Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]([F:32])([O:23][C:24]1[CH:25]=[C:26]([CH2:30]Br)[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:22])[F:21].O>COCCOC>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:15])[CH:9]([CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:19]([F:18])([F:32])[CH:20]([F:21])[F:22])[CH:25]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)nc1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of ethyl 3-(6-fluoropyridin-3-yl)-3-oxopropionate (3.83 g, 18.1 mmol) in 1,2-dimethoxyethane (30 ml) was added sodium hydride (60% in oil, 725 mg, 18.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene (9.30 g, purity 56%, 18.1 mmol) in 1,2-dimethoxyethane (10 ml), and the mixture was stirred at room temperature for 2 hrs. The reaction solution was poured into water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene-toluene:ethyl acetate=5:1) to give ethyl 3-(6-fluoropyridin-3-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate (6.67 g, 88%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[I-:11].[K+].CC1C=CC(S(NCl)(=O)=O)=CC=1>C(#N)C.O>[I:11][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[C:6]([CH:7]=[O:8])[C:5]=1[OH:10]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=Cc1cc(Br)cc(I)c1O
Temperature: 50 °C
Yield: 79.5 %

Procedure:
To a solution of 5-bromosalicylaldehyde (20.0 g, 0.1 mole) and potassium iodide (17 g, 0.1 mole) in acetonitrile (150 mL) and water (50 mL) in a 500 mL round bottom flask with magnetic stirrer was added chloramine T (23 g, 0.1 mole). The mixture was allowed to react for one hour. The reaction mixture was partitioned between hydrochloric acid (10%, 200 mL) and ethyl acetate. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. To the residue was added hexanes and the reaction mixture heated to 50° C. for 15 minutes. The undissolved material was removed by filtration. The filtrate was concentrated in vacuo to leave canary yellow 3-iodo-5-bromosalicylaldehyde (26 g).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[C:7](Cl)(=[O:11])[O:8][CH2:9][CH3:10].[OH-].[K+]>C(OCC)C>[C:7](=[O:11])([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[O:8][CH2:9][CH3:10]
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CCOC(=O)OCC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.7 %

Procedure:
In a flask (5-liter volume), 2,2,2-trifluoroethanol (800 g, 8.0 mol), ethyl chlorocarbonate (867 g, 8.0 mol) and diethyl ether (1000 ml) were charged. While the flask was cooled so that the reaction was carried out at -5° C. to 0 ° C., a 29.5% by weight aqueous solution of potassium hydroxide (1500 g) was added dropwise to the flask for 6 hours and the mixture was stirred for 12 hours at room temperature. The ether layer was separated, washed with water, dried and distilled to give ethyl 2,2,2-trifluoroethyl carbonate as a colorless liquid (960 g, yield 70%). The chemical structure of the produced compound was determined based on the IR and NMR absorbance spectra shown in FIG. 5 and FIG. 6 respectively and the mass spectrometry spectrum (M/e=172).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:26]O>>[CH3:26][O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([C:8](=[O:9])[C:7]2[CH:19]=[CH:20][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 94 %

Procedure:
A solution of 4-(4-nitro-benzoyl)-benzoic acid (Dinsmore, Christopher J.; et al., Bioorg. Med. Chem. Lett., 7, 10, 1997, 1345-1348) (4.00 g, 14.7 mmol) and sulfuric acid (1.2 mL) in MeOH (40 mL) was heated at reflux for 18 h. The mixture was filtered and after work-up gave 4-(4-nitro-benzoyl)-benzoic acid methyl ester as a yellow solid (3.97 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[N:4][CH:3]=1.N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])N(C3C4CCCCC=4C(C#N)=CC=3)[C:36]2=[O:38])[CH2:32][CH2:31]1>>[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])[N:1]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]([C:12]#[N:13])=[N:4][CH:3]=3)[C:36]2=[O:38])[CH2:32][CH2:31]1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Reactant: N#Cc1ncc(N)c2ccccc12
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: N#Cc1ncc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2ccccc12

Procedure:
The title compound was synthesized from compound 13D by procedures analogous to those described in Experiment 2E to 2F. HPLC: 97.6% at 1.54 min (retention time) (Conditions: YMC S5 C-18 (4.6×50 mm); Eluted with 0% to 100% B; 4 min gradient; (A=90% H2O-10% MeCN-0.1% TFA and B=10% H2O-90% MeCN-0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm). LC/MS m/z 309 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([NH:13][C:14](=[O:16])[CH3:15])=[C:8]([F:17])[CH:7]=1>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:7]=[C:8]([F:17])[C:9]([NH:13][C:14](=[O:16])[CH3:15])=[C:10]([F:12])[C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1c(F)cc(Cl)cc1F
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c(F)cc(Cl)c([N+](=O)[O-])c1F
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
30.7 g (487 mmol) of concentrated nitric acid were added dropwise at 0-5° C. to a solution of 100 g (487 mmol) of N-(4-chloro-2,6-difluorophenyl)acetamide in 500 ml of concentrated sulfuric acid. After the reaction mixture had been stirred for one hour at 0-5° C., it was stirred into ice-water. The resulting solid was separated off, washed twice with water and dried. Yield: 81.3 g (72%);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:27]\[OH:28])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(Br)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-3-(4-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white foam, MS (ESI+): m/z=409.2 ([M+H]+, 1Br).
Reaction SMILES: Cl.[C@@H:2]12[CH:7]([CH2:8][NH:9][C:10]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:18][CH:17]=4)=[C:14]([NH2:29])[N:13]=[CH:12][N:11]=3)[C@@H:6]1[CH2:5][NH:4][CH2:3]2.N1C=CC=CC=1.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38].C(Cl)Cl>>[NH2:29][C:14]1[N:13]=[CH:12][N:11]=[C:10]([NH:9][CH2:8][CH:7]2[C@@H:6]3[C@H:2]2[CH2:3][N:4]([C:36](=[O:39])[CH:37]=[CH2:38])[CH2:5]3)[C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:20][CH:21]=1
Reactant: Nc1ncnc(NCC2[C@H]3CNC[C@@H]23)c1-c1ccc(Oc2ccccc2)cc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)N1C[C@@H]2C(CNc3ncnc(N)c3-c3ccc(Oc4ccccc4)cc3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.8 %

Procedure:
To a round bottom flask containing N-[(1S,5R)-1-(3-Aza-bicyclo[3.1.0]hex-6-yl)methyl]-5-(4-phenoxy-phenyl)-pyrimidine-4,6-diamine hydrochloride (259.68 mg; 0.63 mmol; 1.00 eq.) in pyridine (1.00 ml; 12.36 mmol; 19.52 eq.) was added acryloyl chloride (0.05 ml; 0.63 mmol; 1.00 eq.) in DCM (3.00 ml; 46.80 mmol; 73.88 eq.) over 1 h at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. It was concentrated and the crude product was subjected to preparative HPLC. Fractions containing the desired product were combined and lyophilized overnight to afford 1-((1R,5S)-6-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one as a white solid (2.1 mg, 0.6%). HPLC purity: 99%. MS: m/z=428[M+H]+. 1H NMR (CD3OD) δ 8.24 (s, 1H), 7.21-7.46 (m, 9H), 6.53 (m, 1H), 6.22 (m, 1H), 5.74 (m, 1H), 3.77 (m, 2H), 3.69 (m, 1H), 3.41 (m, 2H), 1.70 (m, 2H), 0.93 (m, 2H).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:9]([O:11][C:12](=[O:16])/[CH:13]=[CH:14]\I)[CH3:10]>>[C:12]([O:11][CH2:9][CH3:10])(=[O:16])/[CH:13]=[CH:14]\[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C#CCCCCCC
Reactant: CCOC(=O)/C=C\I
Product: CCCCCCC#C/C=C\C(=O)OCC

Procedure:
The general procedure was used to convert n-octyne and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (5% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (401 mg, 96% yield). 1H NMR (400 MHz, CDCl3) δ 6.13 (dt, J=10.82, 1H), 6.02 (d, J=10.96, 1H), 4.21 (q, 2H), 2.44 (m, 2H), 1.58 (p, 2H), 1.42 (m, 2H), 1.30-1.28 (m, 7H), 0.89 (t, 3H). 13C NMR (100 MHz, CDCl3) δ 164.87, 127.34, 123.89, 104.17, 77.66, 60.18, 31.30, 28.60, 28.36, 22.49, 20.07, 14.21, 13.99. Anal. Calcd. for C13H20O2: C, 74.96; H, 9.68; Found C, 74.96; H, 9.56.
Reaction SMILES: [Na].[CH2:2]([CH:5]([C:11]([O:13]CC)=O)[C:6](OCC)=[O:7])[CH:3]=[CH2:4].C(O)(=O)C.[CH:20]([NH2:22])=[NH:21]>C(O)C>[CH2:2]([C:5]1[C:11]([OH:13])=[N:21][CH:20]=[N:22][C:6]=1[OH:7])[CH:3]=[CH2:4]
Reactant: N=CN
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: C=CCc1c(O)ncnc1O
Temperature: 0 °C
Reaction time: 24 h
Yield: 43.9 %

Procedure:
Sodium metal (4.5 g) was added slowly into ethanol (100 mL) in a 500 mL round bottom flask under nitrogen atmosphere. The reaction mixture was stirred at room temperature until all the sodium metal dissolved, before being cooled to 0° C. Diethyl 2-allylmalonate (12 g) was added into the reaction mixture, followed by formamidine acetate (6.24 g) under nitrogen atmosphere at 0° C. The reaction was stirred at room temperature for 24 hours under nitrogen atmosphere, before being quenched by acetic acid (20 mL), followed by water (100 mL). The white precipitate was filtered, washed with water (4×50 mL), methanol (2×50 mL) and dried under vacuum to afford 5-allylpyrimidine-4,6-diol (4 g) as white solid. 1H NMR (DMSO-d6): δ 2.96 (d, 2H), 4.85 (dd, 1H), 4.91 (dd, 1H), 5.76 (dd, 1H), 7.89 (s, 1H), 11.64 (bs, 2H).
Reaction SMILES: [C:1]1([P:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[NH:17][CH:16]([CH3:19])[CH2:15][CH2:14]3)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.Cl[SiH](Cl)Cl.[OH-].[Na+]>C(Cl)Cl>[C:20]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[NH:17][CH:16]([CH3:19])[CH2:15][CH2:14]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1CCc2cccc(P(=O)(c3ccccc3)c3ccccc3)c2N1
Agent: Cl[SiH](Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCc2cccc(P(c3ccccc3)c3ccccc3)c2N1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of 8-diphenylphosphinoyl-2-methyl-1,2,3,4-tetrahydroquinoline (6) (1.5 g, 4.5 mmol) in dry degassed toluene (40 mL) was added degassed Et3N (3.15 mL, 22.5 mmol) followed by trichlorosilane (2.25 mL, 22.5 mmol). The mixture was stirred at 80° C. for 30 minutes before cautiously adding 2N NaOH (150 mL) and cooling down to room temperature. Products were then extracted with EtOAc, washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated to give a yellow oil. This oil was taken up in CH2Cl2 (100 mL), and filtered over silica gel (˜25 mL) eluting with further portions of CH2Cl2 (4×100 mL). The combined filtrates were then evaporated to give compound 7 (1.2 g) as a light yellow oil in 80% yield. 1H NMR (400.13 MHz, CDCl3) δ 7.4-7.3 (m, 10H, Ph-H), 6.99 (d, 1H, J=7.2 Hz, C5—H), 6.62 (ddd, 1H, J=7.2, 6.0, 1.2 Hz, C7—H), 6.52 (t, 1H, J=7.6 Hz, C6—H), 4.65 (bs, 1H, N1—H), 3.4-3.3 (m, 1H, C2—H), 2.9-2.7 (m, 2H, C4a/b—H), 2.0-1.9 (m, 1H, C3a—H), 1.6-1.5 (m, 1H, Cab—H), 1.11 (d, 3H, J=6.4 Hz, C1′—CH3) ppm; 13C NMR (100.61 MHz, CDCl3) δ 147.9 (d, J=18.2 Hz), 147.7 (d, J=18.2 Hz), 136.1 (d, J=12.1 Hz), 136.0 (d, J=13.1 Hz), 135.8 (d, J=13.1 Hz), 135.7 (d, J=13.1 Hz), 134.1-133.5 (m), 132.5 (d, J=12.1 Hz), 132.4 (d, J=12.1 Hz), 130.5, (d, J=13.1 Hz), 12 8.7-128.4 (m), 120.7 (d, J=12.1 Hz), 117.0, (d, J=12.1 Hz), 116.3 (d, J=12.1 Hz), 47.4, 39.6, 26.8, 22.4 ppm; 31P NMR (161.97 MHz, CDCl3) δ −21.9 ppm.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][O:7][CH2:8][CH2:9]Cl.[OH-].[Na+]>O>[CH3:6][O:7][CH2:8][CH2:9][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: CCNCC
Reactant: COCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCOC

Procedure:
A solution prepared by mixing together 100 mL of diethylamine and 85 mL of 2-methoxyethyl chloride (both available from Kanto Chemical) was placed in an autoclave and reacted at 120° C. for 12 hours. The internal pressure during the reaction was 0.28 MPa (2.9 kgf/cm2). This yielded a mixture of deposited crystals and reaction solution to which was added, following the 12 hours of reaction, 200 mL of an aqueous solution prepared by dissolving 40 g of sodium hydroxide (Katayama Chemical Industries Co., Ltd.) in 200 mL of water. Each of the two divided organic phases that formed as a result was separated off with a separatory funnel and subjected twice to extraction with 250 mL of tetrahydrofuran (Wako Pure Chemical Industries, Ltd.). The separated organic phases were then combined and washed with a saturated saline solution, following which potassium carbonate (Wako Pure Chemical Industries) was added to remove water and vacuum filtration was carried out. The solvent in the resulting organic phase was distilled off in a rotary evaporator, after which the residue was subjected to normal-pressure distillation, yielding 21 g of 2-methoxyethyldiethylamine.
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].[C:10](OC(=O)C)(=[O:12])C.C(O)=O.[OH-].[Mg+2].[OH-]>O>[CH:10]([N:2]([CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[OH:9])[OH:1])=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=P(O)(O)CCCNO
Agent: [Mg+2]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: O=CN(O)CCCP(=O)(O)O
Yield: 65.8 %

Procedure:
An oily 3-(N-formyl-N-hydroxyamino)propylphosphonic acid (12.05 g.), which was prepared by the reaction of 3-(N-hydroxyamino)propylphosphonic acid (15.5 g.), acetic anhydride (12.3 g.) and formic acid (9.8 ml.) conducted in substantially the same manner as that of Example (31), was dissolved in water (80 ml.) and treated with magnesium hydroxide (5.83 g.) for 15 minutes under ice-cooling with stirring.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[O:30][CH3:31].C1C([N+]([O-])=O)=CC=C([Cl-][C:42]([O-])=[O:43])C=1.[CH3:45][C:46]([CH3:50])([CH3:49])[CH2:47][NH2:48]>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:42]([NH:48][CH2:47][C:46]([CH3:50])([CH3:49])[CH3:45])=[O:43])=[C:3]([O:30][CH3:31])[CH:4]=3)[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)CN
Reactant: COc1cc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)CC2)ccc1N
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)CC2)ccc1NC(=O)NCC(C)(C)C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a stirred solution of 3-((4-(4-amino-3-methoxybenzoyl)piperazin-1-y)methyl)-N-tert-butylbenzamide (0.155 mmol, 66 mg) in dichloromethane (2 mL) was added 4-nitrophenylchloroformate (0.155 mmol, 31.3 mg). After 1 hour stirring, 2,2-dimethylpropan-1-amine (0.311 mmol, 27.1 mg) was added and stirring continued for 1 hour. The reaction was concentrated under vacuum and the residue dissolved in methanol (1 mL). Purification by basic reverse phase HPLC gave the title compound (35 mg). MS (ESI) m/z 539.0 [M+H]+
Reaction SMILES: C1(S([NH:10][C:11](N)=[O:12])(=O)=O)C=CC=CC=1.C1(C)C=CC=CC=1.[Cl:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH2:28]>C(O)(=O)C>[Cl:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH:28][C:11](=[O:12])[NH2:10]
Reactant: NC1CCCCC1Cl
Reactant: NC(=O)NS(=O)(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: NC(=O)NC1CCCCC1Cl

Procedure:
A mixture of 10.3 g of of N-[4-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-ethyl)-benzenesulfonyl-urea (melting point 171° -173°C), 300 ml of toluene, 30 ml of glycolmonomethyl-ether, 1.65 g of glacial acetic acid and 3.3 g of 2-chloro-cyclohexylamine are heated under reflux for 5 hours. Then the whole is concentrated in vacuo and the residue is treated with alcohol. The N-[4-(β<2-methoxy-5-chlorobenzamido> -ethyl)-benzenesulfonyl]-N'-(2-chlorocyclohexyl)-urea obtained as crude product melts at 194° -195°C after recrystallization from methanol/dimethylformamide.
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9](=[O:25])[CH:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[CH:10]([C:9](=[O:25])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH3:26])[OH:11])=[CH:18][CH:19]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)N(C)Cc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(=O)N(C)Cc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using N-benzyl-2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-hydroxy-N-methyl-acetamide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH3:26])[CH:17]=3)=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=2)[O:2]1.O.[NH2:29][NH2:30].C(O)C>>[CH2:1]1[O:2][C:3]2=[CH:4][C:5]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH3:26])[CH:17]=4)=[N:30][NH:29][C:11](=[O:12])[CH2:10][C:6]=3[CH:7]=[C:8]2[O:9]1
Reactant: NN
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])c(OC)c1)OCO2
Solvent: O
Solvent: CCO
Product: COc1cc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from methyl 4,5-methylenedioxy-2-(3-methoxy-4-nitrobenzoyl)phenylacetate (1.2 g, 3.2 mmol) and hydrazine hydrate (0.6 mL, 11 mmol) in ethanol (15 mL) as a yellow solid (0.53 g, 1.5 mmol, 47%), mp: 267°-269° C. 1H NMR (CDCl3) 8.60 (s, 1H), 7.86 (d, J=8.5, 1H), 7.49 (d, J=1.5, 1H), 7.13 (dd, J=8.5, 1.5, 1H), 6.85 (s, 1H), 6.59 (s, 1H), 6.06 (s, 2H), 4.01 (s, 3H), 3.48 (s, 2H). Anal. Calcd. for C17H13N3O6 : C, 57.47; H, 3.69; N, 11.83. Found: C, 57.07; H, 3.42; N, 12.01.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][CH:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]2=O)=[C:4]([F:26])[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][CH:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]2=[S:28])=[C:4]([F:26])[CH:3]=1
Reactant: CCOC(=O)CC1Sc2ccccc2N(Cc2ccc(Br)cc2F)C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1Sc2ccccc2N(Cc2ccc(Br)cc2F)C1=S
Yield: 110.5 %

Procedure:
To 4 ml of toluene was added 440 mg of the compound of Example 20 and 310 mg of phosphorus pentasulfide. After the mixture was heated to reflux for 6 hours, the solvent was distilled off. Methylene chloride was added to the mixture, and the insoluble substance was filtered off and the solvent was distilled off. Then the residue was purified by silica gel chromatography to give 350 mg of ethyl 2-[4-(4-bromo-2-fluorophenylmethyl)-3,4-dihydro-3-thioxo-2H-1,4-benzothiazin-2-yl]acetate. The structural formula and physical data of this compound are shown in Table 24.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12](=[O:19])[CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[O:19][NH:30][C:14](=[O:15])[CH:13]=2)[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)cc(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)cc(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 65.6 %

Procedure:
Cis-methyl 2-(3,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.662 g, 6.94 mmol) was dissolved in MeOH (24 mL) and cooled to −40° C. under nitrogen atmosphere. Sodium hydroxide (0.278 g, 6.94 mmol) dissolved in water (2.400 mL) was added over 13 min. After 20 min with stirring, hydroxylamine (50% by weight in water, 0.425 mL, 6.94 mmol) was added over 9 minutes and the solution was stirred for 3.5 hours at −40° C. The reaction mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (35.8 mL, 214.55 mmol) and the mixture continued to stir at 80° C. for 25 min. The solvent was evaporated and the crude mixture was redissolved in DCM/water. The organic phase was dried and concentrated. The compound was purified by preparative HPLC in 2 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.604 g, 65.6%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.91-2.07 (m, 4H), 2.62-2.80 (m, 2H), 2.97-3.04 (m, 1H), 3.23-3.34 (m, 1H), 3.54 (s, 3H), 3.89-3.99 (m, 1H), 4.26-4.36 (m, 1H), 5.73 (s, 1H), 6.69-6.79 (m, 3H). MS m/z 353 (M+H)+
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[O-:20].[Na+]>>[C:1]1([S:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)(=[O:20])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(S(=O)c2ccccc2)cc1
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
4-Benzenesulfinyl-benzoic acid (0.14 g, 0.5 mmol) was suspended in sodium hypochlorite solution (10 mL) and the reaction mixture stirred for 24 h at room temperature. The progress of the reaction was monitored by TLC. The reaction mixture was acidified with an aq. solution of 10% HCl solution. The resulting precipitate was filtered and washed with water. The residue was then redissolved in methanol and concentrated to get the title compound (0.105 g, 70%).