Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[C:4]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1Cl.C(N(C(C)C)CC)(C)C.[CH:36]([NH:39][CH2:40][CH:41]1[CH2:45][CH2:44][CH2:43][NH:42]1)([CH3:38])[CH3:37]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[C:4]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[N:42]1[CH2:43][CH2:44][CH2:45][CH:41]1[CH2:40][NH:39][CH:36]([CH3:38])[CH3:37]
Reactant: Cn1c(Cl)c(Cl)c(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Reactant: CC(C)NCC1CCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NCC1CCCN1c1c(Cl)c(-c2ccncc2)c(-c2ccc3ccccc3c2)c(=O)n1C
Temperature: 150 °C

Procedure:
A microwave tube was charged with 5,6-dichloro-1-methyl-3-naphthalen-2-yl-1H-[4,4′]bipyridinyl-2-one (0.300 g, 0.8 mmol), diisopropylethylamine (2 eq.) and isopropyl-pyrrolidin-2-ylmethyl-amine (1 eq). The heterogeneous suspension was heated in the microwave at 150° C. for 10 min. The resulting brownish suspension was dissolved in DCM and the crude product was purified by flash chromatography using an ISCO combiflash system with a mixture 97/3 DCM/MeOH to give the title compound. MS (ES+): 487 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C1C=CC2N(O)N=[N:19]C=2C=1.C(Cl)CCl.CN>C(Cl)Cl>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([NH2:19])=[O:5]
Reactant: Cc1cc(C)c(N)c(C(=O)O)c1
Reactant: On1nnc2ccccc21
Agent: CN
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(C)c(N)c(C(N)=O)c1
Reaction time: 16 h
Yield: 209.6 %

Procedure:
A solution of 2-amino-3,5-dimethyl-benzoic acid (550 mg) in DCM (30 mL) was treated with HOBt (225 mg), EDC (1280 mg), and CH3NH2 (8.5 mL, 2N in THF). The reaction mixture was stirred for 16 hours in a sealed bottle, diluted with DCM (100 mL), and washed with brine three times. The organic layer was dried (sodium sulfate), and concentrated in vacuo. The residue was purified by silica gel chromatography to provide 573 mg of 2-amino-3,5-dimethyl-benzamide: 1H NMR (300 MHz, CDCl3) δ 7.9 (s, 1H), 7.8 (s, 1H), 6.1 (bs, 1H), 5.3 (bs, 2H), 2.9 (d, 3H), 2.2 (s, 3H), 2.1 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:14]([O:16]C)=O)[C:10](OC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl.[CH:22]([NH2:24])=[NH:23].Cl>CO>[CH2:1]([O:8][C:9]1[C:14]([OH:16])=[N:23][CH:22]=[N:24][C:10]=1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=CN
Reactant: COC(=O)C(OCc1ccccc1)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Oc1ncnc(O)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.8 %

Procedure:
Dimethyl 2-(benzyloxy)malonate (16.1 g, 0.0675 mol) was dissolved in MeOH (27 ml), NaOMe (42.59 ml of a 30% solution in MeOH, 3.5 eq) was added and the mixture cooled to 0 C. Formamidine hydrochloride (5.68 g, 1.05 eq) was added and the mixture stirred at 0° C. for 30 minutes and then at reflux for 2 hours. After cooling to 0° C. concentrated HCl (21 ml) was added and the solid was collected by filtration (washing with cold water 3×20 ml) to give 15.14 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][Mg]Cl>C1COCC1.CN1C(=O)CCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[Cl:1][C:2]1[N:7]=[C:6]([CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: C[Mg]Cl
Reactant: Fc1cnc(Cl)nc1Cl
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1nc(Cl)ncc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
A solution of 2,4-dichloro-5-fluoropyrimidine (2.5 g, 14.97 mmol) and iron(III) acetylacetonate (1.058 g, 2.99 mmol) in THF (100 mL) and NMP (10 mL) was chilled below 0° C. and methyl magnesium chloride (5.99 mL, 18.0 mmol, 3.0 M solution in THF) was added dropwise over 10 minutes. After stirring for 2 hours at 0° C., the mixture was quenched with 200 mL saturated NH4Cl and extracted twice with 200 mL EtOAc. The combined organic extracts were washed with 200 mL saturated NH4Cl and 200 mL brine, dried over Na2SO4 and concentrated. Purification by chromatography (Grace Reveleris 80 g column, eluted with 0-20% EtOAc/heptane, 35 mL/min) provided the title compound (1.13 g, 7.70 mmol, 51% yield). GC/MS (EI+) m/z 146.0 (M+); 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 2.55 (d, J=2.5, 3H); 13C NMR (101 MHz, CDCl3) δ 158.78, 158.61, 157.34, 154.92, 154.89, 154.74, 145.86, 145.63, 17.74, 17.73.
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([OH:3])=O.[NH:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.Cl>C(Cl)Cl>[N:20]1([C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)OCc1ccccc1
Reactant: C1CCCNCC1
Agent: Cl
Solvent: ClCCl
Product: CC(C)C[C@H](CC(=O)N1CCCCCC1)C(=O)OCc1ccccc1
Yield: 93.5 %

Procedure:
Benzyl(2R)-2-carboxymethyl-4-methylvalerate (1.35 g), hexahydro-1H-azepine (0.610 g) and WSCD.HCl (1.18 g) were reacted in methylene chloride (30 ml) in a similar manner to that of Preparation 1-1) to give benzyl (2R)-2-(hexahydro-1H-azepin-1-ylcarbonylmethyl)-4-methylvalerate (1.65 g).
Reaction SMILES: [CH2:1]=[C:2]([C:7](OS(F)(=O)=O)([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].[I-:15].[Na+].COCCOCCOC>O>[F:4][C:3]([F:6])([F:5])[C:2]([C:7]([F:9])([F:8])[I:15])=[CH2:1]
Reactant: [I-]
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: C=C(C(F)(F)F)C(F)(F)I
Reaction time: 8 h
Yield: 55.2 %

Procedure:
CH2═C(CF3)CF2OSO2F (10 g, 0.04 mole) is added gradually to a mixture of dry sodium iodide (Nal) (7 g, 0.047 mole) and dry diglyme (20 ml) at 10° C. with stirring. The reaction mixture is kept overnight and then poured into water. The organic layer is separated, washed with aqueous sodium bicarbonate solution and then with water and then dried over MgSO4. Distillation gives a mixture (6 g, 54%) of 2-trifluoromethyl-3,3,-difluoro-3-iodopropene (CH2═C(CF3)CF2I) (10%) and 1,1-difluoro-2-trifluoromethyl-3-iodopropene (CF2═C(CF3)CH2I) (90%), as shown by GC-MS and 19F NMR. B.pt. 98-99° C. The difluoromethylene isomer CF2═C(CF3)CH2I predominates in this example. The experience with chloride as nucleophile (Example 17), indicates that reaction conditions, time in the case of Example 17, can be varied to control the ratio of methylene to difluoromethylene isomer. Simple experimentation should identify conditions at which iodide as nucleophile will yield higher amounts of methylene monomer.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1.Cl.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[O:18][CH2:19][CH:20]([NH2:23])[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:1][C:2]1[N:3]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:5]=[C:6]([NH:23][CH:20]([CH2:21][CH3:22])[CH2:19][O:18][C:17]2[CH:24]=[CH:25][CH:26]=[C:15]([C:14]([F:13])([F:27])[F:28])[CH:16]=2)[N:7]=1
Reactant: CCC(N)COc1cccc(C(F)(F)F)c1
Reactant: CC(C)c1nc(N)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(COc1cccc(C(F)(F)F)c1)Nc1nc(N)nc(C(C)C)n1
Temperature: 80 °C
Yield: 75.8 %

Procedure:
2.6 g (0.015 mol) of 2-amino4-chloro-6-isopropyl-1,3,5-triazine, 4.0 g (0.015 mol) of 1-(3-trifluoromethylphenoxy)-2-aminobutane hydrochloride and 6.2 g (0.045 mol) of potassium carbonate were added to 50 ml of dimethylformamide (DMF). The mixture was heated at 80° C. for 3 hours, added into water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and filtered and the solvent was evaporated under reduced pressure. Purification by silica gel column chromatography using ethyl acetate/petroleum ether (1:1) gave 4.2 g (76%) of the title compound.
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC>C1(C)C=CC=CC=1>[CH3:9][CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(O)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC=Cc1ccccc1
Temperature: 75 °C
Yield: 94 %

Procedure:
A mixture of 1-phenyl-1-propanol (0.16 g, 1.17 mmol) and Catalyst A or B (30 mg) in toluene (1 ml) was stirred and heated at 75° C. for 10 h under nitrogen. Ether (20 ml) was added and the mixture was filtered to remove the catalyst. The organic washings were concentrated under reduced pressure at room temperature to afford β-methyl styrene as a colourless oil (0.13 g, 92%).
Reaction SMILES: [OH:1][C@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH3:9]I>>[OH:1][C@H:2]([CH3:8])[C@H:3]([CH3:9])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CI
Reactant: COC(=O)C[C@@H](C)O
Product: COC(=O)[C@@H](C)[C@@H](C)O

Procedure:
This compound was prepared according to the procedure of Example 127, but the methyl 3-(R)-hydroxybutanoate was first alkylated with methyl iodide as described by Keck et al., (J. Org. Chem., 1985, 4317) to give methyl 3-(R)-hydroxy-2-(S)methylbutanoate. The latter was transformed into the thiol according to the procedure of Example 127.
Reaction SMILES: C([O:9][CH:10]1[CH2:13][N:12]([C:14]2[O:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=2)[CH2:11]1)(=O)C1C=CC=CC=1.C[O-].[Na+].Cl>CO.C(Cl)Cl.O1CCOCC1>[OH:9][CH:10]1[CH2:13][N:12]([C:14]2[O:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=2)[CH2:11]1
Reactant: COC(=O)c1coc(N2CC(OC(=O)c3ccccc3)C2)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1coc(N2CC(O)C2)n1
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of 3-benzoyloxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (5.24 g, 17.3 mmol) (obtained as described in Reference Example 70(6)) in a mixture of methanol (260 ml) and methylene chloride (80 ml) was added a catalytic amount of sodium methoxide at room temperature and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was neutralized with 4 N hydrogen chloride gas in dioxane and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:methanol (95:5) as the eluant to afford 3-hydroxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (2.65 g, yield 77%) as pale brown crystals.
Reaction SMILES: CC(C(N[C@@:8]([CH3:20])([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:9](O)=[O:10])=O)(C)C.ClC1C=CC([NH2:26])=CC=1>>[CH3:20][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:9]([NH2:26])=[O:10]
Reactant: COc1ccc([C@](C)(NC(=O)C(C)(C)C)C(=O)O)cc1
Reactant: Nc1ccc(Cl)cc1
Product: COc1ccc(C(C)C(N)=O)cc1

Procedure:
(S)-α-[N-[(1,1-Dimethylethyl)carbonyl]amino]-α-methyl-4-methoxybenzeneacetic acid (preparation described in step A of Example 101) was condensed with 4-chloroaniline following the procedure described in step A of Example 99. Pure (S)-N-(4-chlorophenyl)-α-[N-[(1,1-dimethylethyl)carbonyl]]-amino!-α-methyl-4-methoxybenzeneacetamide, obtained after chromatography on silica gel using 20% EtOAc/hexane as eluant, was converted to the title compound following the procedure described in step A of Example 98.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][NH:3]1.[Cl:25][CH2:26][CH2:27][N:28]=[C:29]=[O:30]>ClCCl>[Cl:25][CH2:26][CH2:27][NH:28][C:29]([N:3]1[CH:2]([CH3:1])[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4]1)=[O:30]
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Reactant: O=C=NCCCl
Solvent: ClCCl
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=O)NCCCl)OCO3
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
A mixture of 1.0 g (3.07 mmol) of (±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine, 25 ml of dry dichloromethane and 0.62 g (5.88 mmol of 2-chloroethyl isocyanate was stirred at room temperature for 24 h, then concentrated. The residue was purified by refluxing in ethanol to yield 1.25 g (94%) of the title compound, Mp.: 222-223° C.
Reaction SMILES: Cl.Cl[C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[NH:17]1[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:9][C:8]1[C:3]([N:17]2[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]2)=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: Cc1cncnc1Cl
Reactant: NC(=O)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cncnc1N1CCC(C(N)=O)CC1
Reaction time: 0.25 h
Yield: 25.2 %

Procedure:
To a solution of 5-methyl-4-chloropyrimidne hydrochloride 22 (75 mg, 0.45 mmol) in DMF (2 mL) was added triethylamine (0.63 mL, 4.5 mmol). After stirring for 15 min, a solution of isonipecotamide (64 mg, 0.50 mmol) in DMF (2 mL) was added and the mixture was stirred at r.t. for a further 20 h. The mixture was poured into a saturated solution of sodium hydrogen carbonate (50 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, gradient 98:2 to 9:1) to furnish the title compound as a white solid (25 mg, 25%), m.p. 182-184° C.; umax (CHCl3)/cm−1 3024, 1678, 1581, 1439, 1359, 1147, 948; m/z (ESI) C11H17N4O requires 221.1397, found [M+H]+ 221.1394.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].C([O-])(=[O:26])C.[Na+].O.N(S([O-])(=O)=O)(S(O)(=O)=O)O.[K+].[K+]>CO>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:3]1[C:2](=[O:1])[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[C:5](=[O:26])[C:4]=1[CH3:12]
Reactant: COc1cc(C)c(CCCCCCCCCCO)c(O)c1OC
Reactant: CC(=O)[O-]
Agent: O=S(=O)([O-])N(O)S(=O)(=O)O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Yield: 93.9 %

Procedure:
In methanol (110 l) was dissolved 10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decan-1-ol (6.84 kg). To this solution were added sodium acetate (27.4 kg) and water (110 l). To the mixture was then added dipotassium nitrosodisulfonate (23.5 kg, content 69.9%), which was stirred at 50°±3° C. for 3 hours. After confirming disappearance of the starting material by means of thin-layer chromatography, water (550 l) was added to the mixture, which was stirred at 10° C. or below for 30 minutes or longer, then precipitating crystals were separated by centrifuge. Wet crystals thus collected were dissolved in ethyl acetate (40 l), followed by washing with water (25). The ethyl acetate layer was concentrated under reduced pressure to obtain a crude product 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (6.70 kg, yield 93.9%). Reference examples using dipotassium nitrosodisulfonate (Fremy's salt) are described in Table 3.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[C:26]([F:44])[CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].CO.O[Li].O>O>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:48])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[C:26]([F:44])[CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:46][CH2:47]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (11 mg, 0.017 mmol, 1 equiv) in 9:1 MeOH:water (1.1 mL) was added LiOH.H2O (28 mg, 0.671 mmol, 40 equiv). The reaction was heated to 70° C. for 1 h. Upon cooling to ambient temperature, the reaction was filtered and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 45-85% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Product isolated (7.2 mg, 77%). 1H NMR (500 MHz, DMSO-d6) δ 7.84 (d, J=7.6 Hz, 1H), 7.76 (d, J=6.1 Hz, 2H), 7.28 (t, J=7.6 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 7.06 (s, 1H), 7.03 (d, J=7.3 Hz, 1H), 6.89 (d, J=11.6 Hz, 1H), 6.62 (t, J=8.1 Hz, 1H), 5.90-5.80 (m, 1H), 5.68 (br. s., 1H), 5.54 (d, J=15.6 Hz, 1H), 4.44 (br. s., 1H), 3.80-3.65 (m, 3H), 3.39 (d, J=11.3 Hz, 1H), 2.87 (d, J=8.5 Hz, 1H), 2.37 (d, J=8.2 Hz, 1H), 2.33-2.29 (m, 1H), 2.28 (br. s., 3H), 2.08-1.98 (m, 1H), 1.76-1.58 (m, 2H), 1.52-1.40 (m, 2H), 1.01 (s, 3H), 0.94 (s, 9H), 0.83 (d, J=5.8 Hz, 3H); LCMS (ESI, M+1): 642.5.
Reaction SMILES: [CH:1](/[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=1>CC(N(C)C)=O.[Cu]>[CH:1](/[C:9]1[N:10]([C:21]2[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=2)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: C(=C/c1nc2ccccc2[nH]1)\c1ccccc1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1cccnc1-n1c(/C=C/c2ccccc2)nc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 4.6 %

Procedure:
To a stirred solution of (E)-2-styryl-1H-benzimidazole (0.49 g, 2.2 mmol) in dimethylacetamide (20 ml) at 0° C. under a nitrogen atmosphere was added sodium hydride (0.11 g, 2.8 mmol). After stirring at 0° C. for 20 min. and then at room temperature for 30 min., a solution of 2-Chloro-3-trifluoromethylpyridine (0.60 g, 3.3 mmol) in dimethylacetamide (5 ml) was added. The resulting mixture was heated to reflux for about 3 h 20 min. After cooling, copper bronze (0.45 g, 7.1 mg-atom) was added and heating was continued for 9 h 20 min. The reaction mixture was filtered through a pad of celite and the filtrate was diluted with dichloromethane (200 ml), washed consecutively with water (3×200 ml) and brine (100 ml), dried (magnesium sulfate) and concentrated to dryness. Purification by column chromatography (silica gel, 150 g; n-hexane/ethyl acetate (2/1)) followed by recrystallization from a mixture of isopropyl ether and n-hexane yielded 37 mg (5%) of the titled compound as white solids. MW: 365.36; mp: 156.0-157.0° C.; 1H-NMR (CDCl3) δ: 8.96 (1H, dd, J=4.8, 1.8 Hz), 8.36 (1H, dd, J=8.1, 1.8 Hz), 7.90 (1H, d, J=15.8 Hz), 7.84 (1H, d, J=8.1 Hz), 7.76 (1H, d, J=8.1, 4.8 Hz), 7.45-7.20 (7H, m), 6.92 (1H, d, J=7.7 Hz), 6.47 (1H, d, J=15.8 Hz).
Reaction SMILES: BrC[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:10][C:11]([F:20])([F:21])[O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCOc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of ethyl 4-bromobutanoate (2 g, 10.26 mmol) in acetone (20 mL) was added 3-(trifluoromethoxy)phenol (1.52 g, 8.54 mmol), followed by potassium carbonate (3.5 g, 25.36 mmol). The reaction was stirred at room temperature overnight. The mixture was partitioned between DCM and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum/ethyl acetate (10:1 to 5:1) to give ethyl 3-(3-(trifluoromethoxy)phenoxy)propanoate (2.3 g, 92.1% yield) as a colorless oil.
Reaction SMILES: Br[CH:2]([C@@H:8]([CH3:13])[C:9]([F:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:14]([CH:2]([C@@H:8]([CH3:13])[C:9]([F:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(Br)[C@@H](C)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(N=[N+]=[N-])[C@@H](C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
48.5 g of crude ethyl (3S)-2-bromo-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture) were dissolved in 130 ml of DMF, and 17.98 g (276.55 mmol) of sodium azide were added at RT. The reaction mixture was stirred vigorously at RT overnight. The mixture was then diluted with 600 ml of ethyl acetate and washed with a 1:1 mixture, adjusted to pH 8, of sat. sodium chloride solution and water. After phase separation, the aqueous phase was re-extracted with 200 ml of ethyl acetate. The combined organic phases were washed successively twice with in each case 100 ml and twice with in each case 50 ml of a 1:1 mixture of sat. sodium chloride solution and water, dried over sodium sulphate and concentrated under reduced pressure without heating. The residue was briefly dried under high vacuum (careful when venting). This gave 32.8 g of ethyl (3R)-2-azido-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture) as a crude product which was directly reacted further.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:44][CH2:45][CH3:46])([CH2:41][CH2:42][CH3:43])[C:7](=[O:40])[C:8]([C:13]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([NH:23][S:24]([NH:27]C(=O)OCC5C=CC=CC=5)(=[O:26])=[O:25])=[CH:22][C:16]=4[S:15](=[O:39])(=[O:38])[N:14]=3)=[C:9]2[OH:12])=[CH:4][CH:3]=1>[Pd].CO.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:44][CH2:45][CH3:46])([CH2:41][CH2:42][CH3:43])[C:7](=[O:40])[C:8]([C:13]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([NH:23][S:24]([NH2:27])(=[O:25])=[O:26])=[CH:22][C:16]=4[S:15](=[O:39])(=[O:38])[N:14]=3)=[C:9]2[OH:12])=[CH:4][CH:3]=1
Reactant: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC(=O)OCc4ccccc4)ccc3N2)=C(O)c2cc(F)ccc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(N)(=O)=O)ccc3N2)=C(O)c2cc(F)ccc21
Yield: 57.7 %

Procedure:
A solution of the product of Example 17D (28 mg, 0.042 mmol) in 2:1 methanol-ethyl acetate (15 mL) was treated with 10% Pd/C (20 mg) and hydrogenated at one atmosphere for 18 h. The mixture was filtered through Celite® and the filtrate concentrated in vacuo to afford the title compound (13 mg).