Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([CH2:24][N:25]([CH3:27])[CH3:26])=[CH:22][CH:23]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][C:21]([CH2:24][N:25]([CH3:26])[CH3:27])=[CH:22][CH:23]=2)=[CH:3][C:2]([C:33]2[CH:34]=[C:29]([Cl:28])[C:30]([OH:45])=[C:31]([Cl:44])[CH:32]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CN(C)Cc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)Cc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cn1
Yield: 56.6 %

Procedure:
Following general procedure F, {6-bromo-4-[6-((dimethylamino)methyl)pyridin-3-ylamino]quinolin-3-yl}(cyclopropyl)methanone (37 mg, 0.087 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (38 mg, 0.131 mmol) to afford the desired product (25 mg, 57%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.37 (s, 1H), 8.75 (s, 1H), 8.32 (dd, J=8.8, 2.1 Hz, 1H), 8.22 (d, J=2.1 Hz, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.96 (dd, J=8.4, 2.6 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.47 (s, 2H), 4.58 (s, 2H), 2.95 (s, 6H), 2.83-2.74 (m, 1H), 1.19-1.07 (m, 4H); ESI MS m/z 507 [C27H24Cl2N4O2+H]+; HPLC 98.9% (AUC), tR=10.66 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH2:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17](O)=[O:18])[CH3:11].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:17]([C@@H:13]2[CH2:14][CH2:15][CH2:16][N:12]2[CH2:10][CH3:11])=[O:18])[NH2:9])=[N:6][CH:7]=1
Reactant: CCN1CCC[C@H]1C(=O)O
Reactant: NNc1ccc(F)cn1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCC[C@H]1C(=O)N(N)c1ccc(F)cn1
Reaction time: 4 h
Yield: 54.2 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (178 mg, 1.39 mmol) in DMF (10.0 mL) was added (S)-1-ethyl-pyrrolidine-2-carboxylic acid (200 mg, 1.39 mmol), EDC (293 mg, 1.53 mmol) and HOBt.H2O (18.0 mg, 0.14 mmol). The reaction was stirred for 4 h then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (190 mg, 54%). LCMS (Method 4): Rt 0.29 min, m/z 253.1 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[O:19]([C:21]#[N:22])[K].C(OCC)(=O)C>CC(O)=O.O>[O:16]1[CH2:17][CH2:18][CH:13]([O:12][C:11]2[CH:10]=[CH:9][CH:8]=[C:3]3[C:2]=2[N:1]=[C:21]([OH:19])[N:22]=[C:4]3[OH:6])[CH2:14][CH2:15]1
Reactant: COC(=O)c1cccc(OC2CCOCC2)c1N
Reactant: N#CO[K]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1nc(O)c2cccc(OC3CCOCC3)c2n1
Temperature: 80 °C
Yield: 48.3 %

Procedure:
To a solution of methyl 2-amino-3-(tetrahydro-2H-pyran-4-yloxy)benzoate (18 g, 0.071 mol) in AcOH (180 mL) was added a solution of KOCN (11.47 g, 142 mmol) in water (22 mL) at 60° C. Then the mixture was heated at 80° C. for 40 h. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. Then the mixture was concentrated in vacuo. The residue was diluted with water (200 mL). The precipitate was filtered to give the title compound (9 g, 42%) as a white solid. 1H NMR (400 MHz, DMSO): δ 11.354 (s, 1H), 10.491 (s, 1H), 7.539 (d, 1H), 7.455 (d, 1H), 7.191 (t, 1H), 4.732 (m, 1H), 4.006 (m, 2H), 3.535 (m, 3H), 2.023 (m, 2H), 1.842 (m, 2H)
Reaction SMILES: [BH4-].[Na+].C(=[C:10]1[CH:21]=[CH:20][C:13]2[CH2:14][C:15]([NH:17][C:18](=[O:19])[C:12]=2[CH2:11]1)=[O:16])C1C=CC=CC=1.O>CO>[CH2:18]([CH:14]1[C:13]2[C:12](=[CH:11][CH:10]=[CH:21][CH:20]=2)[C:18](=[O:19])[NH:17][CH:15]1[OH:16])[C:12]1[CH:13]=[CH:20][CH:21]=[CH:10][CH:11]=1
Reactant: O=C1CC2=C(CC(=Cc3ccccc3)C=C2)C(=O)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1NC(O)C(Cc2ccccc2)c2ccccc21
Temperature: 25 °C

Procedure:
Sodium borohydride (1.2 g, 32 mmol) was added in portions to a stirred suspension of 4-benzylidenehomophthalimide (2 g, 8 mmol) in methanol (50 ml), then the stirred mixture was heated under reflux for 4 hours, cooled to ambient temperature and added to water (200 ml). The product was extracted into ethyl acetate (3×50 ml), the combined extracts were washed with water (2×30 ml), dried (MgSO4) and the solvent was removed in vacuo. The residue was dissolved in the minimum volume of ether and sufficient hexane was added to precipitate the product. The resulting solid was collected by filtration, washed with hexane (20 ml) and dried in vacuo to give the 4-benzyl-3-hydroxy-3,4-dihydro-1-isoquinolinone intermediate which was used without purification.
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:11][O:10][CH2:9][C@@H:8]1[C@:12]([NH2:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[CH3:13])(C)(C)C.[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:27]=1[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCCl>[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:27]=1[CH2:28][NH:21][C@@:12]([C@H:8]1[CH2:9][O:10][CH2:11][C@H:7]1[OH:6])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1COC[C@@H]1[C@](C)(N)c1ccccc1F
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: COc1ccc(CN[C@](C)(c2ccccc2F)[C@H]2COC[C@H]2O)c(OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
Under an atmosphere of argon, a solution of rel-(S)-1-[(3S,4S)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-3-yl]-1-(2-fluoro-phenyl)-ethylamine (8.13 g, 23.9 mmol) in 1,2-dichloroethane (80 ml) was treated with 2,4-dimethoxybenzaldehyde (3.98 g, 23.9 mmol), sodium triacetoxyborohydride (10.2 g, 47.9 mmol) and acetic acid (1.37 ml, 23.9 mmol). The reaction mixture was stirred overnight. In order to complete the reaction, 2,4-dimethoxybenzaldehyde (1.99 g, 12.0 mmol) and sodium triacetoxyborohydride (5.08 g, 23.9 mmol) were added and the mixture was stirred overnight. Thereafter, the reaction mixture was cooled to 0° C. and tetrabutylammonium fluoride trihydrate (7.56 g, 23.9 mmol) was added. The mixture was allowed to reach room temperature while stirring for 4 hours. In order to complete the reaction, tetrabutylammonium fluoride trihydrate (2.27 g, 7.18 mmol) was added again, and stirring continued for 4 days. For the workup, the reaction mixture was extracted twice with a mixture of a saturated solution of sodium hydrogencarbonate and dichloromethane. The combined organic layers were dried over sodium sulphate and evaporated. The residue was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate=100:0 to 50:50 as the eluent. The rel-(3S,4S)-4-[(S)-1-(2,4-dimethoxy-benzylamino)-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-ol (6.8 g, 76% yield) was obtained as a colorless amorphous material.
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.Cl[C:33]1[C:46]([F:47])=[CH:45][C:36]([C:37]([NH:39][C@@H:40]([CH:42]2[CH2:44][CH2:43]2)[CH3:41])=[O:38])=[C:35]([F:48])[CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:28]([CH2:27][C:23]1([N:21]2[CH:22]=[C:18]([C:17]3[C:12]4[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:19]=[N:20]2)[CH2:24][N:25]([C:33]2[C:46]([F:47])=[CH:45][C:36]([C:37]([NH:39][C@@H:40]([CH:42]3[CH2:43][CH2:44]3)[CH3:41])=[O:38])=[C:35]([F:48])[CH:34]=2)[CH2:26]1)#[N:29]
Reactant: C[C@@H](NC(=O)c1cc(F)c(Cl)cc1F)C1CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: C[C@@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1F)C1CC1
Temperature: 105 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
A mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (1.0 g, 2.1 mmol), 4-chloro-N-[(1R)-1-cyclopropylethyl]-2,5-difluorobenzamide (0.54 g, 2.1 mmol), cesium carbonate (2.0 g, 6.2 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.13 g, 0.21 mmol) and palladium acetate (0.046 g, 0.21 mmol) in toluene (20 mL, 200 mmol) was stirred at 105° C. overnight. After the reaction mixture was cooled to room temperature, the solid was filtered off by celite, washed with ethyl acetate. The filtrate was concentrated. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethylene (0-60%) to afford the desired product (0.48 g, 36%). LCMS (M+H)+: m/z=633.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](O)=[CH:10]2)=[CH:5][CH:4]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH2:17][OH:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH2:17][O:18][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:10]=1
Reactant: COc1ccc2ccc(O)cc2c1
Reactant: COc1ccc(Br)c(CO)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Br)c(COc2ccc3ccc(OC)cc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a solution of 7-methoxy-2-naphthol (26.92 g, 0.15 moles), 2-bromo-5-methoxybenzyl alcohol (33.58 g, 0.15 moles), and triphenylphosphine (39.3 g, 0.15 moles) in anhydrous THF (500 mls) was added a solution of DEAD (26.10 g, 0.15 moles) in THF (100 mL) dropwise over 0.5 hr. The solution was stirred at room temperature overnight and, upon evaporation of half the volume, the product precipitated in good purity. The solid was filtered and rinsed with THF, then dried to yield 32.96 g (59%) of a white solid: mp 156–157° C.; 1H NMR (DMSO-d6): δ 3.77 (3H, s), 3.86 (3H, s), 5.18 (2H, s), 6.92 (1H, dd, J=3.2 Hz, J=8.7 Hz), 7.00 (1H, dd, J=2.4 Hz, J=8.7 Hz), 7.09 (1H, dd, J=2.4 Hz, J=8.9 Hz), 7.22 (1H, d, J=3.2 Hz), 7.25 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.59 (1H, d, J=8.7 Hz), 7.74 (1H, d, J=8.7 Hz), 7.76(1H, d, J=8.7 Hz); MS m/z 373/375 ([M+H]+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].C(N(CC)CC)C>CN(C=O)C>[CH3:14][CH2:13][CH:12]([N:8]1[C:6]2=[N:7][C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:3][N:4]=[C:5]2[N:10]=[C:9]1[OH:11])[CH2:15][CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: CCC(CC)n1c(O)nc2ncc(Br)nc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(CC)n1c(O)nc2ncc(C#C[Si](C)(C)C)nc21
Temperature: 80 °C
Yield: 80.2 %

Procedure:
A mixture of 6-bromo-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazin-2-ol (3.75 g, 13.2 mmol)), trimethylsilylacetylene (2.8 mL, 19.8 mmol), PdC12(PPh)2 (0.93g, 1.32 mmol), Cul (0.5 g, 2.64 mmol) and triethylamine (5.5 mL, 39.5 mmol) in DMF (50 mL) was purged with N2 for 30 seconds followed by stirring at 80° C. After 3 hours the reaction mixture was diluted with EtOAc, washed with NH4Cl solution, dried over Na2SO4, and concentrated in vacuo. Purification with over silica gel (Biotage MPLC 10-80% EtOAc/hexanes) provided the title compound (3.2 g, 80%) as a brown solid.
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([C:26]2[N:27]=[CH:28][C:29]3[C:34]([C:35]=2[CH3:36])=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=O)C.C[Mg]Br.Cl>C(OCC)C>[OH:21][C:18]([C:8]1[CH:9]=[CH:4][CH:5]=[CH:6][C:7]=1[S:10]([N:13]([C:26]1[N:27]=[CH:28][C:29]2[C:34]([C:35]=1[CH3:36])=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=1)(=[O:12])=[O:11])([CH3:19])[CH3:17]
Reactant: CC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2ncc3ccccc3c2C)cc1
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)c2ccccc2C(C)(C)O)ncc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 164.7 %

Procedure:
To a solution of 4-acetyl-N-(4-methylisoquinolin-3-yl)-N-[4-(trifluoromethoxy)benzyl]benzenesulfonamide (98 mg, 0.190 mmol) prepared in Example 152 in diethyl ether (2 mL) was added methylmagnesium bromide (tetrahydrofuran solution, 3 mol/L, 0.229 mmol) at 0° C., and the mixture was stirred at room temperature overnight. To the reaction solution was added 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate three times. The organic layer was combined, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→40:60) to give (1-hydroxy-1-methylethyl)-N-(4-methylisoquinolin-3-yl)-N-[4-(trifluoromethoxy)benzyl]benzenesulfonamide (83 mg, 82%) as a colorless powder.
Reaction SMILES: C(O[C:9](=O)[N:10]([CH:12]([C:14](=[O:44])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:29][CH:30]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[CH:33]=3)[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])C)C1C=CC=CC=1>CO>[F:39][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=1[F:38])[O:31][CH:30]1[CH:24]2[N:23]([C:21]([CH:16]([NH:15][C:14](=[O:44])[CH:12]([NH:10][CH3:9])[CH3:13])[C:17]([CH3:19])([CH3:20])[CH3:18])=[O:22])[CH2:27][CH2:26][CH:25]2[N:28]([S:40]([CH3:43])(=[O:41])=[O:42])[CH2:29]1
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2S(C)(=O)=O)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Solvent: CO
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2S(C)(=O)=O)C(C)(C)C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
A 500 mL Parr bottle was charged with the sulfonamide 36 (190 mg, 0.29 mmol) and 10% Pd-on-carbon (wet, 50 mg) in MeOH (15 mL). The mixture was pressurized to 50 PSI H2 then shaken for 3 h. The catalyst was removed by filtration with an Acrodisc® 0.45 μm nylon membrane syringe filter and the solvent was removed in vacuo. The crude product was purified by RP-HPLC (2″ Dynamax® C18; 10-100% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min) to afford 140 mg of compound 37 as a white solid following lyophilization.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:16][C:15]([C:26]#[N:27])=[N:14]1.ClCCl.[F:31][CH:32]([F:35])[S:33]Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[C:16]([S:33][CH:32]([F:35])[F:31])[C:15]([C:26]#[N:27])=[N:14]1
Reactant: N#Cc1cc(NCc2ccccn2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reactant: FC(F)SCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NCc2ccccn2)c1SC(F)F
Temperature: 25 °C
Yield: 90 %

Procedure:
Under a nitrogen atmosphere, 500 mg (1.21 mmol) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(pyridin-2-ylmethylamino)pyrazole-3-carbonitrile was suspended into 5.0 mL of dried dichloromethane, and 2.0 mL of dried dichloromethane containing 180 mg (1.52 mmol, 1.25 eq.) of difluoromethylsulfenyl chloride was added dropwise thereto under stirring at room temperature, followed by reaction for 2 hours. Ethyl acetate (100 mL) was added thereto, and the organic layer was washed successively with 20 mL of a saturated aqueous sodium hydrogen carbonate solution and 20 mL of water, followed by drying over anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the solvent was removed by distillation under reduced pressure and the crude product was recrystallized from a mixed solvent of hexane/ethyl acetate (3/1) to thereby obtain 535 mg of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-difluoromethylthio-5-(pyridin-2-ylmethylamino)pyrazole-3-carbonitrile (yield: 90%, purity: 96%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](Cl)=[O:5].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([C:4]([C:3]2[C:2]([F:1])=[CH:10][C:9]([F:11])=[CH:8][C:7]=2[F:12])=[O:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: O
Product: O=C(c1ccccc1)c1c(F)cc(F)cc1F
Temperature: 25 °C

Procedure:
2,4,6-trifluorobenzoyl chloride (5.0 g), benzene (5 ml) and ferric chloride (1.39 g) were heated at 80° C. for 16 h, then allowed to cool to room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate (×2) and the combined organic extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure (5.80 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([F:21])[C:13]=2[F:22])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(O)(=[O:25])C.OO.S([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:25])=[C:14]([F:21])[C:13]=2[F:22])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCOc1ccc(-c2ccc(B(O)O)c(F)c2F)cc1
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(-c2ccc(O)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (19) (10.0 g) and acetic acid (50 ml) were put in a reaction vessel under a nitrogen atmosphere, hydrogen peroxide (31% aqueous solution; 4.5 ml) was added dropwise thereto in the temperature range of 25° C. to 30° C., and the mixture was stirred for another 2 hours at room temperature. Then, the reaction mixture was poured into a vessel containing an aqueous solution sodium hydrogensulfite (100 ml) and ethyl acetate (200 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, giving 8.9 g of 4′-butoxy-4-hydroxy-2,3-difluoro-1,1′-biphenyl (20). The yield based on the compound (19) was 97.9%.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1)[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:46])[CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[C:43](Br)[CH:44]=1)[CH3:35].C(=O)([O-])[O-].[K+].[K+]>COCCOC.[NH4+].[Cl-].CCOC(C)=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>[CH2:34]([O:36][C:37](=[O:46])[CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[C:43]([C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:22])[F:23])=[CH:20][C:15]=2[CH2:14][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH:44]=1)[CH3:35]
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(=O)C2CC2)OC1(C)C
Reactant: CCOC(=O)Cc1cncc(Br)c1
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: [Cl-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(=O)C2CC2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Cyclopropanecarboxylic acid benzyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-amide (60% pure; 1.07 g, 1.4 mmol), (5-bromo-pyridin-3-yl)-acetic acid ethyl ester (0.375 g, 1.5 mmol), and potassium carbonate (0.484 g, 3.5 mmol) were combined in DME (8 mL) and H2O (4 mL), and the solution was purged with N2 for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.162 g, 0.14 mmol) was added, and the reaction was stirred at 90° C. overnight. The mixture was diluted with saturated aqueous NH4Cl and EtOAc. The aqueous layer was separated and extracted twice with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by preparative HPLC to give (5-{2-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid ethyl ester, which was then hydrolyzed in the following step, as well as the hydrolyzed product.
Reaction SMILES: [Na].Cl.[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([N:16]=[C:17]=[O:18])[CH2:13][CH2:14][CH3:15]>CC(C)=O>[CH2:12]([NH:16][C:17]([NH:10][C:3](=[NH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:18])[CH2:13][CH2:14][CH3:15]
Reactant: N=C(N)c1ccccc1
Reactant: CCCCN=C=O
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCNC(=O)NC(=N)c1ccccc1

Procedure:
Following a procedure similar to that described in Example 23 but using 7.7 g. sodium in 1100 ml. dry sodium, 52.4 g. benzamidine hydrochloride, and 33.1 g. butylisocyanate in 400 ml. dry acetone there was obtained, after recrystallization from ethyl acetate, 62.2 g. 1-butyl-3-(benzimidoyl)urea hydrochloride; m.p. 139°-141°C.
Reaction SMILES: N1CCC[C@H]1C(N)=O.C(N(CC)CC)C.ClCC(Cl)=O.[Cl:21][CH2:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[C:30]([NH2:32])=O)=[O:24].C1(Cl)N=C(Cl)N=C(Cl)N=1>O.CN(C=O)C.C(Cl)Cl>[Cl:21][CH2:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[C:30]#[N:32])=[O:24]
Reactant: NC(=O)[C@@H]1CCCN1C(=O)CCl
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: NC(=O)[C@@H]1CCCN1
Agent: O=C(Cl)CCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: N#C[C@@H]1CCCN1C(=O)CCl
Temperature: 35 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
This example was run in an analogous manner as example 1 but starting from 20.0 g (175.2 mmol) of L-Prolinamide (1), 17.6 g (173.5 mmol) of triethylamine, 22.7 g (199.4 mmol) of Chloroactylchloride and totally 152 mL of methylenechloride. The resulting (S)-1-(2-Chloro-acetyl)-pyrrolidine-2-carboxylic acid amide was treated with 20 mL of DMF and 12.7 g (67.5 mmol) of cyanurchloride at 20° C. The resulting mixture was heated to 35° C., stirred for 2 h at this temperature and treated with 2.6 mL of water. The suspension was stirred for 1 h at RT and filtered with suction. The filter cake was washed with 20 mL of methylenechloride and the filtrate was treated with 100 mL of water. The layers were separated and the aqueous phase was twice washed with a total of 68 mL of methylenechloride. The organic layers were unified and concentrated under vacuum at a jacket temperature of 40° C. (400 mbar to 28 mbar). The remaining oil was treated with 130 mL of Isopropanol and inoculated at 30° C. The suspension was cooled to −22° C. within 4 h, stirred over night at this temperature and treated with 34 mL of n-heptane. The precipitate was filtered with suction, the filter cake was washed with 112 mL of a cold (−10° C. to 20° C.) mixture of n-heptane/2-propanol (8:2 (v/v)) and dried to constant weight (50° C., 50 mbar, 3 h) to afford 24.0 g of (S)-1-(2-Chloroacetyl)-pyrrolidine-2-carbonitrile. (Yield: 80%, assay: 100% (m/m) based on HPLC).