Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]/[O:12]C)/[CH2:6][CH2:5]2.CC(=CCC)C.Cl([O-])=[O:21].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]([OH:12])=[O:21])[CH2:6][CH2:5]2
Reactant: CO/C=C1\CCc2cc(Br)ccc21
Reactant: [O-][Cl+][O-]
Agent: CCC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)C1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To a solution of the product from Example 70, Part B (300 mg, 1.3 mmol) and 2-methyl-2-pentene (8 ml) in tert-butanol (32 ml) was added a solution of sodium chlorite (1.36 g, 0.12 mmol) in H2O (12 ml) containing sodium dihydrogen phosphate (1.07 g, 8.9 mmol) and the mixture was stirred vigorously for 20 min at room temperature. Solvents were concentrated in vacuo and the residue was diluted with H2O, extracted with EtOAc (3×), extracts combined, dried (Na2SO4), and concentrated in vacuo to give the title compound (180 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[C:13]([CH:14]([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH2:8][CH3:9])[C:6]#[N:7].[CH2:17](N)[CH2:18][NH2:19].[S-]SS[S-].[Na+].[Na+]>O>[Cl:1][C:2]1[C:13]([CH:14]([F:15])[F:16])=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([C:6]1[NH:19][CH2:18][CH2:17][N:7]=1)[CH2:8][CH3:9]
Reactant: NCCN
Reactant: CCC(C#N)Oc1cccc(C(F)F)c1Cl
Agent: [Na+]
Agent: [S-]SS[S-]
Solvent: O
Product: CCC(Oc1cccc(C(F)F)c1Cl)C1=NCCN1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-chloro-3-difluoromethyl-phenoxy)-butyronitrile (300 mg, 1.2 mmol), ethylene diamine (0.33 ml, 4.9 mmol) and sodium tetrasulfide (11 mg, 0.1 mmol) was stirred for 2 hrs at 50° C., then cooled to room temperature. Cold water (0° C.) was added to the reaction mixture. The resultant suspension was stirred for ca 15 minutes and then filtered, washed and dried to yield 2-[1-(2-chloro-3-difluoromethyl-phenoxy)-propyl]-4,5-dihydro-1H-imidazole (m.p. 96-97° C.); 1H-NMR (D6-DMSO) 1.0, t, 3H, 1.8-2.0 m, 2H; 3.42 vbr s, 4H, 4.8, dd, 1H, 6.51, br s, 1H, 7.2, t, 1H, 7.25, d, 1H, 7.32, d, 1H, 7.43, t, 1H.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21](O)=[O:22])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[CH3:26][NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:26][N:27]([C:21](=[O:22])[CH2:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:24])([F:25])[F:1])[CH:4]=3)=[CH:13][CH:12]=2)[CH2:15][CH2:16]1)[CH2:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Reactant: CNCC(=O)OC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(C)C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 20 mL scintillation vial was added the product from Example 26C (30 mg, 0.085 mmol), methyl 2-(methylamino)acetate (10.0 mg, 0.097 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30.0 μL, 0.176 mmol). Following 4 hours of stirring at room temperature, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. The NMR spectrum includes a mixture of rotamers, with the major rotamer being reported. 1H NMR (500 (MHz, DMSO-d6) δ ppm 0.98-1.20 (m, 2 H), 1.38-1.55 (m, 2 H), 1.70-1.93 (m, 5 H), 2.20-2.33 (m, 2 H), 2.78-2.88 (m, 1 H), 3.01-3.10 (m, 3 H), 3.64 (s, 3 H), 4.08 (s, 2 H), 7.03-7.19 (m, 1 H), 7.28-7.41 (m, 2 H), 7.66-7.76 (m, 2 H), 13.80-14.09 (m, 1 H); MS (ESI) m/z 438 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:31]=[CH:30][C:22]4[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[O:26][C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>CS(C)=O.CCOC(C)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:19]3[CH:31]=[CH:30][C:22]4[C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[O:26][C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCBr
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)OC(C)(C)OC2=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 57.5 %

Procedure:
To a solution of 7-[4-(4-butyl-phenylethynyl)-benzylamino]-2,2-dimethyl-benzo[1,3]-dioxin-4-one (1.16 g, 2.64 mmol) in DMSO (32 mL) was added sodium hydride (159 mg, 3.96 mmol, 55-65% in oil) and the resulting mixture was stirred 2 min at rt, then 1-bromohexane (559 μl, 3.96 mmol) was added. The red solution was stirred at rt for 2 hrs. The reaction mixture was poured in EtOAc (70 mL) and washed with an aqueous solution of HCl (2×30 mL, 0.1N) and water (6×30 mL). The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. The crude mixture was purified by flash chromatography on silicagel (c-Hex/EtOAc (6/1)) to give 795 mg (56%) of the title compound as a yellow oil. HPLC, Rt: 6.4 min (purity: 98.3%). M+(ESI): 524.5. 1H NMR (CDCl3) δ: 7.71 (d, J=8.7 Hz, 1H), 7.47 (d, J=8.3 Hz, 2H), 7.41 (d, J=7.9 Hz, 2H), 7.13 (m, 4H), 6.36 (m, 1H), 6.04 (m, 1H), 4.58 (s, 2H), 3.40 (t, J=7.7 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H), 1.76-1.48 (m, 8H), 1.42-1.20 (m, 10H), 0.95-0.82 (m, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-])=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([Cl:19])[CH:12]=1)([O-])=O>[Pd].C(O)C>[ClH:19].[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26])[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([Cl:19])[CH:12]=1
Reactant: N#Cc1ccc(N(c2ccccc2[N+](=O)[O-])c2ccccc2[N+](=O)[O-])cc1Cl
Agent: [Pd]
Solvent: CCO
Product: Cl
Product: N#Cc1ccc(N(c2ccccc2N)c2ccccc2N)cc1Cl

Procedure:
N,N-Bis(2-nitrophenyl)-3-chloro-4-cyanoaniline, palladium on carbon (0.70 g, 5%), ethanol (100 ml) was stirred under hydrogen until 2.5 l was consumed. The reaction mixture was filtered through a celite pad, hydrogen chloride in methanol (4M, 30 ml) was added and the solvent was removed by evaporation. The residue was triturated with ethyl acetate to leave the crystalline product. Yield 3.8 g, 53%. M.p. 184-187° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH:11]([CH:16]=[N:17][OH:18])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][C:25]#C.[CH2:28](N(CC)CC)C>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:27])[CH:23]([C:24]1[O:18][N:17]=[C:16]([CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:19])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH:25]=1)[CH3:28]
Reactant: C#CCCC(=O)OC
Reactant: CC(C)CC(C=NO)NC(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)c1cc(C(CC(C)C)NC(=O)OCc2ccccc2)no1

Procedure:
To a stirred solution of [1-(hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid benzyl ester (6.0 g, 22.7 mmol) and pent-4-ynoic acid methyl ester (3.8 g, 34 mmol) in CH2Cl2 (80 ml) was added triethylamine (0.2 ml) followed by Clorox bleach (80 ml). After 4 h at room temperature the organic phase was separated and the aqueous phase was extracted with CH2Cl2 (25 ml×3). The combined organics were dried over MgSO4; filtered and concentrated under reduced pressure to give a yellow oil. Purification by Flash 40 chromatography using a silica gel column and eluting with 10-20% EtOAc/hexane gave 2.5 g of the title compound as a waxy pale yellow solid. MS [M+1]+ 375.3; 1H nmr (400 MHz, CDCl3) δ0.91 (m, 6H), 1.51-1.76 (m, 3H), 2.67 (t, J=7.5 Hz, 2H), 3.02 (t, J=7.5 Hz, 2H), 3.67 (s, 3H), 4.89 (m, 1H), 5.08 (m, 3H), 5.92 (s, 1H), 7.31 (m, 5H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1)=[O:7])[CH3:3].[CH3:20][I:21]>CCOCC>[I-:21].[CH3:1][N+:2]([CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=1)=[O:7])([CH3:20])[CH3:3]
Reactant: COc1cc(C(=O)CCN(C)C)cc(OC)c1OC
Reactant: CI
Solvent: CCOCC
Product: COc1cc(C(=O)CC[N+](C)(C)C)cc(OC)c1OC
Product: [I-]
Reaction time: 2 h

Procedure:
An ambient temperature solution of 3-(N,N-dimethylamino)-1-(3,4,5-trimethoxyphenyl)-propan-1-one (242.5 g, 0.91 mole) in Et2O (1.62 L) under nitrogen atmosphere was treated with methyl iodide (83 mL, 1.27 mole) and stirred for 2 hours. The resulting mixture was filtered and dried under high vacuum overnight at room temperature to provide 3-(N,N,N-trimethylammonio)-1-(3,4,5-trimethoxyphenyl)propan-1-one iodide as a white solid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[CH2:20][NH:19][CH2:18][CH2:17]2.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[CH2:20][N:19]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][N:6]=1)[CH2:18][CH2:17]2
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCc3cc(OC)c(OC)cc3C2)nc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 55.3 %

Procedure:
A mixture of methyl-6-chloronicotinate (170 mg), 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (205 mg), potassium carbonate (150 mg) and dioxane (5 mL) was heated in a 100° C. oil bath overnight. An additional aliquote of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (100 mg) was added and heating was continued for five hours. The reaction was partitioned between water and EtOAc. The organics were washed with water, dried, and the solvent evaporated. The residue was purified by flash chromatography eluting with EtOAc to give methyl 6-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)nicotinate as a white solid (180 mg), m/e=329 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:6]2[C:7]([C:8]3[CH:9]=[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=3)=[C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:3]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:5]=2)=[CH:19][CH:20]=1
Reactant: C1CNCCN1
Reactant: NS(=O)(=O)c1cccc(-c2c(Cl)nc(C(F)(F)F)nc2-c2ccc(F)cc2)c1
Solvent: CC#N
Product: NS(=O)(=O)c1cccc(-c2c(-c3ccc(F)cc3)nc(C(F)(F)F)nc2N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of 3-[4-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide (0.1 g, 0.24 mmol, prepared according to the procedure described above in preparation 4, Step 2a), in acetonitrile (2 ml) was treated with piperazine (0.104 g, 1.203 mmol) and the reaction mixture was stirred overnight at room temperature. Subsequently the reaction mixture was poured into ice-cold water and was extracted with ethylacetate (25 ml). The organic layer was washed with water, brine solution and then evaporated to obtain the title compound. 1H-NMR (DMSO-d6) δ: 2.58 (s, 4H), 3.19 (s, 4H), 7.03-7.14 (m, 4H), 7.32 (d, 1H), 7.41 (brs, D2O exchangeable, 2H), 7.46-7.50 (t, 1H), 7.72 (s, 1H), 7.73 (d, 1H); MS m/z: 482.1 (M++1).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[S:25][C:24]([C:26]5[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=5)=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[S:25][C:24]([C:26]5[CH:33]=[CH:32][C:29]([CH2:30][NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:28][CH:27]=5)=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: CN(C)CCN
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: CN(C)CCNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from N,N-dimethylethylenediamine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 170-183° C.; LC-MS: 443 (MH+); HPLC RT: 3.02 minutes.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][CH2:23][CH2:24][C:25]2([OH:38])[CH2:37][CH2:36][C:28]3([O:33]CC(C)(C)CO3)[CH2:27][CH2:26]2)[CH3:21])=[CH:16][CH:15]=1.C(N(C(C)C)C(C)C)C.Cl>ClCCl.CC(C)=O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C@@H:20]([N:22]2[CH2:23][CH2:24][C:25]3([CH2:26][CH2:27][C:28](=[O:33])[CH2:36][CH2:37]3)[O:38][C:2]2=[O:4])[CH3:21])=[CH:18][CH:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(Br)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](c1ccc(Br)cc1)N1CCC2(CCC(=O)CC2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphosgene (2.51 g) is added to a solution of 9-{2-[(S)-1-(4-bromo-phenyl)-ethylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol (4.00 g) and ethyl-diisopropyl-amine (1.7 mL) in dichloromethane (40 mL) chilled in an ice bath. The cooling bath is removed and the solution is stirred at room temperature overnight. Water is added and the organic phase is separated. The organic phase is dried (Na2SO4) and concentrated to give an oil that is dissolved in acetone (20 mL). 1 M Hydrochloric acid (19 mL) is added and the solution is stirred at room temperature for 3 h. The acetone is then evaporated, and the residue is diluted with saturated aqueous K2CO3 solution and extracted with ethyl acetate. The combined extracts are washed with water and brine, dried (MgSO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→0:1) to give the title compound. Yield: 1.89 g (52% of theory); LC (method 8): tR=1.27 min; Mass spectrum (ESI+): m/z=366/368 (Br) [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[S:8][C:9]([C:16]([OH:18])=O)=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([N:29]2[CH2:34][CH2:33]C[CH2:31][CH2:30]2)[CH2:27][NH2:28])=[CH:22][CH:21]=1.F[P-](F)(F)(F)(F)F.[N:42]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:46]2C=CC=CC=2N=N1.CCOC(C)=O>C(#N)C.O>[CH3:46][N:42]1[CH2:31][CH2:30][N:29]([C:26]2([CH2:27][NH:28][C:16]([C:9]3[S:8][C:7]([C:2]4[N:1]=[CH:6][CH:5]=[CH:4][N:3]=4)=[N:11][C:10]=3[C:12]([F:13])([F:14])[F:15])=[O:18])[CH2:22][CH2:21][CH2:20][CH2:25][CH2:24][CH2:23]2)[CH2:34][CH2:33]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: NCC(c1ccc(Cl)cc1)N1CCCCC1
Reactant: O=C(O)c1sc(-c2ncccn2)nc1C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1CCN(C2(CNC(=O)c3sc(-c4ncccn4)nc3C(F)(F)F)CCCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-pyrimidin-2-yl-4-trifluoromethyl-thiazole-5-carboxylic acid (15 mg), 2-(4-chloro-phenyl)-2-piperidin-1-yl-ethylamine (15 mg), BOP (25 mg) and TEA (10 mg) in ACN (1 mL) is stirred at RT overnight. EtOAc and water are added to the mixture and the organic layer is separated, washed twice with water and concentrated in vacuo. The residue is purified by PTLC (10% MeOH in methylene chloride) to give the title compound. MS (M+1)=483.21; RT=1.15 min. *IC50.
Reaction SMILES: FC(F)(F)C1C=C(C(C)(C)[C:14]([N:16](C)[C:17]2[CH:18]=[N:19][C:20](N3CCN(C)CC3)=[CH:21][C:22]=2[C:23]2[C:24]([CH3:29])=[N:25][CH:26]=[CH:27][CH:28]=2)=[O:15])C=C(C(F)(F)F)C=1.[Cl:42]C1N=CC(C(O)=O)=C(C2C(C)=NC=CC=2)C=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:83]([OH:87])([CH3:86])([CH3:85])[CH3:84]>>[C:83]([O:87][C:14](=[O:15])[NH:16][C:17]1[CH:18]=[N:19][C:20]([Cl:42])=[CH:21][C:22]=1[C:23]1[C:24]([CH3:29])=[N:25][CH:26]=[CH:27][CH:28]=1)([CH3:86])([CH3:85])[CH3:84]
Reactant: Cc1ncccc1-c1cc(Cl)ncc1C(=O)O
Reactant: Cc1ncccc1-c1cc(N2CCN(C)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ncccc1-c1cc(Cl)ncc1NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[2-methyl-6′-(4-methyl-piperazin-1-yl)-[3,4′]bipyridinyl-3′-yl]-isobutyramide of formula I-2 can be prepared as follows: A solution of 6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-carboxylic acid (VI), triethylamine and diphenylphosphoryl azide in tert-butanol is stirred at about 90° C. under argon for 1.5 h. After cooling to room temperature, the solvent is evaporated. The residue is diluted with ethyl acetate and washed with aqueous sodium hydrogencarbonate solution and brine. The organic layer is concentrated and purified to give the compound (6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-carbamic acid tert-butyl ester of formula VIII.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4]/[N:5]=[CH:6]/[C:7]1[C:8]([F:30])=[C:9]([F:29])[C:10]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:11]([CH:19]=1)[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13].CN(C)C=O.CON(C(C)=O)[C:39](=[O:41])[CH3:40]>CO>[C:39]([NH:1][CH2:2][CH2:3][O:4]/[N:5]=[CH:6]/[C:7]1[C:8]([F:30])=[C:9]([F:29])[C:10]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:11]([CH:19]=1)[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13])(=[O:41])[CH3:40]
Reactant: NCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: CON(C(C)=O)C(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)NCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.8 %

Procedure:
To a solution of (E)-5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (8.14 mg, 0.02 mmol) described in Step C in a mixed solvent of dimethylformamide (1 ml) and methanol (5 ml) was added N-methoxydiacetamide (100 mg, 0.76 mmol), and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resultant residue was purified with Mega Bond Elut silica gel (Varian, 5 g). (E)-5-[(2-Acetylamino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (8.10 mg, 92% yield) was obtained as a pale yellow solid from fractions eluted with 6% methanol/methylene chloride.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:9]1[N:10]=[C:11]([NH:14]C(OCC=C)=O)[S:12][CH:13]=1)([OH:8])[CH3:7])(=[O:3])[CH3:2].C(N)CCC.C(O)=O.Cl>C1COCC1>[C:1]([O:4][CH2:5][C:6]([C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)([OH:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)Nc1nc(C(C)(O)COC(C)=O)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCN
Solvent: O=CO
Product: CC(=O)OCC(C)(O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
To a solution of 2-(2-{[(allyloxy)carbonyl]amino}-1,3-thiazol-4-yl)-2-hydroxypropyl acetate (790 mg) in THF (10 mL) were added n-butylamine (0.52 mL), formic acid (0.20 mL), and tetrakistriphenylphosphine palladium (33 mg) at room temperature, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 1 M hydrochloric acid (30 mL) at room temperature, followed by extraction with ethyl acetate. The aqueous layer was adjusted to pH 9 using saturated aqueous sodium bicarbonate, followed by extraction with a solvent (ethyl acetate:isopropyl alcohol=3:1, 100 mL×3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, 2-(2-amino-1,3-thiazol-4-yl)-2-hydroxypropyl acetate (261 mg) was obtained as a pale yellow oily substance. The obtained pale yellow oily substance was subjected to optical resolution with chiral column chromatography (Product Name: Chiralcel OJ-H, hexane:ethanol:diethylamine=30:70:0.1) to obtain optical active products of 2-(2-amino-1,3-thiazol-4-yl)-2-hydroxypropyl acetate at a first peak and a second peak in yields of 37% and 25%, respectively (>95% ee) (absolute arrangement was not determined).
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:13][O-:14].[Na+].O>CO>[Cl:1][C:2]1[C:8]([O:14][CH3:13])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: C[O-]
Reactant: Nc1ccc([N+](=O)[O-])c(Cl)c1Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c([N+](=O)[O-])ccc(N)c1Cl
Yield: 53.1 %

Procedure:
A solution of 2,3-dichloro-4-nitroaniline (25 g) and sodium methoxide (25 g) in methanol (250 ml) is stirred and heated at reflux under a nitrogen atmosphere for 5.5 hours. The reaction mixture is poured into water (1.5 l), the precipitated yellow solid is collected and dried. This material is purified by chromatography on silica gel using 1:1 hexane/ether eluent. The eluents are collected and evaporated to dryness to afford 13 g of title compound, m.p. 118°-123° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]([C:28]#[N:29])[C:14](=[O:27])[NH:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:39](OCC)(=O)C>>[O:27]=[C:14]1[C:13]([C:28]#[N:29])=[CH:12][C:11]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:31][CH:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:39])[N:10]=2)=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[NH:15]1
Reactant: CS(=O)(=O)c1nccc(-c2cc(C#N)c(=O)[nH]c2-c2cccc(C(F)(F)F)c2)n1
Reactant: CNCc1ccccc1
Reactant: CCOC(C)=O
Product: CC(Nc1nccc(-c2cc(C#N)c(=O)[nH]c2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Temperature: 100 °C
Yield: 73 %

Procedure:
To 5-(2-methylsulfonylpyrimidin-4-yl)-2-oxo-6-(3-trifluoromethylphenyl)-1,2-dihydropyridine-3-carbonitrile (150 mg, 0.357 mmol) in a sealed tube was added (S)-∝-methylbenzylamine (150 mg) and the mixture heated under argon at 100° C. for 1 hour. The reaction was cooled and the oil dissolved in ethyl acetate (25 mL). The solution was washed 3 times with a pH 5.3 buffer solution of 10% citric acid/NaOH (15 mL). The ethyl acetate layer was dried over sodium sulfate concentrated and chromatographed on silica using 80% ethyl acetate/hexane to give 120 mg (73%) of the title compound as a solid. The solid was stirred in methanol/hexane (2 mL) for 1 hour, filtered, and dried 40° C. to give 105 mg of a solid.
Reaction SMILES: [Br:1][C:2]([C:24](Cl)=[O:25])=[CH:3][C:4]1[CH:5]=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])[CH:7]=[CH:8][C:9]=1[Cl:10].[CH2:27]([S:29][CH2:30][CH2:31][OH:32])[CH3:28].C(N(CC)CC)C.O>O1CCCC1>[Br:1][C:2]([C:24]([O:32][CH2:31][CH2:30][S:29][CH2:27][CH3:28])=[O:25])=[CH:3][C:4]1[CH:5]=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=C(Br)C(=O)Cl)c2)c1=O
Reactant: CCSCCO
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCSCCOC(=O)C(Br)=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 5 h

Procedure:
2.36 g of 3-[3-(2-bromo-2-chlorocarbonylethenyl)-4-chlorophenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine in 20 ml of tetrahydrofuran were added dropwise to a solution of 0.58 g of 2-ethylmercaptoethanol and 0.56 g of triethylamine in 30 ml of tetrahydrofuran, and stirring was carried out for 5 hours. 100 ml of water were added and the aqueous phase was extracted with twice 100 ml of dichloromethane. The combined organic phases were washed three times with water, dried with sodium sulfate and evaporated down. The solid residue was stirred with diisopropyl ether, removed, washed with diisopropyl ether and petroleum ether and dried.