Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@:3]1([OH:34])[C:8](=[CH2:9])[CH2:7][C@H:6]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:4]12[CH3:5])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[C@H:12]([CH2:24]N(C1C=CC=CC=1)CC)[CH2:11]3)#[CH:2].Cl.O>C1COCC1>[C:1]([C@:3]1([OH:34])[C:8](=[CH2:9])[CH2:7][C@H:6]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:4]12[CH3:5])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[C:12](=[CH2:24])[CH2:11]3)#[CH:2]
Reactant: C#C[C@]1(O)C(=C)C[C@H]2[C@@H]3C[C@@H](CN(CC)c4ccccc4)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C#C[C@]1(O)C(=C)C[C@H]2[C@@H]3CC(=C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 8 h

Procedure:
17α-Ethynyl-17β-hydroxy-6β-(N-phenyl-N-ethylaminomethyl)-16-methyleneandrosta-4-en-3-one (Example 5) in THF (20 ml) are mixed. Degassed hydrochloric acid (6N, 55 ml plus 20 ml THF) are added. The mixture is stirred overnight at 20°-25° under nitrogen, at which time TLC shows the reaction to be complete. Water (110 ml) is added, the mixture filtered, the solids washed with 10% hydrochloric acid, twice with water, once with 5% sodium bicarbonate, and three times with water to neutrality. Solids were then dried under nitrogen overnight to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C@H:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[C:4]=1[C:28](OCC)=[O:29].C(O)(=O)C(O)=O.[CH2:39]([NH:41][NH2:42])[CH3:40]>O1CCOCC1>[CH2:39]([N:41]1[CH2:2][C:3]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[C:7](=[O:19])[NH:6][C@H:5]([C:20]3[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=3)[C:4]=2[C:28](=[O:29])[NH:42]1)[CH3:40]
Reactant: CCNN
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1
Agent: O=C(O)C(=O)O
Solvent: C1COCCO1
Product: CCN1CC2=C(C(=O)N1)[C@@H](c1ccc(C#N)cc1)NC(=O)N2c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
200 mg (0.393 mmol) of ethyl (4R)-6-(bromomethyl)-4-(4-cyanophenyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 6A) were dissolved in 1 ml of dioxane, 71 mg (0.472 mmol) of ethylhydrazine oxalate were added and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was then concentrated, and the residue that remained was purified by preparative HPLC (Method 10). The product fractions were combined and concentrated, and the solid that remained was dried under reduced pressure (Yield: 26.0 mg, 15% of theory).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(S([C:14]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:17]2[CH:26]=[C:27]([C:30]3[C:31]([C:54]4[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=4)=[N:32][N:33]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:34]=3)[CH:28]=[CH:29][C:16]=2[N:15]=1)(=O)=O)C>>[CH2:1]([NH:8][C:14]1[N:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:17]2[CH:26]=[C:27]([C:30]3[C:31]([C:54]4[CH:55]=[CH:56][C:57]([F:60])=[CH:58][CH:59]=4)=[N:32][N:33]([C:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:34]=3)[CH:28]=[CH:29][C:16]=2[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCS(=O)(=O)c1nc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cc2n1-c1ccc(F)cc1
Reactant: NCc1ccccc1
Product: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3nc(NCc4ccccc4)n(-c4ccc(F)cc4)c3c2)cc1
Temperature: 150 °C
Reaction time: 24 h

Procedure:
1 mL benzyl amine was added to 40 mg 2-(ethylsulfonyl)-1-(4-fluorophenyl)-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-1H-benzo[d]imidazole obtained in Example 138, and then stirred at 150° C. for 24 hours. The reaction product was purified by silica gel chromatography (hexane/ethyl acetate) to give 26 mg N2-benzyl-1-(4-fluorophenyl)-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-1H-benzo[d]imidazol-2-amine. This product was subjected to deprotection of the trityl group in the same manner as in Example 84 and then purified by NAM silica gel chromatography (ethyl acetate/hexane), to give 18 mg of the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1cccc(C=O)c1F
Product: COc1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1F

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-fluoro-3-methoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 517.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[CH:10][N:11]=[C:5]2[CH:4]=1)#[CH:2].C[Si]([N:16]=[N+:17]=[N-:18])(C)C.CN(C=O)C>[Cu]I.CO>[NH:16]1[CH:2]=[C:1]([C:3]2[CH:8]=[CH:7][N:6]3[CH:9]=[CH:10][N:11]=[C:5]3[CH:4]=2)[N:18]=[N:17]1
Reactant: C#Cc1ccn2ccnc2c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: c1cn2ccc(-c3c[nH]nn3)cc2n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 57.2 %

Procedure:
Combine 7-ethynyl-imidazo[1,2-a]pyridine (1.10 g, 7.74 mmol), copper (I) iodide (0.074 g, 0.387 mmol), and trimethylsilyl azide (1.53 mL, 11.61 mmol) in a 9:1 mixture of DMF:methanol (13.8 mL) in a pressure flask. Seal the flask with a Teflon screw cap and heat the reaction mixture to 100° C., stir overnight (15 hours), and cool to room temperature. Concentrate the mixture to dryness in vacuo. Slurry the resulting solid into dichloromethane and filter through Celite® 521. Concentrate the solution in vacuo to an orange solid. Purify by column chromatography (ethyl acetate→5% methanol in dichloromethane→8% methanol in dichloromethane) to afford product (0.82 g, 57%). MS(ES), m/z 186 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>>[F:33][C:32]([F:34])([F:35])[C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:21][CH:22]=2)=[CH:31][CH:30]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCBr)cc2)cc1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Product: O=C(O)COc1ccc(SCCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 4-(2-bromo-ethyl)-4′-trifluoromethyl-biphenyl (Compound 22B). MS m/z 487 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)=[C:12]([F:23])[CH:11]=2)=[CH:6][N:5]=[C:4]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:28])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.[Cu]I>[CH:20]1([CH2:19][O:18][C:13]2[C:14]([O:16][CH3:17])=[CH:15][C:10]([C:9]3[O:24][C:2]4[CH:3]=[C:4]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:28])[N:5]=[CH:6][C:7]=4[N:8]=3)=[CH:11][C:12]=2[F:23])[CH2:22][CH2:21]1
Reactant: COc1cc(C(=O)Nc2cnc(OC[C@H](C)NC(=O)OC(C)(C)C)cc2Cl)cc(F)c1OCC1CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(-c2nc3cnc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3o2)cc(F)c1OCC1CC1
Temperature: 150 °C
Reaction time: 1 h
Yield: 24.7 %

Procedure:
A suspension of tert-butyl ((2S)-1-((4-chloro-5-((4-(cyclopropylmethoxy)-3-fluoro-5-methoxybenzoyl)amino)pyridin-2-yl)oxy)propan-2-yl)carbamate (5.87 g), potassium carbonate (3.10 g) and copper(I) iodide (213 mg) in DMF. (40 mL) was stirred at 150° C. for 1 hr, and then at 160° C. for 3 hr. The reaction mixture was subjected to silica gel chromatography (NH, ethyl acetate), and washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.35 g).
Reaction SMILES: [NH2:1][C:2]1[C:33]([Cl:34])=[CH:32][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:35][CH3:36])[CH:3]=1.[CH:37](=O)[CH3:38].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:33]([Cl:34])=[CH:32][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:37][CH3:38])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1ccc(CNCCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(OC)cc1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(6-(4-methoxybenzylamino)hexyl)-piperidin-4-yl)methyl)benzamide (0.9 g) as starting compound, acetaldehyde (0.12 ml) and sodium cyanoborohydride (0.26 g) were reacted and treated in the same manner as in Example 136 to give 0.55 g of 4-amino-5-chloro-N-((1-(6-(N-ethyl-N-(4-methoxybenzyl)amino)hexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[CH2:26]([O:25][C:23]([N:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C@H:10]1[CH3:14])=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
To a solution of 1.50 g (R)-4-N-Boc-2-methyl-piperazine in 10 ml dichloromethane were added at 0° C. 2.29 ml triethylamine and 0.72 ml ethyl chloroformate. After 12 h the reaction mixture was diluted with dichloromethane and extracted with 0.1 M HCl and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and the crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13]2[N:18]3[C:19]([C:23](OCC)=[O:24])=[C:20]([CH3:22])[N:21]=[C:17]3[CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.O>CN(C=O)C>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][N:12]2[C:13]3[N:18]4[C:17](=[N:21][C:20]([CH3:22])=[C:19]4[C:23]2=[O:24])[CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(C)nc2cccc(NCCc3ccc(N)cc3)n12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2cccc3n(CCc4ccc(N)cc4)c(=O)c1n23
Temperature: 25 °C
Yield: 51.7 %

Procedure:
To a suspension of 80 mg (2.0 mmol) of 60% sodium hydride (dispension in oil) in 10 ml of DMF was added, while stirring at room temperature, 338 mg (1.0 mmol) of 5-[2-[4-(amino)phenyl]ethan-1-ylamino]-3-ethoxycarbonyl-2-methylimidazo[1,2-a]pyridine. The mixture was stirred for 30 minutes. The reaction mixture was poured into water, extracted with ethyl acetate. The extract was washed with an aqueous saline solution, dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to give 151 mg of the desired compound (51.7%, pale brown solid).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br>>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][C:2]([CH3:4])([CH3:3])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)C
Reactant: BrCCCCBr
Product: CCOC(=O)C(C)(C)CCCCBr

Procedure:
Using ethyl isobutyrate and 1,4-dibromobutane, the title compound was produced in the same manner as in Reference Example 6.
Reaction SMILES: CO.[C:3]([NH:11][C:12]1[CH:20]=[C:19]([CH:21]2[CH2:25][CH2:24][CH:23]=[CH:22]2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[C:3]([NH:11][C:12]1[CH:20]=[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cc(C2C=CCC2)ccc1C(=O)O)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(C2CCCC2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
5.0 mg of 5% palladium-carbon was added to a mixed solution of 1.0 mL of methanol and 0.5 mL of ethyl acetate containing 25 mg of 2-(benzamido)-4-(2-cyclopenten-1-yl)benzoic acid and stirred at room temperature under hydrogen atmosphere for 7 hours and then at 40° C. for 8 hours and stirred at 45° C. for 15 hours. Insoluble were removed by filtration and the solvent was evaporated under reduced pressure. Methanol was added to the obtained residue and a solid substance was separated by filtration to obtain 16 mg of 2-(benzamido)-4-cyclopentyl benzoic acid as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH3:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([CH3:28])[S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)4-(3-nitrobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[OH:17]O>C(O)(=O)C>[CH3:13][S:12]([C:10]1[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[C:3]([O:2][CH3:1])[CH:11]=1)=[O:17]
Reactant: COc1cc(SC)c([N+](=O)[O-])cc1C(=O)O
Reactant: OO
Solvent: CC(=O)O
Product: COc1cc(S(C)=O)c([N+](=O)[O-])cc1C(=O)O
Reaction time: 12 h

Procedure:
A 0.50 g portion of 2-methoxy-4-methylthio-5-nitrobenzoic acid was suspended in 5 ml of acetic acid, and 0.77 ml of 30% hydrogen peroxide aqueous solution was added thereto, followed by 12 hours of stirring. After completion of the reaction, the reaction solution was poured on crushed ice, and the thus precipitated product of interest was collected by filtration, washed with water and then dried under a reduced pressure to give 0.35 g of 4-methylsulfinyl-2-methoxy-5-nitrobenzoic acid.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)=[N+:2]=[N-:3].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[NH:19])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:1]=[N+:2]=[N-:3])[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:20])=[C:17]([NH2:18])[NH:19][C:17]=1[NH2:18])=[O:20])[CH3:13]
Reactant: [N-]=[N+]=Nc1ccccc1C=O
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1N=[N+]=[N-]
Yield: 46 %

Procedure:
Upon heating a solution of 7.3 g 2-azidobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamino-4-(2-azidophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 250° C (ethanol) is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][NH:5][C:6]1[C:11]([C:12]#[N:13])=[C:10]([CH3:14])[CH:9]=[C:8]([CH3:15])[N:7]=1.Cl[C:18]([O:20][CH3:21])=[O:19]>C1C=CC=CC=1>[C:12]([C:11]1[C:6]([N:5]([CH2:4][CH2:3][N:2]([CH3:16])[CH3:1])[C:18](=[O:19])[O:20][CH3:21])=[N:7][C:8]([CH3:15])=[CH:9][C:10]=1[CH3:14])#[N:13]
Reactant: COC(=O)Cl
Reactant: Cc1cc(C)c(C#N)c(NCCN(C)C)n1
Solvent: c1ccccc1
Product: COC(=O)N(CCN(C)C)c1nc(C)cc(C)c1C#N

Procedure:
To a solution of N,N-dimethyl-N'-(3-cyano-4,6-dimethyl-2-pyridyl)-1,2-diaminoethane (13.5 g, 62 mmol) in dry benzene (150 ml) is added methyl chloroformate (7.1 ml, 92 mmol) and then the resulting mixture is refluxed for 11/2 hours. This mixture is evaporated to dryness and the residue dissolved in water, washed with methylene chloride, made basic with sodium carbonate and the product extracted into methylene chloride. Upon evaporation of the solvent there is obtained 16.6 g of oily title B product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:25])[N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:14]=[C:15]([C:16]([OH:18])=O)[C:5]2=1.[CH3:26][NH:27][CH3:28].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]1[C:12](=[O:25])[N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:14]=[C:15]([C:16]([N:27]([CH3:28])[CH3:26])=[O:18])[C:5]2=1
Reactant: CNC
Reactant: Cn1c2ccc(F)cc2c2c(C(=O)O)cn(-c3ccccn3)c(=O)c21
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1cn(-c2ccccn2)c(=O)c2c1c1cc(F)ccc1n2C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2.5 g (7.4 mmol) of 6-fluoro-9-methyl-1-oxo-2-(pyridin-2-yl)-2,9-dihydro-1H-pyrido[3,4-b]indole-4-carboxylic acid and of 2.4 g (14.8 mmol) of N,N'-carbonyldiimidazole in 65 ml of N,N-dimethylformamide is stirred for 4 h. The reaction mixture is cooled and a large excess of liquefied dimethylamine is added. The mixture is stirred for 48 h at room temperature, poured into water and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulphate, and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate. The product is recrystallized from ethyl acetate.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:30])[CH:13]([NH:17][CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[C:21]([F:29])[CH:22]=[C:23]([F:28])[CH:24]=3)[CH2:19]2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH3:31][NH:32][CH3:33]>>[CH3:31][N:32]([CH3:33])[CH2:3][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:30])[CH:13]([NH:17][CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[C:21]([F:29])[CH:22]=[C:23]([F:28])[CH:24]=3)[CH2:19]2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:1])[CH3:5]
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)C=O)cn1
Reactant: CNC
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN(C)C)cn1

Procedure:
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted with dimethyl amine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 19.6, 26.2, 26.2, 26.3, 28.2, 28.3, 28.8, 29.6, 29.8, 36.6, 48.0, 52.3, 52.8, 58.9, 59.0, 60.3, 60.8, 70.0, 101.0, 104.6, 110.7, 131.2, 137.3, 159.8, 162.2, 172.4, 183.1, 183.9; MS m/z 448.4 (M+1).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:35][O:36][CH2:37][CH2:38]Br.[OH-].[Na+]>CN(C=O)C>[CH3:35][O:36][CH2:37][CH2:38][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: COCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCC(c2[nH]nc(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a stirred suspension of 5-(4-piperidyl)-4-(4pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) (500 mg, 1.2 mmol) in 12 mL of DMF was added Hunig's base (790 mg, 6.1 mmol) and 2-bromoethyl methyl ether (850 mg, 6.1 mmol). The solution was stirred at room temperature for 5 days. The solution was poured onto 2.5 N NaOH and was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water (3×100 mL) and brine (1×100 mL). The organic phase was dried over Na2SO4 and was filtered. The solvent was removed under reduced pressure to leave a solid. The solid was triturated and filtered to leave the title compound: 1HNMR (CDCl3) δ8.63 (d, J=4.23 Hz, 2 H), 7.28 (m, 4 H), 7.14 (d, J=4.43 Hz, 2 H), 3.57 (t, J=5.24 Hz, 2 H), 3.38 (s, 3 H), 3.14 (bd, J=10.1 Hz, 2 H), 2.79 (m, 1 H), 2.68 (t, J=5.04, 2 H), 2.08 (m, 4 H), 1.92 (m, 2 H). MS (M+H): 397 (base peak).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH:28]3[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]3)=[CH:24][NH:25]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH:28]3[CH2:33][CH2:32][CH:31]([N:4]4[CH2:5][CH2:6][CH2:7][N:1]([C:8]5[CH:9]=[CH:10][CH:11]=[C:12]6[C:17]=5[N:16]=[CH:15][CH:14]=[CH:13]6)[CH2:2][CH2:3]4)[CH2:30][CH2:29]3)=[CH:24][NH:25]2)=[CH:21][CH:20]=1
Reactant: O=C1CCC(c2c[nH]c3cc(F)ccc23)CC1
Reactant: c1cnc2c(N3CCCNCC3)cccc2c1
Product: Fc1ccc2c(C3CCC(N4CCCN(c5cccc6cccnc56)CC4)CC3)c[nH]c2c1
Yield: 89 %

Procedure:
The title compound was prepared according to Example 3, Step 4 except that 8-[1,4]diazepan-1-yl-quinoline was used instead of 1-(2-methoxy-phenyl)-[1,4]diazepane and 4-(6-fluoro-1H-indol-3-yl)-cyclohexanone was used in place of 4-(5-fluoro-1H-3-indolyl)-cyclohexanone. Yield: 89%; MS (ES) m/z (relative intensity): 443 (M++H, 100).
Reaction SMILES: C[O:2][C:3](=[O:14])[CH:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH2:5][OH:6].O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH:4]([CH2:5][OH:6])[C:3]([OH:14])=[O:2])=[CH:12][CH:11]=1
Reactant: COC(=O)C(CO)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a stirred solution of 2-(4-Chloro-phenyl)-3-hydroxy-propionic acid methyl ester (Preparation 243, 500 mg, 2.33 mmol) in THF (7 mL) was added a solution of lithium hydroxide monohydrate (244 mg, 5.82 mmol) in water (2 mL) dropwise at 0° C. and the resulting mixture stirred at room temperature for 1 hour. The reaction mixture was acidified (pH˜3) with 2N hydrochloric acid and extracted with DCM (3×20 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4) and evaporated in vacuo to afford the title compound as a white solid in 90% yield, 420 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].CN(C=O)C.[CH2:17]([S-:19])[CH3:18].[Na+]>O>[CH2:17]([S:19][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:18]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CC[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10.0 g (46.3 mmol) of 2-nitrobenzyl bromide were introduced into 100 ml of DMF at 0° C., 3.89 g (46.3 mmol) of sodium ethanethiolate were added in portions, and the mixture was stirred at RT for 4 h. It was diluted with water and extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 9/1) to result in 7.40 g (81% of theory) of the title compound.