Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8]C(=O)C)=[C:4](F)[CH:3]=1.O.[NH2:14][NH2:15].C([O-])(O)=O.[Na+]>C(O)C>[NH:14]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH:8]=[N:15]1
Reactant: NN
Reactant: CC(=O)Cc1ccc(Br)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc2[nH]ncc2c1
Temperature: 162.5 °C
Yield: 148.8 %

Procedure:
A solution of 4-bromo-2-fluoro-N-methoxy-N-methyl-benzamide (CAS [801303-33-3]) (24.9 g, 95.0 mmol) in THF (100 mL) at −78° C. was treated with a 3 N solution of ethyl magnesium bromide in diethyl ether (33.25 mL, 115 mmol) and allowed to warm to 0 C and stir for a 6 h period, after which time the reaction mixture was quenched with a half saturated aqueous solution of NH4Cl (200 mL) and EtOAc (100 mL). The mixture was separated and the organic component, washed with brine (2×50 mL), dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 20% EtOAc/hexanes as eluant to afford 1-(4-bromo-2-fluorophenyl)-propanone as a pale yellow solid (16.25 g, 74%). The propanone (21.15 g, 91.6 mmol) was then dissolved in ethanol (100 mL), treated with hydrazine hydrate (4.9 mL, 100.7 mmol), and heated at reflux for 4 h. The reaction mixture was then evaporated and dissolved in ethylene glycol (100 mL) and heated at 160-165° C. for 8 h after which time the cooled reaction mixture was poured onto water (500 mL) with stirring. The aqueous mixture was neutralized, with rapid stirring, using a small amount of an aqueous saturated solution of NaHCO3 to afford a pale yellow precipitate. The solids were filtered, washed with water, and air dried to afford cyclized indazole product (16.1 g, 78%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[O:35])=[CH:29][CH:28]=1)[CH3:24]
Reactant: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)cc1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-2H-indazol-3-yl)-amine (example 1.1) was reacted with 4-isocyanato-benzoic acid ethyl ester ([30806-83-8]) in toluene to give the title compound as yellow solid. MS: m/e=483.3 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: Nc1ccccc1Cl
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Nc1cccc(Cl)c1C(=O)Nc1ccccc1Cl
Yield: 25.6 %

Procedure:
Prepared according to Procedure A using 2-amino-6-chlorobenzoic acid (2.5 g, 14.6 mmol) and SOCl2 (2.7 mL, 36.4 mmol) in benzene (75 mL), followed by 2-chloroaniline (3.1 mL, 29.1 mmol) and CHCl3 (75 mL). The product chromatographed in CH2Cl2 to provide 1.05 g of a yellow orange solid (26%). 1H NMR (CDCl3) δ: 8.54 (d, J=8.1 Hz, 1H); 8.30 (br s, 1H); 7.41 (dd, J=1.5, 8.0 Hz, 1H); 7.33 (t, J=7.8 Hz, 1H); 7.10 (t, J=8.1 Hz, 1H); 7.09 (dt, J=1.6, 7.8 Hz, 1H); 6.78 (dd, J=0.4, 7.9 Hz, 1H); 6.63 (dd, J=0.9, 8.2 Hz, 1H); 4.69 (br s, 2H). MS (ES): m/z 303.0 (M+22), 281.0 (M+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].S([O-])(=O)(=O)C.S(O[CH:15]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1)(C)(=O)=O>O>[N:1]([CH:19]1[CH2:15][CH2:16][CH:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)C1CCC(OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)C1CCC(N=[N+]=[N-])C1

Procedure:
Sodium azide (156 mg) was added to the mesylate [prepared in (1) ]dissolved in hexamethylphosphamide (3 ml). The mixture was poured into water. The mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then evaporated to obtain the title compound having the following physical data.
Reaction SMILES: [Mg].[CH2:2](Br)[CH3:3].Cl[CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[Cl-].[NH4+]>O1CCCC1>[CH3:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:2][CH3:3]
Reactant: CCCCCCCCCC/C=C\CCCl
Reactant: CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC/C=C\CCCCCCCCCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 915.2 %

Procedure:
A 1-liter reactor was charged with 5.0 g (0.206 mole) of magnesium and 90 g of tetrahydrofuran, and the reaction was initiated by adding 2 g of ethyl bromide and 46 g (0.2 mole) of 1-chloro-cis-3-tetradecene dropwise thereto under an atmosphere of nitrogen. After completion of the addition, the mixture was stirred for 2 hours under reflux of tetrahydrofuran and the resulting liquid was transferred to a 300-ml dropping funnel. Next, 30 g of tetrahydrofuran, 0.5 g of cuprous bromide and 22 g (0.204 mole) of ethyl bromide were placed in another 1-liter reactor and cooled to 0° C. Then, the above-described Grignard reagent was added dropwise thereto so that the temperature did not exceed 10° C. After completion of the reaction, 100 g of a saturated aqueous ammonium chloride solution was added and the resulting mixture was allowed to separate into two layers. The organic layer was recovered, freed of tetrahydrofuran under reduced pressure, and distilled to obtain 37.7 g of cis-5-hexadecene (purity 96%, yield 81%, b.p. 149°-152° C./3 mmHg). MS(m/e): 56(100%), 224 (M+, 21%).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1.[B:15](OC)([O:18]C)[O:16]C.Cl>C(OCC)C>[F:14][C:9]1[CH:8]=[C:7]([B:15]([OH:18])[OH:16])[CH:12]=[C:11]([F:13])[CH:10]=1
Reactant: COB(OC)OC
Reactant: Fc1cc(F)cc(Br)c1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: OB(O)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
91.5 ml of tert-butyllithium are added at −78° C. to 20 g of 1-bromo-3,5-difluorobenzene in 300 ml of diethyl ether. The reaction mixture is stirred for 1 hour at −78° C. and 14.2 ml of trimethyl borate are then added. The reaction mixture is stirred for 1 hour at −78° C. and then for 12 hours at room temperature. 200 ml of aqueous 1 N hydrochloric acid solution are added. The resulting mixture is extracted with diethyl ether, the organic phase is washed with saturated sodium hydrogen carbonate solution and dried over magnesium sulphate, and the solvents are evaporated off under reduced pressure. The residue is taken up in cyclohexane and the precipitate obtained is isolated by filtration.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25](O)=[O:26])=[CH:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.C[O:39][C:40](=[O:43])[CH2:41][NH2:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:32][C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25]([NH:42][CH2:41][C:40]([OH:39])=[O:43])=[O:26])=[CH:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)O)cc2c1
Reactant: COC(=O)CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)NCC(=O)O)cc2c1
Yield: 48.6 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-2-carboxylic acid (730 mg, 1.672 mmol) in CH2Cl2 (30 mL) and DMAP (612 mg, 5.02 mmol), EDC (481 mg, 2.51 mmol), and glycine methyl ester hydrochloride (313 mg, 2.51 mmol) are reacted and hydrolyzed analogous to Example 7 to yield title compound (401 mg, 47%).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.C(N)=O.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=O.[CH:29]([NH2:31])=[S:30].[OH-].[Na+]>O1CCOCC1>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[N:31]=[CH:29][S:30][CH:19]=2)=[CH:23][CH:24]=1
Reactant: NC=S
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: NC=O
Solvent: C1COCCO1
Product: Brc1ccc(-c2cscn2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of phosphorus pentasulfide (24.5 g, 55 mmol) in dioxane (250 ml) was added formamide (28.4 g, 630 mmol), and the mixture was heated at reflux temperature for 2 hours. The reaction mixture was cooled down to room temperature, and the solution was decanted away from solids. To a stirred solution of 2,4′-dibromoacetophenone (15 g, 54 mmol) in dioxane (100 ml) was added the thioformamide solution, and the mixture was heated at reflux temperature for 6 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 2N NaOH aqueous solution. The whole was extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with CH2Cl2 to give title compound (12.3 g, 95% yield).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].Br[CH2:19][CH2:20][O:21][CH3:22].CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:15][CH2:19][CH2:20][O:21][CH3:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[C:6]=1[CH3:7]
Reactant: COCCBr
Reactant: Cc1c(I)cnn1CC1(O)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOC1(Cn2ncc(I)c2C)CCCCC1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 101B (260 mg) in tetrahydrofuran (15 mL) was added NaH (97 mg). The mixture was stirred for 30 minutes. 1-Bromo-2-methoxyethane (564 mg) was added to the mixture and the mixture was stirred for 3 hours. The mixture was then stirred at reflux for 2 hours. Hexamethylphosphoramide (5 mL) and additional NaH (200 mg) were added to the mixture and the mixture was stirred at reflux overnight. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water and brine and dried over Na2SO4. The residue, after filtration and evaporation of the solvent, was loaded on a 40 g column and eluted with 20% ethyl acetate in hexane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C([O:35][C:36](=O)[CH2:37][CH2:38][CH2:39]Br)C>CN1C(=O)CCC1.CCOC(C)=O>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:1]3[CH2:39][CH2:38][CH2:37][C:36]3=[O:35])[CH:10]=2)[C:6]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:7]1[CH:18]([CH3:19])[CH3:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N)cc2n1Cc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N3CCCC3=O)cc2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 125, 20 mg, 0.046 mmol) and ethyl4-bromobutanoate (13 μl, 0.092 mmol) in NMP (1 ml) was heated at 168° C. for 16 h, cooled to room temperature, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][CH:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21]([NH2:24])=[N:22][OH:23])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.[C:29](C1NC=CN=1)(C1NC=CN=1)=[O:30].C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>C1COCC1.ClCCl>[F:1][C:2]1[C:3]([NH:18][CH:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21]2[NH:22][O:23][C:29](=[O:30])[N:24]=2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)C(CC(N)=NO)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)C(Cc1nc(=O)o[nH]1)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of racemic 3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]-N′-hydroxy-4,4-dimethyl-pentanamidine, 125a, (0.034 g, 0.087 mmol) and carbonyl diimidazole (0.014 g, 0.087 mmol) in THF (1 mL) was added N,N-diisopropylethylamine (0.045 mL, 0.260 mmol). The reaction mixture was stirred at room temperature for 48 hours. Aqueous ammonium chloride and dichloromethane were added and the layers were separated with a phase separator. The residue was purified on a C18 column (acetonitrile/0.1% formic acid) to afford the final product: 1H NMR (400 MHz, Acetone) δ 11.23 (s, 1H), 8.54 (dd, J=9.8, 2.8 Hz, 1H), 8.36 (s, 1H), 8.20 (s, 1H), 8.13 (d, J=3.7 Hz, 1H), 6.81 (s, 1H), 5.00 (d, J=11.2 Hz, 1H), 3.15 (d, J=14.8 Hz, 3H), 2.94 (dd, J=14.4, 11.9 Hz, 2H), 1.16 (s, 8H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=1.58 minutes (M+H) 390.06.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][OH:22])[C:16]([O:18]CC)=[O:17])=[CH:11][C:10]=1[O:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][OH:22])[C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[O:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CO)c1ccc(OCc2ccccc2)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(CO)C(=O)O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of ethyl 2-(4-benzyloxy-3-methoxyphenyl)-3-hydroxy-propionate (1.29 g; 3.29 mmol; from step (iii) above) in THF (12.5 mL) was added a solution of LiOH (0.273 g; 6.75 mmol) in H2O (5 mL), and the mixture was stirred at room temperature for 2.5 hours. The resultant mixture was partially concentrated, water (25 mL) was added, the mixture was washed with two portions of CH2Cl2, made acidic with HCl/aq (2M), and extracted with 3 portions of CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4), and evaporated to yield 10.55 g (quant.) of a yellow powder. Purity 83.2%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=[NH:16])[NH:14]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1([C:22](N2C=CN=C2)=[S:23])C=CN=C1.B(F)(F)F.CC[O:35]CC>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[NH:14][C:22](=[O:35])[S:23][N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=N)NO)C1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2nsc(=O)[nH]2)C1
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
(R)-3-(N-Hydroxycarbamimidoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.54 g, 2.36 mmol) and di-imidazol-1-yl-methanethione (0.70 g, 3.53 mmol) were dissolved in THF (15 mL) and stirred for 30 min. The reaction was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried by MgSO4 and concentrated in vacuo. The residue was dissolved in THF (20 mL) and BF3.Et2O (0.89 ml, 7.06 mmol) was added dropwise. After 1 h of stirring, the reaction was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (20-50% EtOAc/Hexane) to give (R)-3-(5-oxo-4,5-dihydro-[1,2,4]thiadiazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.42 g, 1.55 mmol, 66%) as a white solid.
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:18][NH2+:19][CH3:20].[C:21](Cl)(=O)C.Cl.ClCCl.[OH-].[Na+]>C(#N)C.CCOCC>[CH:1](=[C:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:18][N:19]([CH3:21])[CH3:20])[C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1=Cc1ccccc1
Reactant: CC(=O)Cl
Reactant: C[NH2+]C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC#N
Product: CN(C)CC1CCCC(=Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
43 g (0.23 mole) of 2-benzylidene-cyclohexanone obtained from Stage 2, and 21.6 g (0.23 mole) of dimethylammonium methylene chloride were stirred in 200 ml of dry acetonitrile at room temperature. After adding 0.2 ml of acetyl chloride the reaction mixture was stirred for a further 3 hours at room temperature, a colorless clear solution being formed. 200 ml of dry ether were then added dropwise to the reaction mixture, whereupon the hydrochloride crystallized out. 56.1 g (87% of theory) of colorless crystals were obtained. The base was released from the hydrochloride with dichloromethane/sodium hydroxide and, after drying the solution, the dichloromethane was removed by distillation.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[F:23])[CH2:11][CH2:10]2)[N:5]=[C:4]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C(OCC)(=O)C>[Cl:22][C:18]1[C:17]([F:23])=[C:16]([CH:21]=[CH:20][CH:19]=1)[C:15]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:6]2[CH:7]=[C:2]([N:31]3[CH2:35][CH2:34][CH2:33][C:32]3=[O:36])[CH:3]=[C:4]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[N:5]=2)[CH2:10][CH2:11]1)=[O:24]
Reactant: O=C1CCCN1
Reactant: O=C(c1cccc(Cl)c1F)N1CCN(Cc2cc(Br)cc(Nc3nccs3)n2)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(c1cccc(Cl)c1F)N1CCN(Cc2cc(N3CCCC3=O)cc(Nc3nccs3)n2)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 25.5 mg of 4-bromo-6-((4-(3-chloro-2-fluorobenzoyl)piperazin-1-yl)methyl)-N-thiazol-2-ylpyridin-2-amine obtained in Example 81 in 1 mL of 1,4-dioxane was added 0.011 mL of pyrrolidin-2-one, 32 mg of potassium phosphate, 8.7 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and 7.8 mg of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, successively. The reaction solution was stirred at 100° C. for 3 hours. The reaction solution was cooled, diluted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo and the resulting residue was purified by a reversed phase medium pressure liquid chromatography [ODS-AS-360-CC (manufactured by YMC company), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The obtained fraction was diluted with ethyl acetate, washed with saturated sodium bicarbonate, and then dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo to give the title compound.
Reaction SMILES: [Cl-].[C:2]([O-:5])(=[O:4])[CH3:3].[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:22])([CH3:21])[CH:16]=[C:17]([F:20])[CH2:18]O)=[CH:11][CH:10]=1)[CH3:7].C1C=CC=CC=1>N1C=CC=CC=1>[C:2]([O:5][CH2:18][C:17]([F:20])=[CH:16][C:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:6][CH3:7])=[CH:14][CH:13]=1)([CH3:21])[CH3:22])(=[O:4])[CH3:3]
Reactant: CC(=O)[O-]
Reactant: CCOc1ccc(C(C)(C)C=C(F)CO)cc1
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOc1ccc(C(C)(C)C=C(F)COC(C)=O)cc1
Yield: 99 %

Procedure:
The method of Example 11 was repeated using acetate chloride (0.17 ml), 4-(4-ethoxyphenyl)-2-fluoro-4-methylpent-2-enol (Example 9) (86 mg), benzene (4 ml) and pyridine (0.04 ml) to yield the title compound (0.1 g, 99%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][O:11][CH3:12])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:20][CH:21]([F:31])[C:22]1[C:26]([C:27](Cl)=[O:28])=[CH:25][N:24]([CH3:30])[N:23]=1>ClCCl.O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]([N:10]([O:11][CH3:12])[C:27]([C:26]2[C:22]([CH:21]([F:31])[F:20])=[N:23][N:24]([CH3:30])[CH:25]=2)=[O:28])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)c1cccc(I)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a solution of N-[1-(3-iodo-phenyl)-ethyl]-O-methyl-hydroxylamine (3 g, 10.8 mmol), prepared as described in example P11, in dichloromethane (30 ml), was added triethylamine (2.5 ml, 26.3 mmol) followed by a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (2.2 g, 11.3 mmol) slowly at 0° C. After complete addition of acid chloride, the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3×60 ml). The combined dichloromethane layer was washed with 2N HCl, sat. NaHCO3 and brine, dried over anh. sodium sulfate and concentrated. The crude mass was purified by column chromatography using 35% ethyl acetate in hexane to yield 2.7 g (60% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [1-(3-iodo-phenyl)-ethyl]methoxy-amide in form of a solid. Mp 136-138° C.