Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][C:3]=1[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:4][C:3]=1[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13]
Reactant: Nc1c(C(=O)C2CCCCC2)cc(Br)cc1[N+](=O)[O-]
Reactant: c1cncc(B2OCCCO2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1c(C(=O)C2CCCCC2)cc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 88.5 %

Procedure:
To a solution of (2-amino-5-bromo-3-nitro-phenyl)-cyclohexyl-methanone (600 mg, 1.83 mmol) in DME (25 mL) was added, successively, pyridine-3-boronic acid 1,3-propanediol cyclic ester (388 mg, 2.38 mmol), (tetrakistriphenylphosphine) palladium(0) (212 mg, 0.18 mmol), and 1N NaHCO3 (3.7 mL, 3.7 mmol). The resulting mixture was stirred at 90° C. for 90 minutes then cooled to room temperature. The reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and the filtrate concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO2, hexanes to 3:1 hexanes:EtOAc) to afford 527 mg (89%) of the title compound as a pale orange solid: 1H NMR (CDCl3, 500 MHz) δ 8.92 (d, 1H), 8.69 (d, 1H), 8.66 (d, 1H), 8.31 (d, 1H), 8.20 (d, 1H), 7.71 (dd, 1H), 3.36 (m, 1H), 1.88 (m, 3H), 1.77 (m, 1H), 1.40-1.61 (m, 3H), 1.24-1.32 (m, 2H), 0.89 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11].S(Cl)(Cl)=O.[CH:17](O)([CH3:19])[CH3:18]>>[CH:17]([O:11][C:10]([C@@H:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1)=[O:12])([CH3:19])[CH3:18]
Reactant: CC(C)O
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)[C@@H]1Cc2ccccc2N1
Yield: 89 %

Procedure:
To the solution of (2S)-2,3-dihydroindole-2-carboxylic acid (163 mg, 1.0 mmol) in isopropyl alcohol (40 mL), was added thionyl chloride (0.1 mL) slowly. The reaction mixture was heated at reflux for 4 hr with stirring. After cooling, all volatiles were removed under reduced pressure. To the residue saturated aqueous solution of NaHCO3 (10 mL) was added, which was extracted with ethyl acetate (10 mL×3). The extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give the desired compound (182 mg, 89%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCCBr
Reactant: CCOC(=O)Cc1cc(F)cc(OCc2ccccc2)c1
Product: CCOC(=O)C1(c2cc(F)cc(OCc3ccccc3)c2)CCCCC1

Procedure:
The titled compound was prepared from ethyl 3-benzyloxy-5-fluorophenylacetate according to the procedure described in Example 2F except that 1,5-dibromopentane was used in place of bis(2-chloroethyl) ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH:15]([C:19]([NH2:21])=[O:20])[CH2:14]2)=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH:33]=[C:34]([Cl:41])[C:35]=1[NH:36][C:37](=[O:40])[CH2:38]Cl.C(N(CC)CC)C>CN(C)C=O>[NH2:21][C:19]([CH:15]1[CH2:14][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH:8]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:18][CH2:17][N:16]1[CH2:38][C:37]([NH:36][C:35]1[C:34]([Cl:41])=[CH:33][C:32]([CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[CH:31][C:30]=1[Cl:29])=[O:40])=[O:20]
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Reactant: NC(=O)C1CN(CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc(Cl)c(NC(=O)CN2CCN(CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2C(N)=O)c(Cl)c1
Temperature: 70 °C
Yield: 80.7 %

Procedure:
A mixture of 7 parts of 4-[5,5-bis(4-fluorophenyl)pentyl]-2-piperazinecarboxamide, 6.6 parts of (1,1-dimethylethyl) [[3,5-dichloro-4-[(2-chloroacetyl)amino]phenyl)methyl)carbamate, 2.8 parts of N,N-diethylethanamine and 94 parts of N,N-dimethylformamide was stirred over weekend at 70° C. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The desired fractions were collected and the eluent was evaporated, yielding 8.7 parts (80.7%) of (1,1-dimethylethyl) [[4-[[2-[2-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-1-piperazinyl]acetyl]amino]-3,5-dichlorophenyl]methyl]carbamate as a residue (int. 102).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:13]([N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])[CH2:14][C:15](O)=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:42][OH:43]>O1CCCC1>[OH:43][NH:42][C:15](=[O:16])[CH2:14][CH:13]([C:7]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH:2]([CH3:3])[CH3:1])[CH:6]=1)[N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC(C)C
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2C(=O)c3ccccc3C2=O)cc1OC(C)C
Yield: 68.5 %

Procedure:
N-Hydroxy-3-{3-(2-propoxy)-4-methoxyphenyl}-3-phthalimidopropionamide was prepared by the procedure of Example 1 from 3-{3-(2-propoxy)-4-methoxyphenyl}-3-phthalimidopropanoic acid (2.0 g, 5.2 mmol), carbonyldiimidazole (1.02 g, 6.29 mmol), and hydroxylamine hydrochloride (481 mg, 6.92 mmol) in tetrahydrofuran (10 mL) to afford N-hydroxy-3-{3-(2-propoxy)-4-methoxyphenyl}-3-phthalimidopropionamide as a white solid (1.42 g, 68% yield): mp, 119.0-121.0° C.; 1H NMR (DMSO-d6) δ1.24 (d, J=6.0 Hz, 3H, CH3), 1.243 (d, J=6.0 Hz, 3H, CH3), 3.12 (d, J=7.9 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 4.45-4.51 (m, 1H, CH), 5.68 (t, J=7.9 Hz, 1H, NCH), 6.91 (br s, 2H, Ar), 7.05 (br s, 1H, Ar), 7.84-7.86 (m, 4H, Ar), 8.79 (br s, 1H, OH), 10.60 (1H, NH); 13C NMR (DMSO-d6) δ21.80, 21.88, 34.19, 50.13, 55.49, 70.44, 112.18, 114.97, 120.12, 123.11, 131.13, 131.21, 134.59, 146.37, 149.51, 165.99, 167.62; Anal Calcd for C21H22N2O60.9H2O: C, 60.83; H, 5.79; N, 6.76. Found: C, 60.83; H, 5.73; N, 6.56; H2O, 4.02.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([F:17])[CH:9]=2)=[C:5]([CH3:7])[N:6]=1.[CH:18]1[N:22]=[CH:21][N:20]([C:23](N2C=NC=C2)=[O:24])[CH:19]=1>C(Cl)Cl>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:4]2[S:3][C:2]([NH:1][C:23]([N:20]3[CH:19]=[CH:18][N:22]=[CH:21]3)=[O:24])=[N:6][C:5]=2[CH3:7])=[CH:9][C:10]=1[F:17])(=[O:16])[CH3:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)c1ccc(-c2sc(N)nc2C)cc1F
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2sc(NC(=O)n3ccnc3)nc2C)cc1F

Procedure:
Dry DCM (10 ml) is added to 1-[4-(2-amino-4-methyl-thiazol-5-yl)-2-fluoro-phenyl]-ethanone (0.25 g, 1.0 mmol) and CDI (0.259 g, 1.6 mmol) and the mixture is heated at reflux for 4 hours. The resulting suspension is filtered and dried under vacuum to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[N:3]=1.[CH:8]1[C:21]2[CH:20]([C:22](Cl)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:22]([CH:20]2[C:21]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:23])[N:3]=1
Reactant: Cc1nc(N)no1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: Cc1nc(NC(=O)C2c3ccccc3Oc3ccccc32)no1

Procedure:
The title compound, white solid, m.p. 186° C. and MS: m/e=307 (M+) was prepared in accordance with the general method of example 44a from 5-methyl-[1,2,4]oxadiazol-3-ylamine and 9H-xanthene-carboxylic acid chloride.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=1)[C:8]([NH:10][C:11]1[S:12][C:13](Br)=[CH:14][N:15]=1)=[O:9])([CH3:3])[CH3:2].[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:31][SH:32]>>[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:31][S:32][C:13]1[S:12][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:17]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)=[N:15][CH:14]=1
Reactant: CC(C)Oc1cc(Oc2ccccc2)cc(C(=O)Nc2ncc(Br)s2)c1
Reactant: COC(=O)CCS
Product: COC(=O)CCSc1cnc(NC(=O)c2cc(Oc3ccccc3)cc(OC(C)C)c2)s1
Yield: 7.5 %

Procedure:
3-[2-(3-Isopropoxy-5-phenoxy-benzoylamino)-thiazol-5-yl-sulfanyl]-propionic acid methyl ester (30 mg) was prepared from 3-isopropyloxy-5-phenoxy-N-(5-bromothiazol-2-yl)benzamide (example 1, step 2) (370 mg, 0.85 mmol) and 3-mercaptopropionic acid methyl ester (0.5 mL, 4.0 mmol) in 7% yield following general procedure F.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][NH:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[C:22](Cl)(=[O:33])[O:23][CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=1.[OH-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12]([C:22]([O:23][CH2:24][C:25]2[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=2)=[O:33])[CH2:11]1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC1CNCCO1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture comprising of t-butyl(2-morpholin-2-ylethyl)carbamate (3 g, 13.03 mmol) in DCM (100 ml), was added saturated aqueous sodium bicarbonate solution (100 ml, 13.03 mmol), followed by 3,5-dichlorobenzyl carbonochloridate (3.43 g, 14.33 mmol). The biphasic mixture was stirred at room temperature for 2 hours. The resulting mixture was treated with 2M NaOH solution (50 ml). The reaction mixture was separated and the organic portion was dried over MgSO4 and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reaction time: 4 h

Procedure:
To a round-bottom flask was added 1-(4-(6-nitropyridin-3-yl)piperazin-1-yl)ethanone 111-3 (2.6 g, 10.4 mmol), Pd/C (0.5 g) and methanol (50 mL). The reaction was stirred for 4 hours under hydrogen atmosphere by attaching a hydrogen balloon. The reaction was flashed with nitrogen and the solid was removed by filtration. The solvent was removed by rotary evaporation. The crude product was purified by silica-gel flash chromatography to give 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 as an off-white solid. MS m/z 221.1 (M+1). 1H NMR 400 MHz (DMSO-d6) δ7.62 (d, 1H, J=2.8 Hz), 7.20 (dd, 1H, J1=8.8 Hz, J2=2.8 Hz), 6.41 (d, 1H, J=8.8 Hz), 5.47 (s, 2H), 3.55 (m, 4H), 2.93 (t, 2H, J=5.2 Hz), 2.86 (t, 2H, J=5.2 Hz), 2.03 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(O)cc23)cc1Cl
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCc4ccccn4)cc23)cc1Cl
Temperature: 120 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A starting compound (N-{2-chloro-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 2-(chloromethyl)pyridine hydrochloride (41 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 120° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ethyl acetate to give 54 mg (yield 55%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CC.C[O-].[Na+]>C(O)C>[CH3:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:9][CH2:8][O:7][C:5]([CH:4]([N:2]([CH3:3])[CH3:1])[CH3:10])=[O:6]
Reactant: CCCCCCCCCCCCO
Reactant: CCOC(=O)C(C)N(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCOC(=O)C(C)N(C)C

Procedure:
The ethyl 2-(N,N-dimethylamino)-propionate is preferably refluxed for about 2 hours in the presence of 10 percent stoichiometric excess 1-dodecanol and a catalytic amount of sodium methoxide (predissolved in toluene). During this process, the ethanol formed is removed from the reaction medium by azeotropic distillation. Following the reaction phase, the solids of the remaining mixture are filtered off, resulting in a DDAIP filtrate.
Reaction SMILES: Cl.C([N:5]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6]1)(=O)C.FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O.C(N(CC)CC)C>CC(C)=O>[F:27][C:26]([F:29])([F:28])[CH2:25][N:10]1[CH2:9][CH2:8][C:7]2([C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:5][CH2:6]2)[CH2:12][CH2:11]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(=O)N1CC2(CCNCC2)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: FC(F)(F)CN1CCC2(CC1)CNc1ccccc12

Procedure:
A mixture of 1-acetyl-1,2-dihydrospiro[indole-3,4′-piperidine] hydrochloride, [Chen et al. Tetrahedron Lett. 1996, 37(30), 5233-5234] (200 mg, 0.750 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.128 mL, 0.900 mmol), and triethylamine (0.522 mL, 3.75 mmol) in acetone (2 mL) was heated at reflux for 15 h. The mixture was allowed to cool, and the solvent removed under reduced pressure. The residue was taken up in CH2Cl2 (10 mL) and washed with saturated aqueous NaHCO3 (10 mL). The aqueous layer was further extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 50:50, to provide the title compound. MS: m/z=271 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][CH:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:19]1([NH:22][CH:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)[CH2:13][CH2:14]2)[CH2:21][CH2:20]1
Reactant: O=C1CCC(Nc2cccc3cnccc23)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1cc(NC2CCC(NC3CC3)CC2)c2ccncc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.7 %

Procedure:
4-(5-Isoquinolylamino)-1-cyclohexanone (intermediate 4) (60 mg) and cyclopropylamine (30 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was. stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (11 mg) and a syn-form compound (12 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[NH2:22][C:23]1[CH:39]=[CH:38][C:26]([O:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([C:34]([NH:36][CH3:37])=[O:35])[CH:29]=2)=[CH:25][CH:24]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[NH:22][C:23]2[CH:39]=[CH:38][C:26]([O:27][C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]([NH:36][CH3:37])=[O:35])[CH:29]=3)=[CH:25][CH:24]=2)=[CH:4][C:3]=1[C:18]([F:19])([F:20])[F:21]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 42.5 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
Phenyl 4-chloro-3-(trifluoromethyl)phenylcarbamate (100 g, 0.3174 mol) and 4-(4-aminophenoxy)-N-methylpicolinamide (77.14 g, 0.3174 mol) were dissolved in N,N-dimethyl formamide (300 ml) to obtain a clear reaction mass. The reaction mass was agitated at 40-45° C. for 2-3 hours, cooled to room temperature and diluted with ethyl acetate (1000 ml). The organic layer was washed with water (250 ml) followed by 1N HCl (250 ml) and finally with brine (250 ml). The organic layer was separated, dried over sodium sulfate and degassed to obtain solid. This solid was stripped with ethyl acetate and finally slurried in ethyl acetate (1000 ml) at room temperature. It was then filtered and vacuum dried to give (118 g) of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][NH:33][CH3:34])=[CH:26][CH:25]=2)=O)=[CH:18][CH:17]=1>>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1)=[C:22]([C:19]1[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=1)[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][NH:33][CH3:34])=[CH:26][CH:25]=1
Reactant: CNCCOc1ccc(C(=O)c2ccc(O)cc2)cc1
Reactant: O=C(CCCl)c1ccc2c(c1)CCO2
Product: CNCCOc1ccc(C(=C(CCCl)c2ccc3c(c2)CCO3)c2ccc(O)cc2)cc1
Yield: 72.4 %

Procedure:
According to general procedure of McMurry reaction as example 1, step D described, 3-chloro-1-(2,3-dihydrobenzofuran-5-yl)propan-1-one (0.85 g, 1.0 eq) was reacted with (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone (1.0 g, 1.0 eq) to give 1.2 g desired product (85%, Z/E=1/1). 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.02-7.54 (m, 6H), 6.70-6.84 (m, 5H), 4.22 (t, J=8.4 Hz, 2H), 4.03 (t, J=6.0 Hz, 2H), 3.48 (t, J=5.6 Hz, 2H), 2.89-3.05 (m, 4H), 2.42 (s, 3H), 2.13 (t, J=8.4 Hz, 2H); m/z=450[M+1]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])[O:3]1.[OH-].[Na+].Cl.[CH2:35]([OH:37])[CH3:36]>>[CH2:35]([O:37][C:2](=[O:1])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:4](=[O:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][S:19]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)(=[O:21])=[O:20])[CH3:36]
Reactant: CCO
Reactant: O=c1oc(-c2ccccc2NS(=O)(=O)c2ccc3ccccc3c2)nc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1ccccc1NC(=O)c1ccccc1NS(=O)(=O)c1ccc2ccccc2c1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A 1 L three-necked flask was charged with 67.7 g (0.158 mol) N-[2-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-2-naphthalenesulfonamide) and 200 g ethanol. Under stirring, 0.33 g sodium hydroxide (0.0083 mol, correlates to 5.2% of applied raw material) was added. After 15 minutes, the reaction mixture was heated until reflux for 5 hours. Completion of the reaction was monitored by thin layer chromatography. After the 5 hours, the intermediate mixture was cooled to 20° C., and within 20 minutes 4.5 g of 10% hydrochloric acid solution (0.012 mol) was added drop wise. The precipitate consisted of tiny white crystals, and was stirred for 1 hour at room temperature, then filtered by suction, washed with first 150 ml ethanol, then 300 ml water and dried at 85° C. in a circulating air oven.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:41][S:42]([CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:44])=[O:43]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:51]3[CH2:50][CH2:49][N:48]([CH2:47][CH2:46][CH2:45][S:42]([CH3:41])(=[O:43])=[O:44])[CH2:53][CH2:52]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% isopropanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C39H51N4O4SCl2 [(M+H)+] 741.3003, observed 741.2998.