Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:9])=[O:5].[Cl:25][C:26]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Cl.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:28][C:27]2[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:26]=2[Cl:25])[CH2:12]1)=[O:9])=[O:5]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-3-[[N-(2-amino-5-(trifluoromethoxyl)benzoyl)glycyl]amino]pyrrolidine (0.050 mmol) with 2,4-dichlorobenzyl chloride (0.066 mL), a piperidinomethylpolystyrene (60 mg), acetonitrile (0.8 mL) and chloroform (0.5 mL) was stirred at 60° C. for 12 hours. The resulting reaction mixture was cooled to room temperature, loaded onto a Varian™ SCX column and washed with a 50% chloroform/methanol (10 mL) and methanol (10 mL). The obtained crude product was eluted with a solution of 2 M NH3 in methanol (5 mL) and concentrated. A 1,4-dioxane (2 mL) solution of 4 M HCl was added to the resulting residue, and the obtained mixture was stirred at room temperature overnight, concentrated and then purified by preparative TLC to afford (R)-3-[[N-(2-amino-5-(trifluoromethoxy)benzoyl]glycyl]amino]-1-(2,4-dichlorobenzyl)pyrrolidine (Compd. No. 1905) (17.6 mg, 70%). The purity was determined by RPLC/MS (93%). ESI/MS m/e 505 (M++H, C21H21Cl2F3N4O3).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.II.C1(C)C=CC=CC=1.C1[O:35][CH:33]1C>O>[CH3:33][O:35][C:21]1[CH:20]=[CH:19][C:18]2[C:7]3[C:6](=[CH:5][CH:4]=[CH:3][CH:8]=3)[C:9]3[C:10](=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[C:17]=2[CH:22]=1
Reactant: CC1CO1
Reactant: COc1ccc(-c2ccc(OC)cc2-c2ccccc2)cc1
Agent: II
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c3ccccc3c3ccc(OC)cc3c2c1
Reaction time: 18 h
Yield: 72 %

Procedure:
12.4 g (42.7 mmol) of 4,4′dimethoxy-o-terphenyl and 16 g (63.0 mmol) iodine chips was placed in a 250 mL reaction vessel. 200 mL of toluene was added followed by 30 mL of propylene oxide. The photoreactor was set up with a condenser cooled by a circulating chiller. A 400 W medium pressure mercury lamp was used as the light source. The reaction vessel was placed in a cabinet. The lamp was ignited and the chiller temperature was set such that the water exiting the reactor was maintained at between 20° C. and 25° C. (monitored by a thermocouple attached the exit stream). The reaction was left on for 18 hours. A solid was filtered off and washed with hexanes, only recovered 2.2 g of material. The filtrate was diluted with toluene and washed with sodium sulfate solution. The aqueous layer was back extracted with toluene and the organic layers were dried over magnesium sulfate, filtered, and evaporated. Material was dissolved in toluene and added sodium sulfite solution and stirred. The layers were separated, the aqueous layer extracted with toluene and the combined organic layers were dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography eluting with 0 to 100% ethyl acetate/hexane. 8.8 g material (72%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](I)[C:25]=1[F:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:23][C:24]1[C:25]([F:31])=[C:26]([C:21]#[C:20][C:17]2[CH:18]=[CH:19][C:14]([N:12]3[C:11](=[O:22])[NH:10][C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:13]3)=[CH:15][CH:16]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: Fc1c(Cl)cccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2cccc(Cl)c2F)cc1
Yield: 28.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 1-chloro-2-fluoro-3-iodobenzene (0.123 g, 0.470 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.040 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.29 (t, J=7.8 Hz, 1H), 7.50 (t, J=8.7 Hz, 1H), 7.57-7.72 (m, 6H), 8.04 (d, J=9.0 Hz, 2H), 12.74 (br s, 1H). MS (m/z): 442.35 (M+).
Reaction SMILES: [C:1]([N:8]([CH3:40])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Br[C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1>>[Cl:27][C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:28][C:29]1[CH:30]=[C:31]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:40])[C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][CH2:11]1)=[O:17]
Reactant: Brc1ccncc1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: COc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 5 (350 mg, 0.59 mmol) is coupled to 4-bromopyridine hydrochloride (115 mg, 0.59 mmol) using Method B to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:37](O)=[O:38])=[CH:32][CH:33]=[C:34]([CH3:36])[CH:35]=2)=[CH:26][CH:25]=1)([CH3:23])[CH3:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCN(CC)CC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:37]([C:31]3[C:30]([C:27]4[CH:28]=[CH:29][C:24]([CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=4)=[CH:35][C:34]([CH3:36])=[CH:33][CH:32]=3)=[O:38])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(C(=O)O)c(-c2ccc(C(C)C)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(-c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a stirred solution of 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (4.15 g), 4′-isopropyl-5-methyl-biphenyl-2-carboxylic acid (3.81 g), HOBt (2.36 g), and Et3N (1.97 g) in CH2Cl2 (50 mL) was added EDCl (3.72 g) and the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO3, with brine and dried over Na2SO4. After filtration and evaporation of the filtrate, the residue was crystallized from diisopropyl ether to give the title compound (4 g) as white crystals.
Reaction SMILES: [CH2:1]([CH:6]1[C:10](O)([CH3:11])[CH:9]=[CH:8][C:7]1=[O:13])[CH2:2][CH2:3][CH2:4][CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25]([OH:28])[CH2:26][CH3:27]>>[CH2:1]([C:6]1[C:7](=[O:13])[CH2:8][CH:9]([O:28][CH2:25][CH2:26][CH3:27])[C:10]=1[CH3:11])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1C(=O)C=CC1(C)O
Reactant: CCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCC1=C(C)C(OCCC)CC1=O
Reaction time: 5 h

Procedure:
Into the same flask as used in Example 1, 2-n-pentyl-3-hydroxy-3-methyl-4-cyclopentenone (0.1 mol; 1 part), n-propanol (5 parts) and p-toluenesulfonic acid (1/20 part) were charged, and the mixture was stirred at a temperature of 40° to 70° C. for 5 hours. After completion of the reaction, the mixture was treated in the same manner as in Example 25 to obtain 2-n-pentyl-3-methyl-4-n-propoxy-2-cyclopentenone. Yield, 96%. nD19 1.4792.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]1[CH:18]=[C:17]([S:19][CH3:20])[C:16](=[O:21])[C:15]2[S:22][CH:23]=[CH:24][C:14]1=2>ClCCl>[CH3:12][N:13]1[CH:18]=[C:17]([S:19]([CH3:20])=[O:9])[C:16](=[O:21])[C:15]2[S:22][CH:23]=[CH:24][C:14]1=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cn(C)c2ccsc2c1=O
Solvent: ClCCl
Product: Cn1cc(S(C)=O)c(=O)c2sccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-chloroperbenzoic acid (85%; 1.63 g) in dichloromethane (60 ml) can be added dropwise during 20 minutes to a stirred solution of 4-methyl-6-methylthiothieno[3,2-b]pyrid-7(4H)-one (2.0 g) in dichloromethane (60 ml) at 0° C.-5° C. After 4 hours, more 3-chloroperbenzoic acid (0.15 g) in dichloromethane (10 ml) can be added and the mixture stirred overnight at ambient temperature. More 3-chloroperbenzoic acid (0.15 g) in dichloromethane (10 ml) can be added and the mixture can again be stirred overnight at ambient temperature. The resulting solution can be extracted with saturated aqueous sodium bicarbonate solution (5×150 ml) and saturated aqueous sodium chloride solution (1×150 ml) and the organic phase can be discarded. The aqueous extracts are combined and extracted with dichloromethane (5×100 ml). The organic extracts are combined, dried over anhydrous magnesium sulphate and evaporated to give a solid product. This product can be crystallised from industrial methylated spirit to give the compound 4-methyl-6-methylsulphinylthieno [3,2-b]pyrid-7(4H)-one, m.p. 174° C.-176° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[CH:22]1([CH2:25]Br)[CH2:24][CH2:23]1>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[O:8][CH2:25][CH:22]1[CH2:24][CH2:23]1
Reactant: CCOC(=O)Cc1cc(Cl)c(O)c(Br)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)Cc1cc(Cl)c(OCC2CC2)c(Br)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 589.5 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (12 g, 40.816 mmol) in DMSO (80 mL) were added K2CO3 (14.08 g, 102.020 mmol) and cyclopropylmethylbromide (5 mL, 4.880 mmol) at RT under inert atmosphere. The reaction mixture was stirred at 80° C. temperature over a period of 14 h. After completion of starting material (by TLC), the reaction mixture was cooled to RT and quenched with water and extracted with EtOAc (3×100 mL). Combined organic layers were washed with water (3×75 mL), brine and dried over Na2SO4. After filtration and concentration under reduced pressure, the crude material was purified by column chromatography to afford ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate (10 g) yellow solid.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[N:12]=2)=[C:7]([F:27])[CH:6]=1.[C:33]([C:35](=[CH:39][CH:40]([CH3:42])[CH3:41])[C:36](O)=[O:37])#[N:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:36]([C:35](=[CH:39][CH:40]([CH3:42])[CH3:41])[C:33]#[N:34])=[O:37])[CH2:22]3)[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])=[CH:6][C:7]=3[F:27])[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1F)nn2[C@@H]1CCCNC1
Reactant: CC(C)C=C(C#N)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3F)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 19.4 %

Procedure:
To a mixture of (R)-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.23 mmol, 1.0 eq), 2-cyano-4-methyl-pent-2-enoic acid (38 mg, 0.27 mmol, 1.2 eq) and DIEA (88 mg, 0.68 mmol, 3.0 eq) in 10 ml DCM was added HATU (130 mg, 0.34 mmol, 1.5 eq). The reaction mixture was stirred for 4 h at RT under N2. The mixture was purified by Pre-HPLC to give the title compound (25 mg 40% yield). LCMS: m/Z+ (562.2) (M+H)+1HNMR (400 MHz, CDCl3): δ 0.784˜1.186 (m, 7H), 1.765˜2.254 (m, 5H), 2.861˜4.937 (m, 4H), 6.218 (m, 0.4H), 6.857˜7.600 (m, 6H), 8.255 (s, 1H) and 9.888 (m, 1H).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:38]([CH3:39])[C:37]4[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:36]=4[N:35]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:38]([CH3:39])[C:37]4[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:36]=4[N:35]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccc(F)cc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3nc4ccc(F)cc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-methyl-6-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>C(O)(C)(C)C>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][C:7]([C:8]#[N:9])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13]
Reactant: N#CCc1ccccc1
Reactant: C=CC(=O)OC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccccc1
Temperature: 25 °C

Procedure:
Phenylacetonitrile (11.7 g, 0.1 mole) and methyl acrylate (47 ml, 0.5 mole) were added to tert-butanol (60 ml) and heated to boiling point. The source of heat was then removed. Triton B (benzyltrimethylammonium hydroxide, 40% in methanol, 15.2 ml) dissolved in tert-butanol (23 ml) was added dropwise, first of all slowly and then at a faster rate. After the dropwise addition the reaction mixture was boiled under reflux for 4 hours. The reaction mixture was cooled to room temperature overnight. The reaction mixture was worked up by adding toluene (100 ml) and water (70 ml). The organic phase was separated and washed with water (1×70 ml) and saturated sodium chloride solution (1×50 ml). After drying over Na2SO4, the solvent was distilled off in a fume cupboard on account of the strong smell. Purification was carried out by bulb tube distillation at a pressure of 7.8×10−2 mbar and at a temperature of 235° C. The desired 4-cyano-4-phenylheptanedioic acid dimethyl ester was obtained in a yield of 21.45 g (72%) as a colourless viscous substance.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:30][CH:29]=4)=[O:25])[CH2:20][CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.O>N1CCOCC1>[CH2:35]([O:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][O:26][C:24]([N:21]2[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]2)=[O:25])=[CH:33][CH:32]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(OCc1ccc(OCc2ccccc2)cc1)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: C1COCCN1
Solvent: O
Product: O=C(OCc1ccc(OCc2ccccc2)cc1)N1CCNCC1

Procedure:
A solution of 274 mg (0.5 mmol) piperazine-1,4-dicarboxylic acid 4-benzyloxy-benzyl ester 9H-fluoren-9-ylmethyl ester in 13 ml morpholine was stirred at rt for 1 h. Then 23 ml of chilled water was added, the suspension filtered and the filtrate extracted with TBME. The organic layer was washed with water, brine, dried over Na2SO4 and evaporated: 54 mg piperazine-1-carboxylic acid 4-benzyloxy-benzyl ester as light yellow, waxy solid. MIR: 3300 cm−1, 1688 cm−1. 1H-NMR (CDCl3): 1.77 br, 1H; 2.75–2.90 m, 4H and 3.40–3.50 m, 4H; 5.06 s and 5.07 s, 4H; 6.96 d, J=8.8 Hz, 2H and 7.28–7.44 m, 7H. MS (ISP): 327.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([N:12]([CH3:24])[CH2:13][C:14]2[N:15]([CH3:23])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])=[CH:4][CH:3]=1.[C:25]1(=O)[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>O1CCOCC1>[O:29]=[C:28]1[CH2:27][CH2:26][C:25](=[O:30])[N:1]1[C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH3:24])[CH2:13][C:14]2[N:15]([CH3:23])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])=[CH:4][CH:3]=1
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)C=Cc1ccc(N)nc1
Reactant: O=C1CCC(=O)O1
Solvent: C1COCCO1
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N2C(=O)CCC2=O)nc1
Yield: 66.4 %

Procedure:
A solution of 3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (1.40 g, 4.37 mol) and succinic anhydride (520 mg, 5.24 mmol) in 1,4-dioxane (50 mL) was heated to reflux for 5 h. Another portion of succinic anhydride (520 mg, 5.24 mmol) was then added, and the solution was maintained at reflux overnight. The solvent was removed in vacuo. The residue was dissolved in CH2Cl2, and the solution was washed with satd NaHCO3, water and brine, dried over Na2SO4, and concentrated. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 98:2 to 97:3) gave the title compound (1.40 g, 76%) as an off-white solid and as a mixture of amide rotamers: mp 185-187° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.92-8.88 (m, 1H), 8.41-8.32 (m, 1H), 7.69-7.64 (m, 1H), 7.52-7.34 (m, 4H), 7.15-7.09 (m, 1H), 7.04-6.99 (m, 1H), 6.44-6.21 (m, 1H), 5.08-4.87 (m, 2H), 3.73-3.70 (m, 3H), 3.14-3.00 (m, 3H), 2.83-2.81 (m, 4H); MS (ESI) m/e 403 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[NH:13][C:12]2=[O:18])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)c(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.3 %

Procedure:
To a solution of 4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (65.4 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (85 mg, 69%).
Reaction SMILES: Cl.Cl.[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]1)([CH3:5])[CH3:4].[CH3:30][O:31][CH:32]1[C:37](=O)[CH2:36][CH2:35][O:34][CH2:33]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH:11][CH:37]2[CH2:36][CH2:35][O:34][CH2:33][CH:32]2[O:31][CH3:30])[CH2:7]1)([CH3:5])[CH3:4]
Reactant: COC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-(4-[6-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (110 mg, 0.24 mmol), 3-methoxytetrahydro-4H-pyran-4-one (80 mg, 0.61 mmol), and triethylamine (0.16 mL, 1.2 mmol) in methylene chloride (8 mL) was added sodium triacetoxyborohydride (190 mg, 0.88 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/Et3N=10:0.1) to give 123 mg of desired product as a mixture of two isomers. The two isomers were separated by chiral HPLC to give isomer 1 (45 mg after converting to TFA salt) and isomer 2 (35 mg after converting to TFA salt). LCMS calculated for C25H37F3N4O3: (M+H) 498.2; found 498.2 for both isomers.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][NH2:20])[N:14]=[CH:13]1>>[NH:12]1[CH:16]=[C:15]([CH2:17][CH2:18][CH2:19][NH:20][C:9](=[O:11])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:14]=[CH:13]1
Reactant: O=C(O)CCc1ccccc1
Reactant: NCCCc1c[nH]cn1
Product: O=C(CCc1ccccc1)NCCCc1c[nH]cn1

Procedure:
The preparation is carried out as in Example 1 with 10 mmol of 3-phenylpropanoic acid and 3-(1H-imidazol-4-yl)propanamine as the amine component. The title compound is purified by chromatography and recrystallized in the hydrogenmaleate forth from ethyl acetate/ acetonitrile.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13](O)=[O:14])=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[N:8]=1)[CH2:4][CH3:5])[CH3:2].CSC>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[C:12]([CH2:13][OH:14])=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[N:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1C(=O)O
Solvent: CSC
Solvent: C1CCOC1
Product: CCC(CC)Oc1nc(C)nc(Nc2c(C)cc(C)cc2C)c1CO
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carboxylic acid in dry THF was added BH3.DMS. The resulting mixture was heated at reflux. The mixture was quenched with dilute HCl and stirred for 30 minutes, adjusted pH to 7.5–8.5, then extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a crude material. The crude material was purified through silica gel column chromatography to give the title compound as a solid, mp. 121–123° C., Anal. For C20H29N3O2 calc. C, 69.94; H, 8.51; N, 12.23; found: C, 69.73; H, 8.47; N, 11.99.