Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[C:18](Cl)[CH:17]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:23]([NH:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][S:28]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([C:18]2[CH:17]=[C:16]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:14]=[C:13]([CH3:15])[N:12]=3)[CH:21]=[CH:20][N:19]=2)[CH:36]=1)(=[O:30])=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
3-{4-[4-(3,4-Dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 4-(3,4-dichloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-methyl-pyrimidine (example E.63) (0.35 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light brown solid (0.54 g), which was subsequently deprotected.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]C(=O)OC(C)(C)C)=[CH:18][CH:17]=1)=[O:3].Cl.CCOCC>C(Cl)Cl>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][NH:14][C:9]2[C:8]3[C:13](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=[CH:6][CH:7]=3)[N:12]=[CH:11][N:10]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CNc2ncnc3c(C(N)=O)cccc23)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: NC(=O)c1cccc2c(NCc3ccc(N)cc3)ncnc12
Yield: 95 %

Procedure:
The title compound was prepared as light yellow solid in 95% yield by treating tert-butyl [4-({[8-(aminocarbonyl)quinazolin-4-yl]amino}methyl)phenyl]carbamate with 2N HCl/ether in DCM overnight. The precipitate was filtered, washed with ether and dried. Mass: M+H+: 294.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][CH:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[CH3:26])[C:13]21[C:34]1[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=1)[NH:28][C:27]2=[O:36].[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C>CN(C=O)C>[Cl:35][C:31]1[CH:30]=[C:29]2[NH:28][C:27](=[O:36])[C:13]3([CH:12]([C:6]4[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:17][C:16](=[O:18])[NH:15][CH:14]3[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[CH3:26])[C:34]2=[CH:33][CH:32]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCN)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCNS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
At 0° C., to a mixture of racemic (2′S,3S,4′R)-4′-[2-(2-amino-ethoxy)5-chloro-phenyl]-6-chloro-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.076 mmol) and methanesulfonyl chloride (85 mg, 0.76 mmol) in DMF (1 mL) was added triethylamine slowly (75 mg, 0.76 mmol). After stirring for 0.5 h, the mixture was filtered, concentrated and the residue was purified by Prep-HPLC to give title compound as a white solid (20 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[CH3:27][C:28]1([CH3:38])[CH2:33][NH:32][C@H:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:30][O:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:32]2[CH2:33][C:28]([CH3:27])([CH3:38])[O:29][CH2:30][C@H:31]2[C:34]([O:36][CH3:37])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: COC(=O)[C@@H]1COC(C)(C)CN1
Product: CCOC(=O)C1=C(CN2CC(C)(C)OC[C@H]2C(=O)OC)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 26.5 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.76 g, 1.52 mmol) was reacted with (S)-methyl 6,6-dimethylmorpholine-3-carboxylate (0.26 g, 1.52 mmol) according to the procedure as described in Example 24 to give the title compound as yellow oil (0.24 g, 27%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH2:14][N:12]2[CH2:13][C@@H:5]([CH2:6][C@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C@@:28]56[C@@H:39]([N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[C@@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:33]3([CH2:51][CH3:52])[CH:34]=[CH:35][CH2:36][N:31]([C@H:32]53)[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[CH2:10][CH2:11]2)[CH:4]=1.C[OH:60]>>[CH3:1][CH2:2][C@@:3]1([OH:60])[CH2:14][N:12]2[CH2:13][C@H:5]([CH2:6][C@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C@:28]56[C@@H:32]7[C@:33]([CH2:51][CH3:52])([C@@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@@H:39]5[N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[CH:34]=[CH:35][CH2:36][N:31]7[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:9]=3[CH2:10][CH2:11]2)[CH2:4]1
Reactant: CO
Reactant: CCC1=C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Product: CC[C@]1(O)C[C@@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Reaction time: 0.5 h
Yield: 1 %

Procedure:
To a 50 ml-reaction vessel were put 10 ml of MeOH, 1.9 mg of 3',4'-anhydrovinblastine (AVLB), and 1 ml of a MeOH solution of FeCl3 (1.2M), and the mixture was stirred for 30 min. under cooling with ice, while air was bubbled. Following addition of 9 mg of NaBH4, the mixture was stirred for additional 30 min. Then, 2 ml of 25% aqueous ammonia and 20 ml of water were added to make the solution basic. The products were extracted 3 times with 30 ml each of ethyl acetate. The extracts were combined and evaporated to dryness under reduced pressure at 40° or less. The resulting sample was analyzed by HPLC under the same condition of AVLB as well as less than 1% yield of vinblastine (VLB) and leurosidine (LEU) were obtained.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:18])[C:16]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:18])[C:16]=1[N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 82.2 %

Procedure:
General procedure C (See Example 1) was followed using isonipecotamide (380 mg, 3.0 mmol), 3,4,5-trichloropyridine (600 mg, 3.3 mmol), triethylamine (0.84 mL, 6.0 mmol) and NMP (18 mL). The crude product was purified by flash column chromatography on silica gel (CH2Cl2/EtOH, 95:5-91:9) to furnish the title compound as a white solid (0.676 g, 83%); LC-MS (ESI, 4 min) Rt 1.46 min, m/z 274 (100%, [M+H]+); m/z (ESI) C11H13N3OCl2 requires 273.0436, found [M+H]+ 273.0446.
Reaction SMILES: F[C:2]1[N:25]=[C:24](F)[C:23]([I:27])=[CH:22][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH2:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>CN(C=O)C>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH:38][C:24]1[N:25]=[C:2]2[C:3]([C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][N:13]2[CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[CH2:20][CH3:21])=[CH:22][C:23]=1[I:27]
Reactant: CN(C)CCN
Reactant: CCOC(=O)C(=CNC[C@@H]1CCCN1CC)C(=O)c1cc(I)c(F)nc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C[C@@H]2CCCN2CC)c2nc(NCCN(C)C)c(I)cc2c1=O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
(S)-ethyl 2-(2,6-difluoro-5-iodonicotinoyl)-3-((1-ethylpyrrolidin-2-yl)methylamino)acrylate (Intermediate 38, 0.360 g, 0.73 mmol) was taken up in DMF (5 mL), K2CO3 (0.303 g, 2.19 mmol) was added and reaction mixture was heated to 90° C. for 15 min. The reaction mixture cooled to room temperature and N1,N1-dimethylethane-1,2-diamine (0.080 mL, 0.73 mmol) was added and stirred for 15 min. The reaction mixture was quenched with water and extracted with EtOAc 3 times. The combined organics were washed with brine two times, dried over Mg2SO4, and the solvent removed. Crude product was carried on without purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:21][CH3:22])=[O:4].[CH3:24][NH:25][CH3:26]>>[CH3:24][N:25]([CH3:26])[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[C:8](=[C:9]([CH2:21][CH3:22])[CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CCc1cccc2c(-c3ccccc3)c(C(=O)OC)c(Cl)nc12
Reactant: CNC
Product: CCc1cccc2c(-c3ccccc3)c(C(=O)O)c(N(C)C)nc12

Procedure:
The title compound was prepared in analogy to example 43 step E from 2-chloro-8-ethyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 43 step D) and dimethylamine (40% in water). Yellow solid. MS (ESI): 321.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:24])([CH3:23])[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[I-:25].[Na+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[CH3:23][C:14]1([CH3:24])[O:13]/[C:12](=[C:6]2/[C:7](=[O:11])[NH:8][C:9]3[C:5]/2=[CH:4][CH:3]=[C:2]([I:25])[CH:10]=3)/[CH:16]=[C:15]1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(Br)ccc32)C=C1N1CCOCC1
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(I)ccc32)C=C1N1CCOCC1
Temperature: 110 °C

Procedure:
To a heavy-wall pressure tube were added (3E)-6-bromo-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-1,3-dihydro-2H-indol-2-one (1.6 g, 4.09 mmol), copper (I) iodide (39 mg, 0.20 mmol), sodium iodide (1.23 g, 8.18 mmol), rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (58 mg, 0.41 mmol), and 20 mL of anhydrous 1,4-dioxane. The mixture was purged with nitrogen, sealed and heated in 110° C. bath for 3 days. The mixture was poured into 200 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude product, (3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-6-iodo-1,3-dihydro-2H-indol-2-one, as a brown solid. Yield: 2.1 g. This crude material was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:7][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14].C(N(CC)CC)C>O1CCCC1>[C:1]([OH:5])(=[O:7])[C:2]([CH3:4])=[CH2:3].[OH:7][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14]
Reactant: C=C(C)C(=O)Cl
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)O

Procedure:
Methacryloyl chloride (0.1 mol) in 25 ml of tetrahydrofuran was added dropwise with stirring and ice cooling to the solution of N-hydroxysuccinimide (0.1 mol) and triethylamine (0.1 mol) in 100 ml of tetrahydrofuran. After 1 hour of stirring at room temperature the precipitate is removed and filtrate is evaporated in vacuum. The residue was crystallized from methanol to give the product with 75% yield. M.P. 102-104° C.; M.p. lit. 103° C. (H.-G. Batz et al. Angew. Chem. Intern. Edit., 1972, v.11, N12, 1103-1104).
Reaction SMILES: [CH3:1][OH:2].[O:3]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4]1>>[CH3:1][O:2][CH2:4][CH:5]([OH:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CO
Reactant: CCCCCCCCCCC1CO1
Product: CCCCCCCCCCC(O)COC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The same reactor that was used in Production Example 5 was charged with 64 g (2 mol) of methanol and 2 g of boron trifluoride diethyl ether complex and then the mixture was raised to 60° C. Then, 184.3 g (1 mol) of 1,2-epoxydodecane was added dropwise to the mixture over one hour and the resulting mixture was kept as it was for 3 hours. The reaction was terminated just after confirming that 1,2-epoxydodecane left unreacted was less than 1% by gas chromatography and then the reaction mixture was cooled. Thereafter, methanol was removed in the same manner as in Production Example 5 to obtain 2-hydroxydodecyl methyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2Cl)CC1
Reactant: Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2-c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 79.2 %

Procedure:
To a stirred solution of (88) (142 mg, 0.48 mmol) in dioxane (10 mL) was added phenylboronic acid (78) (87 mg, 0.71 mmol), Na2CO3 (152 mg, 1.4 mmol) and H2O (2 mL). The reaction mixture was degassed with N2 and then PdCl2(dppf) (35 mg, 0.05 mmol) was added. The reaction mixture was stirred at 80° C. for 12 h. The reaction mixture was left to reach RT and filtered through a pad of CELITE® and the filter cake was washed with CH2Cl2 (20 mL×3). The combined filtrates were evaporated in vacuo and the residue was purified by column chromatography ((EtOAc:Petrol ether=1:1) to give 4-(3-Phenyl-pyrazin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (89) (128 mg, 0.38 mmol, 80% yield).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:18]([O:21][CH3:22])([CH3:20])[CH3:19])C1C=CC=CC=1>CO.[Pd]>[CH3:22][O:21][C:18]([CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1)([CH3:20])[CH3:19]
Reactant: COC(C)(C)C1c2ccccc2CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(C)(C)C1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
10% palladium-supported carbon (300 mg) was added to a solution of 2-benzyl-1-(1-methoxy-1-methylethyl)-1,2,3,4-tetrahydroisoquinoline (1.17 g) in MeOH (12 mL). The reaction material was stirred under a hydrogen atmosphere at room temperature for 8 hours. The reaction liquid was filtered through celite and the filtrate was concentrated under reduced pressure to obtain 1-(1-methoxy-1-methylethyl)-1,2,3,4-tetrahydroisoquinoline (770 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[OH-:14].[Na+]>CN1CCCC1=O>[Cl:1][C:2]1[C:10]([F:11])=[C:9]([Cl:12])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:14]
Reactant: [OH-]
Reactant: O=C(O)c1cc(Cl)c(F)c(Cl)c1F
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(O)c1cc(Cl)c(F)c(Cl)c1O
Temperature: 130 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
2.27 g (0.01 mole) of 3,5-dichloro-2,4-difluorobenzoic acid, 1.62 g (0.04 mole) of powdery 99% sodium hydroxide and 20 ml of 1-methyl-2-pyrrolidone were fed into a 100-ml four-necked flask provided with a thermometer, a stirrer and a reflux condenser. The mixture was stirred at 130° C. for 2 hours to give rise to a reaction. Then, the same post-treatment as in Example 2 was conducted to obtain 2.07 g of 3,5-dichloro-4-fluorosalicylic acid. The isolated yield was 91.4% relative to the 3,5-dichloro-2,4-difluorobenzoic acid used.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(I)c3)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(I)c4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 690.2 (M+H)+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].O.[Cl-].[C:14]1([N+:20]#[N:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:14]1([NH:20][N:21]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)CC(=O)OCC(C)C
Reactant: N#[N+]c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(=O)C(=NNc1ccccc1)C(=O)OCC(C)C
Yield: 88.1 %

Procedure:
15.8 g (0.1 mol) of i-butyl acetoacetate, 12 g (0.146 mol) of CH3 COONa, 20 ml of water, 75 ml of ethanol and a solution of 0.1 mol of phenyldiazonium chloride were treated as described in preparation 2. The precipitated solid was filtered an dried in vacuo yielding 23.1 g of the title compound. M.p.=45°-50° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23](/[CH:25]=[CH:26]/[C:27]1([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:31][CH2:30][CH2:29][CH2:28]1)#[N:24].C(/C=C\C1(CNC(=O)OC(C)(C)C)CCCC1)#N.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:23]([CH2:25][CH:26]([C:27]1([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH2:30][CH2:29][CH2:28]1)[N:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1)#[N:24]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC(C)(C)OC(=O)NCC1(/C=C/C#N)CCCC1
Agent: CC(C)(C)OC(=O)NCC1(/C=C\C#N)CCCC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NCC1(C(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (355 mg, 1.12 mmol) and tert-butyl (1-[(E)-2-cyanovinyl]cyclopentylmethyl)carbamate and tert-butyl (1-[(Z)-2-cyanovinyl]cyclopentylmethyl)carbamate as a mixture of isomers (329 mg, 1.31 mmol) in ACN (10 mL) was added DBU (0.168 mL, 1.12 mmol). The resulting mixture was stirred at ambient temperature for 3 hours followed by heating to 60° C. for 2.5 hours. The ACN was removed in vacuo and the resulting residue was purified by flash column chromatography (eluting with 0-55% ethyl acetate in hexanes) to afford the product (350 mg, 55%).
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=O)[O:11][C:9](=[O:10])[C:8]2=[CH:14][CH:15]=1.Cl>C(O)C>[Br:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:14][CH:15]=1)[C:9](=[O:10])[NH:3][NH:2][C:12]2=[O:11]
Reactant: NN
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1[nH][nH]c(=O)c2cc(Br)ccc12
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Hydrazine monohydrate (2 ml, 33.0 mmol) was added to a suspension of 4-bromophthalic anhydride (7.5 g, 33.0 mmol) in ethanol (70 ml) and the resulting mixture was stirred at 90° C. for 24 hr. The volume of the reaction mixture was then reduced to half volume under reduced pressure and the residue was treated 0.5 N aq. HCl (20 mL). The title compound precipitated as a white solid and was collected by filtration (4.86 g, 61%); LRMS ESI+ (M+H)+ 241.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.C([O-])(=O)C.[Na+].Cl.C(OC(=O)[C@H](CS)N)C.C(Cl)Cl>C(O)C>[OH:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[C:14](=[CH:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][CH2:10]2)[CH2:19]1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CC(=O)[O-]
Agent: CCOC(=O)[C@@H](N)CS
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: C[C@@]12CCC[C@H]1[C@@H]1CC=C3C[C@@H](O)CC[C@]3(C)[C@H]1CC2

Procedure:
Following the procedure described by Djerassi (C. Djerassi, N. Crossley and M. A. Kielczewski, J. Org. Chem. 27, 1112, 1962), dehydroepiandrosterone (2.88 g, 10 mmol) is dissolved in anhydrous ethanol, sodium acetate is added followed by L-cysteine ethyl ester hydrochloride (18g, 100 mmol) and the mixture is heated overnight under an argon atmosphere. The reaction mixture is then evaported under vacuum. Methylene chloride is added to precipitate excess of L-cysteine ethyl ester hydrochloride. The solution is then filtered and the filtrate is washed twice with water, dried on magnesium sulfate, filtered and evaporated under vacuum. The residue is triturated with ethanol to give crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:42])=[O:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:50][CH2:49]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:31])([CH3:30])[C:32]#[N:33])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-methanesulfonyl-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 696.3 [(M+H)+]