Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][N:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:7]1=[O:28])C.O.[OH-].[Li+].Cl>O.CO>[C:24]([O:23][C:21]([N:16]([CH2:17][CH:18]1[CH2:19][CH2:20]1)[CH2:15][CH2:14][CH2:13][NH:12][C:8]1[C:7](=[O:28])[N:6]([CH2:5][C:4]([OH:29])=[O:3])[CH:11]=[CH:10][N:9]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)Cn1ccnc(NCCCN(CC2CC2)C(=O)OC(C)(C)C)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCNc1nccn(CC(=O)O)c1=O)CC1CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of {3-[3-(tert-butoxycarbonyl-cyclopropylmethyl-amino)-propylamino]-2-oxo-2H-pyrazin-1-yl}-acetic acid ethyl ester (250 mg, 0.61 mmol) and lithium hydroxide monohydrate (33 mg, 0.79 mmol) in water (0.72 ml) and methanol (3.6 ml) was stirred at room temperature for 2 h. hydrochloric acid solution (1N, 0.79 ml) was added and the reaction mixture was stirred at room temperature for 10 min. Concentration from methanol gave {3-[3-(tert-butoxycarbonyl-cyclopropylmethyl-amino)-propylamino]-2-oxo-2H-pyrazin-1-yl}-acetic acid; 1H NMR (CD3OD, 400 MHz) δ 6.78 (d, 1H, J=4.8 Hz), 6.69 (d, 1H, J=4.9 Hz), 4.61 (s, 2H), 3.32 (m, 4H), 3.12 (d, 2H, J=6.8 Hz), 1.89 (m, 2H), 1.45 (s, 9H), 1.00 (m, 1H), 0.48 (m, 2H), 0.22 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:51])([CH3:50])[C:29]([F:49])([F:48])[C@:30]([C:33]3[CH:38]=[C:37](B4OCC(C)(C)CO4)[CH:36]=[CH:35][C:34]=3[F:47])([CH3:32])[N:31]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Br[C:53]1[N:54]=[CH:55][N:56]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[CH:57]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:51])([CH3:50])[C:29]([F:48])([F:49])[C@:30]([C:33]3[CH:38]=[C:37]([C:53]4[N:54]=[CH:55][N:56]([C:58]5[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=5)[CH:57]=4)[CH:36]=[CH:35][C:34]=3[F:47])([CH3:32])[N:31]=2)([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][CH:8]=1
Reactant: Brc1cn(-c2ccccn2)cn1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(B4OCC(C)(C)CO4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4cn(-c5ccccn5)cn4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 25 %

Procedure:
Reaction of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (intermediate B10.1) (300 mg, 380 μmol) with 2-(4-bromo-1H-imidazol-1-yl)pyridine [CAS 556775-77-0; J. Med. Chem. 47(19), 4645 (2004)) (111 mg, 494 μmol) yielded the [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-6,6-difluoro-5-[2-fluoro-5-(1-pyridin-2-yl-1H-imidazol-4-yl)-phenyl]-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (71 mg, 25% yield) as a light red foam. MS (ISP): m/z=732.5 [M+H]+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=O)=[CH:8][CH:7]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.Cl>ClC1C=CC=CC=1>[F:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: c1ccsc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Fc1ccc(Cc2cccs2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
33.8 g of aluminium trichloride were suspended in 217 g of chlorobenzene, and a solution of 40.3 g of 4-fluorobenzoyl chloride in 37.4 g of chlorobenzene was added dropwise to this at 0° C. over the course of 15 minutes. The mixture was then stirred for 1 hour and then, at 0° C., 21.8 g of thiophene were added dropwise over the course of 20 minutes. The resulting hydrogen chloride was drawn off and absorbed in sodium hydroxide solution. The mixture was subsequently heated to 80° C. and the remaining hydrogen chloride was removed. The resulting solution was added dropwise to a suspension of 7.2 g of sodium borohydride in 47.2 g of digylme while stirring at 70° C. over the course of 45 minutes. The reaction mixture was then stirred for 90 minutes and then cooled to room temperature and discharged into a mixture of 250 g of ice, 44.6 g of concentrated aqueous hydrochloric acid and 500 g of water. The organic phase which formed thereby was separated off, the aqueous phase was extracted by shaking with chlorobenzene, and the combined organic phases were distilled. 35.0 g of product with a boiling point of 83° C./1.0 mbar and a purity of 99.7% (GC) were obtained. This corresponds to 73.9% of theory. The product contained less than 0.1% by weight of defluorinated compounds (GC).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1OS(C(F)(F)F)(=O)=O)[O:8][CH:7]([C:20]([F:23])([F:22])[F:21])[C:6]([C:24]([O:26]CC)=[O:25])=[CH:5]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[CH2:58]([C:60]1[CH:65]=[CH:64][C:63]([OH:66])=[CH:62][CH:61]=1)[CH3:59]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.C1(C)C=CC=CC=1>[CH2:58]([C:60]1[CH:65]=[CH:64][C:63]([O:66][C:11]2[CH:10]=[C:9]3[C:4]([CH:5]=[C:6]([C:24]([OH:26])=[O:25])[CH:7]([C:20]([F:23])([F:21])[F:22])[O:8]3)=[CH:3][C:2]=2[CH3:1])=[CH:62][CH:61]=1)[CH3:59]
Reactant: CCc1ccc(O)cc1
Reactant: CCOC(=O)C1=Cc2cc(C)c(OS(=O)(=O)C(F)(F)F)cc2OC1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1ccc(Oc2cc3c(cc2C)C=C(C(=O)O)C(C(F)(F)F)O3)cc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To the mixture of ethyl 6-methyl-2-(trifluoromethyl)-7-{[(trifluoromethyl)-sulfonyl]-oxy}-2H-chromene-3-carboxylate (0.3 g, 0.7 mmol ), powdered potassium phosphate(297 mg, 1.4 mmol), palladium acetate (15.7 mg, 0.07 mmol), and 2-(di-tert-butyl phosphino)biphenyl (31.3 mg, 0.105 mmol) and 4-ethyl- phenol (103 mg, 0.84 mmol) was added 4 mL of anhydrous toluene. The resulting mixture was heated to 110° C. and stirred at 110° C. for four hrs. LC-MS indicated that the reaction was completed. After cooling to room temperature, to the reaction was added 100 mL of EtOAc. The organic phase was then extracted with brine three times, and dried over anhydous magnesium sulfate. After removing the volatiles, the residue was purified on silica gel column with 1:18 EtOAc/hexane. The collected product was dissolved in THF(3 mL), and to the resulting solution was added ethanol (3 mL), and water (3 mL), followed by addition of lithium hydroxide hydrate (90 mg). The resulting mixture was heated to 80° C. and stirred for 1.5 hrs. LC-MS indicated that the reaction was done. The volatiles were removed, the residue was diluted with water, and acidified at 0° C. with ice-cold dilute hydrochloric acid. The product was extracted with EtOAc. After removing the solvent, the residue was purified on reverse phase HPLC. The product was isolated as light yellow solid, 100 mg. LC-MS(ES+): 379.2(M+1, 100). 1H NMR (CDCl3/CD3CD/300 MHz) 7.86(s, 1H), 7.25(d, J=8.4 Hz, 2H), 7.14(s, 1H), 6.99(d, J=8.4 Hz, 2H), 6.40(s, 1H), 5.64(q, J=6.6 Hz, 1H), 2.70(q, J=7.5 Hz, 2H), 2.30(s, 3H), 1.30(t, J=7.5 Hz, 3H). 13C NMR(CDCl3/CD3OD/300 MHz) 170.0, 161.2, 153.5, 153.4, 140.9, 139.8, 132.2, 129.6, 123.7(q, J=287.9 Hz), 122.9, 120.1, 113.5, 112.7, 104.2, 70.6(q, J=33.3 Hz), 28.5, 15.9, 15.7. High resolution MS(ES−): m/z cacl. For C20H16F3O4: 377.1001(M−H), found: 377.0987.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:30])=[C:16]([NH:21][C:22](=[O:29])OCC(Cl)(Cl)Cl)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH:31][CH2:32][CH2:33][NH2:34]>>[OH:31][CH2:32][CH2:33][NH:34][C:22]([NH:21][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]=1[CH3:30])=[O:29]
Reactant: NCCO
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Product: Cc1c(C)c2c(c(C)c1NC(=O)NCCO)C(c1ccc(C(C)C)cc1)CO2
Yield: 89 %

Procedure:
Using 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 2-hydroxyethylamine, the title compound was obtained in the same manner as in Example 143.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: c1ccccc1
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)c2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 4-bromo-3-methylbenzoic acid (1.00 g, 4.65 mmol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed on the pump. Benzene (20 mL, 0.2 mol) and aluminum trichloride (0.676 g, 5.07 mmol) were added to the reaction mixture. The reaction mixture turned yellow in color on addition of AlCl3. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:29]=[C:28]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40]C(=O)C3C=C(F)C=C(F)C=3)[CH:35]=2)=[O:31])[CH:27]=[C:26]([CH3:51])[C:5]=1[C:6]([NH:8][C@H:9]([C:22]([O:24]C)=[O:23])[CH2:10][NH:11][C:12](=[O:21])[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)=[O:7]>CO>[Cl:3][C:4]1[CH:29]=[C:28]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=2)=[O:31])[CH:27]=[C:26]([CH3:51])[C:5]=1[C:6]([NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][NH:11][C:12](=[O:21])[C:13]1[CH:14]=[C:15]([F:20])[CH:16]=[C:17]([F:19])[CH:18]=1)=[O:7]
Reactant: COC(=O)[C@H](CNC(=O)c1cc(F)cc(F)c1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(OC(=O)c3cc(F)cc(F)c3)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)NCc2cccc(O)c2)cc(Cl)c1C(=O)N[C@@H](CNC(=O)c1cc(F)cc(F)c1)C(=O)O
Reaction time: 8 h
Yield: 43.6 %

Procedure:
An aqueous solution of sodium hydroxide (1 M; 0.123 mL, 0.123 mmol) was added to a solution of N-[2-chloro-4-[[[[3-[(3,5-difluoro-benzoyl)oxy]phenyl]methyl]amino]carbonyl]-6-methylbenzoyl]-3-[(3,5-difluorobenzoyl)amino]-L-alanine, methyl ester (43 mg, 0.0614 mmol) in methanol (1 mL). The solution was allowed to stir overnight and then concentrated. The residue was purified by HPLC and lyophilized to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3-[(3,5-difluorobenzoyl)amino]-L-alanine (14.6 mg, 43%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:7]1=[O:28])[CH3:2].[OH:31][CH2:32][CH2:33][NH:34][C:35](=[O:40])[CH2:36][CH2:37][C:38]#[CH:39]>>[CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12]([C:39]#[C:38][CH2:37][CH2:36][C:35](=[O:40])[NH:34][CH2:33][CH2:32][OH:31])[CH:13]=2)[C:8]([OH:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:7]1=[O:28])[CH3:2]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c1cc(I)cc2C(F)(F)F
Reactant: C#CCCC(=O)NCCO
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c1cc(C#CCCC(=O)NCCO)cc2C(F)(F)F

Procedure:
The title compound (740 mg) was prepared from (+)-1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodo-3-hydroxy-3-(2-chlorophenyl)oxindole of Example 72(1) (102 mg, 0.185 mmol) and N-hydroxyethyl-4-pentynamide by the procedure similar to that described in Reference Example 21. The hydrochloride of the title compound was obtained by treating with 4 N HCl in dioxane followed by concentration to dryness.
Reaction SMILES: OC1C2C(=CC(C3C=CC(C(OC(C)(C)C)=O)=CC=3)=CC=2)N(C)C(=O)C=1C(=O)CCC=O.[O:33]1CCC[O:35][CH:34]1[CH2:39][CH2:40][C:41]([C:43]1[C:44](=[O:68])[N:45]([CH3:67])[C:46]2[C:51]([C:52]=1[OH:53])=[CH:50][CH:49]=[C:48]([C:54]1[CH:66]=[CH:65][C:57]([C:58]([O:60]C(C)(C)C)=[O:59])=[CH:56][CH:55]=1)[CH:47]=2)=[O:42]>CC(O)=O>[C:34]([CH2:39][CH2:40][C:41]([C:43]1[C:44](=[O:68])[N:45]([CH3:67])[C:46]2[C:51]([C:52]=1[OH:53])=[CH:50][CH:49]=[C:48]([C:54]1[CH:55]=[CH:56][C:57]([C:58]([OH:60])=[O:59])=[CH:65][CH:66]=1)[CH:47]=2)=[O:42])([OH:35])=[O:33]
Reactant: Cn1c(=O)c(C(=O)CCC2OCCCO2)c(O)c2ccc(-c3ccc(C(=O)OC(C)(C)C)cc3)cc21
Agent: Cn1c(=O)c(C(=O)CCC=O)c(O)c2ccc(-c3ccc(C(=O)OC(C)(C)C)cc3)cc21
Solvent: CC(=O)O
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2ccc(-c3ccc(C(=O)O)cc3)cc21
Temperature: 90 °C

Procedure:
tert-Butyl 4-(4-hydroxy-1-methyl-2-oxo-3-(4-oxobutanoyl)-1,2-dihydroquinolin-7-yl)benzoate. AcOH (80%, 15 mL) was added to tert-butyl 4-(3-(3-(1,3-dioxan-2-yl)propanoyl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)benzoate (150 mg, 304 mmol), and the resulting mixture was heated at 90° C. for 1 hour. The reaction mixture was quenched with water and cooled to room temperature. A solid precipitated from solution and was filtered and stuck to the frit. The frit was washed with EtOAc (5×) to give the title compound as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:13][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:12])([CH3:13])[CH:9]([F:11])[F:10])=[CH:6][CH:7]=1
Reactant: C[Mg]Cl
Reactant: O=C(c1ccc(Br)cc1)C(F)F
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Br)cc1)C(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-bromophenyl)-2,2-difluoroethanone (2.5 g, 10.6 mmol) in THF (60 mL) was added methylmagnesium chloride (10 mL, 30 mmol; 3 M in THF) at 0° C. over ˜10 min and the mixture was stirred at 0° C. for 1 h. A mini-worked up showed starting material remained and more methylmagnesium chloride (5 mL, 15 mmol, 3 M in THF) was added. After further stirred for 15 min., the mixture was quenched with H2O, carefully acidified with 1 M HCl (100 mL) and extracted with Ethyl acetate. Purification by combi-flash chromatography (120 g column; eluted with hexanes—Ethyl acetate (5% -25%) in 20 min.; flow rate: 70 mL/min and collected 25 mL/fraction) yielded the title compound as a colorless liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(=O)C.[NH:21]1[CH2:24][CH:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:22]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:24][CH:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:22]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C1
Yield: 33.3 %

Procedure:
Prepared according to general procedure 21. A solution of 4-bromo-N-(thiazol-2-yl)benzenesulfonamide (2.0 g, 6.3 mmol), tert-butyl azetidin-3-ylcarbamate acetate (1.61 g, 6.9 mmol) sodium tert-butoxide (2.55 g, 26.5 mmol), biphenyl-2-yl-di-tert-butylphosphine (224 mg, 0.76 mmol), and Pd2(dba)3 (172 mg, 0.19 mmol) in toluene (16 mL) was stirred at 75° C. for 16 h. The reaction mixture was poured into H2O, and the pH was adjusted to 6. The aqueous layer was extracted 4 times with CH2Cl2, and the organics were combined, washed with saturated aqueous NaCl solution, dried over MgSO4, and concentrated. Purification via silica gel chromatography using 50-70% EtOAc in hexanes gave tert-butyl 1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)azetidin-3-ylcarbamate (0.86 g, 33%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=411.0; tR=2.54 min.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([O:13]CC)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(c1ccccc1)N1CCN(C(C)=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCN(C(C(=O)O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
Ethyl 2-(4-acetylpiperazin-1-yl)-2-phenylacetate (285 mg, 0.98 mmol) was dissolved in a mixture EtOH (6.5 ml) and water (3.3 ml). LiOH (23.5 mg, 0.98 mmol) was added and the reaction was stirred at room temperature overnight. LiOH (23.5 mg, 0.982 mmol) was added again and the mixture was stirred for additional 24 hours. EtOH was evaporated and 1N HCl was added dropwise to the aqueous solution till pH 6-7 before evaporating to dryness. The crude was purified by flash chromatography (DCM/MeOH=75/25) to obtain 2-(4-acetylpiperazin-1-yl)-2-phenylacetic acid (246 mg, 96% yield) as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:21])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=2[C:13]=1[CH3:14])(=O)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(O)C.CC(OC)(C)C>[CH3:20][O:19][C:17]1[CH:16]=[CH:15][C:12]2[C:13]([CH3:14])=[C:8]([CH2:7][CH2:6][N:33]3[CH2:32][CH2:31][N:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])[CH2:35][CH2:34]3)[C:9](=[O:21])[O:10][C:11]=2[CH:18]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1ccc2c(C)c(CCOS(C)(=O)=O)c(=O)oc2c1
Solvent: COC(C)(C)C
Solvent: CCO
Product: COc1ccc2c(C)c(CCN3CCN(c4ccccc4OC)CC3)c(=O)oc2c1
Yield: 29 %

Procedure:
Process A; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-7-methoxy-4-methyl-2H-1-benzopyran-2-one (Example 26) and 1-(2-methoxyphenyl)piperazine; yield 29%; m.p. 129°-130° C. (from ethanol/TBME).
Reaction SMILES: [OH-].[NH4+:2].II.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=2)[C:19]#[N:20])=[CH:8][C:7]=1[CH:22]=O>O1CCCC1>[C:22]([C:7]1[CH:8]=[C:9]([C:12]#[C:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=2)[C:19]#[N:20])[CH:10]=[CH:11][C:6]=1[F:5])#[N:2]
Reactant: [NH4+]
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(C=O)c2)c1
Agent: II
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1cncc(C#Cc2ccc(F)c(C#N)c2)c1
Reaction time: 0.33 h
Yield: 57 %

Procedure:
Add a 28% aqueous solution of ammonium hydroxide (10 mL) and iodine (279 mg, 1.10 mmol) to a solution of 5-(4-fluoro-3-formylphenylethynyl) -nicotinonitrile, (prepared as described in PREPARATION 38), (250 mg, 1.00 mmol) in tetrahydrofuran (5 mL). After 3.25 h quench with a 5% aqueous solution of sodium bisulfite (5 mL) and extract twice with ethyl acetate. Wash the organic layers with saturated aqueous sodium chloride, dry (sodium sulfate), filter, and concentrate. Dissolve the crude solid in dichloromethane and add PS-TsNNH2 (3g, ˜1.2 mmol, Argonaut). Stir the mixture for 20 min and filter through diatomaceous earth. Purify by silica gel chromatography, eluting with 90:10 to 80:20 (70:30 hexanes:dichloromethane):ethyl acetate, to give the title compound as a white crystalline solid (140 mg, 57%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(CBr)cc1

Procedure:
38.1 g (0.2 mol) of 4-methylbenzenesulphonyl chloride are dissolved in 300 ml of carbon tetrachloride, 35.6 g (0.2 mol) of N-bromosuccinimide are added and, after addition of 0.2 g (1.2 mmol) of azobisisobutyronitrile (ABU), the mixture is heated under reflux for 4 hours. After cooling, the solids are filtered off and the filtrate is freed from the solvent. Flash chromatography (petroleum ether/toluene 4:1, 50 μm particle size) and subsequent recrystallisation from 100 ml of cyclohexane give 24.0 g (45% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]2[O:23][CH3:24])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:25][C:26]([Br:30])=[CH:27][CH2:28]Br.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[N:14]=[C:13]2[O:23][CH3:24])=[CH:7][C:3]=1[C:4]([O:6][CH2:28][CH:27]=[C:26]([Br:30])[Br:25])=[O:5]
Reactant: BrCC=C(Br)Br
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)OCC=C(Br)Br)c(Cl)cc1F

Procedure:
A mixture of 1.5 g of 2-chloro-4-fluoro-5-[2methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-benzoic acid, 1.37 g of 1,1,3-tribromo-1-propene and 0.52 g of sodium carbonate in 50 ml of anhydrous acetone is heated for 8 hours while stirring. Subsequently, the insoluble constituents are filtered off under suction and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in 100 ml of diethyl ether and the solution is extracted three times with 50 ml of water each time. The organic phase is then dried over anhydrous sodium sulphate and evaporated to dryness, and the residue is purified by chromatography on a silica gel column using n-hexane/diethyl ether (3:1) as the eluent. There is obtained 3,3-dibromo-2-propenyl 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]benzoate, 1H-NMR (CDCl3, 400 MHz): 7.89 ppm (d, 1H), 7.42 ppm (d, 1H), 6.72 ppm (t, 1H), 6.62 ppm (s. 1H), 4.82 ppm (d, 2H), 4.02 ppm (d, 3H).
Reaction SMILES: CC([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[C:16](\[CH2:22][CH2:23][OH:24])/[C:17]([O:19]CC)=O)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)C>FC(F)(F)C(O)=O>[S:6]([C:9]1[CH:14]=[CH:13][C:12](/[C:15](=[C:16]2/[C:17](=[O:19])[O:24][CH2:23][CH2:22]/2)/[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:11][CH:10]=1)(=[O:7])(=[O:8])[NH2:5]
Reactant: CCOC(=O)/C(CCO)=C(\c1ccc(F)cc1)c1ccc(S(=O)(=O)NC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(/C(=C2\CCOC2=O)c2ccc(F)cc2)cc1
Yield: 66 %

Procedure:
A solution of 10 g of ethyl (E)-3-(4-(1,1-dimethylethyl)sulfamoylphenyl)-3-(4-fluorophenyl)-2-(2-hydroxyethyl)prop-2-enoate, prepared in example 20, in 50 ml of trifluoroacetic acid is heated under reflux for 16 hours. The solution is evaporated to dryness in vacuo and the residue is taken up into an acetone/diethyl ether mixture. The crystals formed are filtered off and dried to give 5.1 g of (E)-3-[1-(4-sulfamoylphenyl)-1-(4-fluorophenyl)methylene]-2,3,4,5-tetrahydrofuran-2-one as crystals with a melting point of 202° C.