Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15].N#N>CN(C=O)C.C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:13])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: N#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.08 h
Yield: 76.7 %

Procedure:
To a solution of 5.0 g (1.0 eq, 28.6 mmol) 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine in 30 mL DMF under N2 at rt was added 1.37 g (1.2 eq, 34.3 mmol) of a 60% oil dispersion of NaB. After stirring for 5 minutes, 8.64 g (1.4 eq, 40.0 mmol) of p-nitrobenzyl bromide was added. The dark brown mixture was stirred for 2 hours under a blanket of N2 at rt. The mixture was diluted with 1 L CH2Cl2 and washed with 500 mL H2O and 500 mL saturated aqueous NaCl. The organic phase was dried over MgSO4 and concentrated to a yellow oil. The oil was flash chromatographed with 50% ethyl acetate/hexane. The product containing fractions were combined and concentrated to a yellow oil which crystallized on standing, yielding 6.81 g (76.8%) of the title compound.
Reaction SMILES: C(OC[N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[C:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=2)=[C:11]1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH:40]2[CH2:42][CH2:41]2)[CH:30]=1)C1C=CC=CC=1.C(OCN1C2C=NNC(=O)C=2C(CC2C=CC=CC=2F)=C1C1C=CC(OC(F)F)=C(OC2CC2)C=1)C1C=CC=CC=1>>[C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][C:12]1[C:13]2[C:18](=[O:19])[NH:17][N:16]=[CH:15][C:14]=2[NH:10][C:11]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:37])[F:38])=[C:31]([O:39][CH:40]2[CH2:42][CH2:41]2)[CH:30]=1)#[N:28]
Reactant: N#Cc1cccc(Cc2c(-c3ccc(OC(F)F)c(OC4CC4)c3)n(COCc3ccccc3)c3cn[nH]c(=O)c23)c1
Agent: O=c1[nH]ncc2c1c(Cc1ccccc1F)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2COCc1ccccc1
Product: N#Cc1cccc(Cc2c(-c3ccc(OC(F)F)c(OC4CC4)c3)[nH]c3cn[nH]c(=O)c23)c1
Reaction time: 1 h
Yield: 20.8 %

Procedure:
Reaction was carried out in the same manner as in Example 22-(b) except for using 110 mg (0.193 mmol) of 1-benzyloxymethyl-3-(3-cyanobenzyl)-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 26-(a) in place of 1-benzyloxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(2-fluorobenzyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, the reaction suspension was filtered, the filtrate was concentrated under reduced pressure, methanol and 28% aqueous ammonia were added to the obtained solid, and the mixture was stirred for 1 hour. Then, the solution was concentrated under reduced pressure and the obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1→0:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 18 mg of the title compound as a white solid. (Yield: 20%)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[N:30][OH:31])[CH2:17][O:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[C:21]([OH:29])[CH:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>>[C:1]([C:5]1[CH:6]=[C:7]([C:16](=[N:30][OH:31])[CH2:17][O:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[C:21]([OH:29])[CH:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OCC(=NO)c2ccc(N3CCCC3)c(C(C)(C)C)c2)cc1O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1cc(C(COc2ccc(C(=O)O)c(O)c2)=NO)ccc1N1CCCC1

Procedure:
In a manner similar to that of Example 1.g, by reaction of 193 mg (0.45 mmol) of methyl 4-[2-(3-tert-butyl4-pyrrolidin-1-ylphenyl)-2-hydroxyiminoethoxy]-2-hydroxybenzoate with 90 mg (2.3 mmol) of powdered sodium hydroxide. The final product is then recrystallized from a heptane/ethyl ether system. A beige-colored crystalline solid is obtained (m.p.=234° C., m=25 mg, yield=13%); (1H NMR (DMSO): 1.35 (s, 9H); 1.86 (s, 4H); 2.89 (s, 4H); 5.26 (s, 2H); 6.46-6.49 (d, J=8.6 Hz, 1H); 6.5 (s, 1 H); 7.40-7.42 (d, J=8.2 Hz, 1H); 7.49-7.51 (d, J=7.9 Hz, 1H); 7.66-7.68 (d, J=8.5 Hz, 2H); 11.9 (s, 1H)).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:13]([O:4][CH2:1][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A solution of compound 7, the properly substituted benzyl alcohol (1.1 eq), palladium(II) acetate (0.02 eq), 2-dit-butylphosphino-3,4,5,6-tertamethyl-2′,4′,6′-triisopropyl-1,1′biphenyl (0.02 eq), cesium carbonate (1.5 eq) in degassed toluene (4 ml/mmol) was heated at 75° C. for 16 hrs. Conversion was checked by TLC analysis. The solution was cooled to room temperature, diluted with DCM, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give compound 9 in yields varying from 30-80%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:29][OH:30])[C:5]([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.[H-].[Na+].[CH3:33]I>CN(C=O)C>[CH3:33][O:30][CH2:29][C:4]1[C:5]([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[N:9]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(CO)cc(C)c32)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1COC1CCCCO1
Reaction time: 0.17 h

Procedure:
To a solution of (±)-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)methanol (Example 52-C) (170 mg, 0.40 mmol) in DMF (1 mL) was added NaH (31.7 mg, 60% in mineral oil, 0.79 mmol) at room temperature, and then the mixture was stirred for 10 min. To the mixture was added MeI (25 uL, 0.40 mmol) at room temperature, and then the mixture was stirred for 2.5 h. The reaction was quenched by half saturated aqueous solution of KHSO4, and diluted with EtOAc. The bi-layer was partitioned. The organic phase was washed successively H2O and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave the title compound, without need of any further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J=3.79 Hz, 1H), 7.62 (d, J=8.34 Hz, 2H), 7.39 (d, J=8.34 Hz, 2H), 7.08 (s, 1H), 6.99 (d, J=3.79 Hz, 1H), 4.87 (d, J=11.37 Hz, 1H), 4.67 (d, J=11.37 Hz, 1H), 4.60-4.64 (m, 1H), 4.44-4.54 (m, 2H), 3.73-3.86 (m, 1H), 3.41-3.52 (m, 1H), 3.30 (s, 3H), 2.47 (s, 3H), 2.34 (s, 3H), 1.51-1.78 (m, 2H), 1.34-1.51 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:16]([Cl:17])=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][C:10]=2[Cl:18])=[CH:4][CH:3]=1.F[B-](F)(F)F.C1(C2C=C(C3C=CC=CC=3)C=C(C3C=CC=CC=3)[O+]=2)C=CC=CC=1.[N-:48]=[N+:49]=[N-].[Na+]>C(O)C.CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:16]([Cl:17])=[CH:15][C:12]([CH2:13][N:14]=[N+:48]=[N-:49])=[CH:11][C:10]=2[Cl:18])=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: NCc1cc(Cl)c(Sc2ccc(Cl)cc2)c(Cl)c1
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1cc(Cl)c(Sc2ccc(Cl)cc2)c(Cl)c1
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
A stirred solution of 4-(4-chlorophenylthio)-3,5-dichlorobenzylamine (3.59 g, 11.3 mmol) in absolute ethanol (30 ml) at ambient temperature was treated in one portion with 2,4,6-triphenylpyrylium tetrafluoroborate (3.58 g, 9.06 mmol). The mixture was stirred 30 minutes, diluted with dimethylformamide (30 ml), and stirred 16 hours. The solvent was evaporated under vacuum at 60° C. and the residue was triturated with diethyl ether (2×25 ml). The residual solid was dissolved in dry dimethylformamide (23 ml), dry sodium azide (2.27 g, 34.9 mmol) was added, and the mixture was stirred at 130° C. for 6 hours and ambient temperature for 4 days. The mixture was diluted with water (250 ml) and extracted twice with diethyl ether. The combined extracts were washed with water (2X) and brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum. The residue was disolved in dichloromethane, silica gel (60 g) was added, and the mixture was dried under vacuum, placed on a column of silica gel (600 ml), and eluted in 50 ml fractions with 1:2 (v/v) dichloromethane-hexane. After a forerun, fractions 8-14 were combined and evaporated under vacuum to provide 320 mg oily 4-(4-chlorophenylthio)-3,5-dichlorobenzyl azide. Fractions 15-22 were combined, evaporated under vacuum, and the residue was chromatographed on one 20 cm×20 cm 1500μ silica gel preparative thick layer chromatography plate developed with 1:2 (v/v) dichloromethanehexane. Product was eluted with dichloromethane and solvent was evaporated under vacuum to provide an additional 62 mg of oily azide (total yield: 382 mg [10%]).
Reaction SMILES: [CH2:1]([CH2:8][N:9]=[C:10]([NH:12][N+:13]([O-])=O)[NH2:11])[CH2:2][C@H:3]([NH2:7])[C:4]([OH:6])=[O:5]>C(O)(=O)C.[Pt]=O>[CH2:1]([CH2:8][N:9]=[C:10]([NH:12][NH2:13])[NH2:11])[CH2:2][C@H:3]([NH2:7])[C:4]([OH:6])=[O:5]
Reactant: NC(=NCCC[C@H](N)C(=O)O)N[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: NNC(N)=NCCC[C@H](N)C(=O)O
Temperature: 100 °C
Reaction time: 60 h
Yield: 35 %

Procedure:
4.38 (20 mmol) NG -nitro-L-arginine (Sigma Chemicals) was dissolved in 25 ml of I5% aqueous acetic acid with 0.1 gm platinum oxide. The reaction was carried out at 40 psi H2 pressure and room temperature for about 60 hours. Catalyst was removed by filtration under argon, and the filtrate was rotary evaporated under reduced pressure to an oil. The oil was repeatedly dissolved in water and evaporated under vacuum and finally dissolved in 40 ml water. Analysis indicated 55% NG -amino-L-arginine and 45% L-arginine. The solution was adjusted to pH of 9.5 with NaOH and 5 mg arginase was added (1050 IU). The resulting solution was incubated at 37° C. overnight. After this treatment the solution contained NG -amino-L-arginine and L-orthinine but no L-arginine. The arginase was denatured by heating the solution to 100° C. for 5 to 10 minutes and removed by filtration. An aqueous solution of flavianic acid (6.28 gm in 100 ml) was added until the pH was about 3.8 and precipitate began to form. The solution was chilled to 40° C. overnight to complete precipitation of the product and the precipitate was collected by filtration (about 3.0 gm). The solid was redissolved in hot water (100 ml) by dropwise addition of 1M NaOH. Addition to that solution of HCl to pH 3.8 caused formation of crystals of NG -amino-L-arginine monoflavianic acid salt. After chilling of the solution at 4° C. for 4 hours, the yellow crystals were collected by filtration and washed sequentially with absolute ethanol and ethyl ether. The product (2.4 grams) was pure NG -amino-L-arginine monoflavianic acid salt (C16H21N7O10S requires: C=38.2%; H=4.2%; N=19.5%. Found: C=38.4%, H=4.2%; N=19.5%). The monoflavianic acid salt was suspended in 100 ml of water at 100° C. and 10 grams of Dowex 1 (OH-), a strong base ion exchange resin, was added. After stirring at 100° C. for 5 hrs the supernatant was clear and all of the yellow flavianic acid was bound to the Dowex 1 resin. The resin was removed by filtration, and the clear filtrate was dried to an oil by rotary evaporation at reduced pressure. The oil was dissolved in 50 ml of ethanol and the ethanol was evaporated at reduced pressure. Addition and removal of ethanol was repeated again, and then 50 ml of ethyl ether was similarly added and removed The solid residue was dried under high vacuum over P2O5 for 12 hours. The yield was 1.2 grams of pure (99.9+% pure) NG -amino-L-arginine (35% yield based on starting NG -nitro-L-arginine).
Reaction SMILES: C(O[C:9]1[CH:17]=[CH:16][C:15]2[N:14]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:13]=[CH:12][C:11]=2[C:10]=1[CH:27]=[O:28])C1C=CC=CC=1.[CH3:29][NH:30][CH2:31][CH2:32][OH:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N#N>ClCCCl>[OH:33][CH2:32][CH2:31][N:30]([CH2:9][C:10]1[C:27]([OH:28])=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][N:14]2[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:29]
Reactant: CNCCO
Reactant: O=Cc1c(OCc2ccccc2)ccc2c1ccn2S(=O)(=O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N#N
Agent: [Na+]
Solvent: ClCCCl
Product: CN(CCO)Cc1c(O)ccc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 40 °C

Procedure:
To a solution of 5-(Benzyloxy)-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (50 mg, 0.12 mmol, Intermediate 62) in DCE (3 mL) was added N-methyl ethanolamine, 22 mg (0.26 mmol) and sodium triacetoxyborohydride, 80 mg (0.38 mmol) and the mixture was heated in a sealed test tube at 40° C. over night. The solvent was removed at reduced pressure and the residue was dissolved in MeOH (2 mL), 10% Pd/C, 20 mg was added and the mixture was flushed with N2, NH4+HCOO− (50 mg, 0.8 mmol) was added, the reaction mixture was again flushed with N2 and the reaction mixture was stirred at 40° C. over night. The solvent was removed at reduced pressure, the semisolid was taken up between CHCl3/H2O, washed with H2O (×1), brine (×1), dried (MgSO4) and the solvent was removed at reduced pressure. A sample was withdrawn and purified with on a preparative HPLC, method B, to yield 6.3 mg of a colorless oil. MS (ESI+) for C18H20N2O4S m/z 361 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1)(=O)[CH3:2].Cl.[NH2:23][OH:24]>N1C=CC=CC=1>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([C:1](=[N:23][OH:24])[CH3:2])[CH:21]=[CH:20][C:7]=2[CH2:8][CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: NO
Reactant: CC(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
7-Acetyl-3-(tert-butyloxycarbonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (8.9 g, 30.8 mmol) was dissolved in pyridine (30 ml) and hydroxylamine hydrochloride (2.3 g, 33 mmol) was added and the mixture stirred for 2 h at room temperature. The solvent was evaporated and hexane (300 ml) and water (100 ml) were added and the colourless precipitate was filtered and washed with hexane (3×100 ml). The compound was dried in vacuo to give the title compound (6.23 g, 66%).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][O:8][CH:9]1[CH2:12][NH:11][CH2:10]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:44]=[C:45]1[NH:58][C:48]2=[N:49][CH:50]=[C:51](/[CH:53]=[CH:54]/[C:55](O)=[O:56])[CH:52]=[C:47]2[NH:46]1>CN(C)C=O>[O:56]=[C:55]([N:11]1[CH2:12][CH:9]([O:8][CH2:7][C:3]2[S:2][CH:6]=[CH:5][CH:4]=2)[CH2:10]1)/[CH:54]=[CH:53]/[C:51]1[CH:52]=[C:47]2[NH:46][C:45](=[O:44])[NH:58][C:48]2=[N:49][CH:50]=1
Reactant: O=C(O)/C=C/c1cnc2[nH]c(=O)[nH]c2c1
Reactant: c1csc(COC2CNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cnc2[nH]c(=O)[nH]c2c1)N1CC(OCc2cccs2)C1
Reaction time: 8 h
Yield: 14.4 %

Procedure:
3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (127 mg, 0.62 mmol), EDCI (120 mg, 0.62 mmol), HOBt (86 mg, 0.62 mmol) and diisopropylethylamine (180 μL, 1.03 mmol) were successively added to a solution of (E)-3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)acrylic acid hydrochloride (100 mg, 0.41 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred overnight then partitioned between ethyl acetate (20 mL) and water (30 mL). The aqueous layer was separated and successively extracted with ethyl acetate (2×20 mL) and dichloromethane (2×20 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (98:2 to 93:7) as eluent. The residue was triturated in pentane to afford the title product as a pale orange solid (21 mg, 14%).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[F:26][C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][C:33](O)=[O:34])=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH:31]=[CH:32][C:33]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:3]([CH3:2])[CH:4]=2)=[O:34])=[CH:36][CH:37]=1
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccc(F)cc1
Yield: 95.4 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (2.0 g), triethylamine (1.1 mL), 4-fluorocinnamic acid (1.4 g), WSC.HCl (1.6 g), and methylene chloride (80 mL), to give the captioned compound (2.7 g, 94%) as an oily product.
Reaction SMILES: [CH2:1]=[C:2]1[S:6][C:5](=[NH:7])[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[O:15][C:10]=3[CH:9]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34](Cl)=[O:35]>C(#N)C.C(Cl)Cl>[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34](/[N:7]=[C:5]1\[S:6][C:2](=[CH2:1])[CH2:3][N:4]\1[C:8]1[CH:21]=[CH:20][C:11]2[O:12][C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[O:15][C:10]=2[CH:9]=1)=[O:35]
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)C(F)(F)O3)C(=N)S1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: C=C1CN(c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/C(=N/C(=O)CC(C)(C)C)S1
Temperature: 65 °C

Procedure:
To a solution of 5-methylene-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazolidin-2-imine (Example 22C, 0.14 g, 0.44 mmol) in acetonitrile (3 mL) was added Hunig's base (0.062 g, 0.48 mmol) followed by 3,3-dimethylbutanoyl chloride (0.088 g, 0.66 mmol). The mixture was heated for 12 hours at 65° C. The reaction mixture was cooled down, diluted with CH2Cl2 (50 mL), and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and dried. After evaporation under reduced pressure, the residue was chromatographed over silica using CH2Cl2-5% MeOH/CH2Cl2 to supply the titled compound. 1H NMR (CDCl3) δ ppm 1.00 (9 H), 2.35 (2 H), 4.65 (2 H), 5.25 (1 H), 5.35 (1 H), 7.15 (1 H), 7.25 (1 H), 7.55 (1 H); MS (ESI) m/z 419(M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:24]2[C:25]([CH3:36])=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[O:27][C:23]=2[CH:22]=[CH:21][CH:20]=1)[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:26]1[O:27][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([O:18][CH2:17][CH2:16][CH2:15][NH:7][CH2:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[C:24]=2[C:25]=1[CH3:36]
Reactant: COc1ccccc1-c1oc2cccc(OCCCN(Cc3cccnc3)C(=O)OC(C)(C)C)c2c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1oc2cccc(OCCCNCc3cccnc3)c2c1C
Yield: 88.5 %

Procedure:
{3-[2-(2-Methoxy-phenyl)-3-methyl-benzofuran-4-yloxy]-propyl}-pyridin-3-ylmethyl-carbamic acid tert-butyl ester (24 mg) was treated in 10% trifluoroacetic acid in dichloromethane at room temperature for 18 hours. The mixture was washed with saturated sodium bicarbonate solution and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was purified by silica gel TLC (dichloromethane-methanol=10:1) to give a pale yellow oil (17 mg, 88%). FAB-MS: m/z 402 (MH+); 1H-NMR (CDCl3) δ: 2.07 (2H, tt, J=6.6 Hz, 5.9 Hz), 2.28 (3H, s), 2.90 (2H, t, 6.6 Hz), 3.84 (3H, s), 3.85 (2H, s), 4.17 (2H, t, J=5.9 Hz), 6.61 (1H, d, J=7.6 Hz), 6.95-7.23 (5H, m), 7.40 (1H, dt, J=7.6 Hz, 1.7 Hz), 7.46 (1H, dd, J=7.6, 1.7 Hz), 7.67 (1H, d, J=7.4 Hz), 8.48 (1H, d, J=3.0 Hz), 8.56 (1H, s).
Reaction SMILES: [C:1]([NH:14][C@H:15]([C:19]([OH:21])=[O:20])[CH:16]([CH3:18])[CH3:17])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(=O)(=O)(O)O.[CH:27](O)([CH3:29])[CH3:28]>>[CH:27]([O:20][C:19](=[O:21])[C@H:15]([CH:16]([CH3:18])[CH3:17])[NH:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([CH3:29])[CH3:28]
Reactant: CC(C)O
Reactant: CCCCCCCCCCCC(=O)N[C@H](C(=O)O)C(C)C
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCC(=O)N[C@H](C(=O)OC(C)C)C(C)C

Procedure:
Forty-nine(49) grams of N-lauroylvaline and 197 g of isopropanol were charged into a 500-milliliter flask. Further, 1.61 g of conc. sulfuric acid were added as the catalyst. The mixture was heated under reflux for reaction for 6 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:27])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:27])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][C:23]([F:24])([F:25])[F:26])[CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-{3-[(trifluoromethyl)thio]benzyl}propanoate (5.30 g, 13.17 mmol) in methanol (150 ml) was added 2N aqueous sodium hydroxide solution (13.2 ml, 26.4 mmol), and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated, 1N hydrochloric acid was added. The mixture was acidified and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the objective substance (3.98 g, 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[OH:10].[H-].[Na+].O=O.I[CH2:16][CH3:17]>CN(C=O)C>[CH2:16]([O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[CH3:1])[C:6]#[N:7])[CH3:17]
Reactant: CCI
Reactant: Cc1ccc(C#N)cc1O
Agent: O=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(C#N)ccc1C
Yield: 72.8 %

Procedure:
10 g (75 mmol) of 4-methyl-3-hydroxybenzonitrile were deprotonated with 1 eq. of NaH in 100 ml of DMF and then ethylated on the oxygen with 112 mmol of iodoethane. 8.8 g of product were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11](O)=[O:12])[O:8][C:7]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[CH:26]=1.C(N1C=CN=C1)([N:29]1C=CN=C1)=O.[NH4+].[OH-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([NH2:29])=[O:12])[O:8][C:7]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[CH:26]=1
Reactant: O=C(O)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4.8 g 6-chloro-4,4-dicyclohexyl-4H-benzo[1,3]dioxine-2-carboxylic acid and 2.44 g 1,1′-carbonyl diimidazole in 122 ml THF was stirred for 2 h at room temperature. Then 122 ml 25% aqueous NH4OH was added and the reaction mixture stirred for 16 h at room temperature. The precipitate was filtered, washed with cold water and dried over P2O5. Recrystallization from EtOAc yielded the desired product. Yield: 3.55 g.