Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][N:12]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:20]([OH:22])=O)[C:13]2=[O:16])=[CH:8][CH:7]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:39][C:40]1[CH:44]=[CH:43][O:42][N:41]=1>C(Cl)Cl.CO>[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][N:12]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:20]([NH:39][C:40]3[CH:44]=[CH:43][O:42][N:41]=3)=[O:22])[C:13]2=[O:16])=[CH:8][CH:7]=1
Reactant: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(CCCN(C)C)cc2c1=O
Reactant: Nc1ccon1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1ccc2ccc(CCCN(C)C)cc2c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-[7-[3-(dimethylamino)propyl]-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoic acid (151 mg) in methylene chloride (3 ml) was cooled to 0° C. and oxalyl chloride (72 μl) was added. After the addition of DMF (25 μl), the reaction mixture was stirred at room temperature for 2 hours, 3-aminoisoxazole (153 μl) was added and stirring continued at room temperature for 2.5 hours. The reaction mixture was dissolved in methanol and water and purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution yielded an orange oil. The oil was triturated with water resulted in a solid which was collected by filtration washed with diethyl ether and air dried to give 3-[7-[3-(dimethylamino)propyl]-1-oxoisoquinolin-2(1H)-yl]-N-isoxazol-3-yl-4-methylbenzamide as a tan solid (124 mg); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.71 (m, 2H), 1.35 (s, 3H), 2.09 (s, 3H), 6.64 (d, 1H), 7.10 (d, 1H), 7.23 (m, 1H), 7.45 (d, 1H), 7.59 (m, 3H), 7.72 (s, 1H), 7.83 (d, 1H), 8.63 (s, 1H), 9.98 (s, 1H); Mass Spectrum: M+H+ 349.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.Cl[C:29]([O:31][CH3:32])=[O:30]>N1C=CC=CC=1.CCOC(C)=O>[CH3:32][O:31][C:29](=[O:30])[NH:25][C:23]1[S:24][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:15][C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:26])([F:1])[F:27])=[CH:4][CH:5]=4)[N:14]=[CH:13][N:12]=3)[C:21]=2[N:22]=1
Reactant: COC(=O)Cl
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65) (100 mg, 0.26 mmol) in pyridine (2 mL) was added methyl chloroformate (28 mg, 0.29 mmol, Aldrich) at 0° C. The reaction mixture was stirred at room temperature for 2 h, diluted with EtOAc and washed with 1 N NaOH and water. The EtOAc layer was separated, dried over Na2SO4, filtered and evaporated in vacuum. Purification of the residue by silica gel chromatography with gradient: 40 to 80% EtOAc in hexanes gave the title compound as an off white solid. MS (ESI, pos. ion.) m/z: 447 (M+1).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].C(N(CC)CC)C>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:15]#[C:14][CH2:13][CH2:12][OH:16])=[CH:3][N:4]=1
Reactant: Brc1cncc2ccccc12
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCC#Cc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
In an inert atmosphere, 0.268 g of bis(triphenylphosphine) palladium dichloride and 0.072 g of cuprous iodide was added with stirring to a deoxygenated solution of 5 g of 4-bromoisoquinoline. 3.02 g of 3-butyn-1-ol and 10 mL of triethylamine in 20 mL of dichloromethane. The reaction was stirred at room temperature for 1 hour and then at reflux for 18 hours. The cooled mixture was filtered and the filtrate was washed with water. The dried (Na2SO4) organic phase was concentrated in vacuo and the residual oil was purified by HPLC (ethyl acetate-toluene; 2:3) to yield 3.4 g of 4-(4-isoquinolinyl)-3-butyn-1-ol as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[CH:18][CH:17]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)=[CH:30][CH:31]=2)=[O:10])=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)cc1
Reaction time: 2 h
Yield: 96.5 %

Procedure:
Tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)phenyl)acetate (20 mg, 0.043 mmol) was diluted with DCM (1 mL) followed by the addition of TFA (1 mL). After stirring for 2 hours, the reaction was concentrated, diluted with ether and concentrated to yield 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)phenyl)acetic acid (17 mg, 97% yield) as a white solid. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.70 (d, 2H), 7.30 (m, 4H), 7.19 (m, 2H), 7.00 (m, 4H), 3.62 (m, 4H), 2.90 (t, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([OH:16])=[O:15])[CH:10]=2)[CH:5]=1)([OH:3])=[O:2].C1C2C(=CC=CC=2)C=CC=1.S(Cl)([Cl:29])=O>>[C:14]([C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[C:10]=1[Cl:29])([OH:16])=[O:15]
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Reactant: O=S(Cl)Cl
Solvent: c1ccc2ccccc2c1
Product: O=C(O)c1ccc2c(Cl)c(C(=O)O)ccc2c1
Temperature: 80 °C

Procedure:
2,6-Dicarboxynaphthalene having carboxyl groups bonded to a naphthalene nucleus, designated compound A, is chosen as a starting compound. Two moles of thionyl chloride is added to one mole of compound A, and the mixture is heated to about 75 to 90° C., preferably about 80° C., with stirring in a nitrogen atmosphere. Then the stirring force is diminished, and the reaction mixture is refluxed for about 6 to 18 hours, desirably about 10 to 12 hours. The bath temperature is set at about 90 to 100° C., at which unreacted thionyl chloride is removed by evaporation over about 2 hours to obtain 2,6-dicarboxychloronaphthalene, designated compound B.
Reaction SMILES: [SH:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+].CN(C=O)C.[Cl:21][C:22]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:23]=1[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)=[O:25]>C(O)C.O>[Cl:21][C:22]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:23]=1[C:24]([C:26]1[CH:27]=[CH:28][C:29]([CH2:30][S:1][C:2]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:32][CH:33]=1)=[O:25]
Reactant: Cn1c(S)nc2ccccc2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)nc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of 2-mercapto-3-methyl-4(3H)-quinazolinone (1.0 g) and sodium hydroxide (250 mg) in 50% ethanol (15 ml)-DMF (15 ml) was added 4-(2,4-dichlorobenzoyl)benzyl bromide (1.88 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixtrue was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol, and recrystallized from methanol to provide the title compound as colorless solid (2.16 g). IH-NMR (CDCl3) δ: 3.59(3H,s), 4.59(2H,s), 7.25-7.80(10H,m), 8.22(1H,dd,J=8.2,1.4Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([NH:19][NH2:20])=[O:18])[CH2:11][CH2:10]1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]([NH:19][NH:20][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])=[O:18])[CH2:13][CH2:14]1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccccc1N1CCN(CCC(=O)NN)CC1
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(CCC(=O)NNC(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a suspension of 3-[4-(2-methoxyphenyl)piperazino]propanohydrazide D2 (1.00 g, 3.60 mmol) in anhydrous toluene (2 mL), phenyl isocyanate (0.45 g, 0.41 mL, 3.78 mmol) was added and the mixture was stirred at room temperature for 30 min and then heated at reflux for 1 h. The solution was allowed to cool slowly to room temperature and the resulting precipitate was filtered and washed with hexane to afford 1.2 g (83.9%) 2-{3-[4-(2-methoxyphenyl)piperazino]propanoyl}-N-phenyl-1-hydrazinecarboxamide D5 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)[C:21](=[O:23])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: CCNCc1cccc(C)n1
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)cn1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:18][CH:17]([NH:19][C:20](=[O:36])[CH2:21][NH:22][C:23](=[O:35])[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)[CH2:16]1)=O)(C)(C)C>>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:21][NH:22][C:23](=[O:35])[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([C:31]([F:33])([F:34])[F:32])[CH:25]=2)=[O:36])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cc(F)cc(C(F)(F)F)c2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cc(F)cc(C(F)(F)F)c1)NC1CNC1

Procedure:
The title compound was prepared as colorless oil from the TFA de-protection of 3-[2-(5-fluoro-3-trifluoromethyl-benzoylamino)-acetylamino]-azetidine-1-carboxylic acid tert-butylester (as prepared in the previous step) using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.O.C1(C)C=CC(S(O)(=O)=[O:20])=CC=1>CC(CC)=O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:20])[CH2:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Solvent: O
Solvent: CCC(C)=O
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A solution of 5.0 g. of acetonine in 33.8 g. of methylethyl ketone was added with 6.2 g. of p-toluenesulfonic acid monohydrate under stirring. The mixture was stirred at room temperature for 8 hours to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 8 to obtain triacetonamine in a yield of 91.7%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:9].NC1C=C([N+]([O-])=O)C=CC=1C.N[C:22](N)=[O:23].[C]=O.[CH2:27]([OH:29])C>Cl[Pd]Cl>[N:1]([C:2]1[CH:7]=[C:6]([N:8]=[C:22]=[O:23])[CH:5]=[CH:4][C:3]=1[CH3:9])=[C:27]=[O:29]
Reactant: NC(N)=O
Reactant: Cc1ccc(N)cc1N
Reactant: CCO
Agent: Cl[Pd]Cl
Agent: Cc1ccc([N+](=O)[O-])cc1N
Agent: [C]=O
Product: Cc1ccc(N=C=O)cc1N=C=O

Procedure:
250 g of the following mixture were introduced into a 0.7 liter autoclave: 2×10-3 % by weight of PdCl2, 4% by weight of FeOCl, 14.8% by weight of a bis-urea of 2,4-diamino toluene and 2-amino-4-nitrotoluene and 81% by weight of ethanol. The nitro groups of the urea used are oxidizing agents for the oxycarbonylation of the urea function. 120 bar of carbon monoxide were forced in at room temperature. The mixture was allowed to react for two hours at 180° C. The bis-urea was converted quantitatively. The bis-urethane of 2,4-diisocyanatotoluene was obtained with a selectivity of 50 mol % in addition to 10 mol % of isomeric aminourethanes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([OH:19])([CH2:13]OS(C)(=O)=O)[CH2:10][C@H:9]1[C:20](=[O:31])[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([CH2:13][N:32]=[N+:33]=[N-:34])([OH:19])[CH2:10][C@H:9]1[C:20](=[O:31])[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@](O)(COS(C)(=O)=O)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@](O)(CN=[N+]=[N-])C[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-hydroxy-4-methanesulfonyloxy methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (580 mg, 1.21 mmol) (prepared as described Scheme B13) in DMF (20 mL) was added sodium azide (392 mL, 6.03 mmol) and the solution was stirred for 16 h at 80° C. The reaction mixture was diluted with EtOAc, washed with a saturated aqueous solution of NaHCO3 (3 times). The organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1) to give the desired material. MS (LC/MS): 430.1/432.1 [M+H]+, 374.1 [MH−tBu]+, 332 [MH−Boc]+; tR (HPLC conditions f): 2.22 min.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]([C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(O)cc1
Reaction time: 4 h
Yield: 109.9 %

Procedure:
3.00 g of {2-hydroxy-2-[4-(phenylmethoxy)phenyl]propyl}[(methylethyl)sulfonyl]amine (prepared in example 32) and 3.10 g. of 10% Pd/C in ethyl acetate (300 mL) were subjected to a hydrogen atmosphere while shaking at 60 psi's for 4 hours. Solution was filtered through a Celite mat and the resulting filtrate was concentrated under reduced vacuum to yield intermediate title compound (2.48 g, 100%) as a foam. This material slowly crystallized and was used without further purification. Ion spray M.S. 272.1 (M*−1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:27][CH:28]=2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[C:26]([N:29]3[CH2:30][CH2:31][N:32]([C:9]([NH:8][C:5]4[O:4][N:3]=[C:2]([CH3:1])[C:6]=4[CH3:7])=[O:16])[CH2:33][CH2:34]3)[S:27][CH:28]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cccc(-c2csc(N3CCNCC3)n2)c1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4cccc(Cl)c4)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 15 h
Yield: 41.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (226 mg, 0.786 mmol), 1-[4-(3-chlorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.715 mmol) and diisopropylethylamine (0.249 ml, 1.43 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and recrystallized from a mixed solvent of hexane and ethyl acetate to give 124 mg (41.4%) of the desired product as a solid. mp 201-202° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1([Cl:8])[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].N1C=[CH:18][N:17]=[N:16]1.[C:20](#[N:22])C>>[Cl:8][C:5]1([C:3](=[O:4])[CH2:2][N:17]2[CH:18]=[N:22][CH:20]=[N:16]2)[CH2:7][CH2:6]1
Reactant: O=C(CCl)C1(Cl)CC1
Reactant: c1c[nH]nn1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(Cn1cncn1)C1(Cl)CC1
Yield: 51 %

Procedure:
100 g (0.66 mol) of 1-chloro-cyclopropyl chloromethyl ketone in 80 ml of acetonitrile are added dropwise to a refluxing suspension of 83 g (0.6 mol) of potassium carbonate and 58 g (0.84 mol) of triazole in 330 ml of acetonitrile. The mixture is refluxed for 8 hours and then filtered off with suction and concentrated. The residue is taken up in ethyl acetate/toluene, and the mixture is washed with water, dried over sodium sulphate and concentrated. The subsequent purification by column chromatography in which dichloromethane was used as the mobile phase gave 62 g (51% of theory) of 1-(1-chlorocyclopropyl)-2-(1,2,4-triazol-1-yl)-ethan-1-one.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][CH2:32][CH2:33][O:34][CH3:35].C(OCC)(=O)C>CN(C=O)C.O>[O:23]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:12])=[O:13])[CH2:4][CH2:3]1
Reactant: COCCCBr
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCN1CCS(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCCCN(CCN1CCS(=O)(=O)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109 %

Procedure:
N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide (0.400 g, 1.10 mmol) was combined with cesium carbonate (0.538 g, 1.65 mmol) in DMF (5 mL). The slurry was stirred at rt for 30 min, then to it was added 1-bromo-3-methoxypropane (0.337 g, 2.20 mmol). The resulting mixture was stirred at rt for 72 h. LCMS indicated incomplete conversion, so additional 1-bromo-3-methoxypropane (0.337 g, 2.20 mmol) and cesium carbonate (0.538 g, 1.65 mmol) were added and the mixture was heated to 70° C. for 1 hour. Dilution with ethyl acetate (60 mL) and water (40 mL) followed by shaking gave a separation of phases. The organic phase was isolated, washed with water (2×30 mL) and brine (25 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a residue. Purification by silica gel chromatography (gradient 100% DCM to 60:1 DCM:MeOH) gave the title compound as a yellow oil (0.522 g, 109% yield). LCMS: m/z 436 (M+H+), retention time 1.50 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.68-1.77 (m, 2H) 2.67 (t, J=6.26 Hz, 2H) 3.02 (br. s., 8H) 3.16 (s, 3H) 3.27 (t, J=5.80 Hz, 2H) 3.31-3.37 (m, 2H) 3.41 (t, J=6.26 Hz, 2H) 7.61-7.65 (m, 1H) 7.66-7.74 (m, 2H) 7.99-8.03 (m, 1H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][CH2:11][CH2:12][CH2:13][CH:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:15]([OH:17])=O.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.Cl.Cl.[CH3:42][O:43][C:44]1[CH:45]=[C:46](/[CH:56]=[CH:57]/[C:58]([NH:60][NH2:61])=O)[CH:47]=[CH:48][C:49]=1[N:50]1[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]1>C(Cl)Cl.O>[Cl:10][CH2:11][CH2:12][CH2:13][CH:14]([C:15]1[O:17][C:58](/[CH:57]=[CH:56]/[C:46]2[CH:47]=[CH:48][C:49]([N:50]3[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]3)=[C:44]([O:43][CH3:42])[CH:45]=2)=[N:60][N:61]=1)[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1
Reactant: O=C(O)C(CCCCl)c1ccc(Cl)cc1
Reactant: COc1cc(/C=C/C(=O)NN)ccc1-n1cnc(C)c1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1cc(/C=C/c2nnc(C(CCCCl)c3ccc(Cl)cc3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 52.3 %

Procedure:
IPEA (2.5 mL), 5-chloro-2-(4-chlorophenyl)pentanoic acid (430 mg) and BOPCl (0.44 g) were added to a suspension of (E)-3-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]acrylic acid hydrazide dihydrochloride (500 mg) in methylene chloride (15 mL) at room temperature, and the reaction solution was stirred at room temperature for 14 hours. Water was added to the reaction solution, followed by extraction with chloroform. The resulting extract washed with a saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. A solution of the residue in phosphorus oxychloride (4 mL) was heated under reflux for five hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 366 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[C@H:8]([NH:10][C:11]([C:13]1([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14]1)=[O:12])[CH3:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:34][C:35]([F:56])([F:55])[S:36]([O:39][C:40]1[C:45](OS(C(F)(F)F)(=O)=O)=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:54])(=[O:38])=[O:37]>O1CCOCC1.CO.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>[F:56][C:35]([F:34])([F:55])[S:36]([O:39][C:40]1[C:41]([Cl:54])=[CH:42][CH:43]=[CH:44][C:45]=1[C:4]1[CH:5]=[CH:6][C:7]([C@H:8]([NH:10][C:11]([C:13]2([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[C:2]([F:1])[CH:3]=1)(=[O:38])=[O:37]
Reactant: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(B(O)O)cc1F
Reactant: O=S(=O)(Oc1cccc(Cl)c1OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(-c2cccc(Cl)c2OS(=O)(=O)C(F)(F)F)cc1F
Temperature: 90 °C

Procedure:
3-Fluoro-4-{(1R)-1-[({1-[(trifluoroacetyl)amino]cyclopropyl}carbonyl)amino]ethyl}-phenylboronic acid (0.050 g, 0.138 mmol), tetrakis(triphenylphosphine)palladium (0) (0.016 g, 0.014 mmol), and potassium phosphate (0.035 g, 0.166 mmol) were added to a flame-dried flask under argon. 2-Chloro-6-{[(trifluoromethyl)sulfonyl]oxy}phenyl trifluoromethanesulfonate (0.068 g, 1.66 mmol) as a solution in dioxane (0.33M) was added to the solids and heated to 90° C. After 3 hours the reaction was diluted with methanol, filtered and purified by reverse phase chromatography using a gradient from 95/5H2O/CH3CN to 5/95H2O/CH3CN. The product was lyophilized to yield the title compound as a solid.