Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:19]([OH:21])=O)[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[I:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[C:19](=[O:21])[NH:34][C:33]2[CH:35]=[CH:36][C:30]([I:29])=[CH:31][CH:32]=2)=[CH:8][CH:9]=1
Reactant: Nc1ccc(I)cc1
Reactant: COC(=O)c1ccc(CC(C(=O)O)c2ccc(O)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CC(C(=O)Nc2ccc(I)cc2)c2ccc(O)cc2)cc1
Reaction time: 14 h
Yield: 63.8 %

Procedure:
To a stirred suspension of 4-[2-carboxy-2-(4-hydroxy-phenyl)-ethyl]-benzoic acid methyl ester (Step C, 1.5 g, 5.0 mmol) in anhydrous CH2Cl2 (10 mL), was added oxalylchloride (1.57 g, 12.5 mmol) at rt, the reaction mixture was stirred for 14 h. The reaction mixture was concentrated under reduced pressure and azeotroped with CH2Cl2 (2×10 mL) dried under vacuum for 3 h, The crude acid chloride (1.8 g, 5.66 mmol) was treated with 4-iodoaniline (1.48 g, 6.79 mmol) and N,N-diispropylethylamine (3.0 mL, 16.9 mmol) in CH2Cl2 at 0° C. The reaction mixture was stirred for 14 h at rt and the reaction mixture was concentrated under reduced pressure. The mixture was extracted with ethyl acetate (100 mL) and the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was treated with CH2Cl2 to get solid compound, which was filtered and washed with CH2Cl2 to give 4-[2-(4-hydroxy-phenyl)-2-(4-iodo-phenyl-carbamoyl)-ethyl]-benzoic acid methyl ester as a yellowish solid (1.6 g, 64%): 1H NMR (300 MHz, DMSO-d6): δ 10.05 (s, 1H, NH), 9.28 (s, 1H, OH), 7.81 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.7 Hz, 2H), 7.31 (t, J=8.4 Hz, 4H), 7.18 (d, J=8.4 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H), 3.85 (t, J=6.9 Hz, 1H), 3.77 (s, 3H), 3.40-3.36 (m, 1H), 2.95 (dd, J=6.0, 12.9 Hz, 1H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate/hexanes (1:2); Rf=0.5.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:22])([F:21])[S:10]([O:13]S(C(F)(F)F)(=O)=O)(=[O:12])=[O:11].O[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[N:28]([CH3:34])[C:27]2([CH3:36])[CH3:35].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:8][C:9]([F:22])([F:21])[S:10]([O:13][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[N:28]([CH3:34])[C:27]2([CH3:36])[CH3:35])(=[O:12])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CN1C(=O)c2ccc(O)cc2C1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1C(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2C1(C)C
Reaction time: 1 h

Procedure:
With cooling with ice, 0.192 mL of triethylamine and 0.174 mL of trifluoromethanesulfonic acid anhydride were added to 4.3 mL of a chloroform solution of 165 mg of 5-hydroxy-2,3,3-trimethylisoindolin-1-one obtained in Production Example 49-2, and stirred for 1 hour with cooling with ice. 2 mL of aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The crude product was purified through silica gel column chromatography (chloroform) to obtain 257 mg of the entitled compound as a colorless solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=1.[N:21]#[C:22]Br.ClCCl>ClCCCl.O>[CH3:5][C:6]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:13])[C:7]=1[C:22]#[N:21]
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C)c2)cc1
Reactant: N#CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc(C)c2C#N)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Aluminium chloride (19.4 g, 0.15 mol) is added all at once to a solution of 3-methyl-1-(4-methylbenzenesulphonyl)-1H-pyrrole (13.0 g, 55.3 mmol) in 1,2-dichloroethane (230 mL) at ambient temperature. After stirring for 20 minutes, cyanogen bromide (11.11 g, 0.10 mol) is added in portions over a period of 20 minutes. After 4.5 hours, an additional amount of cyanogen bromide (1.94 g, 18.3 mmol) is added. After stirring for 17 hours at ambient temperature, the reaction mixture is poured slowly into a mixture of dichloromethane (300 mL) and water (600 mL) cooled to 0° C. The resulting mixture is stirred for 1 hour. Subsequently the phases are separated and the aqueous phase is extracted with dichloromethane (3×150 mL). The combined organic phases are washed with water (2×150 mL) and brine (150 mL). The organic phase is dried over Na2SO4, filtered and concentrated in vacuo to obtain the expected compound in the form of a solid.
Reaction SMILES: [CH:1]([C:3]1[C:4]([N:28]2[CH:40]=[CH:39][N:31]3[C:32]4[CH2:33][CH2:34][CH2:35][CH2:36][C:37]=4[CH:38]=[C:30]3[C:29]2=[O:41])=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:25]=[C:19]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][N:18]3[N:17]=2)[C:12](=[O:26])[N:11]([CH3:27])[CH:10]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[C:4]([N:28]2[CH:40]=[CH:39][N:31]3[C:32]4[CH2:33][CH2:34][CH2:35][CH2:36][C:37]=4[CH:38]=[C:30]3[C:29]2=[O:41])=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:25]=[C:19]3[CH2:20][N:21]([CH3:24])[CH2:22][CH2:23][N:18]3[N:17]=2)[C:12](=[O:26])[N:11]([CH3:27])[CH:10]=1
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ccn6c7c(cc6c5=O)CCCC7)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ccn6c7c(cc6c5=O)CCCC7)c4CO)cn(C)c3=O)cc2C1
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a solution of 195g (120 mg, 0.22 mmol) in methanol (5 mL) at 0° C. was added sodium borohydride (25 mg, 0.66 mmol). The reaction mixture was stirred for 30 minutes. It was then quenched with water (1.0 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 195 (70 mg, 58%). MS-ESI: [M+H]+ 553.3. 1H NMR (500 MHz, CDCl3) δ 8.56 (d, J=5.0 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.49 (d, J=4.5 Hz, 1H), 7.43 (s, 1H), 7.07 (s, 1H), 6.97 (d, J=6.0 Hz, 1H), 6.67 (d, J=6.0 Hz, 1H), 5.70 (s, 1H), 5.08-5.06 (m, 1H), 4.51-4.49 (m, 1H), 4.36-4.34 (m, 1H), 4.14-4.05 (m, 2H), 3.72 (s, 3H), 3.62-3.60 (m, 2H), 2.91-2.89 (m, 2H), 2.75-2.70 (m, 4H), 2.49 (s, 3H), 1.97-1.95 (m, 2H), 1.86-1.84 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[N:3]=1.[NH2:10][C:11]1[S:12][C:13]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[CH:21][C:20]=2[F:29])=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17]>>[F:29][C:20]1[CH:21]=[C:22]([C:25]([OH:28])([CH3:26])[CH3:27])[CH:23]=[CH:24][C:19]=1[C:13]1[S:12][C:11]([NH:10][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[N:3]=2)=[C:15]([C:16]([NH2:18])=[O:17])[CH:14]=1
Reactant: OCc1nccc(Cl)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccnc(CO)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using (4-chloropyrimidin-2-yl)methanol (54.0 mg, 0.37 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.34 mmol) as the starting materials.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH2:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])[S:14][N:13]=1)[CH3:2].[NH:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31]([OH:33])=[O:32].C([BH3-])#N.[Na+]>C(O)C>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:14][N:13]=[C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:29]4[CH2:36][CH2:35][CH2:34][C@H:30]4[C:31]([OH:33])=[O:32])[CH:7]=[CH:6][CH:5]=3)[N:16]=2)[CH:18]=[CH:19][C:20]=1[CH2:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CCc1c(CC=O)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCc1c(CCN2CCC[C@H]2C(=O)O)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.9 %

Procedure:
To a solution of 5-{3-[2-ethyl-3-(2-oxoethyl)phenyl]-1,2,4-thiadiazol-5-yl}-2-(2-methylpropyl)benzonitrile (D62) (100 mg, 0.257 mmol) and L-proline (59.1 mg, 0.513 mmol) stirred in Ethanol (10 mL) for 20 min was added sodium cyanoborohydride (48.4 mg, 0.770 mmol). This mixture was stirred at room temperature for 2 h. The reaction was quenched with water, then dried and dissolved in DMF. The residue was purified by for Mass Directed AutoPrep to afford 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)ethyl]-L-proline (E76) (20 mg) as a TFA salt (white solid).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)([Cl:16])=O>>[CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Product: CS(=O)(=O)c1ccc(C(=O)Cl)cc1

Procedure:
A mixture of 11.2 g (0.056 mol) of p-methylsulfonyl-benzoic acid prepared in Example 4 and 30 ml of thionyl chloride were heated under reflux to give a clear solution. Removal of the excess of thionyl chloride under reduced pressure obtained white solid and without purification put into the next reaction.
Reaction SMILES: [CH:1]1([N:7]([CH3:17])[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[OH-].[OH-].[Pd+2]>[CH:1]1([N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][N:9]=2)[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(c1ccc([N+](=O)[O-])cn1)C1CCCCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN(c1ccc(N)cn1)C1CCCCC1
Reaction time: 6 h

Procedure:
Cyclohexyl-methyl-(5-nitro-pyridin-2-yl)-amine (1.72 g, 7.3 mmol) was dissolved in ethanol (80 mL) and treated with 20% palladium hydroxide on carbon (Pearlman's catalyst, 0.5 g) and the mixture was shaken under a hydrogen atmosphere (50 psi) for 6 hours. The catalyst was removed by filtration through celite then the filtrate was concentrated in vacuo and the resultant oil was chromotographed on SiO2 using 1:1 ethyl acetate/hexanes as eluent. MS (m/z): 206 (M+H)+; C12H19N3 requires 205.3.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].Br[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21].O>CS(C)=O>[CH2:21]([N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5])[CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCCBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.33 h
Yield: 77.9 %

Procedure:
This example illustrates a synthesis of 1-(4,5-Oxipentyl)-3,7- dimethylxanthine. Sodium hydride (95%) (1.38 g, 55 mmol) was added to a solution of theobromine (9.0 g, 50 mmol) in dimethylsulfoxide (300 mL). After 20 minutes of stirring, 1-bromo-4-pentene(7.45 g, 50 mmol) was added. After 16 hours of stirring at room temperature, the reaction was poured into a separatory funnel containing 1 L of water and extracted with dichloromethane (5×200 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 20% petroleum ether/ethyl acetate eluant to yield 9.67 g (92% yield) 1-(4-pentenyl)-3,7-dimethylxanthine (inventive compound no. 1575).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br-].[Li+].[F:12][C:13]([F:29])([F:28])[C:14]1[CH:15]=[C:16]([C:20]2([CH:26]=O)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1.[CH3:30][CH2:31][O:32][C:33]([CH3:35])=[O:34]>C1COCC1.Cl>[F:12][C:13]([F:29])([F:28])[C:14]1[CH:15]=[C:16]([C:20]2([CH:26]=[CH:35][C:33]([O:32][CH2:31][CH3:30])=[O:34])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=CC1(c2cccc(C(F)(F)F)c2)CCOCC1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C=CC1(c2cccc(C(F)(F)F)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
N,N-diisopropylethylamine (2.95 mL, 16.9 mmol) and anhydrous lithium bromide (489 mg, 5.63 mmol) were added to a stirred solution of 4-(3-(trifluoromethyl)phenyl)-tetrahydro-2H-pyran-4-carbaldehyde (485 mg, 1.88 mmol) in THF (15 mL). After 20 min., triethyl phosphonoacetate (1.12 mL, 5.63 mmol) was added and the mixture was stirred at room temperature for 16 h. Additional N,N-diisopropylethylamine (980 μL, 5.64 mmol) was added and stirring was continued for additional 160 min. The reaction mixture was diluted with EtOAc and 1N aq. HCl solution. The organic layer was separated, washed with 1N aq. HCl solution, brine, dried (Na2SO4), filtered, and concentrated under vacuum to obtain a thin yellow oil which was chromatographed on silica gel (Teledyne-Isco RediSep 12 g column). Elution with 5%, 10%, and 20% EtOAc in hexanes afforded ethyl 3-(4-(3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-yl)acrylate (569 mg, 92% yield) as a viscous yellow oil. 1H NMR (400 MHz, CDCl3): δ ppm 7.38-7.68 (m, 4H), 6.98 (d, 1H), 5.71 (d, 1H), 4.19 (q, 2H), 3.76 (dd, 4H), 2.06-2.34 (m, 4H), 1.29 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[F:14][C:15]1[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=1[O:17][S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19]>C(Cl)Cl>[CH3:13][O:12][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=[C:2]([NH:1][C:22]([NH:21][S:18]([O:17][C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[F:14])(=[O:20])=[O:19])=[O:23])[N:11]=1
Reactant: O=C=NS(=O)(=O)Oc1ccccc1F
Reactant: COc1nc(N)nc2nccnc12
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)Oc2ccccc2F)nc2nccnc12
Reaction time: 0.17 h

Procedure:
0.88 g (0.005 mol) of 2-amino-4-methoxypteridine were suspended in 40 ml of methylene chloride and 1.2 g (0.0055 mol) of 2-fluorophenoxysulfonyl isocyanate were added thereto rapidly to obtain a clear solution. The solution was heated to reflux for a short time, thereafter stirred for 10 minutes and then was concentrated by evaporation to dryness. The residue was treated with diisopropyl ether and a little acetone and the mixture was vacuum filtered. The product was dried to obtain 1.95 of N-(4-methoxypteridin-2-yl)-N'-(2-fluorophenoxysulfonyl)-urea in the form of light yellow crystals melting at 135° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.[CH:13]([NH:16][NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:15])[CH3:14].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:16]([CH:13]([CH3:15])[CH3:14])[NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:12]
Reactant: O=C(O)CCc1ccccc1Br
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Yield: 59.2 %

Procedure:
A solution of (3-(2-bromophenyl)propionic acid (257 mg, 1.12 mmoles) and benzoic acid N′-isopropyl-hydrazide (200 mg, 1.12 mmoles) in DMF (6 mL) was treated with triethylamine (0.47 mL, 3.36 mmol), HOBT (182 mg, 1.34 mmoles) and EDCI (2.58 g, 1.34 mmol) at room temperature for 72 h. The reaction mixture was partitioned between water and dichloromethane. The organic layer was successively washed with water and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a solid (258 mg, 59%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[Cl:10][CH2:11][C:12](Cl)=[O:13]>C(Cl)Cl>[Cl:10][CH2:11][C:12]([N:4]1[CH2:5][CH2:6][CH2:7][CH:3]1[C:2]([F:9])([F:8])[F:1])=[O:13]
Reactant: FC(F)(F)C1CCCN1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: O=C(CCl)N1CCCC1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(trifluoromethyl)pyrrolidine (500 mg, 3.59 mmol) in DCM (10 ml) was treated with chloroacetyl chloride (0.31 ml, 3.77 mmol) and stirred at RT for 1 h. The resulting mixture was concentrated in vacuo to afford the title compound as a yellow oil which was used without further purification; 1H NMR (400 MHz, CDCl3) δ 4.84 (1H, m), 4.11 (2H, s), 3.71 (2H, m), 2.23 (2H, m), 2.07 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]2[CH2:22][CH2:23][CH2:24][C:19]([OH:25])([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=3)[CH2:20]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc(Cl)cc3)C2)c1

Procedure:
The compound of Example 19 was prepared according to the general preparation protocol A from 4-chlorobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]1[CH:46]=[CH:45][CH:44]=[CH:43][C:19]=1[CH:20]([N:28]1[C:36]2[C:31](=[CH:32][C:33](/[C:37](/[CH3:42])=[CH:38]/[C:39](O)=[O:40])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1>>[CH3:17][C:18]1[CH:46]=[CH:45][CH:44]=[CH:43][C:19]=1[CH:20]([N:28]1[C:36]2[C:31](=[CH:32][C:33](/[C:37](/[CH3:42])=[CH:38]/[C:39]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:40])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2cccc(C)c2)c2ccccc2C)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2cccc(C)c2)c2ccccc2C)c1

Procedure:
0.20 g of compound 73 was obtained in a similar manner to those described in the Examples 1 and 2 using 0.41 g of ethyl 4-(2-aminophenoxy)butyrate and 0.36 g of 3-[1-(2,3'-dimethylbenzhydryl)indol-5yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:22])[CH2:8][NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:3]1.[OH:23][C:24]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(CC)CC)C>C1COCC1>[OH:23][C:24]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:25][CH2:26][CH:27]([NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7](=[O:22])[CH2:8][NH:9][C:10](=[O:21])[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=3)[CH2:3]2)[CH2:28][CH2:29]1
Reactant: O=C1CCC(O)(c2ccccc2)CC1
Reactant: N[C@H]1CCN(C(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC(=O)N1CC[C@H](NC2CCC(O)(c3ccccc3)CC2)C1)c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a solution of the pyrrolidine intermediate from step C (0.3 g, 0.85 mmol) and the ketone from step E (0.16 g, 0.85 mmol) in THF (5 mL) was added Na(OAc)3BH (0.35 g, 2.5 mmol) followed by triethylamine (0.2 mL, 1.5 mmol). The reaction was continued at room temperature overnight and quenched by addition of a saturated NaHCO3 solution. The resulting solution was extracted with EtOAc and the EtOAc layer was dried over MgSO4 and concentrated. Separation on silica gel eluting with 10% to 30% MeOH/EtOAc provided the cis (fast moving spot) and trans (slow moving spot) isomers of the title compound. MS (M+H)+ 490.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[CH2:23][CH2:22]1>>[F:12][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:4][N:3]=[C:2]2[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)[CH2:25][CH2:26]2)=[CH:7][CH:8]=1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: Fc1ccc(-c2nnc(Cl)c3cc(F)ccc23)cc1
Product: Fc1ccc(-c2nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c3cc(F)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-fluoro-4-(4-fluorophenyl)phthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:10]1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([C:13]1[C:12]([I:1])=[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:10][N:9]=1)=[O:15])[CH3:18]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1n[nH]c(C(=O)OCC)c1I
Temperature: 80 °C
Reaction time: 24 h
Yield: 104.5 %

Procedure:
N-iodosuccinimide (0.6 g, 2.59 mmol) was added to a solution of diethyl 3,5-pyrazoledicarboxylate (0.5 g, 2.35 mmol) in CHCl3 (10 mL) and the mixture was stirred at 80° C. for 24 hours. Then more of N-iodosuccinimide (0.6 g, 2.59 mmol) was added and the mixture was stirred at 100° C. for 48 hours more. Then the mixture was stirred at room temperature for 5 days. Then the mixture was treated with a saturated solution of Na2S2O3 and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 4-iodo-1H-pyrazole-3,5-dicarboxylic acid diethyl ester (0.83 g, 90% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([CH2:23][C:24](=O)[CH3:25])=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])O.[Na+]>ClCCl>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[CH:23]=[C:24]([CH3:25])[NH:15]2
Reactant: CC(=O)Cc1c(F)cccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(F)cccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.3 %

Procedure:
1.43 ml of trifluoroacetic acid are added to a solution of 0.35 g of tert-butyl [3-fluoro-2-(2-oxopropyl)phenyl]carbamate in 13 ml of anhydrous dichloromethane at ambient temperature. The reaction mixture is then stirred at ambient temperature for 24 h, and is then diluted with 27 ml of dichloromethane and treated with 25 ml of a 5% sodium hydrogen carbonate solution. After stirring at ambient temperature for 1 hour and then settling out, the organic phase is separated and the aqueous phase is extracted with 25 ml of dichloromethane. The organic phases are combined, washed with saturated brine, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. 0.19 g of 4-fluoro-2-methylindole is thus obtained in the form of a dark red-colored oil, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:6]([OH:8])=O)[CH3:2].[O-:13][C:14]#[N:15].[Na+].[OH-].[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:4]2[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:8])[NH:15][C:14]1=[O:13])[CH3:2]
Reactant: CCNc1ccccc1C(=O)O
Reactant: N#C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCn1c(=O)[nH]c(=O)c2ccccc21

Procedure:
Am. Chem. Soc. (1933), pages 2113-2116 describes the reaction of N-ethylanthranilic acid with sodium cyanate and acetic acid and subsequent addition of sodium hydroxide to give 1,2,3,4-tetrahydro-1-ethyl-2,4-dioxoquinazoline. However, disadvantages of this process are the low space yield, because of the dilute reaction solution, and the very high excess of sodium hydroxide.