>[CH2:1]([S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1)[CH:14]=[CH2:15]
Reactant: CSc1c[nH]nc1-c1cccnc1
Reactant: C=CCSSCC=C
Agent: Ic1c[nH]nc1-c1cccnc1
Solvent: CCOC(C)=O
Product: C=CCSc1c[nH]nc1-c1cccnc1
Yield: 27 %

Procedure:
Compound 21Q was prepared following the procedure as described for the synthesis of compound 21A (see Scheme 3) using 3-allyldisulfanyl-propene as the disulfide and 3-(4-iodo-1H-pyrazol-3-yl)-pyridine (compound 20B). (conditions flash chromatography (ethyl acetate)) Yield: 27%. (oil). 1H-NMR (200 MHz, CDCl3): δ 9.20 (d, J=2 Hz, 1H), 8.60 (dd, J=5 Hz, 2 Hz, 1H), 8.29 (dt, J=8 Hz, 2 Hz, 1H), 7.70 (s, 1H), 7.40-7.36 (m, 1H), 5.77-5.66 (m, 1H), 4.94 (bdd, J=11 Hz, 1 Hz, 1H), 4.83 (bdd, J=17 Hz, 1 Hz, 1H), 3.19 (bd, J=8 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([O:13]CC)=[O:12].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+].Cl>CC#N.O.CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCO
Product: O=C(O)COc1cccc(F)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 3-fluorophenol (100 mg, 0.893 mmol) in MeCN (5 mL) was added ethyl bromoacetate (222 mg, 1.34 mmol) and K2CO3 (369 mg, 2.68 mmol). The mixture was stirred at 80° C. for 4 hours. The mixture was then filtered and the filtrate concentrated. NaOH (71 mg, 1.79 mmol) and water:EtOH (1:1, 10 mL) was added to the residue and the mixture stirred at 50° C. for 4 hours. The mixture was acidified by adding 1M HCl, and then extracted with ethyl acetate (2×30 mL). The combined extracts were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was directly for the next step. LCMS (m/z): 171.0 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:27])([C:19]2[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[CH:5][CH:4]=1.Br.[K+].[Br-].S([O-])([O-])=O.[Na+].[Na+].CBr>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:27])([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(P(=O)(c2ccc(OC)cc2)c2cc(C)c(C)cc2C)cc1
Agent: Br
Agent: CBr
Agent: O=S([O-])[O-]
Product: Cc1cc(C)c(P(=O)(c2ccc(O)cc2)c2ccc(O)cc2)cc1C
Temperature: 118 °C
Yield: 68.9 %

Procedure:
A reaction flask containing the bis(4-methoxyphenyl)-2,4,5-trimethylphenylphosphine oxide mixture (443.7 g) was charged with 48% aq. HBr (934 mL) and KBr (59.5 g). The flask was fitted with a sodium sulfite scrubber for containment of methyl bromide. The reaction mixture was heated to reflux (118° C.) and maintained at reflux until complete based on HPLC analysis. The molten product was worked up to give 283.3 g of bis(4-hydroxyphenyl)-2,4,5-trimethylphenylphosphine oxide mixture as a cream solid (68.9% yield). The ratio of products in the mixture based on 31P NMR was 39% tris(4-hydroxyphenyl)phosphine oxide, 49% bis(4-hydroxyphenyl)-2,4,5-trimethylphenylphosphine oxide, 11% di-2,4,5-trimethylphenyl-4-hydroxyphenyl-phosphine oxide, and 1% tris(2,4,5-trimethylphenyl)phosphine oxide.