Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH:3]=[C:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[CH3:18][NH:19][CH3:20].O.[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl.CC(C)=O>[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24].[Cl:17][C:14]1[CH:15]=[CH:16][C:11](/[C:4](/[C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)=[CH:3]/[CH2:2][N:19]([CH3:20])[CH3:18])=[CH:12][CH:13]=1
Reactant: ClCC=C(c1ccc(Cl)cc1)c1cccnc1
Reactant: CNC
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CN(C)C/C=C(/c1ccc(Cl)cc1)c1cccnc1
Yield: 35 %

Procedure:
A solution of crude 3-chloro-1-(4-chlorophenyl)-1-(3-pyridyl)-1-propene (40 mmol) was added to dimethylamine (18.0 g, 400 mmol) in 25 ml methylene chloride at 10° C. After stirring at room temperature for 1.5 h 25 ml water were added, the phases separated and the solvent removed from the organic phase. The residue was taken up in ether and extracted with dilute hydrochloric acid to pH 4.5. The aqueous phase was made alkaline, extracted with ether and the solvent removed. The residual oil (6.8 g) was dissolved in acetone and one equivalent of oxalic acid in acetone was added. The precipitated oxalate was recrystallized twice from ethanol to give 5.1 g (35%) of pure product mainly (95%) containing the Z-isomer. M.p. 164°-168° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6](O)=[CH:5][C:4](=[O:9])[CH2:3]1.[CH3:10][O:11][C:12](=[O:17])/[CH:13]=[C:14](\[NH2:16])/[CH3:15].[F:18][C:19]1[C:24]([CH:25]=O)=[C:23]([F:27])[C:22]([F:28])=[C:21]([F:29])[C:20]=1[F:30]>CO>[CH3:10][O:11][C:12]([C:13]1[CH:25]([C:24]2[C:23]([F:27])=[C:22]([F:28])[C:21]([F:29])=[C:20]([F:30])[C:19]=2[F:18])[C:5]2[C:4](=[O:9])[CH2:3][N:2]([CH3:1])[CH2:7][C:6]=2[NH:16][C:14]=1[CH3:15])=[O:17]
Reactant: COC(=O)/C=C(/C)N
Reactant: CN1CC(=O)C=C(O)C1
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Solvent: CO
Product: COC(=O)C1=C(C)NC2=C(C(=O)CN(C)C2)C1c1c(F)c(F)c(F)c(F)c1F

Procedure:
1-Methyl-3-oxo-5-hydroxy-1,2,3,6-tetrahydropyridine (6.36 g.), 5.92 g. of methyl-3-aminocrotonate, 9.8 g. of pentafluorobenzaldehyde and 125 ml. of methanol were refluxed for 4 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residue was slurried with ethanol and filtered. Recrystallization from methanol afforded the title compound; m.p. 250°-253° C. dec.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][CH2:5]1.[S:12](Cl)([OH:15])(=O)=[O:13].[F:17][C:18]([F:26])([F:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[OH:11][CH2:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([CH2:3][N:2]([CH3:1])[S:12]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:26])([F:25])[F:17])=[CH:20][CH:21]=2)(=[O:15])=[O:13])[CH2:5][CH2:6]1
Reactant: O=S(=O)(O)Cl
Reactant: CNC[C@H]1CC[C@H](CO)CC1
Reactant: FC(F)(F)c1ccccc1
Product: CN(C[C@H]1CC[C@H](CO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in examples 1.6, trans-(4-methylaminomethyl-cyclohexyl)-methanol (example 1.1) was acylated with 4-trifluoromethyl-benzene sulfochloride giving trans-N-(4-hydroxymethyl-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless solid, MS: 366 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]COCC[Si](C)(C)C)=[C:10]([O:23][CH3:24])[CH:9]=2)[C:4](=[O:25])[CH:3]=1.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C(Cl)Cl.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>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:30]=[CH:31][C:32]([C:27]([F:39])([F:38])[F:26])=[CH:33][CH:34]=3)=[CH:3][C:4]2=[O:25])=[CH:9][C:10]=1[O:23][CH3:24].[OH:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:34][CH:33]=3)=[CH:3][C:4]2=[O:25])=[CH:9][C:10]=1[O:23][CH3:24]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(-n2ccc(Cl)cc2=O)ccc1OCOCC[Si](C)(C)C
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: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-n2ccc(-c3ccc(C(F)(F)F)cc3)cc2=O)ccc1O
Product: COc1cc(-n2ccc(-c3ccc(OC(F)(F)F)cc3)cc2=O)ccc1O
Temperature: 90 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of 4-chloro-1-(3-methoxy-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-pyridin-2(1H)-one Part A (118 mg, 0.31 mmol), 4-(trifluoromethoxy)phenylboronic acid (95 mg, 0.463 mmol), Potassium phosphate tribasic (197 mg, 0.93 mmol), and PalladiumTetrakis (18 mg, 0.02 mmol) in DMF (1.5 mL) was stirred under nitrogen at 90° C. overnight. The mixture was diluted with DCM, filtered, and concentrated. The crude was dissolved in 10:90 MeOH/CH2Cl2 (5 mL) and 4N HCl in dioxane (1 mL) was added. The mixture was stirred for 30 min at RT. Concentrated and the residue was purified using ISCO flash chromatography (silica gel/hexanes/ethyl acetate/methanol 100:0 to 0:90:10 gradient) to afford the desired product 1-(4-hydroxy-3-methoxyphenyl)-4-(4-(trifluoromethoxy)phenyl)pyridin-2(1H)-one 14B (99 mg, 0.26 mmol, 85% yield) as a yellow solid. LC/MS 362 (M+H)+, tR 0.89 min (method 5).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2([CH2:18][OH:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[CH:7]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: O=C1Nc2ccccc2C1(CO)c1cc(Br)ccc1O
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: O=C1Nc2ccccc2C12COc1ccc(Br)cc12

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 3-(5-bromo-2-hydroxyphenyl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (25%) as a white solid: mp 225-228° C.; 1H NMR (300 MHz, CDCl3) δ 10.65 (s, 1H), 7.35 (dd, 1H), 7.24 (dt, 1H), 7.11 (d, 1H), 6.99-6.88 (m, 3H), 6.83 (d, 1H), 4.81 (d, 1H), 4.69 (d, 1H); MS (ES+) m/z 316.1 (M+1), 318.1 (M+1).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C([O-])([O-])=O.[K+].[K+].C[O:12][C:13]1[CH:14]=[C:15](O)[CH:16]=[C:17](OC)[CH:18]=1.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[O:12]([NH:4][CH2:1][C:2]#[CH:3])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: C#CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C#CCNOc1ccccc1

Procedure:
Part A: To a solution of the propargyl amine of Part B, Example 38 (2 g, 5.6 mmol) and powdered K2CO3 (1.9 g, 13.7 mmol) in N,N-dimethylformamide (20 mL) was added 3,5-dimethoxyphenol (2.18 g, 13.7 mmol) at ambient temperature. The resulting composition was heated to 90 degrees Celsius for 36 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N NaOH, H2O and dried over MgSO4. Chromatography (on silica, ethyl acetate/hexane) provided phenoxy propargyl amine as light yellow gel (2.76 g, quantitative yield).
Reaction SMILES: C(O[C:6](=[O:19])[N:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C@@H:8]([CH3:11])[CH:9]=[O:10])(C)(C)C.Br[C:21]([F:28])([F:27])C(OCC)=O.S([O-])(O)(=O)=O.[K+].C(N(C(C)C)CC)(C)C>O1CCCC1.[Zn].O>[Cl:18][C:14]1[CH:13]=[C:12]([N:7]2[C@@H:8]([CH3:11])[C@H:9]([OH:10])[C:21]([F:28])([F:27])[C:6]2=[O:19])[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C[C@@H](C=O)N(C(=O)OC(C)(C)C)c1cccc(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Zn]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1[C@H](O)C(F)(F)C(=O)N1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
tert-Butyl(3-chlorophenyl)[(1S)-1-methyl-2-oxoethyl]carbamate (19.5 g) and ethyl bromodifluoroacetate (41.3 g) were dissolved in tetrahydrofuran (110 mL), and to a suspension of a zinc powder (13.6 g) in tetrahydrofuran (25 mL) was added dropwise the solution at room temperature. After heating under reflux for 1 hr, the mixture was cooled to room temperature, 1 mol/L aqueous potassium hydrogen sulfate solution (300 mL) was added, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→10%), the obtained oil was dissolved in 4 mol/L hydrogen chloride/ethyl acetate solution (100 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, tetrahydrofuran (275 mL) and diisopropylethylamine (21.3 mL, 119 mmol) were added, and the mixture was heated under reflux for 12 hr. The reaction solution was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=10→40%) to give the title compound as a yellow oil (yield: 3.76 g, 21%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.CCN(CC)CC.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:15][CH2:16][C:17]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[CH2:2][OH:1])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: OC[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCC[C@H]1CO
Temperature: -20 °C
Reaction time: 18 h

Procedure:
To a solution of 2(S)-hydroxymethylpyrrolidine (25.32 g, 250.3 mmol) in CH2Cl2 (720 mL) under argon was added Et3N (38.0 mL, 273 mmol). After cooling this mixture to -20° C., chloroacetyl chloride (20.0 mL, 251 mmol) was added dropwise over 0.75 h maintaining the reaction temperature at -20°±3° C. The reaction was stirred at ambient temperature for 18 h and evaporated in vacuo. An impurity which precipitated during concentration was removed by filtration. The crude product was purified by chromatography (silica gel, 1:39 to 1:19 MeOH/CH2Cl2) to give the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].CCCCCC.C([Li])CCC.[Br:23]C(Cl)(Cl)C(Br)(Cl)Cl.O>O1CCCC1>[Br:23][C:10]1[N:5]2[N:4]=[C:3]([CH2:1][CH3:2])[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=1
Reactant: CCc1cc2ccccn2n1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
After dissolving 2-ethylpyrazolo[1,5-a]pyridine (80 mg) in tetrahydrofuran (1 mL), an n-butyllithiumhexane solution (1.6 M; 0.58 mL) was added dropwise at −78° C. under a nitrogen stream, and the mixture was stirred for 30 minutes. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (196 mg) in tetrahydrofuran (0.5 mL) was added to the reaction mixture, and stirring was continued for 30 minutes. The temperature was increased to room temperature, water was added, extraction was performed with ethyl acetate and the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (90 mg) was obtained from the n-hexane:ethyl acetate (20:1) fraction as a light brown oil.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.Cl.O>O1CCOCC1>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc2c(N3CCSCC3)nc(Cl)cc12
Reactant: C1CNCCN1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Yield: 53 %

Procedure:
1-Thiomorpholino-3-piperazino-5-nitro-isoquinoline was prepared analogous to Example 3 from 1-thiomorpholino-3-chloro-5-nitro-isoquinoline by heating for 5 hours with piperazine in dioxane at 100°C. M.p. of its hydrochloride: 245°-247°C (from water); yield: 53% of theory.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[O:8]1[CH2:13][CH2:12][O:11][C:10]2C(C(O)=O)=C[CH:16]=[CH:17][C:9]1=2.C(Cl)(=O)OCC.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[O:8]1[CH2:13][CH2:12][O:11][C:10]2[C:6]([NH2:3])=[CH:7][CH:16]=[CH:17][C:9]1=2
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cccc2c1OCCO2
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Nc1cccc2c1OCCO2
Temperature: 0 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
Triethylamine in acetone was added dropwise to the solution of 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid (360 mg, 2 mmol) in water and acetone at 0° C. To the mixture was added ethyl carbonochloridate in acetone slowly. The mixture was stirred for 4 h then a solution of NaN3 (196 mg, 3.02 mmol) in water was added dropwise. The reaction mixture was stirred for 1 h then it was poured into ice water and extracted with Et2O. The combined organic extracts were washed with brine, dried with MgSO4, and concentrated in vacuo. The residue was dissolved in anhydrous toluene and the mixture was heated on a steam bath until nitrogen evolution had ceased. The toluene was then removed in vacuo and 20% aq HCl (4 mL) was added and the solution was heated to reflux and stirred overnight. The reaction was concentrated under reduced pressure. The residue was dissolved in water, made strongly alkaline by the addition of 40% aq NaOH, then extracted with Et2O. The combined organic extracts were washed with brine, dried by MgSO4, and purified by flash chromatography on silica gel column (PE:EtOAc=5:1) to give 2,3-dihydrobenzo[b][1,4]dioxin-5-amine (intermediate 60) (270 mg, 70%). HPLC: 99%, RT 1.214 min. MS (ESI) m/z 152.1 [M+H]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:19]=1[O:26][CH3:27]>>[NH2:15][C:7]1[C:6]([C:4]([C:20]2[CH:21]=[C:22]([F:25])[C:23]([F:24])=[C:18]([F:17])[C:19]=2[O:26][CH3:27])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: COc1ccc(F)c(F)c1F
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2cc(F)c(F)c(F)c2OC)c(N)n1

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2,3,4-trifluoroanisole (Matrix) in an analogous manner as described in Example 169.
Reaction SMILES: [C:1]([OH:7])(C(F)(F)F)=[O:2].[CH2:8]([N:15]1[CH:20]([C:21]([O:23]C(C)(C)C)=O)[CH2:19][CH2:18][CH2:17][NH:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:28](N(CC)CC)C>C(Cl)Cl>[O:23]=[C:21]([CH:20]1[CH2:19][CH2:18][CH2:17][NH:16][N:15]1[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:1]([O:7][CH3:28])=[O:2]
Reactant: CCN(CC)CC
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1CCCNN1Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)C(=O)C1CCCNN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
20% TFA in CH2Cl2 was cooled to 0° C. and added dropwise to a solution of tert-butyl 2-benzylperhydropyridazinecarboxylate (13.34 g, 41.7 mmol) in 10 ml CH2Cl2. The mixture was stirred overnight. At this time, the mixture was cooled to 0° C. and 12.66 ml (125 mmol) triethylamine was added, followed by addition dropwise of methyl oxalyl chloride (5.62, 45.9 mmol) in 5 ml CH2Cl2. The mixture was allowed to stirred 2 hours at 0° C. and warmed up to room temperature overnight. The reaction was diluted with addition of CH2Cl2 and washed with water. The organic layer was dried over MgSO4, and filtered and concentrated. The crude product was further purified by silica chromatography to yield 9.2 g (72.4% yield) product as clear oil. 1H NMR (CDCl3, 400 MHz): δ 1.72 (m, 4H); 2.85 (m, 1H); 3.12 (m, 1H); 3.67 (s, 3H); 4.15 (m, 1H); 4.35 (m, 1H); 5.20 (m, 2H); 7.35 (m, 5H)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21](Br)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C1CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3ccccc3)c2n1C1CC1
Temperature: 140 °C
Yield: 15.1 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (68 mg, 0.16 mmol), phenylboronic acid (26 mg, 0.21 mmol), tetrakis(triphenylphosphine)palladium (19 mg, 10 mol %) and caesium carbonate (106 mg, 0.33 mol) in dioxane (3 mL) and H2O (1.5 mL) was purged with argon gas then heated at 140° C., for 30 min, by microwave irradiation. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in DCM) followed by recrystallisation from EtOAc/cyclohexane to afford 415 as a white solid (10 mg, 15%). LCMS (Method K): RT 4.08 min [M+H]+ 414.08. 1H NMR (CDCl3 400 MHz): δ 8.17 (1H, s), 7.65 (1H, dd, J=8.89, 4.63 Hz), 7.43-7.42 (5H, m), 7.09 (1H, dd, J=10.20, 8.76 Hz), 6.35 (1H, d, J=7.83 Hz), 5.96 (1H, m), 5.32 (2H, s), 2.89-2.83 (1H, m), 1.69 (3H, d, J=6.74 Hz), 0.79 (1H, m), 0.61 (1H, m), 0.47 (1H, m), 0.23 (1H, m)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][OH:17])[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.CC(C)=O>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][O:17][CH3:18])[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccccc1C(=NO)C(N)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Product: CON=C(C(N)=O)c1ccccc1COC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
A mixture of 2-(2-acetoxymethylphenyl)-2-hydroxyiminoacetamide (253 mg, E/Z≠65/35), potassium carbonate (177 mg), 95% dimethyl sulfate (148 mg) and acetone (4.0 ml) was stirred at room temperature for 4 hours. A few pieces of ice were added, and the mixture was stirred for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate/hexane=2/1) to obtain the title compound (194 mg, E/Z≠79/21, yield: 72.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][Cl:22])=[CH:16][CH:15]=2)[C:5]([NH2:12])=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:23](O)(=O)[CH:24]([CH3:26])[OH:25]>>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]2[N:12]=[C:23]([CH:24]([OH:25])[CH3:26])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][Cl:22])=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1Nc1ccc(CCCl)cc1
Reactant: CC(O)C(=O)O
Product: CC(O)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCCl)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 339, step 3 & Example 1, step 5 from 4-chloro-N2-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-benzenediamine and lactic acid.
Reaction SMILES: [FH:1].Cl[C:3]([O:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4]>FC(F)(Cl)C(F)(Cl)Cl>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[F:1].[F:1][C:3]([O:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4]
Reactant: F
Reactant: Cc1cccc(C)c1OC(=O)Cl
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: Cc1cccc(C)c1F
Product: Cc1cccc(C)c1OC(=O)F
Temperature: 160 °C

Procedure:
70 ml of hydrogen fluoride and 200 ml of 1,1,2-trifluoro-1,2,2-trichloroethane were placed at 0° C. in a stainless steel autoclave and 100 g of 2,6-dimethylphenyl chloroformate were added dropwise. The autoclave was sealed and heated at a maximum temperature of 160° C. for 5 hours, the pressure of the gases formed being released at 30 bar. The reaction mixture was worked up as described in Example 9. 2,6-Dimethylfluorobenzene was obtained in a yield of 30% and 2,6-dimethylphenyl fluoroformate in a yield of 40%. The latter can be added to a new batch for the preparation of 2,6-dimethylfluorobenzene (see Example 15).
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:37]=[CH:38][CH:39]=1)[C:31](N(OC)C)=[O:32].Cl.O1CCOCC1>O.CCOC(C)=O>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([S:9]([NH:8][C:7]2[C:2]([C:31](=[O:32])[C:30]3[CH:37]=[CH:38][CH:39]=[C:28]([O:27][CH3:26])[CH:29]=3)=[N:3][CH:4]=[C:5]([Cl:25])[CH:6]=2)(=[O:11])=[O:10])=[CH:17][CH:16]=1)([CH3:20])([CH3:19])[CH3:21]
Reactant: COc1cccc(C(=O)N(C)OC)c1
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide (140 mg, 300 mmol) was placed in a dry 2-neck 10 mL round-bottom flask. The flask was evacuated and purged with nitrogen, followed by the addition of THF (1 mL). The homogeneous mixture was lowered to −5° C. and iPrMgCl (0.33 mL, 2.0 M) was added dropwise. Upon completion of the addition, the reaction was stirred 90 minutes, followed by the slow addition of 3,N-dimethoxy-N-methyl-benzamide (146 mg, 750 mmol). The reaction was stirred overnight, during which the ice-bath warmed to room temperature. The following day, the reaction was quenched with a small quantity of MeOH and the solvents evaporated in vacuo. The residue was subsequently treated with 4.0 M HCl in dioxane (1 mL, 4.0 mmol) and H2O (0.33 mL), and then stirred at 80° C. for two hours. The resultant solution was diluted with EtOAc, washed with water, saturated sodium bicarbonate, and brine; dried with MgSO4, and evaporated employing reduced pressure. The crude residue was subsequently purified via reverse phase HPLC (Column: Varian Dynamax 250×21.4 mm Microsorb100-8 C18, 0.1% TFA/H2O (Eluent A): 0.1% TFA/MeCN (Eluent B)): 1H NMR (400 MHz, CDCl3) δ 10.61 (s, 1H), 8.29 (d, 1H), 8.20 (d, 1H), 7.74 (d, 2H), 7.58 (s, 1H), 7.50 (d, 1H), 7.42 (d, 2H), 7.37 (d, 1H), 7.29 (t, 1H), 2.40 (s, 3H), 1.25 (s, 9H); MS (ES) M+H expect 459.1, found 459.5.