Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[N:17][CH:18]=1.C(N(CC)C(C)C)(C)C>C(COC)OC.O.[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>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[N:17][CH:18]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1ccc(CBr)cn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Cc2cccc(F)c2)cn1
Yield: 264.2 %

Procedure:
A mixture of 3-fluorophenylboronic acid (0.319 g; 2.28 mmol), methyl 5-(bromomethyl)picolinate (0.350 g; 0.230 mmol), tetrakis-(triphenylphosphine)-palladium(0) (0.175; 0.152 mmol) and N,N diisopropylethylamine (0.524 g; 3.04 mmol) in dimethoxyethane (9 mL) and water (3 mL) was irradiated in a microwave oven at 130° C. for 20 minutes. The resulting solution was partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichlomethane) to afford 0.149 g (40%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[OH-].[CH2:24]([N+:28]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>N1C=CC=CC=1>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([O:9][C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([O-:8])[CH:4]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:20])[CH3:21].[CH2:37]([N+:28]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:38][CH2:39][CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)[nH]cc2Cl)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc([O-])ncc2Cl)CC1
Temperature: 80 °C

Procedure:
A one liter round bottom flask was charged with t-butyl 4-(5-chloro-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (69.2 g, 210 mmol) and pyridine (421 mL). The slurry was heated to 80° C. until all of the material dissolved to form a clear solution. At this temperature, tetrabutylammonium hydroxide solution (152 mL, 232 mmol) was added. The mixture was concentrated in vacuo and the residual water was azeotropically removed with toluene (3×300 ml). The residue was dried under high vacuum for 12 hours to give a wet solid which was used directly in the next reaction. 1H-NMR (CDCl3, 400 MHz) δ 7.65 (s, 1H), 5.83 (s, 1H), 4.40-4.60 (m, 1H), 3.55-3.75 (m, 2H), 3.20-3.46 (m, 10H), 1.72-2.0 (m, 4H); 1.55-1.72 (m, 8H), 1.30-1.55 (m, 17H), 1.0 (t, 12H, J=7.4 Hz); Anal. Calcd for C31H56ClN3O4.0.76H2O: C, 63.76; H, 9.93; N, 7.20; Cl, 6.07. Found: C, 63.76; H, 9.87; N, 7.09; Cl, 6.21.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[O:11][C:10](=[O:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:9][C:10](=[O:19])[O:11]2)=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(-c3cccc(F)c3)cc(=O)oc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1cc(-c2cccc(F)c2)c2ccc(CBr)cc2o1
Reaction time: 8 h

Procedure:
To a solution of 4-(3-fluorophenyl)-7-methyl-2H-chromen-2-one (1.25 g, 4.9 mmol) in carbontetrachloride (30 mL), N-bromosuccinimide (963 mg, 5.41 mmol) and benzoylperoxide (60 mg, 0.25 mmol) were added. The reaction was then stirred overnight at reflux. After cooling, the reaction mixture was concentrated under reduced pressure. The crude residue obtained was purified on a short column of silica gel (eluting with CH2Cl2). The filtrate was concentrated and the solid obtained was swished in a mixture of CH2Cl2/hexanes. The title product was collected by filtration. 1H NMR (400 MHz, acetone-d6): 7.72-7.6 (m, 1H), 7.55 (s, 1H), 7.47 (s, 1H), 7.45-7.3 (m, 4H), 6.4 (s, 1H), 4.78 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:44]([O:43][C:42]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1)=[O:48])([CH3:47])([CH3:46])[CH3:45]
Reactant: CCOC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCCCCNC(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 65 °C
Yield: 55.9 %

Procedure:
To a solution of ethyl 4-(4-(4-hydroxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1.5 g) in DMF (8 mL) was added tert-butyl 6-bromohexylcarbamate (1.1 g) and K2CO3 (0.9 g). The mixture was heated to 65° C. for 16 hours. After cooling to room temperature, the mixture was diluted with EtOAc (250 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified by recrystallization in MeOH to give ethyl 4-(4-(4-(6-(tert-butoxycarbonylamino)hexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1.2 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:7][N:6]=1)=[O:4].O.[Li+].[OH-].Cl>C1COCC1>[F:19][C:15]1[CH:14]=[C:13]([C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C#Cc2cccc(F)c2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C#Cc2cccc(F)c2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
(1.9 g, 7.44 mmol) 5-(3-Fluoro-phenylethynyl)-pyridine-2-carboxylic acid methyl ester (Example 1, step 1) was dissolved in THF (30 ml) and water (30 ml) and LiOH (357 mg, 24.9 mmol, 2 equiv.) was added at room temperature. The mixture was stirred for 16 hours at room temperature. The reaction mixture was acidified with 4N HCl to pH 2.5 and THF was evaporated to form a yellow suspension. The suspension was cooled to 0-5° C. and filtered. The crystals were washed with cold water and evaporated to dryness. The desired 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid (1.71 g, 95% yield) was obtained as a light yellow solid, MS: m/e=239.9 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)Cl.N1C=CC=CC=1.[C:26](Cl)(=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30]>O>[C:26]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCC(=O)Cl
Reactant: CCCCCOc1cc(C(=O)O)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCOc1cc(C(=O)O)ccc1NC(=O)CCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
4-Amino-3-pentyloxybenzoic acid (200 mg, 0.90 mmol), methylene chloride (5 ml) and pyridine (0.081 ml, 1.0 mmol) were mixed, and valeryl chloride (0.11 ml, 0.90 mmol) was added to this solution. The mixture was stirred at room temperature for 0.5 hour. Water was added to the reaction mixture, and the aqueous layer was extracted 3 times with ethyl acetate (5 ml). The organic layers were combined, washed with saturated brine (10 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained crude crystals were washed with hexane to give 4-pentanoylamino-3-pentyloxybenzoic acid (109.5 mg, 400%) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:28]COCC>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[S:11][C:12]3[C:13](=[CH:14][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][CH:17]=3)[CH2:28][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(Sc2ccc(C(C)(C)C)cc2)cc1
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1S2
Yield: 72 %

Procedure:
The red oil obtained as described above from 12 g of bis-(4-t-butylphenyl)-sulfide was dissolved in 100 mL of dry ether, and the solution added dropwise over 15 min. to a suspension of 2.5 g of lithium aluminum hydride in 100 mL of dry ether while cooling in an ice bath. The mixture was refluxed for 3 hours, cooled and excess hydride destroyed by means of saturated ammonium chloride solution. The ether layer was washed with H2O and saturated NaCl solution, dried over MgSO4, and then evaporated to a white solid which was recrystallized from CH2Cl2 -hexane to give 9.0 g (72%) of the thioxanthene as white crystals, m.p. 152°-154°, 'H NMR (CDCl3) δ 1.28 (s, 18H, CH3), 3.84 (s, 2H, CH2), 7.31 (m, 6H, aryl). Anal. calculated for C21H26S: C, 81.23; H, 8.44; S, 10.33. Found: C, 81.45; H, 8.61; S, 10.24.
Reaction SMILES: [Cl:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]2[NH:6][C:7](=S)[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.[CH3:31][O:32][CH:33]([O:36][CH3:37])[CH2:34][NH2:35]>C(O)CCC.CO.CCCCC>[Cl:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]2[N:6]=[C:7]([NH:35][CH2:34][CH:33]([O:36][CH3:37])[O:32][CH3:31])[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: COC(CN)OC
Reactant: Cc1nc2cnccc2n1-c1ccc(C2=Nc3cc(Cl)c(Cl)cc3NC(=S)C2)cc1
Solvent: CCCCO
Solvent: CO
Solvent: CCCCC
Product: COC(CNC1=Nc2cc(Cl)c(Cl)cc2N=C(c2ccc(-n3c(C)nc4cnccc43)cc2)C1)OC

Procedure:
A mixture 7,8-dichloro-2,3-dihydro-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepin-2-thione (1.36 g, 3.0 mmol), aminoacetaldehyde dimethyl acetal (630 mg, 6.0 mmol) and red mercuric oxide (650 mg, 3.0 mmol) in n-butanol (15 ml) was heated at reflux for 2.5 hours. The mixture was cooled, diluted with methanol (50 ml) and filtered through Hyflo filter aid. The solvents were removed under reduced pressure to give a foam, which was suspended in pentane and sonicated for 5 minutes. The pentane was removed in vacuo to give the title compound, 1.10 g (70%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]3[C:26]([CH:27]=[N:28][NH:29]3)=[CH:25][CH:24]=2)[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]2)=[CH:35][CH:34]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:29]1[C:30]2[C:26](=[CH:25][CH:24]=[C:23]([NH:22][C:4]3[C:5]4[C:10]([CH3:11])=[CH:9][N:8]([S:12]([C:15]5[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=5)(=[O:14])=[O:13])[C:6]=4[N:7]=[C:2]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([N:39]5[CH2:40][CH2:41][N:42]([C:45](=[O:47])[CH3:46])[CH2:43][CH2:44]5)=[CH:37][CH:38]=4)[N:3]=3)[CH:31]=2)[CH:27]=[N:28]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5cn[nH]c5c4)c4c(C)cn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 115 °C
Yield: 17.7 %

Procedure:
To a mixture of 2-Chloro-N-(1H-indazol-6-yl)-5-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.18 g, 0.4 mmol) and 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (0.22 g, 1 mmol) in n-butyl alcohol (2 mL) was added trimethylsilyl chloride (TMSCl) (0.026 mL, 0.2 mmol). After heating at 115° C. for 15 h, the mixture was purified by preparative HPLC to give 1-(4-(4-(4-(1H-indazol-6-ylamino)-5-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (0.045 g).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[CH3:31][CH:32]1[CH2:36][CH2:35][CH:34]([CH3:37])[NH:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:33]3[CH:34]([CH3:37])[CH2:35][CH2:36][CH:32]3[CH3:31])[CH:8]=2)[N:3]=1
Reactant: CC1CCC(C)N1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC1CCC(C)N1Cc1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
150 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 3 ml of 1,2-dichloroethane and 3 ml of tetrahydrofuran. 65 μl of 2,5-dimethylpyrrolidine and 22 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 170 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:11]=3[N:10]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)[C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:11]=3[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2nc(C(=O)C3CCCCC3)n(C)c2c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(c2nc3ccc(OC)cc3n2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a mixture of cyclohexyl(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methanone (1.00 g) synthesized above, methyl 4-aminobenzoate (611 mg), triethylamine (4.10 mL) and methylene chloride (20 mL) was added titanium (IV) chloride (482 μL), and the mixture was stirred under argon atmosphere overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, methylene chloride was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown solid. To a solution (20 mL) of the obtained solid in tetrahydrofuran were added acetic acid (1.05 mL) and sodium cyanoborohydride (461 mg), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, tetrahydrofuran was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (625 mg, 42%) as a pale-brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]([O:7][P:8]([CH2:17][CH2:18][NH:19]C(OCC1C=CC=CC=1)=O)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[CH3:6])[CH3:2].C(O)(=O)C>C(O)C.[Pd]>[C:4]([OH:30])(=[O:3])[CH3:5].[CH2:1]([O:3][C:4](=[O:30])[CH:5]([O:7][P:8]([CH2:17][CH2:18][NH2:19])([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)OP(=O)(CCNC(=O)OCc1ccccc1)Oc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)OP(=O)(CCN)Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 174.8 %

Procedure:
A solution of 2-[(2-benzyloxycarbonylamino-ethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl ester 218 (240 mg, 0.551 mmol) with approximately 50% purity and a ratio of 2:1 of diastereomers was dissolved in 5.5 mL of ethanol with acetic acid (63 μL, 1.10 mmol). To this solution was added 36 mg of 10% Pd/C and the solution was degassed under a hydrogen atmosphere three times. The solution was vigorously stirred at room temperature for 3 hours when TLC showed complete consumption of the starting materials. The mixture was filtered through a pad of Celite and dried to provide 174 mg (87%) of 2-[(2-amino-ethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl ester; compound with acetic acid 219 as a clear oil.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[OH-].[Na+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=1[O:16][CH3:17]>C(O)C.O>[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[CH:1][C:2](=[O:3])[CH3:4])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C=CC(C)=O)ccc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.1 %

Procedure:
To a solution of acetone (15.30 g, 263.76 mmol) in a mixture of ethanol (35 mL) and water (15 mL) were added sodium hydroxide (2.90 g, 72.54 mmol) and 4-hydroxy-3-methoxybenzaldehyde (5.01 g, 32.97 mmol). The reaction mixture was stirred at room temperature for 15 h. The reaction was cooled to 0° C. and quenched with 2.0 N hydrochloric acid until the solution became slightly acidic. The solution was extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with water (50 mL) and saturated aqueous sodium chloride (50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated at reduced pressure to afford 4-(4-hydroxy-3-methoxy-phenyl)but-3-ene-2-one (5.52 g, 87% yield) as a yellow solid: MS (EI) for C11H12O3: 193 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:26][CH2:27][C:28]1[C:33](=[O:34])[CH:32]=[C:31]([CH3:35])[NH:30][C:29]=1[CH3:36].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C([O-])(O)=O.[Na+]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:26][CH2:27][C:28]1[C:33](=[O:34])[CH:32]=[C:31]([CH3:35])[NH:30][C:29]=1[CH3:36])=[O:9]
Reactant: Cc1cc(=O)c(CN)c(C)[nH]1
Reactant: Cc1c(OC2CCN(c3ccncn3)CC2)cc(Cl)cc1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1cc(=O)c(CNC(=O)c2cc(Cl)cc(OC3CCN(c4ccncn4)CC3)c2C)c(C)[nH]1
Reaction time: 48 h
Yield: 30 %

Procedure:
A 20 mL vial was charged with 5-chloro-2-methyl-3-((1-(pyrimidin-4-yl)piperidin -4-yl)oxy)benzoic acid (72.0 mg, 0.207 mmol), 3-(aminomethyl)-2,6-dimethylpyridin -4(1H)-one hydrochloride (46.9 mg, 0.248 mmol), EDC (59.5 mg, 0.311 mmol), HOAt (47.9 mg, 0.311 mmol), N,N-dimethylformamide (3 mL) and N-methylmorpholine (0.341 mL, 3.11 mmol). The reaction mixture was stirred for 2 days, at which time it was added drop-wise to a rapidly stirring solution of saturated NaHCO3 (25 mL) and water (10 mL). The resulting cloudy mixture was stirred at room temperature 4 h, then filtered. The collected solid was dried under high vacuum and purified by reverse phase HPLC (Column: Phenomenex Gemini-NX axia, 30×100, 5μ, C18. Eluent: 5-25% acetonitrile/0.1% formic acid in water, 7 minute gradient). The resulting sticky, glassy solid was dissolved in MeOH (6 mL) and DCM (2 mL), then concentrated in vacuo. The resulting residue was then dissolved with DCM (1 mL) and concentrated in vacuo. The residue was partitioned between DCM (20 mL) and saturated NaHCO3 (6 mL) and water (3 mL). The aqueous layer was filtered and the solid dried under vacuum for 20 min to give 5-chloro -N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-2-methyl-3-((1-(pyrimidin-4-yl)piperidin-4-yl)oxy)benzamide (30 mg, 0.062 mmol, 30.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.02 (br. s., 1H), 8.49 (s, 2H), 8.18 (d, J=6.32 Hz, 1H), 7.19 (d, J=2.02 Hz, 1H), 6.88 (dd, J=1.01, 6.32 Hz, 1H), 6.83 (d, J=1.77 Hz, 1H), 5.86 (s, 1H), 4.78 (tt, J=3.82, 7.17 Hz, 1H), 4.20 (d, J=4.80 Hz, 2H), 3.80-3.97 (m, 2H), 3.52-3.69 (m, 2H), 2.29 (s, 3H), 2.14 (s, 3H), 2.07 (s, 3H), 1.87-2.01 (m, 2H), 1.54-1.71 (m, 2H). MS(ES) [M+H]+ 482.2.
Reaction SMILES: BrC1C(OC)=C(C=CC=1CSC1C=CC=CC=1C)C(OCC)=O.[Br:24][C:25]1[C:26]([O:37][CH3:38])=[C:27]([C:32]([CH2:35]Br)=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29].[Br:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=1[SH:47]>>[Br:24][C:25]1[C:26]([O:37][CH3:38])=[C:27]([C:32]([CH2:35][S:47][C:41]2[CH:42]=[CH:43][C:44]([F:46])=[CH:45][C:40]=2[Br:39])=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Reactant: Fc1ccc(S)c(Br)c1
Agent: CCOC(=O)c1ccc(CSc2ccccc2C)c(Br)c1OC
Product: COC(=O)c1c(CSc2ccc(F)cc2Br)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 77, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 2-bromo-4-fluorothiophenol and used without further characterization.
Reaction SMILES: C[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13].[CH2:14](OC(=O)COC)[CH3:15].CCCCCC.CNC>COC(C)(C)C.C(Cl)(Cl)Cl.CC(O)(C)C>[C:11]1([C@@H:12]([NH2:13])[CH:14]=[CH2:15])[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)COC
Reactant: CCCCCCCCCCCCN
Agent: CNC
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: COC(C)(C)C
Product: C=C[C@H](N)c1cccc2ccccc12
Temperature: 30 °C
Reaction time: 120 h

Procedure:
Amine 12 (600 mg, 3.3 mmol) was dissolved in 40 ml of methyl-tert-butyl-ether. 1 ml of ethyl-metoxyacetate and 5.0 g of Novozym 435 were added, and all was stirred for 120 h on 30° C. Reaction was followed by HPLC analysis on the Chiralcel OD column (250×4.6 mm) with hexane:t-BuOH:dimethylamine=92:8:0.2 (1 ml/min, 254 nm, tR(S)=15.31 min, tR(R)=18.28 min) as the mobile phase. The enzyme was separated from the reaction mixture by filtration and the filtrate was evaporated to oil remain which was dispersed in 10 ml of 1 M HCl and extracted twice with 20 ml of dichloromethane. The aqueous layer was alkalified with a solid sodium carbonate to pH=8 and extracted three times with 20 ml of diethyl-ether. Organic layers were combined and dried over anhydrous sodium sulphate. After filtration and solvent removal, S-12 as yellow oil (267 mg; 89%) was yielded. According to HPLC analysis ee>99%. [α]D25=−46 (c=0.05 M, CHCl3).