Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:21]([N:24](CC2C=CC(OC)=CC=2)[C:25]2[S:26][CH:27]=[CH:28][N:29]=2)(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[O:19][CH3:20].Cl[CH:40]([CH3:44])[C:41](Cl)=[O:42].ClCC(Cl)=O>>[CH3:20][O:19][C:10]1[CH:11]=[C:12]([C:15]([F:17])([F:18])[F:16])[CH:13]=[CH:14][C:9]=1[N:8]1[C:41](=[O:42])[CH:40]([CH3:44])[O:1][C:2]2[CH:3]=[C:4]([S:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]1=2
Reactant: CC(Cl)C(=O)Cl
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(Nc3ccc(C(F)(F)F)cc3OC)c(O)c2)cc1
Agent: O=C(Cl)CCl
Product: COc1cc(C(F)(F)F)ccc1N1C(=O)C(C)Oc2cc(S(=O)(=O)Nc3nccs3)ccc21

Procedure:
(+/−)-4-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methyl-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide was prepared in a similar fashion to Example 223, starting from 3-hydroxy-4-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide) (from Step 1, Example 223) and 2-chloropropanoyl chloride instead chloroacetyl chloride. Purification was achieved using reverse-phase HPLC with a Waters-Xbridge C18, 19×100 mm, 10 m column with a gradient 5-95% acetonitrile and water with 0.1% ammonium hydroxide modifier. 1H NMR (500 MHz, DMSO-d6) δ 1.53 (dd, J=16.93, 6.73 Hz, 3 H) 2.54 (s, 3 H) 3.79 (s, 1 H) 4.97-5.04 (m, 1 H) 6.40 (d, J=8.48 Hz, 1 H) 6.83 (d, J=4.58 Hz, 1H) 7.26 (d, J=4.52 Hz, 1 H) 7.30-7.42 (m, 2 H) 7.45-7.63 (m, 3 H). m/z ESI 500.0 (M+H)+.
Reaction SMILES: S([O-])([O-])(=O)=[O:2].[Mg+2:6].[OH-].[Na+].[CH2:9]([O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][OH:23])=[O:21])=[CH:18][CH:17]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(OCC)(=O)C>[OH-:2].[Mg+2:6].[OH-:15].[CH2:9]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][O-:23])=[O:21])=[CH:24][CH:25]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:9]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20](=[O:21])[O:22][O-:23])=[CH:24][CH:25]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Mg+2:6]
Reactant: O=S(=O)([O-])[O-]
Reactant: CCCCCCOc1ccc(C(=O)OO)cc1
Agent: [Mg+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCCCCOc1ccc(C(=O)O[O-])cc1
Reaction time: 0.25 h

Procedure:
A dispersion of magnesium hydroxide (4.20 mmol) was prepared by dissolving magnesium sulfate (0.505 g, 4.20 mmol) 20 ml water and adding 8.4 mmol of 1N sodium hydroxide (0.336 g, 8.40 mmol). To this stirred dispersion was added in one portion a solution of 4-hexyloxyperoxybenzoic acid (2.00 g, 8.40 mmol) in 30 mL ethyl acetate. The resulting mixture was stirred for 15 minutes and the precipitated solid collected by filtration and washed with water and then ethyl acetate. Air drying afforded 1.9 g of magnesium bis(4-hexyloxyperoxybenzoate), AvO (see Example IV) 4.58%, melting point decomposes at from 90°-210° C., liquifies at from 210°-220° C.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:26]=[C:25]([S:27]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:38]>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:23]2[CH:24]=[C:25]([S:27]([CH2:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)(=[O:29])=[O:28])[CH:26]=[CH:21][C:22]=2[CH3:38])[CH:11]=1)#[N:16]
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)CCc2ccccc2)cc1Br
Product: Cc1ccc(S(=O)(=O)CCc2ccccc2)cc1C#Cc1cc(C#N)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 2-bromo-1-methyl-4-[(2-phenylethyl)sulfonyl]benzene (Intermediate 70), the title compound was obtained as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:12][C:13]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:14]=1[CH2:15]Cl.O>CS(C)=O>[CH3:12][C:13]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:14]=1[CH2:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)c(Cn2ccc3ccccc32)c(C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A solution of indole (1.185 g) in dry DMSO (3 ml) is dropped into a suspension of sodium hydride (60% suspension in mineral oil; 0.44 g) in dry DMSO (10 ml). After two hours, the resulting solution is added with a solution of 2,4,6-trimethylbenzyl chloride (1.9 g) in dry DMSO (2 ml) and the reaction mixture is heated at 60° C. for 6 h. After a night at room temperature, the reaction mixture is poured into water (250 ml) and extracted with ethyl acetate, then dried (Na2SO4) The drying agent is filtered off and the solvent is evaporated off under reduced pressure. The resulting residue is purified by column chromatography (silica gel; eluent n-hexane/AcOEt 9/1), to obtain 2.2 g of 1-(2,4,6-trimethylbenzyl)indole.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10]([OH:17])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22](S(C)(=O)=O)[N:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([O:17][C:10]2[C:11]([C:13]([O:15][CH3:16])=[O:14])=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[N:21]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)c1nc(-c2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2ccccc2)ccc1Oc1nc(OC)cc(OC)n1
Reaction time: 72 h

Procedure:
1.0 g (4.4 mmol) of methyl 6-phenyl-3-hydroxypicolinate, 0.8 g (4 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.6 g (4 mmol) of potassium carbonate were added to 20 ml of DMF, and were reacted at 80° C. for 0.5 hour. After the reaction, the reaction content was poured into water, and was extracted with ethyl acetate. The organic layer thus obtained was washed with water and a saturated salt water, dried and treated with an appropriate amount of Florisil. Ethyl acetate was then distilled off under reduced pressure, and the residue was crystallized by adding 20 ml of hexane thereto and allowing to stand for 3 days. The crystal thus obtained was washed with hexane/isopropyl ether to obtain an aimed compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:22][CH:23]([F:32])[CH2:24]S(C(F)(F)F)(=O)=O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([O:16][CH2:24][CH:23]([F:32])[F:22])[CH2:13][C@H:12]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CC(F)F)C(F)(F)F
Reactant: O=C(O)[C@@H]1C[C@H](O)CN1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@H](OCC(F)F)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4S)-1-(benzyloxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.0 g, 18.85 mmol) in THF (100 mL) was added NaH (1.583 g, 39.6 mmol) at 0° C. under N2. The resulting suspension was stirred at RT for 30 min. A solution of 1,1-difluoro-2-(trifluoromethylsulfonyl)ethane (4.11 g, 20.73 mmol) in THF (5 ml) was added to the suspension. The reaction mixture was stirred at RT for 3 h. The reaction mixture was quenched with water and concentrated. The residue was extracted with EtOAc; the aqueous layers was acidified to ph 3 with 1N HCl and extracted with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4, and filtered. The crude product was used in the next step without purification. LC/MS [M−H]+: 328; Ret time (Method F): 0.93 min (Phenomenex-Luna s10 4.6×50 mm column, 4 min gradient, 4 mL/min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[Cl:20])=[O:8].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][C:29]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:30])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:11]=1[Cl:20])=[O:8]
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Br)ccc1O
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Br)ccc1OC(=O)N1CCOCC1
Yield: 68.1 %

Procedure:
Using 5-bromo-N-[2-chloro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=O)[N:8]=2)=[CH:4][CH:3]=1.Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH:32][C:12]([C:9]1[N:8]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:18][CH:17]=2)[O:11][N:10]=1)=[O:14]
Reactant: CCOC(=O)c1noc(Cc2ccc(C)cc2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(Cc2nc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)no2)cc1
Yield: 36.3 %

Procedure:
This compound was prepared according to method F with ethyl 5-(4-methylbenzyl)-1,2,4-oxadiazole-3-carboxylate (0.107 g; 0.433 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol), in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.062 g (36%) of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[CH3:21][N:22]([CH3:28])[CH2:23][CH2:24][CH2:25][NH:26][CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:21][N:22]([CH3:28])[CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][N:6]=1
Reactant: CNCCCN(C)C
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C)CCCN(C)c1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 90 °C

Procedure:
A solution of 3-nitro-5-(trifluoromethyl)pyridin-2-ol (500 mg, 2.4 mmol), CHCl3 (25 mL), oxalyl chloride (0.42 mL, 4.8 mmol) and DMF (1 drop) was allowed to reflux for 16 h. Once consumption of starting material was complete the reaction was concentrated under reduced pressure. A portion of the crude material (182 mg, 0.8 mmol) was removed and added to a mixture of N1,N1,N3-trimethylpropane-1,3-diamine (0.13 mL, 0.88 mmol), K2CO3 (221 mg, 1.6 mmol) and heated at 90° C. for 10 min. The mixture was concentrated under reduced pressure and reconstituted in CH2Cl2 (20 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N-(3-(dimethylamino)propyl)-N-methyl-3-nitro-5-(trifluoromethyl)pyridin-2-amine. MS m/z=307 [M+H]+. Calc'd for C12H17F3N4O2: 306.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][N:3]=1.[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH2:15]([O:14][C:12]([C:5]1[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:29])[F:30])=[CH:25][CH:24]=2)=[N:3][CH:4]=1)=[O:13])[CH3:16]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)F
Product: CCOC(=O)c1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F

Procedure:
In analogy to the procedures described in examples 108B], ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate and 4-(trifluoromethoxy)phenylboronic acid gave the title compound as an off-white powder.
Reaction SMILES: C([C:4]1[S:5][C:6]2[C:12]([O:13]C)=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)(=O)N.Cl>N1C=CC=CC=1>[OH:13][C:12]1[C:6]2[S:5][CH:4]=[N:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc2nc(C(N)=O)sc12
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc2ncsc12

Procedure:
The title compound was prepared as a mixture (60/40) with the 5-hydroxy isomer in the deprotection of 2-carbamoyl-7-methoxybenzothiazole (obtained in Preparation 4 below) with pyridine.HCl, according to the method described in Preparation 1. The mixture of the 5- and 7-hydroxybenzothiazoles was used directly in the preparation of the isomeric glycidyl ethers which were readily separable by chromatography on silica (2% CH3CN/CH2Cl2).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([CH:13]=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[CH2:17](O)[CH2:18][OH:19].C(=O)([O-])O.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[N:11][C:10]([CH:13]3[O:19][CH2:18][CH2:17][O:14]3)=[CH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=Cc1cnc(Oc2ccc(Br)cc2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1ccc(Oc2cnc(C3OCCO3)cn2)cc1
Temperature: 140 °C
Yield: 92.6 %

Procedure:
To a solution in toluene (20 mL) of the compound (1.66 g) obtained in step (1) above, ethylene glycol (1.11 g) and p-toluenesulfonic acid monohydrate (56.6 mg) were added and, thereafter, the mixture was stirred at 140° C. for an hour using a Dean-Stark apparatus. After cooling the reaction mixture to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added to it under cooling with ice and extraction was conducted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (n-hexane:ethyl acetate=100:0-60:40) gave 2-(4-bromophenoxy)-5-(1,3-dioxolan-2-yl)pyrazine as a colorless solid (1.78 g).
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:11]#[N:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH2:2].[CH2:13]([C:20]1[O:24][CH:23]=C(CO)[CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:1]([CH:3]1[CH2:5][C:4]1([C:11]#[N:12])[C:6]([O:8][CH2:9][C:10]1[CH:21]=[C:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:24][CH:23]=1)=[O:7])=[CH2:2]
Reactant: C=CC1CC1(C#N)C(=O)OCC
Reactant: OCc1coc(Cc2ccccc2)c1
Product: C=CC1CC1(C#N)C(=O)OCc1coc(Cc2ccccc2)c1
Yield: 85.9 %

Procedure:
In a manner similar to that described above, a transalcoholysis reaction was carried out using ethyl 2-vinyl-1-cyanocyclopropane-1-carboxylate and (5-benzyl-3-furyl)carbinol. The ratio of reactants, catalyst level, and reaction temperature employed were the same as indicated in Example II. (5-Benzyl-3-furyl)methyl 2-vinyl-1-cyanocyclopropane-1-carboxylate was obtained in 85.9% yield and purified by separation using the liquid chromatographic procedure. The structure of the purified (99.4%) product was confirmed by mass spectroscopy and nuclear magnetic resonance spectroscopy.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[CH2:20][CH2:19][CH2:18]2.Br[CH2:27][C:28]([O:30]CC)=[O:29]>C1COCC1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[CH:20]([CH2:27][C:28]([OH:30])=[O:29])[CH2:19][CH2:18]2
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(CC(=O)O)C2=O
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
n-Butyl lithium (3.27 g, 51.04 mmol) was added to a solution of di-isopropyl amine (6.88 g, 68.11 mmol) in THF (50 mL) at −60° C., and the mixture was stirred for 0.5 h. 6-methoxy-1-tetralone (6 g, 34.09 mmol) in THF (10 mL) was slowly added to the reaction mixture, the mixture was stirred for 45 min and ethyl bromoacetate (11.9 g, 71.25 mmol) was added. The reaction mixture was then stirred at room temperature for 16 h and quenched with saturated NH4Cl solution. The reaction mixture was extracted with EtOAc (X2), combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentration to give 5.3 g of the title compound.
Reaction SMILES: [C:1]([CH:3]([C:23]1([CH3:27])[CH2:26][O:25][CH2:24]1)[NH:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:10]([CH:20]2[CH2:22][CH2:21]2)=[CH:9][N:8]=1)=[O:6])#[N:2].[OH-:28].[Na+].OO>C(O)C>[NH2:2][C:1](=[O:28])[CH:3]([NH:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][C@@H:14]([CH3:19])[C:15]([F:16])([F:18])[F:17])[C:10]([CH:20]2[CH2:21][CH2:22]2)=[CH:9][N:8]=1)=[O:6])[C:23]1([CH3:27])[CH2:26][O:25][CH2:24]1
Reactant: [OH-]
Reactant: C[C@H](Oc1cc(C(=O)NC(C#N)C2(C)COC2)ncc1C1CC1)C(F)(F)F
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1cc(C(=O)NC(C(N)=O)C2(C)COC2)ncc1C1CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[cyano-(3-methyloxetan-3-yl)methyl]-5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxamide (example 251c, 0.17 g, 443 μmol) in ethanol (3 ml) was added a 4M aqueous solution of sodium hydroxide (554 μl, 2.22 mmol) and H2O2 35% aqueous solution (215 mg, 190 μl, 2.22 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was then concentrated in vacuo and diluted with ethyl acetate. The organic phase was extracted with a 1M aqueous solution of sodium bicarbonate. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane-ethyl acetate gradient to yield the mixture of epimers which was then separated into its individual epimers by preparative chiral HPLC (Chiralpak AD, ethanol/heptane) and the title compound was the second epimer collected and isolated as colorless oil; MS (ESI, m/z): 402.6 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])=[CH:13][C:12]=1[C:22]([CH3:26])([CH3:25])[CH2:23][CH3:24])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:21])[CH2:18][CH3:19])=[CH:13][C:12]=1[C:22]([CH3:25])([CH3:26])[CH2:23][CH3:24]
Reactant: CCC(C)(C)c1ccc(Oc2ccncc2[N+](=O)[O-])c(C(C)(C)CC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC(C)(C)c1ccc(Oc2ccncc2N)c(C(C)(C)CC)c1

Procedure:
3-Nitro-4-(2,4-bis(1,1-dimethylpropyl)phenoxy)-pyridine (6.0 g, 0.017 mol) was dissolved in ethanol (50 mL) and catalytically reduced by hydrogen with Pd/C catalyst at room temperature for 2 hours. The mixture was filtered through filter-cel and the ethanol removed in vacuo to yield the pure product 3-amino-4-(2,4-bis(1,1-dimethylpropyl)phenoxy)-pyridine in 98% recovered yield. Mass spectral and NMR data were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C1COCC1.[OH-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCOc1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 50.5 %

Procedure:
To a mixture of methyl 4-allyloxybenzoate (10.0 g), THF (50 mL) and methanol (50 mL) was added 2N aqueous NaOH solution (50 mL), and the mixture was stirred at 50° C. for 40 minutes. The reaction solution was concentrated to about 50 g, washed with hexane, and acidified with conc. hydrochloric acid. The precipitated crystals were collected by filtration, dissolved in ethyl acetate, dried over magnesium sulfate, and the solvent was evaproated under reduced prssure to give crude crystals of 4-allyloxybenzoic acid (4.68 g, 50%). To the crystals were added dichloroethane (50 mL) and DMF (2 drops), and the mixture was heated to 80° C., and thereto was added dropwise thionyl chloride (4.61 g) over a period of 10 minutes. The mixture was stirred for 30 minutes, and the reaction solution was concentrated to give an oily acid chloride (5.3 g). The compound (3.81 g) of Example 6-1 and the above acid chloride (5.07 g) were dissolved in methylene chloride (50 mL), and thereto was added boron trifluoride diethyl ether complex (4.39 g), and the mixture was allowed to stand at room temperature for 5 days. The reaction solution was washed successively with aqueous hydrochloric acid, water, and aqueous sodium hydroxide solution, dried, filtered, and concentrated. The residue was purified by silica gel chromatography to give a mixture of (1-p-toluenesulfonyl-1H-pyrrol-2-yl) (4-allyloxyphenyl) ketone and 4-allyloxybenzoic acid. This mixture was dissolved in 1N aqueous NaOH solution, and extracted three time with ethyl acetate. The combined oil layer was dried and concentrated to give crude crystals of (1-p-toluenesulfonyl-1H-pyrrol-2-yl) (4-allyloxyphenyl) ketone (5.79 g), which was dissolved in methanol (70 mL), and thereto was added 5N aqueous NaOH solution (70 mL), and the mixture was heated for 1.5 hour. The methanol was evaporated under reduced pressure, and extracted with ethyl acetate, dried, and concentrated. The residue was purified by silica gel column chromatography to give (1H-pyrrol-2-yl) (4-allyloxyphenyl) ketone (2.51 g, 43%).
Reaction SMILES: S(=O)(=O)(O)O.C[O:7][CH:8](OC)[C:9]1[CH:13]=[CH:12][S:11][C:10]=1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21]>ClCCl>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][C:10]1[S:11][CH:12]=[CH:13][C:9]=1[CH:8]=[O:7]
Reactant: COC(OC)c1ccsc1Cc1ccccc1F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=Cc1ccsc1Cc1ccccc1F
Reaction time: 2.5 h
Yield: 23.5 %

Procedure:
To silica gel (100 g), 15% aqueous sulfuric acid (15.4 g), and dichloromethane (400 ml) was added 2-(2-fluorobenzyl)-3-thiophenecarboxaldehyde dimethylacetal and dichloromethane (25 ml). The mixture was stirred for 2.5 hrs. The reaction mixture was filtered. The filter cake was washed with ethyl acetate and dichloromethane. The filtrate was concentrated and the residue was purified by flash column chromatography (silica gel, 0.5-10% ethyl acetate/hexanes) to afford 24.0 g (23.5%) of 2-(2-fluorobenzyl)-3-thiophenecarboxaldehyde.
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]2[O:16][C:2](=[O:3])[S:4][N:17]=2)=[CH:11][CH:12]=1
Reactant: NC(=O)CCc1ccc(Cl)cc1
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: O=c1oc(CCc2ccc(Cl)cc2)ns1
Yield: 87.5 %

Procedure:
11.60 g (88.5 mmol) of chlorocarbonylsulphenyl chloride and 13.54 g (73.8 mmol) of 3-(4-chlorophenyl)propionamide are stirred in 25 ml of toluene at 70° C. for 3 h. Subsequently, the mixture is cooled and freed from a solvent under vacuum and the residue is purified by column chromatography. 15.6 g of product are obtained (99.9% purity, 87.6% yield, log P (pH 2.3)=3.36).