Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH:3]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:27]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=3)=[O:28])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(NC(=O)Nc2ccc(Oc3cc(Cl)ncn3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1; 3.77 g, 15 mmol) in THF (55 ml) under N2-atmosphere, 4-tertbutylphenyl isocyanate (5.26 g, 30 mmol) dissolved in THF (5 ml) is added. During stirring for 1 h at rt a suspension is formed. The mixture is then re-dissolved in AcOEt and a solution of NaHCO3 in water, the aqueous layer separated off and extracted twice with AcOEt. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated in vacuo. Stirring of the resulting solid in Et2O finally yields the title compound: m.p.: 111-112° C.; 1H-NMR (DMSO-d6): 8.75 (s, HN), 8.65 (s, 1H), 8.62 (s, HN), 7.51 (d, 2H), 7.36 (d, 2H), 7.33 (s, 1H), 7.31 (d, 2H), 7.17 (d, 2H), 1.27 (Me3C).
Reaction SMILES: [Br:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[N:13][OH:14])=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[CH:25]=1.C(N(CC)CC)C>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH2:31][C:30]([C:28]3[CH:27]=[C:26]([Cl:36])[CH:25]=[C:24]([Cl:23])[CH:29]=3)([C:32]([F:33])([F:35])[F:34])[O:14][N:13]=2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: ON=Cc1ccc(Br)c2ncccc12
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c3ncccc23)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a stirred solution of 8-bromo-5-quinolinecarboxaldehyde oxime (i.e. the product from Step C) (1.7 g, 6.8 mmol) in N,N-dimethylformamide (13.0 mL) was added N-chlorosuccinimide (1.24 g, 9.3 mmol). The reaction mixture was stirred for 1 h at room temperature, and then a solution of 1,3-dichloro-5-[1-(trifluoromethyl)ethenyl]benzene (i.e. the product from Example 1, Step B) (1.96 g, 8.1 mmol) and triethylamine (2.86 mL, 20.4 mmol) in N,N-dimethylformamide (7.0 mL) was added. After stirring for additional 12 h at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate as eluent to afford the title compound as a white solid (2.0 g, 61% yield).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].[OH-].[Na+].Cl.[CH3:12][S:13]([N:16]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[C:17]1=[O:24])(=[O:15])=[O:14]>O.CC(C)=O>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([NH:1][C:21]([N:18]1[CH2:19][CH2:20][N:16]([S:13]([CH3:12])(=[O:15])=[O:14])[C:17]1=[O:24])=[O:22])[C:6]([OH:8])=[O:7]
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C[C@H](O)[C@@H](NC(=O)N1CCN(S(C)(=O)=O)C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
D-Threonine (5.0 g) was suspended in water (50 ml) and treated with 2M aqueous sodium hydroxide solution to pH 10, forming a clear solution. The pH was then re-adjusted to 7.5 with concentrated hydrochloric acid and the still clear solution cooled to 15°. 3-Methanesulphonyl-2-oxoimidazolidine-1-carbonyl chloride (9.5 g) was then added portionwise over 2 minutes, with simultaneous addition of 2M aqueous sodium hydroxide to maintain the pH at 6.0-7.5. Following this, acetone (30 ml) was added to give a clear solution which was then stirred at room temperature for 1 hour whilst still maintaining the pH at 6.0-7.5. After evaporation of the acetone in vacuo the aqueous residue was extracted well with ethyl acetate and the organic extracts were discarded. The pH of the aqueous phase was then adjusted to 1.5 with concentrated hydrochloric acid and the mixture was extracted using 3×50 ml portions of ethyl acetate:tetrahydrofuran (1:1). The organic extracts were dried and the solvent was evaporated to give the title compound as a white solid, (7.3 g).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH3:20])=[CH:15][CH:14]=1.[C:22](O)(=O)C(O)=O>C(O)(=O)C.O>[CH3:20][CH:19]([C:8]1[C:7]([O:10][CH3:22])=[CH:6][C:4]2[O:5][CH2:1][O:2][C:3]=2[CH:9]=1)[C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=C(O)C(=O)O
Reactant: COc1ccc(C(C)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(C)c2cc3c(cc2OC)OCO3)cc1

Procedure:
(α-Methyl-4-methoxybenzyl)-3,4-methylenedioxy-6-methoxybenzene was prepared according to the following procedure: A solution of sesamol (27.6 g, 0.2 mole), 1-(4-methoxyphenyl)ethanol (30.4 g, 0.2 mole), and oxalic acid (2 g) in glacial acetic acid (60 ml) and water (10 ml) was refluxed for 7 hours, diluted with water, and extracted with ether. Distillation of the ether extract gave an oil, b.p. 235°-237° at 5 mm Hg (53 g), which crystallized from benzene-skelly solve F to yield glistening, colorless needles, m.p. 93°-94° (Found: C, 70.5; H, 5.86. Calc. for C16H16O4 : C, 70.6; H, 5.92%); pmr spectrum: δ1.53, 3H, D (J=7 Hz); δ3.77, 3H, S; δ4.21, 1H, Q (J=7 Hz); δ4.58, 1H (OH), S; δ5.86, 2H, S; δ6.35, 1H, S; δ6.70, 1H, S; δ6.81, 2H, D (J=9 Hz); δ7.17, 2H, D (J=9 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:28](O)=[O:29])[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.[N:42]1(OC(N(C)C)=[N+](C)C)[C:46]2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:28]([NH:42][CH3:46])=[O:29])[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CCN(C)CC1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
4-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-1-methylpiperidine-4-carboxylic acid (50 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (2 ml) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (59 mg, 0.15 mmol) and N,N-diisopropylethylamine (89 μl, 0.51 mmol) were added. After a few minutes methylamine hydrochloride (10 mg, 0.15 mmol) was added and the mixture stirred for 1 hour at room temperature. The mixture was absorbed onto an Isolute SCX column, washed with methanol and eluted with ammonia in methanol. Appropriate fractions were combined and concentrated. The residue was purified by column chromatography on silica, eluting with 5% 7N ammonia in methanol/dichloromethane, to give the title product (40 mg, 77%) as a white solid; 1H NMR Spectrum: (DMSO d6) 1.82 (m, 2H); 2.02 (m, 2H); 2.13 (m, 8H); 2.65 (m, 5H); 3.60 (s, 2H); 3.94 (s, 3H); 7.18 (s, 1H); 7.30 (t, 1H); 7.50 (m, 1H); 7.58 (m, 2H); 8.32 (s, 1H); 8.73 (s, 1H); 9.68 (s, 1H). Mass Spectrum: (M+H)+ 501.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[Cl:5][C:6]1[CH:11]=[C:10]([C:12](Cl)=[O:13])[CH:9]=[C:8]([CH3:15])[N:7]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH2:28])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>CC(C)=O.C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([C:12]([NH:3][C:2]([NH:28][C:20]2[CH:21]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:23]=[C:18]([O:17][CH3:16])[CH:19]=2)=[S:1])=[O:13])[CH:9]=[C:8]([CH3:15])[N:7]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: N#C[S-]
Reactant: Cc1cc(C(=O)Cl)cc(Cl)n1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1cc(NC(=S)NC(=O)c2cc(C)nc(Cl)c2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium thiocyanate (6.998 g, 0.08632 mol) was added to a solution of 2-chloro-6-methyl-4-pyridinecarbonyl chloride (14.912 g, 0.078472 mol) in acetone (2 l). The resulting mixture was stirred for 1 hour at room temperature (formation of a brown precipitate). Subsequently, 3-methoxy-5-trifluoromethyl benzenamine (15 g, 0.078472 mol) was added dropwise and the reaction mixture was stirred for 2 hours at room temperature (brown precipitate). The mixture was dissolved in CH2Cl2 (1.5 l) and was then washed with 2×250 ml water and brine. The separated organic layer was evaporated and the residue was triturated overnight with DIPE/heptane. The product was filtered off and dried in vacuo. Yield: 21.32 g of intermediate D5 (67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(OP([CH2:29][C:30]#[N:31])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:29][C:30]#[N:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1
Yield: 95.8 %

Procedure:
(3,4-dimethoxyphenyl)-(4-methoxyphenyl)methanone (2.00 g, 7.35 mmol), cyanomethylphosphonic acid diethyl ester (2.31 ml, 14.69 mmol) in anhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 14.69 ml, 14.69 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (5% EtOAc in hexane gradient to 30% EtOAc in hexane in about 40 min.) to give 3-(3,4-dimethoxy-phenyl)-3-(4-methoxy-phenyl)-acrylonitrile as a pink oil (2.08 g, 96%): 1HNMR (DMSO-d6) δ 7.34-6.7 (m, 7H, Ar), 6.14 (s, 0.50H, double bond proton of one isomer), 6.08 (s, 0.45H, double bond proton of the other isomer), 3.83-3.73 (multiple singlets, 9H, 3OCH3); 13C NMR (CDCl3) δ 162.6, 162.5, 161.6, 161.2, 151.2, 150.7, 149.0, 148.8, 132.2, 131.7, 131.5, 130.3, 129.8, 129.5, 123.2, 122.3, 118.8, 118.8, 114.1, 114.0, 112.9, 111.5, 110.9, 91.9, 91.8, 56.2, 56.1, 56.1, 55.5, 55.5; Anal. Calcd. For C18H17NO3: C, 71.92; H, 6.19; N, 4.32 (+0.04H2O). Found: C, 71.95; H, 6.04; N, 4.54.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=1.CN([CH:25]=[O:26])C>C1COCC1>[Br:13][C:14]1[CH:15]=[C:16]([CH3:21])[C:17]([F:20])=[C:18]([CH:19]=1)[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc(Br)cc(C=O)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a stirred solution of di-isopropyl amine (4.01 g, 39.88 mmol) in THF (20 mL) was added n-butyl lithium (1.6 M in hexane) (19.9 mL, 31.91 mmol) at −78° C. slowly dropwise over the period of 10 min, the reaction mixture was stirred at −78° C. for 30 min. A solution of 4-bromo-1-fluoro-2-methylbenzene (5.0 g, 26.6 mmol) in THF (30.0 mL) was added at −78° C., and the reaction mixture was stirred for 1 h at the same temperature. DMF (5.0 mL) was added and stirred at −78° C. for another 30 min. The reaction was monitored by TLC; then the reaction mixture was quenched with 1N HCl solution (aq) at 0° C. The aqueous layer was extracted with diethyl ether, washed with water and saturated brine solution. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 5% ethyl acetate/pet ether) to afford the title compound as a white solid (3.6 g, 64%); mp 48-50° C.: 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.92 (dd, J=17.6, 10.8 Hz, 1H), 5.52 (d, J=17.6 Hz, 1H), 2.21 (s, 3H); ESIMS m/z 211.35 ([M−H]−).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.Cl>C1COCC1>[C:1]1([N:7]2[C:11]([B:17]([OH:22])[OH:18])=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1ccc(-n2cccn2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccnn1-c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a solution of 1-phenyl-1H-pyrazole (12.8 g, 88.9 mmol) in THF (355 mL) was dropwise added n-BuLi (1.63 M solution in hexane, 57.2 mL, 93.3 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 1 h. To the mixture was added B(Oi-Pr)3 (82.0 mL, 355 mmol) at −78° C. The mixture was stirred at −78° C. for 1 h, gradually warmed to room temperature and stirred at room temperature overnight. The pH of the mixture was adjusted to 5 with 1 M HCl aqueous solution. The mixture was concentrated in vacuo, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and crystallized with MeOH/EtOAc/hexane to yield the title compound (12.6 g, 76% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.73 (1H, brs), 7.28-7.39 (1H, m), 7.39-7.54 (4H, m), 7.66 (1H, s).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[CH3:10].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>C1COCC1>[CH3:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: BrCCOC1CCCCO1
Reactant: Cc1ccc(CC#N)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C#N)CCOC2CCCCO2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
6.6 g of 60% sodium hydride in oil are added portionwise at RT to a solution of 20 g of 3,4-dimethylphenylacetonitrile in 100 ml of anhydrous THF, and the mixture is left stirring at RT for 2 hours. 29 g of 1-bromo-2-(2-tetrahydropyranyloxy)ethane are then added dropwise and the mixture is left stirring at RT for 2 days. The reaction mixture is poured onto ice and extracted with EtOAc, the organic phase is washed with water and with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with toluene and then with a gradient of a toluene/EtOAc mixture from (99/1; v/v) to (90/10; v/v). 17 g of the expected product are obtained.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Br:9]N1C(=O)CCC1=O>CN(C)C=O>[Br:9][C:6]1[O:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccco1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Br)o1

Procedure:
2-Acetylfuran is dissolved in N,N-dimethylformamide (5 g, 1.1 mol/L), and N-bromosuccinimide (1 eq.) is added.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([CH:10]=CC2C=CC=CC=2)=[CH:8][C:7]([F:18])=[C:6]([F:19])[C:5]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27].CC([OH:33])(C)C.C[N+]1([O-])CCOCC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([CH:10]=[O:33])=[CH:8][C:7]([F:18])=[C:6]([F:19])[C:5]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27]
Reactant: CC(C)(C)O
Reactant: COC(=O)c1c(C=Cc2ccccc2)cc(F)c(F)c1Nc1ccccc1Cl
Agent: C[N+]1([O-])CCOCC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(C=O)cc(F)c(F)c1Nc1ccccc1Cl
Reaction time: 1 h
Yield: 755.5 %

Procedure:
A mixture of 2-(2-chlorophenylamino)-3,4-difluoro-6-styrylbenzoic acid methyl ester (1.20 g, 3.00 mmol), 2.5% OSO4 solution in t-BuOH (2.0 mL, 0.165 mmol) and NMO (0.435 g, 3.60 mmol) in 30 mL of 1:1 THF/water was stirred for 1 hour. Sodium periodate (0.963 g, 4.50 mmol) was added. After 1 hour, the reaction mixture was diluted with ethyl acetate and water and the layers separated. The organic layer was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (1:1 methylene chloride/hexanes) gave 0.406 g (42%) pure desired product.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]1[S:12][C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][C:14]1[N:15]=[C:11]([NH:10][CH2:9][CH2:8][NH2:7])[S:12][C:13]=1[CH3:17]
Reactant: Cc1nc(NCCNC(=O)OC(C)(C)C)sc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(NCCN)sc1C
Yield: 24.6 %

Procedure:
A solution of [2-(4,5-dimethyl-thiazol-2-ylamino)-ethyl]-carbamic acid tert-butyl ester (2.71 g) in methylene chloride (50 ml) was treated with TFA (5 ml) overnight at RT and 1 hour at 60° C. The solvent was evaporated. Ethyl acetate and 1N HCl were added. The separated aqueous layer was extracted under basic conditions with ethyl acetate. The obtained organic layer was washed with brine, dried (MgSO4) and evaporated yielding 0.42 g of a light yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+].[F:21][C:22]([F:26])=[C:23]([Cl:25])[Cl:24].O>C(#N)C>[Cl:24][CH:23]([Cl:25])[C:22]([F:26])([F:21])[O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]2[CH:17]=[CH:18][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:11][CH:12]=1
Reactant: FC(F)=C(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(Oc2ccc(OC(F)(F)C(Cl)Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of 5.29 g (0.0200 mole) of 4-(4-(methylsulfonyl)phenoxy)phenol (Example 21) in 100 ml of acetonitrile was added 0.80 g (0.0200 mole) of NaOH. The mixture was stirred at room temperature for 1 hr and then cooled to 3° C. in an ice bath. To the cold slurry was slowly added 4.0 g (0.0300 mole) of 1,1-difluoro-2,2-dichloroethylene dissolved in 15 ml of acetonitrile and the reaction mixture stirred at 3°-5° C. for 3 hrs. To the cold mixture 150 ml of water was added which resulted in the product precipitating as an oil. The product was extracted from the mixture with CH2Cl2. The organic layer was washed with water, dried (Na2SO4) and solvent removed in vacuo, which gave 7.1 g (89.4% yield) of product. Purification was accomplished by column chromatography using silica gel as the support and chloroform as the eluent, which afforded purified 1 -(2,2-dichloro-1,1-difluoroethoxy)-4-(4-(methylsulfonyl)phenoxy)benzene, mp 67°-70° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:6][CH:7]([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O>[CH3:19][O:18][C:17]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[CH2:2][NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(CN)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(CNC(=O)c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
0.40 g of ethyl 2-[3-(aminomethyl)-4-methoxybenzyl]butanoate and 0.29 g of 4-(trifluoromethyl)benzoic acid were dissolved in 5 ml N,N-dimethylformamide, and 0.24 ml diethyl cyanophosphonate and 0.21 ml triethylamine were added under ice-cooling. After stirring the reaction mixture at room temperature for 16 hours, the mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (3:1), 0.59 g of ethyl 2-[4-methoxy-3-({[4-(trifluoromethyl)benzoyl]amino}methyl)benzyl]butanoate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][C:17]([O:19]C)=[O:18])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]([C:12]([F:15])([F:14])[F:13])[CH2:8][CH2:7]2.[OH-].[Na+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][C:17]([OH:19])=[O:18])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]([C:12]([F:14])([F:15])[F:13])[CH2:8][CH2:7]2
Reactant: COC(=O)Cc1cc(Cl)c2c(c1)CCC(C(F)(F)F)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1cc(Cl)c2c(c1)CCC(C(F)(F)F)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
The compound (1.58 g) of Example 14 was added to a mixed liquor of aqueous solution (5 ml) containing sodium hydroxide (310 mg) with ethanol (5 ml) and the mixture was stirred at room temperature for 1 hour. Water (20 ml) was added and the reaction mixutre was brought to pH 4 with concentrated hydrochloric acid, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain aimed product (1.41 g) as white crystals. When recrystallizing from ethyl acetate-hexane, these give a melting point of 127°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([N:8]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[CH2:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:24])=[C:6]([N:8]([CH2:20][CH:21]([CH3:22])[CH3:23])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:19][O:30]3)=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH:7]=1
Reactant: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2cc(Cl)ccc2F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)CN(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(C2CO2)cc1
Reaction time: 6 h
Yield: 58.5 %

Procedure:
To a stirred solution of N-(5-chloro-2-fluorophenyl)-N-isobutyl-4-vinylbenzenesulfonamide (824 mg, 2.240 mmol) in dichloromethane (DCM) at 0° C. was added meta-chloroperoxybenzoic acid (mCPBA) (1546 mg, 8.96 mmol) and the reaction mixture stirred for 6 hours from 0° C. to 25° C. The reaction was then washed with water (5 mL), sodium hydroxide solution (2M, 5 mL) and brine (5 mL), then evaporated in vacuo to give the required product (503 mg). LCMS [LCMS2] Rt 1.34 min, m/z (ES+) 384 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][OH:9])[S:5][CH:6]=1.CO[CH:12](OC)[CH2:13][NH2:14]>>[Br:1][C:2]1[C:3]2[CH:12]([CH2:13][NH2:14])[O:9][CH2:8][CH2:7][C:4]=2[S:5][CH:6]=1
Reactant: OCCc1cc(Br)cs1
Reactant: COC(CN)OC
Product: NCC1OCCc2scc(Br)c21

Procedure:
The title compound was synthesized from 2-(4-bromothiophen-2-yl)ethanol and amino-acetaldehyde dimethylacetal according to General Procedure A.