Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[CH:7]=1>C(O)(=O)C.CO.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]2[N:6]([C:8]([CH:11]([CH3:12])[CH3:13])=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)c1nnc2c([N+](=O)[O-])cc(Br)cn12
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)c1nnc2c(N)cc(Br)cn12

Procedure:
Compound B was prepared by heating A, 6-bromo-3-isopropyl-8-nitro-[1,2,4]triazolo[4,3-a]pyridine, prepared as described in Example 9A, Step 1, (0.777 mmole) in acetic acid (6 mL) in the presence of Zinc dust (3.89 mmole) at 60 C for 1 hour. The reaction mixture was then diluted with methanol and filtered to celite. The filtrate was concentrated down and the residue was then filtered through silica gel with first ethyl acetate and then with 1:4 mixture of methanol and dichloromethane. The filtrate was evaporated in vacuo to yield B, 6-bromo-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-8-amine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=3)[C:28](O)=[O:29])[CH2:20][CH2:19]2)=[C:14]([CH3:34])[N:13]([CH2:35][C:36]2[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[CH:38][C:37]=2[F:46])[C:12]1=[O:47])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH2:55]([O:57][C:58](=[O:63])[CH2:59][CH2:60][CH2:61][NH2:62])[CH3:56].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:55]([O:57][C:58](=[O:63])[CH2:59][CH2:60][CH2:61][NH:62][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([CH2:24][N:21]2[CH2:22][CH2:23][N:18]([C:15]3[C:16](=[O:17])[N:11]([CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:12](=[O:47])[N:13]([CH2:35][C:36]4[C:41]([C:42]([F:44])([F:45])[F:43])=[CH:40][CH:39]=[CH:38][C:37]=4[F:46])[C:14]=3[CH3:34])[CH2:19][CH2:20]2)[CH:26]=1)[CH3:56]
Reactant: Cc1c(N2CCN(Cc3cccc(C(=O)O)c3)CC2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: CCOC(=O)CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNC(=O)c1cccc(CN2CCN(c3c(C)n(Cc4c(F)cccc4C(F)(F)F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c4ccccc4)c3=O)CC2)c1
Yield: 99.7 %

Procedure:
To a solution of 3-{4-[3-((R)-2-tert-butoxycarbonylamino-2-phenyl-ethyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-piperazin-1-ylmethyl}-benzoic acid (40 mg, 0.0541 mmol) and 4-amino-butyric acid ethyl ester chloride (19 mg, 0.108 mmol) in DMF (0.5 mL) was added N,N-diisopropylethylamine(38 μl, 0.216 mmol), after which HBTU (51 mg, 0.162 mmol) was added to the solution, with stirring. The solution was concentrated at room temperature for 6 hrs, with stirring. The residue was diluted in EtOAc and washed with an aqueous saturated sodium bicarbonate solution, an aqueous saturated ammonium chloride solution, and an aqueous saturated sodium chloride solution in that order. After being separated, the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 30/1) and dried in a vacuum to afford 46 mg of the compound as a yellowish solid (yield 99%). 1H NMR (300 MHz, CDCl3) δ 1.24 (3H, t), 1.34 (9H, s), 1.98 (2H, pentet), 2.31 (2H, m), 2.34 (3H, s), 2.44 (2H, t), 2.53 (2H, m), 2.82 (2H, m), 3.53 (2H, q), 3.64 (4H, m), 4.06 (1H, m), 4.12 (2H, q), 4.24 (1H, t), 5.00 (1H, m), 5.45 (2H, dd), 5.78 (1H, m), 6.30 (0.2H, t), 6.77 (0.8H, t), 7.20-7.41 (8H, m), 7.53 (2H, t), 7.83 (1H, d), 7.71 (1H, d), 7.75 (1H, s)
Reaction SMILES: [Si]([O:8][C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]4=[N:26][S:27](=[O:31])(=[O:30])[CH2:28][CH2:29][N:24]4[CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[O:31]=[S:27]1(=[O:30])[CH2:28][CH2:29][N:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][C:12]4[CH:32]=[CH:33][C:9]([OH:8])=[CH:10][CH:11]=4)=[CH:15][CH:16]=3)[C:25]2=[N:26]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(O)cc4)cc3)C2=N1
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A solution of 9-[4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (1.82 g) in THF (dry) (55 mL) was added to tetrabutylammonium fluoride(1 M in THF) (6.79 mL) at room temperature. After stirring for 0.5 hr, the mixture was added with sat.NH4Cl aq. and silica gel, then concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane then MeOH in EtOAc), recrystallized from THF—IPE, then preparative HPLC (C18, eluent; H2O/MeCN with 0.1% TFA). The collected fraction was concentrated in vacuo. The residue was recrystallized from MeCN—H2O to give the title compound (492 mg) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16](B(O)O)[CH:15]=[CH:14]2.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH:15]=[CH:14]2
Reactant: Nc1ncccc1Br
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc2cc(-c3cccnc3N)ccc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 115.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (95 mg) was added to a suspension of 3-bromopyridin-2-amine (713.7 mg), 6-methoxynaphthalen-2-ylboronic acid (1000 mg) and sodium carbonate decahydrate (2361 mg) in DME (15 mL) and water (3 mL) and the mixture was stirred at 80° C. under nitrogen for 3 hr and at 70° C. overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the volatiles were removed in vacuo to give the title compound (1194 mg) as a crude orange solid. This product was subjected to the next reaction without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]2.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([SH:36])[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([S:36][C:2]2[CH:3]=[CH:4][N:5]3[C:10]=2[C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[N:6]3)[CH:33]=[CH:34][CH:35]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(I)c2c(=O)n1-c1ccccc1
Reactant: COc1cccc(S)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(Sc2ccn3nc([C@H](C)NC(=O)OC(C)(C)C)n(-c4ccccc4)c(=O)c23)c1
Yield: 30 %

Procedure:
(S)-tert-Butyl (1-(5-iodo-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (500 mg, 1.04 mmol) was treated with 3-methoxybenzenethiol (219 mg, 1.56 mmol), potassium carbonate (216 mg, 1.56 mmol) and copper(I) iodide (297 mg, 1.56 mmol) according to the method described in Preparation 44. The residue was purified by reverse phase using Isolera® Purification System to give 154 mg (30% yield) to the title compound. Purity 100%.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].NCC[CH2:9][CH2:10][CH2:11][CH2:12]N>O>[CH3:9][CH2:10][CH2:11][CH2:12][NH:4][C:3]([NH2:5])=[N:2][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: N=C(N)N
Reactant: NCCCCCCN
Agent: Cl
Solvent: O
Product: CCCCN=C(N)NCCCC
Temperature: 120 °C

Procedure:
A mixture of guanidine hydrochloride (200 parts) and hexamethylene diamine (292 parts) were heated to 120° C. for 4 hours under a nitrogen atmosphere The temperature was then raised to 150–170° C. for a further 5 hours. The mixture was cooled to 80° C. and water (400 parts) was added, maintaining the temperature at 80° C. until dissolution occurred. The mixture was then cooled to give a solution in water of polyhexamethyleneguanidine, referred to as Prepolymer 1, having a weight average molecular weight (Mw) of 1010 and a number average molecular weight (Mn) of 710, as determined by aqueous gel permeation chromatography.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13](=[O:31])[CH2:14][CH:15]([OH:30])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[C:8]([O:12][C:13](=[O:31])[CH2:14][CH:15]([O:30][C:1](=[O:3])[CH3:2])[CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:22][CH:23]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)CC(O)CCc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(CCc1ccc(-c2ccccc2)cc1)CC(=O)OC(C)(C)C
Yield: 71.8 %

Procedure:
Acetic anhydride (40 μL, 0.42 mmol) was added to a stirred solution of 5-biphenyl-4-yl-3-hydroxy-pentanoic acid tert-butyl ester (Intermediate 3, 54 mg, 0.17 mmol), 4-dimethylaminopyridine (5.0 mg, 41 μmol) and pyridine (54 μL, 0.66 mol) in dichloromethane (1 mL) at room temperature under nitrogen. Stirring was continued for 12 hours at room temperature before the addition of 2 M hydrochloric acid (5 mL) and dichloromethane (5 mL). The phases were separated and aqueous phase extracted with dichloromethane (3×5 mL). The organic phases were combined, washed with brine (5 mL) and dried (MgSO4). The solvent was removed by evaporation under reduced pressure to give the title compound (45 mg, 74%) as a colourless gum. LC/MS: 3.91 min; z/e 386, calcd (M+NH4) 386. 1H NMR (400 MHz: CDCl3): 7.59 (2 H), 7.52 (2 H), 7.42 (2 H), 7.33 (1 H), 7.25 (2 H), 5.29 (1 H), 2.70 (2 H), 2.53 (2 H), 2.05 (3 H), 1.97 (2H), 1.42 (9 H).
Reaction SMILES: C([NH:8][CH2:9][CH:10]([OH:20])[CH2:11][O:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:8][CH2:9][CH:10]([OH:20])[CH2:11][O:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Cc1cccnc1OCC(O)CNCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cccnc1OCC(O)CN

Procedure:
Catalytic debenzylation of a solution of 28.3 g of 2-(3'-benzylamino-2'-hydroxy-propoxy)-3-methyl-pyridine in 300 ml of ethyl acetate, with the addition of a total of 12 g of palladium on charcoal (5% strength), gives 2-(3'-amino-2'-hydroxy-propoxy)-3-methylpyridine of boiling point 120°-130° C./0.07 mm Hg in a bulb tube.
Reaction SMILES: [N+]([O:4][C@H:5]([CH2:12][O:13][N+]([O-])=O)[CH2:6][CH2:7][CH2:8][C:9](O)=[O:10])([O-])=O.[N+:17]([O:20][C@@H:21]([CH3:28])[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])([O-:19])=[O:18]>>[N+:17]([O:20][C@@H:21]([CH3:28])[CH2:22][CH2:23][CH2:24][C:25]([O:27][C@@H:8]1[CH2:9][O:10][C@@H:6]2[C@H:5]([OH:4])[CH2:12][O:13][C@H:7]12)=[O:26])([O-:19])=[O:18]
Reactant: C[C@@H](CCCC(=O)O)O[N+](=O)[O-]
Reactant: O=C(O)CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Product: C[C@@H](CCCC(=O)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O)O[N+](=O)[O-]

Procedure:
The title compound was prepared by following the procedure for the synthesis of EXAMPLE 4, except that in Step F the reagent (S)-5,6-di(nitrooxy)hexanoic acid was replaced by (S)-5-(nitrooxy)hexanoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:10][C:11]1[CH:16]=[CH:15][C:14](F)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1
Reactant: O=Cc1ccccc1O
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Oc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
A mixture of 2-hydroxybenzaldehyde (16.7 g) and Al2O3 /KF (65.5 g) in DMF was heated to 120° C. under a N2 atmosphere and 4-bromo-1-fluoro-2-nitrobenzene (30 g) in DMF was added. The mixture was stirred at 120° C. for 3 hours. The precipitate was filtered off and the filtrate evaporated. The residue was purified by open column chromatography over silica gel (eluent 1: hexane/CH2Cl2 /AcOEt 8/1/1; eluent 2: CH2Cl2 /2-propanone 9/1) and the pure fractions were collected, yielding 26 g (59%) of 2-(4-bromo-2-nitrophenoxy)benzaldehyde (interm. 3). Analogously, 5-chloro-2-(2-nitrophenoxy)benzaldehyde (interm. 4) was prepared.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[CH:21][NH:20][N:19]=2)=[CH:14][C:13]=1[CH2:23][NH2:24]>ClCCl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[CH:21][NH:20][N:19]=2)=[CH:14][C:13]=1[CH2:23][NH:24][CH:5]=[O:7]
Reactant: NCc1cc(-c2cc[nH]n2)ccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O=CO
Product: O=CNCc1cc(-c2cc[nH]n2)ccc1Cl
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of acetic anhydride (0.82 mL, 9.7 mmol) and formic acid (0.4 mL, 9.7 mmol) was heated to 50° C. for 30 minutes and then cooled to 0° C. 2-Chloro-5-(1H-pyrazol-3-yl)benzenemethanamine (i.e. the product of Step C) (1.0 g, 4.8 mmol) was added, and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was then diluted with dichloromethane, washed with saturated sodium bicarbonate solution and brine, then dried (Na2SO4) and concentrated. The crude residue was purified by preparative thin layer chromatography (TLC) (2% methanol in chloroform as eluant) to provide the title product as a solid (0.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[NH2:18][C:19](=[N:31]O)[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([Cl:30])[CH:21]=1>>[Cl:30][C:22]1[CH:21]=[C:20]([C:19]2[N:18]=[C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH3:17])=[C:2]([CH3:1])[CH:7]=3)[O:10][N:31]=2)[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1Cl
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Product: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(C)c3)n2)cc1Cl

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 3 (113.14 mg; 0.50 mmol) and Intermediate 34 (114.32 mg; 0.50 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound as an off-white solid. LC/MS (Method B): 419.3 (M−H)−, 460.3 (M+ACN)+. HPLC (Method A) Rt 6.51 min (Purity: 99.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([CH2:23][OH:24])[O:20][C:19]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][F:16])[C:10](=[O:17])[CH2:9]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([CH2:23][O:24][S:34]([CH3:33])(=[O:36])=[O:35])[O:20][C:19]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][F:16])[C:10](=[O:17])[CH2:9]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CCN1CCF
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(N3CCN(CCF)C(=O)C3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
(5R)-3-(3-Fluoro-4-[4-(2-fluoroethyl)-3-oxopiperazin-1-yl]phenyl)-5-hydroxymethyloxazolidin-2-one (0.8 g) is dissolved in pyridine (15 ml) and the mixture cooled to 0°. Triethylamine (0.38 ml) and methanesulfonyl chloride (0.19 ml) are added to the mixture, and stirring continued at 20–25° for 2 hours. The solvent is removed and the residue dissolved in dichloromethane, washed with water, saline, dried over magnesium sulfate and concentrated. The resulting residue is triturated with ether to give (5R)-3-(3-fluoro-4-[4-(2-fluoroethyl)-3-oxopiperazin-1-yl]phenyl)-5-(methanesulfonyloxymethyl)oxazolidin-2-one (0.76 g) which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[CH:6]=2.C(OC([NH:21][CH2:22][C:23]([NH:25][C@H:26]1[CH2:30][N:29](C(OC(C)(C)C)=O)[C@H:28]([C:38](O)=[O:39])[CH2:27]1)=[O:24])=O)(C)(C)C>>[NH2:21][CH2:22][C:23]([NH:25][C@H:26]1[CH2:30][NH:29][C@H:28]([C:38]([NH:1][C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[CH:6]=3)=[O:39])[CH2:27]1)=[O:24]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCc1ccc2cc(N)cnc2c1
Product: CCc1ccc2cc(NC(=O)[C@@H]3C[C@@H](NC(=O)CN)CN3)cnc2c1

Procedure:
3-Amino-7-ethylquinoline was coupled with trans-4-(N-tert-butoxycarbonylglycyl)amino-N-tert-butoxycarbonyl-L-proline and deprotected according to Compound M1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:35](Cl)(=[O:37])[CH3:36]>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:35](=[O:37])[CH3:36])[C@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H]2CCc3ccccc32)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [2′-((R)-indan-1-ylaminomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([S:9][CH3:10])=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CC(=O)OCC>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]([S:9][CH3:10])=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: CSc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CSc1cnc(Cl)nc1N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
A solution of the 2,4-dichloro-5-(methylthio)pyrimidine (1.16 g, 6 mmole) in acetone (10 ml) at 0° C. containing Na2CO3 (1.1 eq, 6.6 mmole, 0.7 g) was treated dropwise with a solution of morpholine (1.0 eq, 6.6 mmole, 0.6 ml) in acetone (2 ml) and stirred for 1 hr at 0° C. TLC (EA:Hex=1:2, Rf=0.6) showed completion of the reaction to give two products. The acetone was removed in vacuo, the residue was partitioned between water and EA, and the organic layer was dried (MgSO4) and evaporated in vacuo. Column chromatography (EA/Hex=1/6) gave the product (700 mg, 47%).
Reaction SMILES: [CH3:1][N:2]([C:15]1[NH:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)[CH2:3][CH2:4][CH2:5][N:6]([CH3:14])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][N:2]([C:15]1[N:16]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=2)[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)[CH2:3][CH2:4][CH2:5][N:6]([CH3:14])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CN(CCCN(C)c1nc2ccccc2[nH]1)C(=O)OC(C)(C)C
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCCN(C)c1nc2ccccc2n1Cc1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
A solution comprising 1.0 g of N-methyl-N-(benzimidazol-2-yl)-N'-methyl-N'-t-butoxycarbonyl-1,3-propylenediamine, 540 mg of 4-fluorobenzyl chloride, 3 g of potassium carbonate and 20 ml of dimethylformamide, was reacted at room temperature overnight under a stirring condition. Further, it was reacted at a temperature of from 50 to 60° C. for 10 hours. Then, 50 ml of water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate (30 ml×3), and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 1.4 g of the above identified compound as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.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.[F:50][C:51]1[C:59]2[N:58]=[C:57]([CH2:60][CH:61]3[CH2:66][CH2:65][CH2:64][CH2:63][NH:62]3)[NH:56][C:55]=2[CH:54]=[CH:53][C:52]=1[F:67]>CN(C=O)C>[F:50][C:51]1[C:59]2[N:58]=[C:57]([CH2:60][CH:61]3[CH2:66][CH2:65][CH2:64][CH2:63][N:62]3[C:14]([C:9]3[N:10]=[C:11]([CH3:13])[S:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:16])[NH:56][C:55]=2[CH:54]=[CH:53][C:52]=1[F:67]
Reactant: Fc1ccc2[nH]c(CC3CCCCN3)nc2c1F
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(F)c(F)ccc3[nH]2)c(-c2ccc(F)cc2)s1
Reaction time: 16 h
Yield: 85 %

Procedure:
A solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (1.00 g, 4.2 mmol), HATU (1.60 g, 4.2 mmol) and N,N-diisopropylethylamine (2.00 ml, 11.6 mmol) in DMF (20 ml) was stirred at room temperature under argon for 2 min. The mixture was then treated with (RS)-4,5-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D21 (1.06 g, 4.2 mmol) and stirring was continued for 16 h. The solvent was removed in vacuo and the residue was washed with water then was triturated with ethyl acetate to afford the title compound as an off-white solid (1.68 g, 85%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[C:7]1(=[O:14])[O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:14])=[O:13]
Reactant: O=C1CCCCCO1
Reactant: Sc1cccs1
Product: O=C(O)CCCCCSc1cccs1

Procedure:
Method in which thiophene-2-thiol is reacted with ε-caprolactone to obtain 6-(2-thienylsulfanyl) hexanoic acid represented by Chemical Formula [5].
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[O:18][N:17]=[C:16]([CH3:19])[CH:15]=2)=[CH:6][CH:5]=1)(=[S:3])[NH2:2].Cl[CH2:23][CH:24]=O>C(O)C>[CH3:19][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([C:1]3[S:3][CH:23]=[CH:24][N:2]=3)=[CH:21][CH:20]=2)[O:18][N:17]=1
Reactant: Cc1cc(CCCCCOc2ccc(C(N)=S)cc2)on1
Reactant: O=CCCl
Solvent: CCO
Product: Cc1cc(CCCCCOc2ccc(-c3nccs3)cc2)on1
Yield: 55.6 %

Procedure:
A suspension of 7.5 g 5-[5(4-thiocarbamylphenoxy)pentyl]-3-methylisoxazole and 24.6 g chloroacetaldehyde (50% in water) in 150 ml absolute ethanol was refluxed for 3.5 hours. The reaction mixture was concentrated in vacuo and the residue recrystallized from ethyl acetate-hexane to give 4.5 g 3-methyl-5-{5-[4-(2-thiazolyl)phenoxy]pentyl}isoxazole, m.p. 78-80° C.