Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[CH:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][NH:18]2)[CH:12]=[CH:11][C:10]=1[N:27]1[S:31](=[O:33])(=[O:32])[N:30](CC[Si](C)(C)C)[C:29](=[O:40])[CH2:28]1)C1C=CC=CC=1.[CH2:41]([S:48](Cl)(=[O:50])=[O:49])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][N:18]2[S:48]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:50])=[O:49])[CH:12]=[CH:11][C:10]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:40])[CH2:28]1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3Cc4ccccc4CN3)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: O=C1CN(c2ccc(CCC3Cc4ccccc4CN3S(=O)(=O)Cc3ccccc3)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-{2-benzyloxy-4-[(E)-2-(1,2,3,4-tetrahydroisoquinolin-3-yl)-vinyl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and benzylsulfonyl chloride analogous to Example 200, steps F, G and H: (M−1)−=492.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][C:7](=O)[C:8]([F:11])([F:10])[F:9].[NH2:13][C:14]1[C:18]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:17]([NH2:25])[NH:16][N:15]=1.[OH-].[K+]>O1CCOCC1>[NH2:25][C:17]1[C:18]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]2[N:13]=[C:7]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:2][N:15]2[N:16]=1
Reactant: O=C(CC1OCCO1)C(F)(F)F
Reactant: C=CCOC(=O)c1c(N)n[nH]c1N
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CCOC(=O)c1c(N)nn2ccc(C(F)(F)F)nc12
Temperature: 25 °C
Yield: 78.7 %

Procedure:
3-(1,3-Dioxolan-2-yl)-1,1,1-trifluoro-propan-2-one (55.58 g, 301.9 mmol) and allyl 3,5-diamino-1H-pyrazole-4-carboxylate 3 (55 g, 301.9 mmol) were dissolved in 1,4-dioxane (330 mL). KOH (1.694 g, 30.19 mmol) was added and the yellow suspension was stirred at room temperature for 4 h30 min. The reaction mixture was heated at 90° C. for 16 h. The mixture was cooled down to room temperature. The reaction mixture was concentrated and purified by column chromatography (CombiFlash Companion XL, 1.5 kg column, 0.5 to 40% EtOAc in DCM) to afford allyl 2-amino-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate 4a as a bright yellow solid (68 g, 79% yield). LC-MS (M+H)+ 287.2; 1H NMR (500 MHz, DMSO-d6) δ 9.18 (m, 1H), 7.46 (m, 1H), 6.77 (s, 2H), 6.05 (m, 1H), 5.62 (m, 1H), 5.26 (m, 1H), 4.78 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)[OH:12]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(Br)cc2C1(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 5-bromoindoline-2,3-dione (120 g, 530 mmol, 1.0 eq) in THF (1 L) was added dropwise (4-fluorophenyl)magnesium bromide in THF (0.8 M, 1.6 L, 1280 mmol, 2.4 eq) at 0° C.˜15° C., the mixture was stirred for overnight at room temperature. Then mixture was cooled to 0° C., quenched with H2O (20 mL), concentrated to give crude product, which was dissolved in EtOAc (2 L), washed with 1N HCl.aq (2 L), brine (1 L×2), dried over Na2SO4, the organic phase was concentrated to give crude product. Then the crude product was stirred in PE, filtered to obtained yellow solid, and dried in air to give 136 g (yield 80%) product, which was used to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δH 10.58 (s, 1H), 7.44-7.46 (dd, 1H, J1=8.4 Hz, 2.0 Hz), 7.28-7.32 (m, 2H), 7.22-7.25 (m, 1H), 7.14-7.18 (t, 2H, J=8.8 Hz), 6.87-6.89 (d, 1H, J=8.4 Hz), 6.84 (s, 1H). MS (ESI) [M+1-18]+ 304, 306.
Reaction SMILES: C([O:3][C:4]([C:6](O)([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1)=O)[C:7](OCC)=[O:8])=[O:5])C.O.[NH2:25][NH2:26].[OH-].[Na+].Cl>>[C:4]([C:6]1[C:7](=[O:8])[NH:25][N:26]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)[CH:12]=1)([OH:3])=[O:5]
Reactant: CCOC(=O)C(O)(CC(=O)c1ccc(C)c(F)c1)C(=O)OCC
Reactant: NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)c(=O)[nH]n2)cc1F
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl 2-ethoxycarbonyl-4-(3-fluoro-4-methylphenyl)-2-hydroxy-4-oxobutanoate (8.41 g, 25.8 mmol) inisopropanol (100 mL) was added hydrazine monohydrate (2.84 g, 56.8 mmol), and the mixture was heated under stirring at 100° C. for 6 hours. Then, 2 mol/L sodium hydroxide was added, and the mixture was stirred further at the same temperature for 4 hours. The reaction mixture was ice-cooled, and concentrated hydrochloric acid was added to acidify the system. The precipitate was collected by filtration, thoroughly washed with water and dried to yield the title compound as a slightly yellow crystalline powder (5.67 g, 87.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C1(C(C2C=CC=CC=2)(O)[C@H](C2C=CC=CC=2)O)C=CC=CC=1>C(#N)C>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S@@:12]([C:13]2[NH:21][C:20]3[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:15]=3[N:14]=2)=[O:24])=[N:4][CH:3]=1
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of omeprazole (250 mg, 0.72 mmol) and (S)-1,1,2-triphenyl-1,2-ethanediol (315 mg, 1.08 mmol) was dissolved in a minimum volume of acetonitrile (4 ml) at reflux temperature. On dissolution, the solution was cooled to ambient temperature slowly with vigorous stirring, and on reaching this temperature was stirred for a further 1 h. The precipitate was filtered, was washed with acetonitrile (2×2 ml) and was dried in vacuo to afford (S)-omeprazole.2[(S)-1,1,2-triphenyl-1,2-ethanediol] inclusion complex (239 mg, 71%, 95% e.e.) as an off-white powder.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([C:9]2([NH:17]C=O)[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10]2)[CH:5]=[CH:4]1>CO>[ClH:1].[NH2:17][C:9]1([C:6]2[CH:5]=[CH:4][C:3](=[O:2])[NH:8][CH:7]=2)[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10]1
Reactant: CC1(C)CCC(NC=O)(c2ccc(=O)[nH]c2)CC1
Agent: Cl
Solvent: CO
Product: CC1(C)CCC(N)(c2ccc(=O)[nH]c2)CC1

Procedure:
A solution of N-[1-(1,6-dihydro-6-oxo-3-pyridinyl)-4,4-dimethylcyclohexyl]formamide hydrochloride (7.05 g) in 125 ml of methanol was heated at reflux for 24 hours, and then the solution was cooled and concentrated in vacuo to a volume of 25 ml. The precipitated powder was collected, affording 3.07 g of analytically pure 5-(1-amino-4,4-dimethylcyclohexyl)-2(1H)-pyridinone hydrochloride, m.p. 229°-230° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]4([OH:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])=[CH:9][CH:8]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2([OH:36])[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCOCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCOCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.157 mL, 0.157 mmol) was added to a solution of [4′-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-pyran-4-yl)-vinyl]-3-methyl-phenyl}-propyl)-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example 131-(4); 27.6 mg, 0.052 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature overnight. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol=5:1) to give the target compound as a colorless oil (24.4 mg, 92%).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8](O)=[O:9])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=1>CN(C)C=O>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][C:4]([CH:7]([CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:8]([NH:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=2)=[O:9])=[CH:5][CH:6]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Yield: 20.9 %

Procedure:
A solution of 2-biphenyl-4-yl-3-cyclopentylpropionic acid (300 mg, 1.02 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (386 mg, 1.02 mmol), N,N-diisopropylethylamine (220 μL, 1.22 mmol), and 2-aminopyridine (144 mg, 1.53 mmol) in dry N,N-dimethylformamide (5 ml) was stirred at 25° C. under nitrogen for 15 h. The reaction mixture was partitioned between water and ethyl acetate, and the layers were separated. The organic layer was washed with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 2-biphenyl-4-yl-3-cyclopentyl-N-pyridin-2-yl-propionamide (79 mg, 21%) as a white solid: mp 57-59° C.; EI-HRMS m/e calcd for C25H26NO (M+) 370.2045, found 370.2049.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH:8]([CH3:10])[CH3:9])[NH:5][C:6]=1[I:7].[H-].[Na+].[C:13]([NH:20][CH2:21][CH2:22]Br)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>CN(C=O)C>[C:16]([O:15][C:13](=[O:14])[NH:20][CH2:21][CH2:22][N:3]1[C:2]([I:1])=[C:6]([I:7])[N:5]=[C:4]1[CH:8]([CH3:10])[CH3:9])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CC(C)c1nc(I)c(I)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nc(I)c(I)n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a yellow solution of 4,5-diiodo-2-isopropyl-1H-imidazole (10.000 g; 27.629 mmol) in anhydrous DMF (140 ml) was added portionwise, at rt, 55-65% sodium hydride moistened with oil (1.326 g; 33.154 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 20 min. The mixture was then heated to 100° C., and a colorless homogeneous solution of 2-(Boc-amino)-ethylbromide (6.810 g; 30.391 mmol) in anhydrous DMF (100 ml) was added dropwise, over 1 h, with an addition funnel. After completion of the addition, the resulting mixture was further heated at 100° C. for 1 h30. The reaction mixture was cooled to 0° C., and water (300 ml) was added slowly. This mixture was extracted with ether (5×150 ml). The combined organic layers were washed with brine (100 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give an orange oil. The crude was purified by FC (DCM/MeOH=30/1) to give the pure product [2-(4,5-diiodo-2-isopropyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester as a yellow solid which was further dried under HV (9.720 g; 70%). LC-MS: tR=0.82 min.; [M+H]+=506.32 g/mol.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:7](=[O:20])[C@@H:6]([CH2:21][F:22])[N:5]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:4]=2[N:3]=1.[F:28][C:29]1[CH:30]=[C:31]([NH2:38])[CH:32]=[C:33]2[C:37]=1[NH:36][N:35]=[CH:34]2>>[CH:23]1([N:5]2[C:4]3[N:3]=[C:2]([NH:38][C:31]4[CH:32]=[C:33]5[C:37](=[C:29]([F:28])[CH:30]=4)[NH:36][N:35]=[CH:34]5)[N:11]=[CH:10][C:9]=3[N:8]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:7](=[O:20])[C@H:6]2[CH2:21][F:22])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N#Cc1cccc(N2C(=O)[C@@H](CF)N(C3CCCC3)c3nc(Cl)ncc32)c1
Reactant: Nc1cc(F)c2[nH]ncc2c1
Product: N#Cc1cccc(N2C(=O)[C@@H](CF)N(C3CCCC3)c3nc(Nc4cc(F)c5[nH]ncc5c4)ncc32)c1

Procedure:
This compound was prepared from 3-[(7S)-2-chloro-8-cyclopentyl-7-(fluoromethyl)-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile and 7-fluoro-1H-indazol-5-amine, according to procedures similar to step e for the preparation of Example 18.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(I)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1ccc(OCc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
2.4 g of 50% sodium hydride in oil is added at 0° C. and under an inert atmosphere to 10 g of para-iodo-phenol in 150 ml of dimethylformamide, the mixture is maintained under agitation for 30 minutes and 5.9 ml of benzyl bromide is added. After agitation for 30 minutes while allowing the reaction medium to return to ambient temperature, the reaction medium is poured onto ice and a precipitation of the product is observed. After drying, 14.7 g of expected product is obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]([CH3:14])[CH:10]([C:15]([O:17]CC)=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>O>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]([CH3:14])[CH:10]([C:15]([OH:17])=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)C(=O)C1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1C(=O)N(Cc2ccccc2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 42 h
Yield: 74.2 %

Procedure:
A mixture of 5.13 g of ethyl 1-benzyl-4-methyl-5-oxo-3-pyrrolidinecarboxylate (42, cf. JP-A-62-4284), 40 ml of 50% ethanol, and 2 g of sodium hydroxide was stirred at room temperature for 42 hours. To the reaction mixture was added 100 ml of water, and the mixture was washed with chloroform. The aqueous layer was neutralized with hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 3.40 g of (±)-1-benzyl-4-methyl-5-oxo-3-pyrrolidinecarboxylic acid (43) as a colorless crystal.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH:12][C:13]([C:15]3[CH:37]=[CH:36][C:18]([O:19][C:20]4[CH:29]=[C:28]5[C:23]([CH:24]([C:30]([O:32]CC)=[O:31])[CH2:25][CH2:26][O:27]5)=[CH:22][C:21]=4[Cl:35])=[CH:17][CH:16]=3)=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1CCO.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH:12][C:13]([C:15]3[CH:37]=[CH:36][C:18]([O:19][C:20]4[CH:29]=[C:28]5[C:23]([CH:24]([C:30]([OH:32])=[O:31])[CH2:25][CH2:26][O:27]5)=[CH:22][C:21]=4[Cl:35])=[CH:17][CH:16]=3)=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc5c(c4)OCO5)cc3)c(Cl)cc21
Agent: Cl
Agent: OCCC1CCCO1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccc2c(c1)OCO2)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 3 h
Yield: 99.2 %

Procedure:
Ethyl 7-(4-(2-(benzo[d][1,3]dioxol-5-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (65 mg, 0.124 mmol) was dissolved in 2:1 tetrahydrofuran-ethanol and treated with 1.0 molar sodium hydroxide (496 μl, 0.496 mmol) at ambient temperature. After 3 hours, the reaction was diluted with ethyl acetate, neutralized with 1.0 molar hydrochloric acid (521 μl, 0.521 mmol), and partitioned between saturated sodium chloride aqueous solution. The organic layer was dried with sodium sulfate, filtered, concentrated, and dried under high vacuum to provide the title compound (61 mg, 0.123 mmol, 99.2% yield) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[CH:6]=[CH:7][C:8]=1[CH2:9]C1C=NC=CC=1.BrCC1C=CC(C2OC3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)=CC=1OC.N1C=CC(B(O)O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][C:39]1[CH:38]=[CH:36][N:37]=[CH:41][CH:40]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1Cc1cccnc1
Agent: OB(O)c1ccncc1
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cc1ccncc1

Procedure:
Utilizing the general procedure outlined for 2-[3-methoxy-4-(pyridin-3-ylmethyl)phenyl]-1,3-benzoxazole, 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (270 mg, 0.81 mmol), 4-pyridylboronic acid (100 mg, 0.81 mmol) reacted to afford the desired 2-[3-methoxy-4-(pyridin-4-ylmethyl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.46 (br s, 2H), 7.75–7.81 (m, 3H), 7.56–7.59 (m, 1H), 7.34–7.36 (m, 2H), 7.22 (d, 1H), 7.13 (d, 2H), 4.00 (s, 2H), 3.92 (s, 3H). MS (ESI) 317 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:16]S(C(C)(C)C)=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][N:5]=1.[ClH:23].CCOCC>CO>[ClH:23].[ClH:23].[NH2:16][C@@H:3]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:13])[F:14])=[CH:6][N:5]=1)[CH2:2][OH:1]
Reactant: CC(C)(C)S(=O)N[C@H](CO)c1ccc(OCC(F)(F)F)cn1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: N[C@H](CO)c1ccc(OCC(F)(F)F)cn1
Yield: 100 %

Procedure:
To a solution of N-{(1S)-2-hydroxy-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}-2-methylpropane-2-sulfinamide (3.84 g, 11.3 mmol) and methanol (50 ml) was added 2.0N HCl in ether (45.1 ml, 90 mmol). The reaction was stirred for an hour and concentrated to give (2S)-2-amino-2-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethanol dihydrochloride as a white foam (3.49 g, 100%). MS (Electrospray): m/z 237.1 (M+H). To a 100 ml round bottom flask equipped with a magnetic stir bar were added 4-cyclopropylphenylacetic acid (1.79 g, 10.2 mmol), (2S)-2-amino-2-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethanol dihydrochloride (3.14 g, 10.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.34 g, 12.2 mmol), 1-hydroxy-7-azabenzotriazole (1.66 g, 12.2 mmol) and triethylamine (4.25 ml, 30.5 mmol) into 68 ml of dimethylformamide. The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was washed with brine (3×50 ml) and extracted with ethyl acetate (3×70 ml). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to give an oil. Purification by flash chromatography (SiO2, 50-100% EtOAc/Hexanes, gradient) gave 2-(4-cyclopropylphenyl)-N-{(1S)-2-hydroxy-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide as a light yellow solid (3.00 g, 75%); 1H NMR (400 MHz, CD3OD) δ 8.28 (d, J=2.4 Hz, 1H), 7.42 (dd, J=2.4 Hz and 6.8 Hz, 1H), 7.29 (d, J=7.2 Hz, 1H), 7.16 (d, J=6.4 Hz, 2H), 7.01 (d, J=6.4 Hz, 2H), 5.07-4.99 (m, 1H), 4.63 (q, J=6.4 Hz, 2H), 3.82-3.79 (m, 2H), 3.54 (s, 2H), 1.89-1.84 (m, 1H), 0.92 (m, 2H), 0.64 (m, 2H); MS (Electrospray): m/z 395.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=2)=[CH:6][N:7]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(O)c2)cnc1N
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(-c2cccc(OCCc3ccccc3)c2)cnc1N
Temperature: 85 °C
Yield: 30.9 %

Procedure:
3-Amino-6-(3-hydroxyphenyl)-N-methylpyrazine-2-carboxamide (179 mg, 0.8 mmol) was taken into DMF (3 mL) followed by addition of cesium carbonate (1.3 g, 4 mmol) and 2-(bromoethyl)benzene (550 uL, 4 mmol). The mixture was heated to 85° C. for 12 hours then allowed to cool to room temperature. The mixture was diluted with an excess of ethyl acetate and washed with water (3×) then brine and dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo followed by purification of the residue using silica gel flash chromatography using ethyl acetate:hexanes (2:3) as eluent. The pure fractions were combined and concentrated then dried in vacuo to give 3-amino-N-methyl-6-{3-[(2-phenylethyl)oxy]phenyl}pyrazine-2-carboxamide (86 mg, 31% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO): 8.83 (s, 1H), 8.82 (br m, 1H), 7.74 (d, 1H), 7.67 (tr, 1H), 7.38-7.31 (m, 6H), 7.26-7.22 (m, 1H), 6.95 (d tr, 1H), 4.31 (tr, 2H), 3.08 (tr, 2H), 2.85 (d, 3H); MS (EI) for C20H21N4O2: 349 (MH+).
Reaction SMILES: C(C1C=CC=CC=1)C.Cl.CN(C)C(C)C.[Cl-].[K+].[F:18][C:19]([F:24])([F:23])[S:20](O)=[O:21].CN(C)C(C)C.S(Cl)(Cl)=O.[NH2:35][C:36]1[N:40]([C:41]2[C:46]([Cl:47])=[CH:45][C:44]([C:48]([F:51])([F:50])[F:49])=[CH:43][C:42]=2[Cl:52])[N:39]=[C:38]([C:53]#[N:54])[CH:37]=1>>[CH:45]1[C:44]([C:48]([F:51])([F:50])[F:49])=[CH:43][C:42]([Cl:52])=[C:41]([N:40]2[N:39]=[C:38]([C:53]#[N:54])[C:37]([S+:20]([O-:21])[C:19]([F:24])([F:23])[F:18])=[C:36]2[NH2:35])[C:46]=1[Cl:47]
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: O=S(O)C(F)(F)F
Agent: CC(C)N(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CCc1ccccc1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[S+]([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 500 ml jacketed reactor with stirrer, baffles and condenser was initially charged under a nitrogen atmosphere with 103 g of ethylbenzene, 6.3 g of dimethylisopropylamine hydrochloride (0.050 mol, 99%) and 15.5 g of potassium chloride (0.208 mmol). Subsequently, 31.5 g of trifluoromethanesulfinic acid (0.223 mol, 95.0%), 17.9 g of dimethylisopropylamine (0.203 mol, 99%) and 24.2 g of thionyl chloride (203 mmol, 99.7%) were metered in at 0° C. with cooling. After subsequently adding 54.8 g of 5-amino-3-cyano-1-(2,6-dichlor-4-trifluoromethylphenyl)pyrazole, the reaction mixture was stirred at 0° C. for 1 h, then heated to 35° C. over 45 min and stirred at 35° C. for a further 10 h. After the reaction had been quenched with sodium hydroxide solution and extracted with ethyl acetate and ethylbenzene, a nonisolated yield of fipronil of 80% was obtained in the crude solution (determination by means of quantitative HPLC).