Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2)=[O:23].[ClH:36]>CO.O1CCOCC1>[ClH:36].[Cl:36][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]12[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2)=[O:23]
Reactant: Cc1ccc(N2CCCN(C(=O)OC(C)(C)C)CC2)cc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(N2CCCNCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Hexahydro-4-[4-methyl-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]-phenyl]-1H-1,4-diazepine-1-carboxylic acid, 1,1-dimethylethyl ester (from Example 5c) was dissolved in methanol (5 ml) and hydrochloric acid (0.5 ml of a 4N solution in dioxane) was added. After stirring at room temperature for 14 h, the mixture was evaporated to ⅔ original volume under reduced pressure. Diethyl ether was gradually added to the solution and the resulting precipitate collected by filtration, washed with diethyl ether and dried in vacuo to afford the title compound as a solid (0.027 g)
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([C:28]([OH:30])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1.CC#N>O>[C:28]([C@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)([OH:30])=[O:29]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 17 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with D-tryptophan to provide the title compound in 17% yield as yellow needles (flash chromatography on SiO2, eluent MeCN, H2O, AcOH—20, 1, 0.3).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([N:10]2[C:18]3[CH:17]=[C:16]([C:19]4[CH:24]=[N:23][CH:22]=[C:21]([CH3:25])[N:20]=4)[N:15]=[CH:14][C:13]=3[CH:12]=[N:11]2)[N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([N:10]2[C:18]3[CH:17]=[C:16]([C:19]4[CH:24]=[N:23][CH:22]=[C:21]([CH3:25])[N:20]=4)[N:15]=[CH:14][C:13]=3[CH:12]=[N:11]2)[N:3]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(CO)c(F)n2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C=O)c(F)n2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.3 %

Procedure:
To [2-fluoro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-3-pyridyl]methanol (0.236 mmol; 79.5 mg) in dichloromethane (10 mL) was added DESS-MARTIN periodinane (0.355 mmol; 155 mg). The mixture as stirred at room temperature for 4 hours. The mixture was concentrated and the residue was purified on silica eluted with 0 to 100% EtOAc in DCM to afford 2-fluoro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyridine-3-carbaldehyde as a pale yellow solid (69.7 mg, 88%).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([CH2:8][C:9]1([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[O:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:18])=[O:7])C>O.C(O)C>[OH:7][C:6]([CH2:8][C:9]1([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[O:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:18])=[O:5]
Reactant: CCOC(=O)CC1(NC(=O)Nc2ccc(C)cc2)C(=O)Nc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(NC(=O)NC2(CC(=O)O)C(=O)Nc3ccccc32)cc1
Reaction time: 4 h
Yield: 27.2 %

Procedure:
A solution of 300 mg of potassium hydroxide (85%) in 2 ml of water was added to a solution of 0.35 g of (RS)-3-(ethoxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one in 10 ml of ethanol at room temperature, and the mixture was stirred for 4 hours, followed by concentration. The concentrate was diluted with water, and washed with chloroform. The aqueous layer was adjusted to pH 3 by addition of 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The resulting crude product was recrystallized from isopropyl alcohol to give 0.088 g (27%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH:4](Br)[CH2:5]Br.CCN(CC)CC.[CH2:16]([NH:23][CH2:24][CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][N:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:25][CH2:24][N:23]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8]
Reactant: COC(=O)C(Br)CBr
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
To the preheated solution (50° C.) of 2,3-dibromo-propionic acid methyl ester in toluene (40 ml) and Et3N (5.80 ml, 41.6 mmol), was added N,N′-dibenzyl-ethane-1,2-diamine (4.90 ml, 20.8 mmol) dropwise. Resulting white slurry was heated to reflux to a clear solution and the solution was stirred at reflux overnight. After cooled to room temperature, the reaction mixture was extracted with 2N HCl (ca. 500 ml) and the extract was neutralized with 4N NaOH. The aqueous layer was extracted with EtOAc three times. The organic layer was washed with brine, dried over MgSO4, and concentrated to give 1,4-dibenzyl-piperazine-2-carboxylic acid methyl ester (5.73 g, 84.8%) as a colorless oil: HPLC-MS (ESI): Calcd for C20H24N2O2[M+H]+ 325, found: 325.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].F[C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][N:15]=1>CN(C=O)C>[I:20][C:17]1[CH:18]=[CH:19][C:14]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:15][CH:16]=1
Reactant: Fc1ccc(I)cn1
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(I)cn2)cc1
Reaction time: 18 h

Procedure:
4-Methoxybenzyl alcohol (6.51 g, 47.1 mole) in 15 mL DMF was added to a stirring suspension of sodium hydride (1.973 g, 49.3 mmol) in DMF at 0° C. After 10 minutes a solution of 2-fluoro-5-iodopyridine (10 g, 44.8 mmol) in 15 mL DMF was added dropwise using an addition funnel. The reaction slowly reached room temperature, and was allowed to stir for 18 hours. The homogenous yellow solution was cooled again and quenched with about 50 ml of water. The suspension was then partitioned between ethyl acetate (200 mL) and water (150 mL). The aqueous was extracted a second time with ethyl acetate and the combined organic layers were washed with water three times and with brine twice. The organic layer was dried over sodium sulfate, filtered and evaporated. When the evaporation neared completion a white solid precipitated. Triturated with the addition of hexanes. The solid was filtered and dried on the filter. Repeated partial evaporation trituration and filtration of the resulting white solids gave the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][C:13](C)(C)[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.O1CCOCC1>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)Cc1cccc(C#N)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)Cc1cccc(C#N)c1

Procedure:
Combined tert-butyl 2-(3-cyanophenyl)acetate (500 mg, 2.301 mmol), ethanol (10 mL) and 4 N HCl in dioxane (0.288 mL, 1.151 mmol) and the solution heated at 60° C. for 22 h. The solution was concentrated in vacuo to give the title compound a yellow oil which was used without further purification. MS m/z 190 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ ppm 1.23-1.31 (m, 3 H) 3.65 (s, 2 H) 4.17 (q, J=7.1 Hz, 2 H) 7.40-7.47 (m, 1 H) 7.51-7.56 (m, 1H) 7.56-7.62 (m, 2 H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1.N#N.Cl.[CH:16]1[C:29]2[S:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:21][C:20]=2[CH:19]=[CH:18][C:17]=1[S:30]([NH:33][C@H:34]([C:42](Cl)=[O:43])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:41])[NH2:40])(=[O:32])=[O:31]>C(Cl)(Cl)Cl>[CH:16]1[C:29]2[S:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:21][C:20]=2[CH:19]=[CH:18][C:17]=1[S:30]([NH:33][C@H:34]([C:42]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH:4]1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:43])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:40])[NH2:41])(=[O:31])=[O:32]
Reactant: N=C(N)NCCC[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2)C(=O)Cl
Reactant: CCOC(=O)C1CC(C)CCN1
Agent: Cl
Agent: N#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CC(C)CCN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3.6 g of ethyl 4-methyl-2-piperidinecarboxylate in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N2 -(2-phenoxathiinylsulfonyl)-L-arginyl chloride hydrochloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 50ml of chloroform was added and the chloroform solution was washed twice with 25 ml of saturated sodium chloride solution, dried over Na2SO4 and evaporated in vacuo. The oily residue was washed with ether to give 3.5 g of powdery ethyl 1-[N2 -(2-phenoxathiinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](OCC)(=[O:23])[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16]>>[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:23])[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16]
Reactant: CCCCCCCCCCCCO
Reactant: CCOC(=O)C(O)c1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(O)c1ccccc1
Temperature: 60 °C
Yield: 62.3 %

Procedure:
A mixture of Novozym® 435 (2.21 g), molecular sieves (18.60 g), 1-dodecanol (3.76 g), and ethyl mandelate (3.61 g) in a 150 mL beaker was maintained at 60° C. in a convection oven for 28 hours. Upon work-up, 4.0 g of lauryl mandelate (56% yield) was obtained as a clear viscous liquid. The purity of the product was >95% as assessed by HPLC-DAD.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:20]([NH:22][CH3:23])=[O:21]>>[CH2:24]([C:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:20](=[O:21])[NH:22][CH3:23])[CH2:26][CH3:27])[CH3:25]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CCC(N)(CC)C(=O)NC
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (LC/MS): 360.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[C@H:20]12[CH2:26][C@H:23]([NH:24][CH2:25]1)[CH2:22][N:21]2[C:27]([CH3:31])([CH3:30])[CH2:28][OH:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:24]3[CH2:25][C@@H:20]4[CH2:26][C@H:23]3[CH2:22][N:21]4[C:27]([CH3:31])([CH3:30])[CH2:28][OH:29])[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)(CO)N1C[C@@H]2C[C@H]1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2C[C@@H]3C[C@H]2CN3C(C)(C)CO)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 18 h
Yield: 13.8 %

Procedure:
A solution of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (235 mg, 0.83 mmol), (2-(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl-2-methylpropan-1-ol (168 mg, 0.99 mmol) and molecular sieves (4 Å, powdered, 1 g) in DCE (10 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (265 mg, 1.25 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 90:10) to afford the title compound as a tan solid (50 mg, 14%). LCMS (Method H): RT=2.39 min, M+H+=436.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[K+].[K+]>ClCCl>[C:26]1([NH:32][C:33]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=Nc1ccccc1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.1 %

Procedure:
A solution of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.371 g, 1.00 mmol) (from Example 1, Step 5) and phenylisocyanate (0.143 g, 1.2 mmol) in dichloromethane (20 mL) was treated with diisopropylethylamine (0.155 g, 1.2 mmol) and stirred at RT for 18 h. The reaction mixture was stirred with 10% K2CO3 for 1 h and then partitioned after diluting with additional dichloromethane (200 mL). The combined organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (1% of the 1N NH3 in MeOH, in dichloromethane) to afford the title compound (100 mg, 22%) as a white solid after trituration with diethyl ether. MS (APCI 10V) AP+ 454.28; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (t, J=5.46 Hz, 2H) 2.46 (t, J=5.46 Hz, 2H) 3.29 (s, 3H) 3.46 (t, J=5.46 Hz, 2H) 3.54 (t, J=5.46 Hz, 2H) 6.37 (s, 1H) 6.89 (t, J=8.60 Hz, 1H) 7.03 (m, 2H) 7.12 (d, J=7.60 Hz, 1H) 7.19-7.22 (m, 3H) 7.38 (d, J=7.8 Hz, 1H) 7.41 (d, J=8.77 Hz, 2H) 8.20 (dd, J=8.8 Hz, 2.8 Hz, 1H) 8.50 (s, 1H) 8.55 (s, 1H).
Reaction SMILES: [CH2:1]1[N:9]2[CH:4]([NH:5][S:6](=[O:16])(=[O:15])[C:7]3[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=32)[CH2:3][CH2:2]1.[CH3:17][N:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[S:19]([CH3:22])(=[O:21])=[O:20].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:16]=[S:6]1(=[O:15])[C:7]2[CH:13]=[C:12]([O:14][C:27]3[CH:28]=[CH:29][C:24]([CH2:23][N:18]([CH3:17])[S:19]([CH3:22])(=[O:20])=[O:21])=[CH:25][CH:26]=3)[CH:11]=[CH:10][C:8]=2[N:9]2[CH2:1][CH2:2][CH2:3][CH:4]2[NH:5]1
Reactant: CN(Cc1ccc(B(O)O)cc1)S(C)(=O)=O
Reactant: O=S1(=O)NC2CCCN2c2ccc(O)cc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(Cc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1)S(C)(=O)=O
Reaction time: 8 h

Procedure:
A suspension composed of 5.74 mg (3.37 mmol) of 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4 ]benzothiadiazin-7-ol 5,5-dioxide, 926 mg (4.04 mmol) of (4-{[methyl(methylsulphonyl)amino ]methyl}phenyl)boronic acid, 920 mg (5.06 mmol), of copper(II) acetate, 817 μl (10.10 mmol) of pyridine and about 4 g of 4 Å molecular sieve in 50 ml of CH2Cl2 is stirred overnight. The reaction mixture is filtered, rinsing with CH2Cl2/MeOH (1/1). The filtrate is concentrated and then directly placed on a silica column which is eluted with a CH2Cl2/MeOH 95/5 system. The fractions containing the expected product are combined and evaporated, and the residue is taken up in ethyl ether. After filtering off the solid, the title product is recovered in the form of white powder.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[CH:40]=[CH:39][C:16]([C:17]([NH:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([C:27]([F:36])([C:32]([F:35])([F:34])[F:33])[C:28]([F:31])([F:30])[F:29])=[CH:22][C:21]=2[CH2:37][CH3:38])=[O:18])=[CH:15][CH:14]=1.O.NN>C(O)C.O>[NH2:3][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([C:27]([F:36])([C:28]([F:29])([F:30])[F:31])[C:32]([F:33])([F:34])[F:35])=[CH:22][C:21]=2[CH2:37][CH3:38])=[O:18])=[CH:39][CH:40]=1
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CN)cc1
Temperature: 60 °C

Procedure:
4-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoro propan-2-yl)-6-methylphenyl]benzamide (0.80 g) was dissolved in ethanol (20 ml). To the solution, hydrazine monohydrate (0.28 g) was added and the mixture was stirred under heating at 60° C. for 4 hours. After adjusting to room temperature, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with a saturated sodium bicarbonate solution and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain 4-(aminomethyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl] benzamide as a crude product (0.63 g). Without further purification, the crude product was used for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:14](OCC)(=O)[CH2:15]C(C)=O.P(Cl)(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14]([CH3:15])=[CH:12][C:11]([OH:13])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=O)NNc1ccc(Cl)c(Cl)c1
Solvent: ClP(Cl)Cl
Product: Cc1cc(O)nn1-c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 41.3 %

Procedure:
To a mixture of (V) (5.0 g, 22.8 mmol) and ethyl acetoacetate (2.97 g 22.8 mmol) was slowly added PCl3 (3.13 g, 22.8 mmol). The mixture was warmed to 50° C. for 1.5 h, poured into ice water (150 ml), and the resulting precipitate was collected on a sintered glass funnel and recrystallized from EtOH to yield (VI) (2.29 g, 41%) as white crystals, mp 208-211° C. (lit. 208-209° C.), TLC CHCl3/MeOH 9:1.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([OH:10])[CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+].Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)[N:17]=[C:16]([NH:30][CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[N:15]=1>C1C=CC=CC=1>[Cl:29][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[O:27][CH3:28])[NH:20][C:18]1[N:17]=[C:16]([NH:30][CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[N:15]=[C:14]([O:10][CH:6]2[CH2:7][CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5]2)[N:19]=1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: CC(=O)N1CCCC(O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(OC3CCCN(C(C)=O)C3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of N-acetyl-3-hydroxypiperidine (0.335 g, 2.27 mmol) and sodium hydroxide (95 mg, 2.27 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.3 g, 0.78 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography to afford the title compound E20 as an off-white solid (0.35 g, 91%). mp 138–140° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B═CH3CN], Gradient elution program: T/% B=0/60, 10/60,25/80, 40/80, 45/60, 50/60; 268 mn, Rt 17.20 min, 91.70% purity; MS (CI): m/z 489 (M+, 100).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([C:23](O)=[O:24])[N:14]=1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:23]([C:15]3[N:14]=[CH:13][C:22]4[C:17]([CH:16]=3)=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:24])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2ccccc2cn1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and isoquinoline-3-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 7.93 (d, J=1.4 Hz, 1H), 8.24 (d, J=1.7 Hz, 1H). MS (DCI/NH3) m/z 308. Anal. Calculated for C19H21N3O.HCl: C, 66.37; H, 6.45; N, 12.22. Found: C, 47.6; H, 5.89; N, 8.71.
Reaction SMILES: [NH2:1][C:2]1[C:32]([N:33]([CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])[CH3:34])=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[C:10]([NH:12][C:13]1[CH:18]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:16]=[C:15]([F:25])[CH:14]=1)=[O:11])=[O:5].[CH:41](OCC)(OCC)OCC>>[F:25][C:15]1[CH:14]=[C:13]([NH:12][C:10]([C:9]2[CH:8]=[C:7]([N:6]3[C:4](=[O:5])[C:3]4[C:2](=[C:32]([N:33]([CH2:35][CH2:36][CH2:37][N:38]([CH3:39])[CH3:40])[CH3:34])[CH:31]=[CH:30][CH:29]=4)[N:1]=[CH:41]3)[CH:28]=[CH:27][CH:26]=2)=[O:11])[CH:18]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:16]=1
Reactant: CN(C)CCCN(C)c1cccc(C(=O)Nc2cccc(C(=O)Nc3cc(F)cc(N4CCOCC4)c3)c2)c1N
Reactant: CCOC(OCC)OCC
Product: CN(C)CCCN(C)c1cccc2c(=O)n(-c3cccc(C(=O)Nc4cc(F)cc(N5CCOCC5)c4)c3)cnc12

Procedure:
Using an analogous procedure to that described in Example 1, 3-{2-amino-3-[N-(3-dimethylaminopropyl)-N-methylamino]benzamido]-N-(3-fluoro-5-morpholinophenyl)benzamide was reacted with triethyl orthoformate. The reaction product was purified by column chromatography on an isolute SCX ion exchange column using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound Mass Spectrum: M+H+559.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Cl[C:14](Cl)(Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21]>C(Cl)(Cl)Cl>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:14](=[N:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: Clc1ccccc1C(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(N=C(Nc2ccc(C(=O)OCC)cc2)c2ccccc2Cl)cc1

Procedure:
N,N'-Bis(4-ethoxycarbonylphenyl)-2-chlorobenzamidine (10) was prepared from ethyl 4-aminobenzoate and α,α,α,2-tetrachlorotoluene; tan solid: mp 98°-108° C. 1H-NMR (CDCl3) 8.3-6.4 (m, 13H), 4.2 (q, 4H, J=7 Hz); IR (CHCl3) 3360, 1695, 1600, 1580; MS (m/e) 450, 452 (M+), 286 (base).