Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10])#[N:2].C(N(CC)CC)C.Cl.[F:21][C:22]([F:30])([F:29])[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1COCC1>[F:21][C:22]([F:30])([F:29])[CH:23]1[CH2:28][CH2:27][N:26]([S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])(=[O:11])=[O:10])[CH2:25][CH2:24]1
Reactant: FC(F)(F)C1CCNCC1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1S(=O)(=O)N1CCC(C(F)(F)F)CC1
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To 2-cyanobenzene-1-sulfonyl chloride (201 mg, 1.00 mmol) in THF (5 mL), triethylamine (0.84 mL, 6.00 mmol) and 4-trifluoromethylpiperidine hydrochloride (284 mg, 1.50 mmol) were added. After stirring for 2 h, the reaction was concentrated and diluted with ethyl acetate and washed with water. After drying (Na2SO4), filtering, and concentrating, the residue was purified via silica gel chromatography eluting with 45% ethyl acetate/hexanes to provide 2-(4-(trifluoromethyl)piperidin-1-ylsulfonyl)benzonitrile [95 mg, LC-MS: 319.19 (M+H)+]. The product (52 mg) was dissolved in MeOH (5 mL), conc. HCl (25.0 mg) was added, and the whole was hydrogenated at 50 psi overnight. The reaction was concentrated and purified via preparative HPLC(CH3CN/water/TFA) to provide 210A. LC-MS: 323.21 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.O>C(Cl)Cl.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:19]#[C:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC(=O)Oc1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)Oc1ccc(C#Cc2ccccc2)cc1
Reaction time: 2 h
Yield: 108.6 %

Procedure:
4-Iodophenyl acetate (50.00 g, 0.191 mol), phenylacetylene (23.40 g, 0.229 mol), and triethylamine (54 mL) are added to a 250-mL round bottom flask fitted with a condenser/nitrogen inlet, a thermometer, and a stopper. PdCl2 (PPh3)2 (0.200 g, 0.286 mmol) and PPh3 (1.50 g, 5.73 mmol) are then added and the mixture heated to reflux. When the reaction mixture reaches 40° C., CuI (0.054 g, 0.286 mmol) is added. After 2 hours, the reaction is allowed to cool. The mixture is diluted with methylene chloride and poured into water (500 mL). The aqueous layer is extracted with methylene chloride (100 mL). The combined organic layers are washed with three 300-mL portions of water, dried (MgSO4), and filtered. The solvent is removed in vacuo to give 49 g of a yellow solid. The material is recrystallized from hexanes to give light yellow crystals, mp 104.5° C. to 105.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25](=[O:35])[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19]C)=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:24]=[C:23]([CH:25]([OH:35])[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC[C@H](NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl)C(=O)O)c1cccs1

Procedure:
A solution of N-[2-chloro-4-[1-oxo-3-(3-hydroxyphenyl)propyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (120 mg, 0.23 mmol) and lithium hydroxide monohydrate (40 mg, 0.95 mmol) in tetrahydrofuran/methanol/water (2:2:1; 2.5 mL) was stirred at room temperature for 90 min. The solvent was evaporated, then water was added, followed by 1 M HCl (1.1 mL). The resulting solid was filtered off, washed with water, dried, and purified by
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([OH:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:33][C:34]=2[CH3:35])=[N:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([O:19][CH2:21][C:22]2[CH:27]=[N:26][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[CH:24][CH:23]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
A mixture of ethyl (1-benzyl-3-hydroxy-1H-pyrazol-4-yl)acetate (390 mg), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (472 mg), potassium carbonate (414 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl [1-benzyl-3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (649 mg, yield 80%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16]1)[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[CH:5]=1.[C:27]([C@@H:31]1[CH2:36][CH2:35][C@H:34](O)[CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[C:27]([C@H:31]1[CH2:36][CH2:35][C@H:34]([O:14][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH:5]=[C:4]([CH:3]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16]2)[C:2]([F:1])([F:25])[F:26])[CH:13]=[CH:12]3)[CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)C1CCN(C(c2ccc3cc(O)ccc3c2)C(F)(F)F)CC1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(C(c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirring mixture of methyl 1-(2,2,2-trifluoro-1-(6-hydroxynaphthalen-2-yl)ethyl)piperidine-4-carboxylate (300 mg, 0.8 mmol), cis-4-(t-butyl)cyclohexanol (245 mg, 1.6 mmol, 2 eq) and PPh3 (420 mg, 1.6 mmol, 2 eq) in THF (3 mL) was added DIAD (323 g, 1.6 mmol, 2 eq) at room temperate under N2 atmosphere. The mixture was stirred at 80° C. for 2 h, diluted with ethyl acetate (10 mL) and washed with water (5 mL*3). The organic solvent was removed in vacuum and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give methyl 1-(1-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)-2,2,2-trifluoroethyl)piperidine-4-carboxylate (130 mg, yield: 31%) as a yellow solid. ESI-MS (M+1)+: 506.1. 1HNMR (400 MHz, CDCl3) δ: 7.86˜7.80 (m, 3H), 7.46 (d, J=8.8 Hz, 1H), 7.27 (s, 1H), 7.16 (d, J=8.8 Hz, 1H), 4.68˜4.66 (m, 1H), 4.39˜4.36 (m, 1H), 3.56 (s, 3H), 3.32˜3.30 (m, 2H), 2.65˜2.64 (m, 1H), 2.44-2.43 (m, 1H), 2.30-2.27 (m, 3H), 1.93-1.90 (m, 3H), 1.80-1.79 (m, 2H), 1.44˜1.41 (m, 2H), 1.29˜1.27 (m, 3H), 1.14˜1.13 (m, 1H), 0.90 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].[P:10](Cl)(Cl)(=[O:22])[O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C(Cl)[Cl:26]>>[Cl:26][C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]=1[O:11][P:10](=[N:5][C@@H:4]([CH:6]([CH3:8])[CH3:7])[C:3]([O:2][CH3:1])=[O:9])=[O:22]
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: ClCCl
Reactant: COC(=O)[C@@H](N)C(C)C
Product: COC(=O)[C@@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)C(C)C
Yield: 62 %

Procedure:
Using the general procedure for synthesizing naphthyl (amino acid ester) phosphorochloridates the hydrochloride salt of L-valine methyl ester (2.00 g, 11.93 mmol), naphthalen-1-yl phosphorodichloridate (0.77 g, 11.93 mmol) and TEA (4.11 mL, 23.85 mmol) in 20 mL of dry DCM, were combined to give (2S)-methyl 2-(chloro(naphthalen-1-yloxy)-phosphorylamino)-3-methylbutanoate in 62% yield (2.63 g), as a clear, yellow, thick oil.
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[C:7]([Cl:10])[CH:6]=[C:5]([SH:11])[C:3]=1[NH2:4].[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13]>ClCCl>[Cl:1][C:2]1[C:3]2[NH:4][C:12](=[O:13])[S:11][C:5]=2[CH:6]=[C:7]([Cl:10])[C:8]=1[CH3:9]
Reactant: Cc1c(Cl)cc(S)c(N)c1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1c(Cl)cc2sc(=O)[nH]c2c1Cl
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a solution of 2,4-dichloro-6-mercapto-3-methylaniline (2.08 g) in dichloromethane (40 ml) was added 1,1'-carbonyldiimidazole (1.78 g) at ambient temperature. The mixture was stirred for one hour at the same temperature. The separated precipitate was collected by filtration, washed with dichloromethane, and dried to give 4,6-dichloro-5-methyl-2-benzothiazolinone (1.40 g).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22](OC)=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:28][NH2:29]>C(O)COCCO>[CH2:1]([NH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([NH:28][NH2:29])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NN
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1
Solvent: OCCOCCO
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NN)cc1
Temperature: 125 °C
Reaction time: 3 h

Procedure:
A mixture of 6.59 g. of methyl 4-(hexadecylamino)benzoate, 100 ml. of diethylene glycol, and 45 ml. of 95% hydrazine was heated and stirred in an oil bath at 125° C. under nitrogen for 3 hours and cooled to room temperature. The separated crystals were collected in a suction funnel and washed with ethanol several times and dried in air to give 7.6 g. of white crystals. The crystals were dissolved in 140 ml. of boiling ethanol and recrystallized to give 5.95 g. of fine white crystals, melting point 154°-156° C.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.[CH2:12]([N:14](CC)[CH2:15][CH3:16])[CH3:13].C(Cl)(=O)C(C)(C)C.C(NCC)C>O1CCCC1>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: CCN(CC)CC
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCNCC
Product: CCN(CC)C(=O)c1ccc(C=O)cc1
Temperature: -4 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
To a 12 L flask equipped with mechanical stirrer and cold bath was charged 300 g (2 mol) of 4-carboxybenzaldehyde, 4.5 L of tetrahydrofuran and 245 g (2.4 mol) of triethylamine. This solution was cooled to −4° C. with methanol/ice bath. To the reaction was charged 236 g (1.9 mol) of pivaloyl chloride at a rate that maintained the temperature below 5° C. After stirring for 2 h the resulting slurry was filtered and the filter cake was washed with 1 L of THF. The filtrates were returned to the reactor and cooled below −5° C. Diethylamine (438 g, 6 mol) was slowly added maintaining the temperature below 0° C. The reaction was stirred for several hours and allowed to warm. The solvent was then removed under vacuum and the resulting residue was dissolved in 2 L of ethyl acetate. The resulting solution was washed with 1 L of water and the aqueous layer was back-extracted with 2×500 mL ethyl acetate. The combined organic layer was washed with 3×500 mL of 1 N HCl and 3×500 mL of NaHCO3 (aq, sat). This solution was dried with Na2SO4 and the solvent was removed under vacuum to give a golden brown oil (172 g, 85%) containing ˜13% impurity by NMR. The aldehyde was used with out further purification.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=3)[N:19]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[C:26]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:18]=[C:17]2[CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)#[N:27]
Reactant: CS(=O)(=O)n1cc(C2CCN(C(=O)OCc3ccccc3)CC2)c2cc(C#N)ccc21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)n1cc(C2CCNCC2)c2cc(C#N)ccc21
Reaction time: 2 h
Yield: 97 %

Procedure:
10% Palladium on carbon (0.49 g) was added to a solution of 1-benzyloxycarbonyl-4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (0.98 g, 2.24 mmol) [prepared as described in Step 2 above] in 80% ethanol/tetrahydrofuran (10 ml) under an argon atmosphere. The reaction mixture was stirred under an atmosphere of hydrogen gas (1 atm) for 2 h. The reaction mixture was degassed, filtered through Celite and concentrated in vacuo to give 4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (97%) as a white solid. This material was converted to N-hydroxy-1-[4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl]-piperidine-2-(R)-carboxamide by converting it to 4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl chloride by following Example 16, Step 1, coupling the sulfonyl chloride with (R)-pipecolinic acid (L)-tartrate salt to give 1-[4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (86%) by following Example 14, Step 6 and then converting the acid to the final compound by following Example 16, Steps 3 and 5; mp: 143.3-143.9° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.[CH2:10](O)[CH2:11][CH2:12][OH:13].O>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:9]1[CH2:10][CH2:11][CH2:12][O:13][CH:8]1[C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: OCCCO
Reactant: Cc1ncc(C=O)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(C2OCCCO2)cn1
Temperature: 65 °C
Yield: 52 %

Procedure:
To a solution of 2-methylpyrimidine-5-carbaldehyde (0.808 g, 6.62 mmol) and propane-1,3-diol (1.01 g, 0.868 ml, 13.2 mmol) in toluene (7.6 ml) and THF (1.9 ml) was added p-toluenesulfonic acid (11 mg, 0.066 mmol). The reaction was heated at 65° C. for 4.5 hours. The reaction mixture was then poured into H2O (50 mL) and extracted with AcOEt (3×50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to yield 5-(1,3-dioxan-2-yl)-2-methylpyrimidine (620 mg, 3.44 mmol, 52%) used for next step without further purification.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:4]=1N.N([O-])=O.[Na+]>O>[Cl:1][C:4]1[C:3]([F:2])=[CH:9][CH:8]=[CH:7][C:6]=1[F:10]
Reactant: Cl
Reactant: Nc1c(F)cccc1F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cccc(F)c1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
550 g of hydrochloric acid was added to a reactor having 270 g of water placed therein, and 129 g of 2,6-difluoroaniline (b1) was further added thereto, followed by stirring for 30 minutes at 60° C. Thereafter, the mixture was cooled to −10° C., and 192.5 g of a 37.6% sodium nitrite aqueous solution was added dropwise thereto over 30 minutes in a temperature range of −10 to −5° C., followed by stirring for 30 minutes at −10° C. The resulting reaction mixture was added to another reactor having 122 g of 30% hydrochloric acid and 22 g of cuprous chloride placed therein over 90 minutes in a temperature range of 25 to 30° C., followed by stirring for 30 minutes in that temperature range. A reaction mixture obtained by the reaction was subjected to steam distillation. The resulting organic phase was washed with water in three times and then dried to obtain 124 g of 2-chloro-1,3-difluorobenzene (b2).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:13]([C:23]([NH:25][NH2:26])=[O:24])=[N:14][C:15]([Br:22])=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.CCOC(C)=O>[NH2:11][C:12]1[C:13]([C:23]([NH:25][NH:26][C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:24])=[N:14][C:15]([Br:22])=[C:16]([C:18]([F:20])([F:21])[F:19])[N:17]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: NNC(=O)c1nc(Br)c(C(F)(F)F)nc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)NNC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of phenyl acetic acid (95.0 mg, 0.698 mmol) in NMP (6 ml) was added a solution 3-amino-6-bromo-5-(trifluoromethyl)pyrazine-2-carbohydrazide (step 1) (250 mg, 0.837 mmol) in NMP (6 ml) followed by DIPEA (609 ul, 3.49 mmol). The resulting mixture was treated with HATU (398 mg, 1.047 mmol) portionwise and stirred at RT for 90 min. The mixture was added to EtOAc (50 ml) and washed with 0.1M NaOH (50 ml). The aqueous layer was back extracted with EtOAc (50 ml). The combined organic portions were washed with water (50 ml), brine (50 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 1:1 EtOAc/iso-hexane to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.65 (1H, s), 10.29 (1H, s), 8.02 (2H, s), 7.30 (5H, m), 3.52 (2H, s). 19F NMR (400 MHz, DMSO-d6) δ-66 (s, CF3).
Reaction SMILES: [C:1]([C:5]1([CH:9]=[O:10])[CH2:8][O:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.[C-:21]#[N:22].[Na+]>C(OCC)C.O>[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O-:7])=[O:17])=[CH:14][CH:13]=1.[C:1]([C:5]1([CH:9]([C:21]#[N:22])[OH:10])[CH2:8][O:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)C1(C=O)COC1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)C1(C(O)C#N)COC1
Product: O=C([O-])c1ccc(I)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of 3-t-butyl-3-formyl-oxetane (1.0 g) and 4-iodobenzoyl chloride (2.6 g) in dry diethyl ether (35 ml), under nitrogen, was added a solution of sodium cyanide (1.25 g) in water (1.0 ml). The mixture was stirred overnight. The mixture was poured into water (50 ml.) and the aqueous mixture was extracted with diethyl ether. The ethereal solution was dried over anhydrous sodium sulphate and then evaporated in vacuo. The residue was chromatographed on silica pre-treated with triethylamine eluting with hexane:chloroform 1:3. The 4-iodobenzoate of 3-t-butyl-3-(cyano-hydroxymethyl)-oxetane was obtained as a colourless solid (2.54 g.). Nuclear magnetic resonance spectrum (NMR) was as follows: 1H (ppm from TMS in CDCl3, integral, number of peaks): 7.90-7.70, 4H, q; 5.80, 1H, s; 4.80-4.60, 4H, m; 1.10, 9H, s.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11]N=C(CN3C=CN=C3)[C:8]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=CC=1.[CH3:25]C1C=CC(C(C2C=CC(C)=CC=2)O)=CC=1.S(Cl)(Cl)=O.[NH:45]1[CH:49]=[CH:48][N:47]=[CH:46]1>>[CH3:25][C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:8]([C:7]1[CH:1]=[CH:6][CH:5]=[CH:4][C:12]=1[CH3:11])[N:45]1[CH:49]=[CH:48][N:47]=[CH:46]1
Reactant: c1ccc(-c2ccnc(Cn3ccnc3)c2-c2ccccc2)cc1
Reactant: Cc1ccc(C(O)c2ccc(C)cc2)cc1
Reactant: c1c[nH]cn1
Solvent: O=S(Cl)Cl
Product: Cc1ccccc1C(c1ccccc1C)n1ccnc1

Procedure:
With the same method as for Compound 40, Compound 14 described above, thionyl chloride (Wako Pure Chemical Industries, Ltd.), and imidazole (Wako Pure Chemical Industries, Ltd.) were used, to thereby obtain the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH:7][C@H:8]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[Cl:20])=[O:15])=[O:6])[CH3:4].[N:35]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37](O)=[O:38].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(Cl)(Cl)Cl.CO>[N:35]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37]([NH:2][C@H:3]([C:5]([NH:7][C@H:8]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[Cl:20])=[O:15])=[O:6])[CH3:4])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: C[C@H](N)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
At 0° C. the solution of 657 mg (1.28 mmol) of HCl.Ala-Lys(ClZ)-OBzl in 5 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 280 mg (1.3 mmol) of Boc-Pro-OH, 170 mg (1.26 mmol) of 1-hydroxybenzotriazole and 270 mg (1.31 mmol) of dicyclohexylcarbodiimide in 30 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 6 h and TLC (chloroform/methanol, 20:1) indicated complete disappearance of HCl.Ala-Lys(ClZ)-OBzl. The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 80 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (50 ml×3), saturated NaCl in water (50 ml×3) and KHSO4 in water (5%, 30 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, and then evaporated to provide 134 mg (98%) of the title compound as a colorless powder. Mp86–88° C., FAB-MS (m/e) 674[M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.CC1OC(C)=CC=1C(O)=O.CC1OC(C)=CC=1C(Cl)=O.[CH3:25][C:26]1[O:27][C:28]([CH3:36])=[CH:29][C:30]=1[C:31]([N:33]=[C:34]=[S:35])=[O:32].[CH3:37][O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][C:48]=1[O:49][CH3:50])[N:45]=[CH:44][CH:43]=[C:42]2[O:51][C:52]1[CH:58]=[CH:57][C:55]([NH2:56])=[CH:54][C:53]=1[F:59]>C(O)C.C1(C)C=CC=CC=1>[CH3:37][O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][C:48]=1[O:49][CH3:50])[N:45]=[CH:44][CH:43]=[C:42]2[O:51][C:52]1[CH:58]=[CH:57][C:55]([NH:56][C:34]([NH:33][C:31]([C:30]2[CH:29]=[C:28]([CH3:36])[O:27][C:26]=2[CH3:25])=[O:32])=[S:35])=[CH:54][C:53]=1[F:59]
Reactant: Cc1cc(C(=O)N=C=S)c(C)o1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: Cc1cc(C(=O)Cl)c(C)o1
Agent: Cc1cc(C(=O)O)c(C)o1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(C)oc4C)cc3F)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2,5-dimethyl-3-furoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2,5-dimethyl-3-furancarbonyl isothiocyanate was prepared using the resultant 2,5-dimethyl-3-furancarbonyl chloride as a starting compound according to the description of the literature. 2,5-Dimethyl-3-furancarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (51 mg, yield 64%).