Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[C:11]([CH:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][C:14]([OH:16])=O)[C:4]=12.C1C[N:26]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:25]C1.F[P-](F)(F)(F)(F)F.CN>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[C:11]([CH:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][C:14]([NH:26][CH3:25])=[O:16])[C:4]=12
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: COc1ccnc2[nH]cc(C(CC(=O)O)c3ccccc3)c12
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CNC(=O)CC(c1ccccc1)c1c[nH]c2nccc(OC)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a RT suspension of 3-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-phenyl-propionic acid (635 mg, 2.14 mmol) in DCM (20 mL) was added TEA (0.45 mL, 3.21 mmol). To this mixture was added PyBOP (1.22 g, 2.35 mmol) and MeNH2 (2 M in THF, 1.60 mL, 3.21 mmol). The resulting mixture was stirred at RT for 30 min, and the white precipitate was collected by filtration to afford 3-(4-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methyl-3-phenyl-propionamide in 72% yield (477 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:13][O:14][CH2:15][CH2:16][CH2:17]CCCCCCCCCCCCCC)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32](C1OCC(CO)CO1)(C)C.C(Br)C1C=CC=CC=1>>[CH:16]([CH:15]1[O:12][CH2:11][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][O:14]1)([CH3:17])[CH3:32]
Reactant: CCCCCCCCCCCCCCCCCOCC(CO)COCc1ccccc1
Reactant: CC(C)C1OCC(CO)CO1
Agent: BrCc1ccccc1
Product: CC(C)C1OCC(COCc2ccccc2)CO1

Procedure:
The 2-benzyloxymethyl-3-heptadecyloxy-1-propanol used as starting material is obtained by reacting 2-isopropyl-5-hydroxymethyl-1,3-dioxan with benzyl bromide to give 2-isopropyl-5-benzyloxymethyl-1,3-dioxan (oil), subsequent splitting with sulfuric acid and reaction with an equimolar amount of heptadecyl bromide.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH3:7].[Mg].II.[CH:11]([SiH:14]([CH:16]([CH3:18])[CH3:17])Cl)([CH3:13])[CH3:12].[Cl-].[NH4+]>C1COCC1>[CH2:6]([O:5][CH2:4][CH2:3][CH2:2][SiH:14]([CH:16]([CH3:18])[CH3:17])[CH:11]([CH3:13])[CH3:12])[CH3:7]
Reactant: CCOCCCBr
Reactant: CC(C)[SiH](Cl)C(C)C
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOCCC[SiH](C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 107.4 %

Procedure:
1-Bromo-3-ethoxypropane (5.85 g, 35.0 mmol) was dissolved in THF (30 mL). Magnesium (900 mg, 37.0 mmol) and iodine (catalytic amount) were added thereto, and the resultant mixture was stirred at room temperature for 30 minutes and at 60° C. for 10 minutes. The resultant mixture was added dropwise to diisopropylchlorosilane (5.12 mL, 30.0 mmol) in THF (40 mL), followed by stirring at room temperature for 15 minutes and at 60° C. for 1.5 hours. Saturated aqueous ammonium chloride was added thereto, and the resultant mixture was extracted with pentane, followed by washing with water six times and drying over sodium sulfate anhydrate. The solvent was removed under reduced pressure, whereby the Compound 61a was obtained as an yellow liquid (6.52 g, 92%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[N:5][C:6]([CH:9]([NH:11][C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:10])=[CH:7][N:8]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:10][C:9]1[N:11]=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:6]=1[CH:7]=[N:8][C:3]([S:2][CH3:1])=[N:4]2
Reactant: CSc1ncc(C(C)NC(=O)c2ccccc2)nn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Yield: 63.5 %

Procedure:
Applying the Cyclization Procedure 1, using N-{1-[3-(methylthio)-1,2,4-triazin-6-yl]ethyl}benzamide (Intermediate 70) (590 mg, 2.15 mmol), 1,2-dichloroethane (10 mL) and phosphorus oxychloride (1.60 mL, 17.17 mmol), to afford 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (350 mg) as a yellow solid. MS m/z 257 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3](=O)[CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13].N1C=CC=CC=1.Cl.[CH3:22][O:23][NH2:24]>CO>[CH3:22][O:23][N:24]=[C:3]([CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13])[CH2:2][OH:1]
Reactant: O=C(CO)Cc1c(Cl)cc(Cl)cc1Cl
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C(CO)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 24 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a stirred solution of 1-hydroxy-3-(2,4,6-trichloro-phenyl)-propan-2-one (30 g; 118 mmol) in methanol (240 ml) was added pyridine (15 ml; 189 mmol) followed by a portionwise addition of methoxyamine hydrochloride (15 g; 178 mmol). The reaction mixture was stirred at 24° C. for 18 h under nitrogen. Methanol was removed under reduced pressure, the residue poured in water (300 ml) and 1N hydrochloric acid was added (100 ml). The solution was extracted with dichloromethane (3×150 ml). Combined organic layers were washed with water (300 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 33 g (99% of theory) of 1-hydroxy-3-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime (isomers E/Z 1:1) as a brown oil.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>ClCCl>[CH:1]1([NH:5][S:22]([C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=2)(=[O:23])=[O:24])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NC2CCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
To a stirred solution of cyclobutylamine (4.3 g, 59.7 mmol) and triethylamine (11.2 mL, 79.6 mmol) in dichloromethane (300 mL) was added the solution of 4-nitro-benzenesulfonyl chloride (8.8 g, 39.8 mmol) in dichloromethane (50 mL) at 0° C. The mixture was stirred at room temperature for 4 h and then washed with brine (50 mL×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford N-cyclobutyl-4-nitro-benzenesulfonamide (9.4 g, 92.5%) as a white powder: MS (ESI) M+1=257.1.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:53][C:54]([F:70])([F:69])[O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([NH2:68])[CH:63]=1>CN(C=O)C>[F:53][C:54]([F:69])([F:70])[O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([NH:68][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:63]=1
Reactant: Nc1cccc(-c2ccccc2OC(F)(F)F)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[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(Nc1cccc(-c2ccccc2OC(F)(F)F)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 89.8 %

Procedure:
DIEA (0.011 mL, 0.065 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.016 g, 0.059 mmol) and HATU (0.025 g, 0.065 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-trifluoromethoxy-biphenyl-3-ylamine (0.015 g, 0.059 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected were collected and the solvent removed under vacuum to give 0.027 g of product in 90% yield: LCMS (ESI) m/z 510 (MH+).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH:7]([O:8][CH3:9])[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1>C(O)C>[ClH:1].[ClH:1].[NH2:2][C@H:3]1[C@@H:7]([O:8][CH3:9])[CH2:6][NH:5][CH2:4]1
Reactant: COC1CN(C(=O)OC(C)(C)C)CC1N
Agent: Cl
Solvent: CCO
Product: CO[C@H]1CNC[C@H]1N

Procedure:
64 ml of 6N aqueous hydrochloric acid were added to a solution of 4.16 g (0.019 mole) of 3-amino-1-t-butoxycarbonyl-4-methoxypyrrolidine in 200 ml of ethanol, and the mixture was heated under reflux for 1 hour. At the end of this time, the solvent was completely removed by evaporation to dryness under reduced pressure to obtain cis-3-amino-4-methoxypyrrolidine dihydrochloride as a brown powder. The whole of this dihydrochloride was dissolved in 20 ml of water, 1.97 g (0.037 mole) of sodium methoxide was added thereto, and the solvent was removed by evaporation under reduced pressure to give a residue, which was washed with a 1:1 by volume mixture of ethanol and ethyl acetate. The washings were concentrated by evaporation under reduced pressure to afford 2.06 g of cis-3-amino-4-methoxypyrrolidine as a brown oily substance.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[C:6]([C:15]([NH:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:16])[CH:5]=1)([O-])=O.[ClH:23].[CH3:24]O>[Zn]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[C:6]([C:15]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH3:24])=[O:21])=[O:16])[CH:5]=1.[ClH:23]
Reactant: CO
Reactant: O=C(O)CCNC(=O)c1cc([N+](=O)[O-])c2ccccc2c1O
Agent: Cl
Agent: [Zn]
Product: COC(=O)CCNC(=O)c1cc(N)c2ccccc2c1O
Reaction time: 0.5 h

Procedure:
An amount of 210 g of 4-nitro-2-(2-carboxyethylamino)carbonyl-1-naphthol was dissolved in 28 liters of methanol at 40° C. Into this solution was added 1,200 ml conc. hydrochloric acid, followed subsequently by portionwise addition of 430 g of zinc powder. After 30 minutes, zinc was removed and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in 25 liters of ethyl acetate, washed with water and then dried over magnesium sulfate, followed by evaporation of the solvent, to give crystals. The crystals were washed with acetonitrile to obtain substantially pure desired product as hydrochloride. Yield was 75%. The product was confirmed by NMR, Mass spectra.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=2[N:21]=1)[CH2:13][CH2:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1)=O)C1C=CC=CC=1.I[Si](C)(C)C.CO>ClCCl>[Cl:29][C:27]1[CH:26]=[CH:25][C:23]2[NH:24][C:20]([C@@H:12]([NH2:11])[CH2:13][CH2:14][C:15]3[NH:19][N:18]=[N:17][N:16]=3)=[N:21][C:22]=2[CH:28]=1
Reactant: O=C(N[C@@H](CCc1nnn[nH]1)c1nc2cc(Cl)ccc2[nH]1)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClCCl
Product: N[C@@H](CCc1nnn[nH]1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.10 g (4.45 mmol) (1S)—N-(benzyloxycarbonyl)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propylamine in 30 ml dichloromethane are combined with 1.9 ml (13.4 mmol) iodo-trimethylsilane and stirred for 16 hours at ambient temperature. Then 20 ml of methanol are added, the mixture is stirred for a further 30 minutes at ambient temperature and the reaction mixture is evaporated down completely i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/(ethanol/conc. ammonia 95:5)=70/30→60:40).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:9][C:8]=1[C:20](=[O:31])[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=1[F:30])C.[OH-].[Na+]>C(O)C>[Br:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][NH:21][C:20]([C:8]2[CH:9]=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:11]([F:13])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:32])=[O:3])=[O:31])=[C:24]([F:30])[CH:25]=1
Reactant: CCOC(=O)COc1cc(F)c(N2CCOCC2)cc1C(=O)NCc1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc(F)c(N2CCOCC2)cc1C(=O)NCc1ccc(Br)cc1F
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
A suspension of [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-morpholin-4-yl-phenoxy]-acetic acid ethyl ester (0.8 g, 1.73 mmol) in ethanol (9 mL) was treated with aq 2 N NaOH (5.0 mL, 10.4 mmol). After stirring for 30 min, the reaction was concentrated in vacuo until most of the ethanol was removed. The mixture was acidified to pH 3 with aq 2 N HCl, extrated with ethyl acetate, and washed with saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated to give [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-morpholin-4-yl-phenoxy]-acetic acid (0.7 g, 93%) as a white crystalline solid: mp 180° C.; Rf 0.17 (20% methanol in dichloromethane); 1H NMR (DMSO-d6 300 MHz) δ 9.21 (t, J=5.4 Hz, 1H), 8.17 (s, 1H), 8.09 (dd, J1=8.1 Hz, J2=2.4 Hz, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.65-7.52 (m, 2H), 7.13 (d, J=13.8 Hz, 1H), 4.85 (s, 2H), 4.62 (d, J=6 Hz, 2H), 3.71 (t, J=4.7 Hz, 4H), 2.91 (t, J=4.8 Hz, 4H). Anal. calcd for C20H20FN3O7: C, 55.43; H, 4.65; N, 9.70. Found C, 55.49; H, 4.68; N, 9.60.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[S:11][C:12]3[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2].[BH4-].[Na+].[ClH:22]>CO.O1CCCC1.O.O.O.O.O.O.[Co](Cl)Cl>[ClH:22].[ClH:22].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:10]2[S:11][C:12]3[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(-c2nc3c(s2)NCCCC3)cc1C#N
Agent: Cl[Co]Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nc3c(s2)NCCCC3)cc1CN
Reaction time: 1 h
Yield: 22.7 %

Procedure:
Then, a solution of 2-(3-cyano-4-methylphenyl)-5,6,7,8-tetrahydro-4H-thiazolo[5,4-b]azepine (6.12 g) and cobalt chloride hexahydrate (10.8 g) in a mixture of methanol (30 ml) and tetrahydrofuran (20 ml) was ice-cooled, followed by adding a powder of sodium borohydride (8.6 g) gradually, and further stirred for 1 hr. at the same temperature. After acidifying with an aqueous 4N-hydrochloric acid, the reaction mixture was extracted with diethyl ether, the aqueous layer was alkalified with an aqueous ammonia and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography on silica gel, and neutralized with hydrogen chloride to give the title compound (yield 22.7%). m.p. 245°-248° (recrystallized from methanol).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH:26]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH3:27])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[OH:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH3:27])=[CH:19][CH:20]=2)=[N:13][CH:14]=1
Reactant: [H][H]
Reactant: CC(CCCC#Cc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1)OC1CCCCO1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(CCCCCc1ccc(-c2ncc(O)cn2)cc1)OC1CCCCO1

Procedure:
In a reactor equipped with a stirrer and a thermometer, 5-benzyloxy-2-[4-(6-tetrahydropyranyloxy-1-heptynyl)phenyl]pyrimidine, 5% Pd/C and THF are charged. After replacing an internal atmosphere of the reactor by hydrogen gas under atmospheric pressure, the mixture is reacted at room temperature for 10 hours in a hydrogen atmosphere under ordinary pressure. After filtrating the catalyst off, the reaction mixture is evaporated under reduced pressure. A resulting residue is purified by silica gel column chromatography to obtain 5-hydroxy-2-[4-(6-tetrahydropyranyloxy1-heptyl)phenyl]pyrimidine.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)=[S:11].BrBr>C(Cl)(Cl)(Cl)Cl.O>[C:1]1([CH3:23])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:14]2[C:15]([N+:20]([O-:22])=[O:21])=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: Cc1cc(C)c(NC(=S)Nc2ccc(C)c([N+](=O)[O-])c2)c(C)c1
Agent: BrBr
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(C)c(Nc2nc3ccc(C)c([N+](=O)[O-])c3s2)c(C)c1
Yield: 45.2 %

Procedure:
To a mixture of 1-mesityl-3-(4-methyl-3-nitrophenyl)thiourea (500 mg, 1.52 mmol) in carbon tetrachloride (25 ml) was added dropwise bromine (0.097 ml, 1.90 mmol) in carbon tetrachloride (10 ml) over 1 h. The mixture was refluxed for 18 h and diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with water and brine and concentrated under vacuum. The residue was triturated with ether. The resulting solid was collected by filtration to afford 225 mg of the title compound.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([O:15][CH3:16])=[N:9][C:8]=1[CH3:17])C.O.[NH2:20]N>C(O)(=O)C>[CH2:13]([C:11]1[C:10]([O:15][CH3:16])=[N:9][C:8]([CH3:17])=[C:7]([C:6]2[N:5]=[CH:4][NH:2][N:20]=2)[CH:12]=1)[CH3:14]
Reactant: NN
Reactant: CCc1cc(C(=O)N=CN(C)C)c(C)nc1OC
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(-c2nc[nH]n2)c(C)nc1OC
Temperature: 90 °C
Reaction time: 3.75 h
Yield: 51.9 %

Procedure:
In a round bottom flask under a nitrogen atmosphere N-dimethylaminomethylene-5-ethyl-6-methoxy-2-methylnicotinamide (synthesized on 0.309 mmol scale) is treated with glacial acetic acid (1 mL) followed by hydrazine hydrate (16.5 μL, 0.340 mmol). The resulting mixture is stirred at 90° C. for 3.75 hr. The reaction mixture is evaporated, then partitioned between water and dichloromethane and the pH adjusted to 6-7 by treating with solid sodium bicarbonate. The aqueous layer is separated and then further extracted with five portions of dichloromethane. The combined extract is dried over magnesium sulfate, filtered and evaporated to give 3-ethyl-2-methoxy-6-methyl-5-(1H-1,2,4-triazol-3-yl)-pyridine (35 mg, 52% yield, 2 steps) as a white solid. MS: m/e=219 (M+H); 1H NMR (300 MHz, CDCl3, δ, ppm): 11.52 (1H, s), 8.18 (1H, s), 7.78 (1H, s), 3.98 (3H, s), 2.68 (3H, s), 2.57 (2H, q), 1.19 (3H, t).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:31]([NH:33][C@H:34]([C:39]([OH:41])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:30])[NH:17][S:18]([C:21]1[C:28]([CH3:29])=[CH:27][C:25]([CH3:26])=[CH:24][C:22]=1[CH3:23])(=[O:20])=[O:19])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[NH:52]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C@H:53]([C:58](ON1C(=O)CCC1=O)=[O:59])[CH2:54][CH:55]([CH3:57])[CH3:56].CN1CCOCC1.NCCN1CCNCC1>CN(C)C=O.[Pd]>[NH:52]([C:68]([O:70][C:71]([CH3:73])([CH3:72])[CH3:74])=[O:69])[C@H:53]([C:58]([NH:1][C@H:2]([C:8]([NH:10][C@H:11]([C:31]([NH:33][C@H:34]([C:39]([OH:41])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:30])[NH:17][S:18]([C:21]1[C:28]([CH3:29])=[CH:27][C:25]([CH3:26])=[CH:24][C:22]=1[CH3:23])(=[O:20])=[O:19])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:59])[CH2:54][CH:55]([CH3:57])[CH3:56]
Reactant: Cc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CC(C)C)C(=O)O)c(C)c1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: [Pd]
Agent: NCCN1CCNCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O)c(C)c1
Reaction time: 5 h
Yield: 90.1 %

Procedure:
In 120 ml of dimethylformamide are dissolved 9.5 g (13 millimoles) of Z-Gln-Arg(Mts)-Leu-OH obtained according to the process of Example 20 and 5.2 g (16 millimoles) of Boc-Leu-OSu, and 1.43 ml of N-methylmorpholine is added to the solution. Then 0.5 g of 10% Pd-C is added to the mixture, and the mixture is stirred for 5 hours in a current of H2. The N-(2-aminoethyl)piperazine is added to the mixture, the mixture is stirred for 1 hour. The 10% Pd-C is recovered by filtration, and the mixture is cancentrated under reduced pressure. The residue is added to a liquid mixture of 100 ml of ethyl acetate and 200 ml of a dilute aqueous solution of citric acid. The mixture is sufficiently stirred, and the ethyl acetate layer is recovered, washed with water, dried and concentrated under reduced pressure. Ether is added to the concentrate and the precipitate is recovered by filtration to obtain 9.5 g of intended Boc-Leu-Gln-Arg(Mts)-Leu-OH (the yield being 86.5%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][O:16][C:15]3[CH:18]=[C:19]4[C:23](=[CH:24][C:14]2=3)[CH2:22][CH2:21][O:20]4)[C:6]1=[O:25].C(N(CC)CC)C.[F:33][C:34]([F:46])([F:45])[O:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>ClCCl>[O:25]=[C:6]1[C:7]2([CH2:17][O:16][C:15]3[CH:18]=[C:19]4[C:23](=[CH:24][C:14]2=3)[CH2:22][CH2:21][O:20]4)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]1[CH2:4][CH2:3][CH2:2][NH:1][C:38](=[O:39])[C:37]1[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=1[O:35][C:34]([F:33])([F:45])[F:46]
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Reactant: NCCCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21)c1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
To a solution of 1′-(3-aminopropyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.20 g, 0.59 mmol) in anhydrous dichloromethane (10 mL) was added triethylamine (0.10 mL, 0.71 mmol) followed by 2-(trifluoromethoxy)benzoyl chloride. The reaction mixture was stirred at ambient temperature for 20 h and concentrated in vacuo. The residue was purified by column chromatography to afford N-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propyl]-2-(trifluoromethoxy)benzamide (0.21 g, 67%) as a colorless foam: mp 65-70° C.; 1H NMR (300 MHz, CDCl3) δ 7.81 (dd, J=7.6, 1.7 Hz, 1H), 7.47 (ddd, J=9.4, 7.6, 1.5 Hz, 1H), 7.39-7.30 (m, 3H), 7.20 (d, J=6.9 Hz, 1H), 7.09 (dd, J=7.5, 7.5 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 6.47 (s, 1H), 6.41 (s, 1H), 4.90 (d, J=9.0 Hz, 1H), 4.67 (d, J=9.0 Hz, 1H), 4.53 (t, J=8.6 Hz, 1H), 4.02-3.83 (m, 2H), 3.58-3.33 (m, 2H), 2.99 (t, J=8.6 Hz, 2H), 2.05-2.01 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 179.0, 164.9, 161.9, 161.3, 145.7, 141.8, 132.8, 131.8, 130.7, 129.3, 128.9, 127.3, 124.1, 123.7, 121.5, 120.3 (d, JC-F=259.2 Hz), 120.0, 119.8, 118.7, 108.4, 93.3, 80.5, 72.4, 57.8, 37.1, 36.1, 29.0, 27.0; MS (ES+) m/z 524.5 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[C:25]1([CH3:28])[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:27][CH:26]=1.[C:25]1([CH3:28])[CH:24]=[CH:23][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:27][CH:26]=1
Reactant: Cc1ccc(Oc2ccc(OC[C@@H]3CCCN3C(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(Oc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Yield: 93 %

Procedure:
(S)-2-(4-p-Tolyloxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.02 g, 7.88 mmol) was taken into 4M HCl in dioxane (10 mL) and reacted at room temperature for 12 h. The mixture was concentrated to dryness to obtain the title product (2.35 g, 7.35 mmol, 93% yield); MS; m/z 320, found 284 (M-36HCl); 1H NMR (400 MHz, DMSO-d6) δ 1.70-1.78 (m, 1H), 1.87-1.94 (m, 1H), 1.96-2.01 (m, 1H), 2.08-2.14 (m, 1H), 2.27 (s, 3H), 3.17-3.24 (m, 2H), 3.86-3.92 (m, 1H), 4.10-4.15 (m, 1H), 4.20-4.24 (m, 1H), 6.82-6.84 (d, J=8.0, 2H), 6.99-7.0 (m, 4H), 7.15-7.17 (d, J=8.0, 2H), 9.34 (s, 1H).