Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)[C:32]([NH:31][C:23]2[C:22]([CH:19]([CH3:20])[CH3:21])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:28]([CH3:30])[CH3:29])=[O:33])=[CH:6][CH:7]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CN(C)c1ccc(CNc2ccc(Br)cc2)cc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(Br)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 1 using (4-bromophenyl)[(4-dimethylaminophenyl)methyl]amine (0.80 g) and 2,6-diisopropylphenyl isocyanate (0.62 mL) as starting materials, N-(4-bromophenyl)-N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]urea (0.71 g) was obtained. melting point: 165–166° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.CCOC(C)=O>CN(C=O)C>[O:1]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccccc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccccc1O

Procedure:
2-Hydroxyethylphenol (XLVa) (15.2 g, 0.11 mol) and t-butyldimethylsilyl chloride (18.2 g, 0.121 mol) were placed together in DMF (120 mL; Aldrich Sure Seal). While the solution was being stirred, imidazole (16.5 g, 0.242 mol) was added portionwise (slightly exothermic). After stirring for 3 h at room temperature, EtOAc (200 mL) was added and the resultant solution was washed with water (3×200 mL) and brine (200 mL). The EtOAc layer was dried over anhydrous sodium sulfate, filtered and concentrated to leave a yellow oil which was purified by silica gel column chromatography (being eluted with 19:1 hexanes/EtOAc) to obtain 27.7 g (0.11 mol, Y: 100%) of the title compound as an oil; Rf: 0.40 (19:1 hexanes/EtOAc); 1H-NMR (CDCl3) δ ppm: 0.067 (6H, s, SiMe2), 0.893(9H, s, SitBu), 2.87 (2H, t, J=5 Hz, ArCH2), 3.91 (2H, t, J=5 Hz, CH2OSi), 6.80 (1H, dt, J=1.3, 7.4 Hz, 5'-H), 6.90 (1H, dd, J=1.2, 8 Hz, 2'-H), 7.00 (1H, dd, J=1,5, 7.3 Hz, 6'-H), 7.12 (1H, dt, J=1.6, 7.5 Hz, 4'-H), 8.29 (1H, s, OH, D2O exchanged); IR (film) 3300 (OH), 1616 cm-1 ; MS (FAB/NOBA) m/e: 253 (MH+), 237, 209.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:32])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]3[CH:24]=[CH:25][N:26]=[C:27]([C:28]([O:30]C)=[O:29])[C:22]3=[N:21][N:20]=2)=[CH:15][CH:14]=1.C[Si](C)(C)[O-].[K+].Cl>C1COCC1.CCOC(C)=O>[F:34][C:2]([F:1])([F:33])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:32])[NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:23]3[CH:24]=[CH:25][N:26]=[C:27]([C:28]([OH:30])=[O:29])[C:22]3=[N:21][N:20]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1nccn2c(-c3ccc(NC(=O)Nc4ccccc4OC(F)(F)F)cc3)nnc12
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(-c2nnc3c(C(=O)O)nccn23)cc1)Nc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 100.5 %

Procedure:
To a solution of methyl 3-(4-(3-(2-(trifluoromethoxy)phenyl)ureido) phenyl)-[1,2,4]triazolo[4,3-a]pyrazine-8-carboxylate (61F) (72 mg, 0.152 mmol) in THF (3 mL), was added potassium trimethylsilanolate (78 mg, 0.61 mmol). The mixture was stirred at room temperature for 70 min, and then acidified with 1 N aqueous HCl (0.62 mL). The mixture was diluted with EtOAc, washed with water (3×), brine, and dried over Na2SO4. The solvent was removed in vacuo to yield the title compound as a brown solid (70 mg, 100%). HPLC/MS (Method C): retention time=1.83 min, [M+H]+=459.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[CH:25]([NH:28][CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]([N:28]([CH:29]([CH3:31])[CH3:30])[C:8](=[O:10])[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([CH3:27])[CH3:26]
Reactant: CC(C)NC(C)C
Reactant: O=C(O)Cc1cccnc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C(=O)Cc1cccnc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of pyridin-3-ylacetic acid (1.0 g, 7.292 mmol), EDC (2.796 g, 14.584 mmol) and HOAt (992 mg, 7.292 mmol) in 10 mL DMF were added diisopropyl amine (1.476 g, 14.584 mmol) and Hunig's base (1.885 g, 14.584 mmol). The reaction mixture was stirred at room temperature overnight and then partitioned between ether and half-saturated aq NaHCO3. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The resulting residue was purified by flash chromatography using a linear gradient of 0% to 6% MeOH—NH3 (90:10 v/v) in CH2Cl2 to give a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]([OH:18])=O)=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=N[C:29]2[CH:30]=[CH:31][CH:32]=[N:33][C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:43]1(N)C=CC=C[CH:44]=1>CN(C=O)C>[CH2:32]([NH:33][C:16](=[O:18])[C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=[C:12]([Br:15])[N:11]=1)[C:31]1[CH:44]=[CH:43][CH:28]=[CH:29][CH:30]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ccccc1
Reactant: O=C(O)c1nc(Br)ccc1OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1nc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of 3-(benzyloxy)-6-bromopicolinic acid (0.50 g, 1.62 mmol) and HATU (1.23 g, 3.24 mmol) in DMF (5 mL) was added phenylamine (0.52 g, 4.87 mmol) dropwise. After stirring at room temperature overnight, the mixture was concentrated and the residue was diluted with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash gel chromatography (DCM:MeOH=50:1) to afford the product of N-benzyl-3-(benzyloxy)-6-bromopicolinamide (0.60 g, yield: 93.2%). 1H-NMR (CDCl3, 400 MHz) δ 7.79 (br s, 1H), 7.38˜7.41 (m, 3H), 7.19˜7.32 (m, 9H), 5.18 (s, 2H), 4.58 (d, J=5.6 Hz, 2H). MS (M+H)+: 397/399.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:26]=[C:25]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]3[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=3[CH3:19])=[CH:13][CH:14]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Reactant: OB(O)c1cccc(F)c1
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2cccc(F)c2)cc1

Procedure:
Compound (104) was prepared from compound (20) and (3-fluoro-phenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt=1.83 mins, m/z (ES−)=325 (M−H for C19H15FO4).
Reaction SMILES: C([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9](OC)[CH:8]=[CH:7][CH:6]=2)C.[H-].[Na+].C(Br)C1C=CC=CC=1>CN(C=O)C.O>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:3]1
Reactant: CCc1cc2c(OC)cccc2[nH]1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2[nH]ccc2c1
Reaction time: 1.5 h

Procedure:
2-Ethyl-4-methoxy-1H-indole (4.2 g, 24 mmol) was dissolved in 30 mL of DMF and 960 mg (24 mmol) of 60% NaH/minerial oil was added. After 1.5 hours, 2.9 mL(24 mmol) of benzyl bromide was added. After 4 hours, the mixure was diluted with water and extracted twice with ethyl acetate. The combined ethyl acetate was washed with brine, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 3.1 g (49% yield) of 2-ethyl-4-methoxy-1-phenylmethyl)-1H-indole.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[F:30])(=[O:39])=[O:38])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccccc3F)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (100 mg, 0.31 mmol) in pyridine (49 mg, 0.62 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of 2-fluoro-benzenesulfonyl chloride (73 mg, 0.37 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford N-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide (97 mg, 65.1%) as a white solid. MS (ESI+APCI) M+1=479.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.4 %

Procedure:
In a sealed 25 mL round-bottom flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (32 mg, 0.061 mmol) and TFA (1.2 ml, 15.6 mmol) were combined with dichloromethane (4 ml) to give an orange solution. The reaction mixture was stirred at room temperature until the consumption of starting material (2.5 h). The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (2 mL) and ethylenediamine (300 μl, 4.5 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (9:1 dichloromethane/heptane) to afford 22 mg (93%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=399; 1H NMR (DMSO-d6) δ: 12.72 (br. s., 1H), 9.11 (s, 1H), 8.53 (d, J=8.7 Hz, 1H), 8.44 (s, 1H), 8.20 (d, J=8.7 Hz, 1H), 8.01 (d, J=1.9 Hz, 1H), 7.28 (dd, J=8.7, 1.9 Hz, 1H), 4.30-4.45 (m, 1H), 4.18 (s, 3H), 3.50 (qd, J=9.6, 4.7 Hz, 2H), 3.27 (s, 3H), 1.31 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]([CH3:30])([C:25]1[O:26][CH:27]=[CH:28][N:29]=1)[NH2:24]>>[CH3:22][C:23]([NH:24][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:25]1[O:26][CH:27]=[CH:28][N:29]=1)[CH3:30]
Reactant: O=C(O)c1ccc(C2CCCO2)c(-c2cccc(Cl)c2)n1
Reactant: CC(C)(N)c1ncco1
Product: CC(C)(NC(=O)c1ccc(C2CCCO2)c(-c2cccc(Cl)c2)n1)c1ncco1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid (Example 125 b) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=412.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]#[N:10])[NH2:5].[F-].[Cs+].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1C(=O)CCC1.CCOC(C)=O.Cl[Pd](Cl)(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)P(C1CCCCC1)(C1CCCCC1)C1CCCCC1>[C:9]([C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:10]
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1ccc(N)cc1Cl
Agent: Cl[Pd](Cl)([PH](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[PH](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N)cc1-c1ccccc1
Temperature: 100 °C
Yield: 95.5 %

Procedure:
Commercially available 3-chloro-4-cyanoaniline (305 mg, 2.0 mmol) was dissolved in NMP (8 mL), and CsF (608 mg, 4.0 mmol), phenyl boronic acid (268 mg, 2.2 mmol) and dichlorobis(tricyclohexylphosphino)palladium (73 mg, 0.1 mmol) were added. The reaction was then heated to 100° C. for 16 h. After cooling to rt, the reaction mixture was taken up in EtOAc, washed with water (2×), dried (Na2SO4), concentrated under reduced pressure, and purified by silica gel flash chromatography eluting with EtOAc/hexanes (1:1) to give compound 47A (371 mg, 96%) as a yellow solid. LC/MS m/z 195 [M+H]+.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25][NH2:26]>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25][NH:26][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]3[O:18][C:14]([CH3:13])=[CH:15][CH:16]=3)=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: Cc1ccc(CN)o1
Reactant: NCc1cc(F)cc(F)c1
Product: Cc1ccc(CNc2ccc3c(NCc4cc(F)cc(F)c4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=380.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, 5-methyl-2-furanmethanamine and 3,5-difluorobenzylamine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.CS(C)=O.[C@H:30]1([NH2:37])[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31]1>CCOC(C)=O>[NH2:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([NH:37][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[C:11]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:31][CH2:32]1
Reactant: N#Cc1cc(NCc2cccc(F)c2)nc(-c2cc(F)ncc2Cl)c1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1cc(NCc2cccc(F)c2)nc(-c2cc(N[C@H]3CC[C@H](N)CC3)ncc2Cl)c1
Temperature: 105 °C

Procedure:
To a scintillation vial containing 5′-chloro-2′-fluoro-6-(3-fluorobenzylamino)-2,4′-bipyridine-4-carbonitrile (72 mg, 0.202 mmol) was added DMSO (3 ml) and trans-cyclohexane-1,4-diamine (230 mg, 2.018 mmol). The homogenous yellow reaction mixture was capped and heated to 105° C. in a oil bath for 3 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3, sat NaCl. The organic layer was dried Na2SO4, filtered and concentrated. The crude solid was purified by Prep HPLC and the collected fractions were combined and diluted with EtOAc and neutralized with sat NaHCO3 and then sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to afford 2′-(trans-4-aminocyclohexylamino)-5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridine-4-carbonitrile (73 mg, 80%). LCMS (m/z): 451.2 (MH+), retention time=0.70 min. 1H NMR (400 MHz, METHANOL-d4) d ppm 1.34-1.48 (m, 2 H) 1.50-1.64 (m, 2 H) 2.06-2.22 (m, 4 H) 3.08-3.20 (m, 1 H) 3.63-3.74 (m, 1 H) 4.61 (s, 2H) 6.81 (s, 1 H) 6.87 (s, 1 H) 6.91-6.99 (m, 1 H) 7.02 (s, 1H) 7.04-7.10 (m, 1H) 7.12-7.18 (m, 1 H) 7.25-7.36 (m, 1 H) 8.00 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](Br)=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].[CH2:33]1[CH2:37]O[CH2:35][CH2:34]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH:33]([CH2:37][CH3:27])[CH2:34][CH3:35])=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Br)cc3C(F)(F)F)[C@@H]2C1
Reactant: C1CCOC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)c1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring degassed solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (66 mg, 0.15 mmol) and potassium carbonate (105 mg, 0.76 mmol) in DMF (1.0 mL) was added 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (12 mg, 0.015 mmol). After 15 min., 0.5 M THF solution of 3-propenylzinc bromide (0.45 mL, 0.9 mmol) was added. The reaction was heated to reflux for 15 min and then cooled to room temp. The reaction was quenched with 1M aq. NaOH and extracted with EtOAc (3×10 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a black oil. The oil was purified by flash chromatography (silica gel, 0–50% EtOAc in hexanes) to give 36 mg of the desired product as a colorless oil. MS (ESI) 427 (M+H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17]C=1>C1COCC1>[N:1]1([C:7]2[N:8]=[C:9]([N:15]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH:10]=[C:11]([Cl:13])[N:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: c1ccncc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: Clc1cc(N2CCCC2)nc(N2CCCC2)n1
Temperature: 0 °C

Procedure:
A solution of pyrrolidine (80 g) in THF (500 ml) is chilled in an ice water bath and stirred mechanically under nitrogen. With a syringe pump of 2,4,6-trichloropyrimidine (50 g) is added over 35 minutes. The reaction is stirred in the ice bath for 1 hour and is then warmed to 20°-25° over 4 h. Pyridine (100 ml) is added to the reaction and the mixture stirred at 20°-25° overnight. The reaction is concentrated. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is concentrated and the residue chromatographed on silica gel (10% ethyl acetate/hexane) to yield 51 g of crystalline 2,4-bis[pyrrolidino]-6-chloropyrimidine. Immediately after the initial addition of reagents, two spots are seen with 25% ethyl acetate on a silica gel plate. These are the 2- and the 4- adducts. The bis product forms over time. It moves between these first two spots. The 51 g of product is reacted with piperazine (40 g) in 100 ml of dry pyridine at 100° for 50 h. The reaction is concentrated. The residue is partitioned between methylene chloride and sodium bicarbonate solution. The organic phase is dried and concentrated. The residue is chromatographed on silica gel eluting with methylene chloride to 10% methanol/1% ammonia/methylene chloride to give the title compound, NMR (CDCl3) 1.90, 2.9, 3.35 and 4.80 δ.
Reaction SMILES: [CH2:1]([C:3]1C=C(C=C(C)C=1O)C=O)[CH3:2].C(C1C=CC=C(C)C=1O)C.[CH2:23]([C:25]1[CH:26]=[C:27]([CH:32]=[C:33]([CH3:36])[C:34]=1[OH:35])[C:28]([NH:30][OH:31])=[NH:29])[CH3:24]>>[CH2:3]([O:35][C:34]1[C:33]([CH3:36])=[CH:32][C:27]([C:28]([NH:30][OH:31])=[NH:29])=[CH:26][C:25]=1[CH2:23][CH3:24])[CH:1]=[CH2:2]
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: CCc1cc(C=O)cc(C)c1O
Agent: CCc1cccc(C)c1O
Product: C=CCOc1c(C)cc(C(=N)NO)cc1CC

Procedure:
The title compound is prepared by allylating 3-ethyl-4-hydroxy-5-methyl-benzaldehyde which is prepared from 2-ethyl-6-methyl-phenol following literature procedures (see 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine). The aldehyde is then transformed into the corresponding hydroxyamidine according to literature procedures (see 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine); LC-MS: tR=0.72 min, [M+1]+=235.09, 1H NMR (CD3OD): δ 7.31 (s, 1H), 7.29 (s, 1H), 6.10 (m, 1H), 5.43 (dd, J=17.0, 1.5 Hz, 1H), 5.27 (dd, J=10.3, 1.2 Hz, 1H), 4.81 (s br, 3H), 4.31 (d, J=5.6 Hz, 2H), 2.67 (q, J=7.6 Hz, 2H), 2.30 (s, 3H), 1.23 (t, J=7.6 Hz, 4H).
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[S:38](Cl)(=[O:40])=[O:39])=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[F:29][C:30]1[CH:31]=[CH:32][C:33](/[CH:36]=[CH:37]/[S:38]([N:13]2[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:11]3[CH2:12]2)(=[O:40])=[O:39])=[CH:34][CH:35]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: O=S(=O)(Cl)/C=C/c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2CN(S(=O)(=O)/C=C/c3ccc(F)cc3)CCN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (50 mg, 0.17 mmol) in chloroform (2 mL) were sequentially added pyridine (0.5 mL) and (E)-2-(4-fluorophenyl)vinylsulfonyl chloride (43 mg, 0.24 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) and crystallized from diisopropyl ether to obtain the title compound (27 mg, yield 64%).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[C:8](I)[CH:7]=[C:6]([OH:11])[CH:5]=1.[SH:13][C:14]1[S:15][CH:16]=[N:17][N:18]=1.[NH2:19][C:20]1[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=1>>[OH:11][CH2:6][CH:5]([CH3:4])[O:11][C:6]1[CH:7]=[C:8]([S:13][C:14]2[S:15][CH:16]=[N:17][N:18]=2)[CH:9]=[C:4]([CH:5]=1)[C:3]([NH:19][C:20]1[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=1)=[O:12]
Reactant: Sc1nncs1
Reactant: COC(=O)c1cc(O)cc(I)c1
Reactant: Cn1ccc(N)n1
Product: CC(CO)Oc1cc(Sc2nncs2)cc(C(=O)Nc2ccn(C)n2)c1

Procedure:
The compound of Production Example 124 was obtained as a colorless amorphous substance using 3-hydroxy-5-iodobenzoic acid methyl ester, 1-tert-dimethylsiloxy-2-hydroxypropane, 2-mercapto-[1,3,4]thiadiazole and 3-amino-1-methyl-1H-pyrazole, by the same method as in Production Example 74 or 82, a corresponding method, or a combination thereof with an ordinary method.