Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:34][C:35]1[CH:52]=[CH:51][C:38]([CH2:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.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>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:45]2[CH:44]=[CH:43][C:42]([O:41][CH2:40][CH2:39][C:38]3[CH:37]=[CH:36][C:35]([F:34])=[CH:52][CH:51]=3)=[CH:47][CH:46]=2)[C:3]=1[N:22]1[CH2:23][CH2:24][CH:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:26][CH2:27]1)[C:11]([O:13][CH:14]([CH3:15])[CH3:16])=[O:12])([CH3:20])([CH3:19])[CH3:21]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(c3ccccc3)CC2)c1Br
Reactant: OB(O)c1ccc(OCCc2ccc(F)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(c3ccccc3)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 51.8 %

Procedure:
The Pd(Ph3P)4 (33.5 mg, 0.029 mmol) was added to a nitrogen purged and degassed solution of (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetate (150 mg, 0.29 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (83 mg, 0.32 mmol), and sodium carbonate (184 mg, 1.74 mmol) in dioxane (4.5 mL) and water (0.9 mL) and stirred in a screw-capped pressure vessel for 4 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (Na2SO4). The crude product was charged (DCM) to a 24 g ISCO silica gel cartridge and gradient elution (5-65% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)acetate 98 mg (52%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.42-7.39 (m, 2H), 7.29-7.23 (m, 3H), 7.17-7.13 (m, 5H), 7.06-7.02 (m, 3H), 6.07 (s, 1H), 4.98-4.93 (m, 1H), 4.25 (t, J=7.0 Hz, 2H), 3.08 (t, J=6.2 Hz, 2H), 2.78-2.72 (m, 1H), 2.62-2.58 (m, 1H), 2.47 (br. s, 1H), 2.46 (s, 3H), 2.28 (br. s, 1H), 2.05 (s, 3H), 1.94-1.90 (m, 1H), 1.77-1.66 (m, 2H), 1.57 (br. s, 2H), 1.18 (br. s, 12H), 1.14 (d, J=5.5 Hz, 3H). UPLC (M+H)=653.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]#[C-:25])=[CH:20][CH:19]=1>CO>[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]2[N:3]3[CH:4]=[CH:5][N:6]=[CH:7][C:2]3=[N:1][C:13]=2[C:12]2[CH:15]=[CH:16][C:9]([F:8])=[CH:10][CH:11]=2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: [C-]#[N+]c1ccc(F)cc1
Reactant: Nc1cnccn1
Solvent: CO
Product: Fc1ccc(Nc2c(-c3ccc(F)cc3)nc3cnccn23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Example 26 was synthesized by the following way: to a stirred solution of 2-aminopyrazine (683 mg, 7.18 mmol) in 50 mL of MeOH were added 4-fluorobenzaldehyde (1.16 mL, 10.8 mmol), 1-fluoro-4-isocyanobenzene (1.0 g, 8.25 mmol), and followed by 1.0 N HClO4 in MeOH (0.72 mL, 0.72 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was subjected to flash chromatography purification. The collected organic solution was concentrated to give the title compound as yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:8][C:7]=1[Cl:19].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[Cl:19][C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:11]([Cl:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:31])([F:20])[F:32])=[CH:27][N:26]=1
Reactant: NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 10.4 %

Procedure:
To a mixture of 0.96 g of 4-(3-aminopropyloxy)-3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)benzene, 0.53 g of 5-(trifluoromethyl)-2-pyridinecarboxylic acid, 0.37 g of triethylamine and 10 ml of chloroform was added 0.64 g of WSC hydrochloride, while stirring at room temperature. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.15 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(5-(trifluoromethyl)picolinamido)propoxy)benzene (10% yield), m.p., 55.1° C.
Reaction SMILES: S(Br)([Br:3])=O.[Br:5][C:6]1[S:7][C:8]([CH3:13])=[C:9]([CH2:11]O)[N:10]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:5][C:6]1[S:7][C:8]([CH3:13])=[C:9]([CH2:11][Br:3])[N:10]=1
Reactant: O=S(Br)Br
Reactant: Cc1sc(Br)nc1CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1sc(Br)nc1CBr
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a stirred solution thionyl bromide (2.27 g, 10.94 mmol, 1.1 eq.) in 25 ml dry DCM, cooled to 5° C., was added dropwise a solution of (2-bromo-5-methyl-1,3-thiazol-4-yl)methanol (2.07 g, 9.94 mmol, 1 eq.) and pyridine (0.865 g, 10.94 mmol, 1.1 eq.) in 15 ml dry DCM. On complete addition, the cooling bath was removed, the reaction warmed to room temperature and stirred 1.5 hr. 100 ml of water and 100 ml of DCM were added and stirring allowed for 2 mins. The organic layer was separated, dried over MgSO4 and evaporated. The residue was purified by chromatography on silica gel to give 2-bromo-4-(bromomethyl)-5-methyl-1,3-thiazole (1.94 g, 72% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[NH2:32][C@@H:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20](=[O:31])[C:21]3[CH:22]=[CH:23][C:24]([C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:25][CH:26]=3)[C:16]([NH:32][C@@H:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34])=[O:18])=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)c1ccc(C(=O)N[C@@H](Cc2ccc(-c3ncc(Br)cn3)cc2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a stirring solution of (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoic acid INT-27 (1.50 g, 3.10 mmol) in DMF (15 mL) were added tert-butyl D-alaninate (680.0 mg, 3.73 mmol) and Et3N (802.3 mg, 6.2 mmol). The reaction was stirred for 1 hour at 0° C. and then HATU (877.5 mg, 3.37 mmol) in 2 mL DMF was added. The reaction was stirred for 1 hour at 0° C. and then warmed to room temperature with stirring for 18 hours. The reaction solution was extracted with aqueous NaHCO3 (3×20 mL). The combined organics were dried over MgSO4 and evaporated. The crude product was purified by column chromatography (50%) EA in hexanes) to afford 1.44 g (76%) of tert-butyl ((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)-propanoyl)-D-alaninate INT-32 as a solid powder. LCMS-ESI (m/z) calculated for C31H37BrN4O4: 609.6. found 610.2 [M+H]+, tR=4.05 min. (Method 16). 1H NMR (400 MHz, DMSO) δ 9.03 (s, 2H), 8.49 (d, J=8.7 Hz, 1H), 8.41 (d, J=7.2 Hz, 1H), 8.24 (d, J=8.2 Hz, 2H), 7.73 (t, J=7.4 Hz, 2H), 7.54-7.37 (m, 4H), 4.85 (td, J=10.1, 4.6 Hz, 1H), 4.16 (t, J=7.2 Hz, 1H), 3.24-2.97 (m, 2H), 1.50-1.29 (m, 9H), 1.32-1.17 (m, 12H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]=[O:10].ClC1C=CC=CC=1.C(O)(=[O:21])C>C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:11])[C:2]=1[C:9]([OH:21])=[O:10]
Reactant: Cc1cc(C)c(C=O)c(C)c1
Reactant: CC(=O)O
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: Clc1ccccc1
Product: Cc1cc(C)c(C(=O)O)c(C)c1
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a flask equipped with a stirrer, condenser and oxygen inlet tube were added mesitaldehyde (14.8 g, 0.10 mol), 25 mL of chlorobenzene and a solution of 10 mg of cobalt (II) acetate in 1 mL of acetic acid. Oxygen was bubbled in while the solution was vigorously stirred. The reaction temperature rose to 88° in 20 min and then returned to room temperature after one hour. The reaction mixture was mixed with 60 mL of methylene chloride, and 100 mL of water was added. Aqueous potassium hydroxide (40%) was added dropwise until the pH reached 8. The aqueous layer was separated, washed successively with 50 mL of methylene chloride and 50 mL of petroleum ether, and acidified with concentrated hydrochloric acid to a pH of 2. The white solid product was collected by filtration, washed with water and air dried to give 9.82 g (60% yield) of mesitoic acid: mp 153.5°-155.5° C.
Reaction SMILES: [F:1][C:2]([F:10])([CH3:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>ClCCl>[F:1][C:2]([F:10])([CH3:9])[C:3]([CH3:8])([CH3:7])[C:4]([Cl:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(F)(F)C(C)(C)C(=O)O
Solvent: ClCCl
Product: CC(F)(F)C(C)(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 1.55 g (9.86 mmol) 3,3-difluoro-2,2-dimethylbutanoic acid in 5 ml of dry dichloromethane was added 3.45 ml (39.5 mmol) of oxalyl chloride. The mixture was stirred at room temperature for 20 hours then solvent and excess reagent removed by distillation followed by addition of carbon tetrachloride and distillation of the solvent. The cooled 3,3-difluoro-2,2-dimethylbutanoyl chloride thus formed was dissolved in 8 ml of dry pyridine and added to a mixture of 2.15 g (4.93 mmol) of [1S-[1α(4R*,6R*),2α, 6β,8β,8aα]]-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy-[2-(1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthalenyl)ethyl]tetrahydro-2H-pyran-2-one, 0.35 g of 4-pyrrolidinopyridine and 10 ml of dry pyridine. The mixture was heated at 50° overnight then cooled and quenched by the addition of ice chips. The mixture was taken up in diethyl ether and washed successively with water, dilute sulfuric acid and saturated sodium bicarbonate. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexane/dichloromethane/ethyl acetate (25:25:50) to give 0.314 g of 3,3-difluoro-2,2-dimethylbutanoic acid, [1S-[1α,3α,7β,8β(2R*,4R*)8aβ]]-8-[2[tetrahydro-4-[[(1,1-dimethylethyl]dimethylsilyl]oxy]-6-oxo-2H-pyran-2-yl]ethyl]-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-1-naphthalenyl ester.
Reaction SMILES: [C:1]1([C@H:7]([CH2:11][CH:12]=[CH2:13])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O>CN(C)C=O.ClCCl>[C:1]1([C@H:7]([CH2:11][CH:12]=[CH2:13])[C:8]([Cl:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC[C@H](C(=O)O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC[C@H](C(=O)Cl)c1ccccc1
Reaction time: 2 h

Procedure:
Combine (S)-2-phenylpent-4-enoic acid (1.53 g, 8.7 mmol), dichloromethane (10 mL), and dimethylformamide (1 drop). Add oxalyl chloride (1 mL, 11.46 mmol). After 2 hours, evaporate in vacuo to give (S)-2-phenylpent-4-enoyl chloride. Combine with toluene (10 mL) and add, with vigorous stirring, to a cooled (ice bath) aqueous solution of methylamine (2 mL, 40%). After 1 hour, partition the reaction mixture between water and dichloromethane. Separate the layers, dry the organic over MgSO4, filter, and evaporate in vacuo to give a residue. Triturate the residue with hexane to give a solid. Collect the solid by filtration and dry to give (S)-2-phenylpent-4-enoic acid, N-methyl amide: mp; 97-99° C. Rf=0.53 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH2:14]([C@@H:21]1[CH2:25][O:24][C:23](=[O:26])[NH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1(C)C=CC=CC=1>[CH2:14]([C@@H:21]1[CH2:25][O:24][C:23](=[O:26])[N:22]1[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][CH:8]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)Cc1ccc(C2CC2)cc1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(C2CC2)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 80 °C
Yield: 63.9 %

Procedure:
2-(4-Cyclopropylphenyl)acetic acid (2.82 g, 16.003 mmol) was combined with (R)-4-benzyloxazolidin-2-one (3.4030 g, 19.204 mmol) in toluene (14 mL) The suspension was treated with triethylamine (6.6917 mL, 48.010 mmol) and then heated to 80° C. The solution was treated dropwise with a solution of pivaloyl chloride (1.9893 mL, 16.003 mmol) in toluene (3.5 mL). The reaction was heated overnight at 80° C. The reaction was cooled and washed with 2N HCl and then separated. The aqueous layer was washed with toluene, and the combined organics were then washed with 2N HCl, water, saturated NaHCO3 (2×), saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The crude product was subjected to chromatography on SiO2 eluting with 9:1 hexanes/ethyl acetate to yield (R)-4-benzyl-3-(2-(4-cyclopropylphenyl)acetyl)oxazolidin-2-one (3.43 g, 64%). 1H NMR (CDCl3, 400 MHz) □ 7.33-7.20 (m, 5H), 7.16-7.11 (m, 2H), 7.05 (d, J=8.2, 2H), 4.70-4.63 (m, 1H), 4.32-4.14 (m, 4H), 3.26 (dd, J1=3.2, J2=13.3, 1H), 2.75 (dd, J1=9.5, J2=13.3, 1H), 1.93-1.85 (m, 1H), 0.98-0.92 (m, 2H), 0.72-0.66 (m, 2H).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9](C(O)=O)[C:10]2[O:14][CH2:13][CH2:12][C:11]=2[CH:15]=1.[N-:19]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl>[NH2:19][C:9]1[C:10]2[O:14][CH2:13][CH2:12][C:11]=2[CH:15]=[C:7]([Br:6])[CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cc(Br)cc2c1OCC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1cc(Br)cc2c1OCC2
Yield: 12.8 %

Procedure:
Concentrated sulfuric acid (8.8 ml) was added over 5 min to a stirred mixture of 5-bromo-2,3 -dihydrobenzofuran-7-carboxylic acid (0.55 g, 2.3 mmol) in chloroform (27 ml) at 45° C. Sodium azide (0.737 g, 11.3 mmol) was then added portion-wise over 0.5 h and the temperature was maintained for a further 1 h after which time the mixture was poured onto ice (100 g) and extracted with chloroform (2×50 ml). The aqueous phase was basified to pH 12 with 40% sodium hydroxide solution and extracted with chloroform (2×50 ml). The extract was dried (Na2SO4), concentrated, and the residue purified by column chromatography over silica gel eluting with a gradient of acetone/toluene to give the title compound (D14) as a solid (63 mg, 13%), MH+ 214/216.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:20][C:21]([O:23]C)=[O:22].[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[C:10]2[O:9][C:8]([N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: COC(=O)Cc1ccc2nc(N3CCc4ccccc43)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc2nc(N3CCc4ccccc43)oc2c1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
To methyl (7-fluoro-2-(1-indolinyl)-6-benzoxazolyl)acetate (330 mg, 1.01 mmol) were added THF/methanol (2:1, 12 ml) and 1N NaOH (4 ml). After stirring at room temperature for 14 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (7-fluoro-2-(1-indolinyl)-6-benzoxazolyl)acetic acid (284 mg, 90%) as a pale brown solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Br-:1].[C:7]([CH:6]([CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2][P+:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([OH:9])=[O:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(CCCCBr)C(=O)O
Solvent: Cc1ccccc1
Product: CC(CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Product: [Br-]
Yield: 65.7 %

Procedure:
A solution of 6-bromo-2-methylhexanoic acid (1.08 g, 5.17 mmole) and triphenylphosphine (1.42 g, 5.4 mmole) in toluene (5 ml) was heated under reflux for 18 hours. After the solution was cooled, the crystals which separated out were collected by filtration and washed with toluene and ethyl acetate to yield 5-carboxy-5-methylpentyltriphenylphosphonium bromide (1.6 g, 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Product: Nc1ccc(Cl)cc1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 73 %

Procedure:
Starting from 2-amino-5-chlorobenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (158 mg; 73% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]#[N:17]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: c1ccc(CN2CCNCC2)cc1
Product: N#CCN1CCN(Cc2ccccc2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Benzyl-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a white solid; ES-MS: M+=216.2: AtRet=1.50.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:15]=[C:14]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[N:13]=[CH:12][C:11]=3[N:28]=2)=[CH:4][CH:3]=1.CS(O[CH2:34][CH2:35][CH:36]1[CH2:38][C:37]1([F:40])[F:39])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:39][C:37]1([F:40])[CH2:38][CH:36]1[CH2:35][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:15]=[C:14]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH3:19])[N:13]=[CH:12][C:11]=3[N:28]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](COc1cc2oc(-c3ccc(O)cc3)nc2cn1)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCCC1CC1(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1cc2oc(-c3ccc(OCCC4CC4(F)F)cc3)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A mixture of tert-butyl ((2S)-1-((2-(4-hydroxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate (300 mg), 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (312 mg), potassium carbonate (215 mg) and DMF (5 mL) was stirred overnight at 70° C. The reaction mixture was allowed to cool to room temperature, and 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (935 mg) and potassium carbonate (645 mg) were added thereto. The obtained mixture was stirred overnight at 70° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (239 mg).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH2:6][CH:5]([S:8][C:9]2[CH:15]([CH3:16])[CH:14]3[N:11]([C:12](=[O:20])[CH:13]3[CH:17]([OH:19])[CH3:18])[C:10]=2[C:21]([OH:23])=[O:22])[CH2:4]1.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].Cl.[C:33](=[NH:38])(OCC)[CH3:34]>>[OH:19][CH:17]([CH:13]1[C:12](=[O:20])[N:11]2[CH:14]1[CH:15]([CH3:16])[C:9]([S:8][CH:5]1[CH2:4][CH:3]([CH2:2][NH:1][C:33](=[NH:38])[CH3:34])[O:7][CH2:6]1)=[C:10]2[C:21]([OH:23])=[O:22])[CH3:18]
Reactant: CCOC(C)=N
Reactant: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN)C3)C(C)C12
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CC(=N)NCC1CC(SC2=C(C(=O)O)N3C(=O)C(C(C)O)C3C2C)CO1
Yield: 77.3 %

Procedure:
The title compound is prepared by the procedure of Example 47 using 0.052 g of product from Example 46, 5 ml of sodium phosphate buffer (pH 7) adjusted to pH 8.5 and 0.097 g of ethyl acetimidate hydrochloride to give 0.045 g of the desired product.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:29]=[CH:28][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH:11]=[C:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[ClH:32].O1CCOCC1>C(Cl)Cl>[ClH:32].[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH:11]=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cc3)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1

Procedure:
tert-Butyl 4-(3-(4-(trifluoromethyl)phenoxy)benzylidene)piperidine-1-carboxylate (1.75 g, 4.0 mmol) from Step 4 was dissolved in CH2Cl2 (15 mL) and treated with HCl in dioxane (7.0 mL, 4.0 M, 28 mmol). After 16 h the reaction was concentrated in vacuo to provide the title compound as a white solid (1.49 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)[CH:2]=1.CN.Cl.[C:17]([BH3-])#[N:18].[Na+]>CO.O1CCOCC1>[CH3:17][NH:18][CH2:12][C:10]1[S:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:8][CH:9]=1
Reactant: [BH3-]C#N
Reactant: O=Cc1ccc(-c2cccnc2)s1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CNCc1ccc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.8 %

Procedure:
To a solution 13 (90 mg, 0.48 mmol) was added a solution of methylamine (2.0 M, 1.43 mL, 2.85 mmol) in anhydrous CH3OH, a solution of HCl (4.0 M, 0.24 mL, 0.95 mmol) in anhydrous 1,4-dioxane and sodium cyanoborohydride (30 mg, 0.48 mmol). The flask was purged with argon and stirred under an atmosphere of argon at room temperature for 24 h. The solution was adjusted to pH 2 with conc. HCl and the solvent was removed in vacuo. The residue was dissolved in water and washed with Et2O (3×10 mL). The aqueous fraction was adjusted to pH 10 with NaOH(aq) (10 N), extracted with Et2O (3×20 mL), dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 10/90, Rf=0.13) to afford the title compound 40 (39 mg, 40% yield) as a yellow oil: 1H NMR (CDCl3) δ 8.84 (m, 1H), 8.49 (m, 1H), 7.82 (m, 1H), 7.28 (m, 1H), 7.21 (d, J=3.6 Hz, 1H), 6.93 (d, J=3.5 Hz, 1H), 3.96 (s, 2H)2.31 (s, 3H); LRMS (ESI) m/z calcd for C11H13N2S [M+H]+ 205. found 205; m/z calcd for C10H8NS [M−NH(CH3)]+ 174. found 174; HRMS (ESI) m/z calcd for C11H13N2S [M+H]+ 205.0799. found 205.0781; HPLC>95%=4.34 min, 80 (A):20 (B): 0.05 (C); tR=3.60 min, 60 (A):40 (B): 0.07 (C)).