Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:27][C:28](=[NH:37])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[O:11][N:37]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=3)[N:27]=2)=[CH:12][CH:13]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Reactant: N=C(NO)c1ccc(CO)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.7 %

Procedure:
A solution of 4-isobutyl-benzoic acid (451 mg, 2.53 mmol) and 1,1′-carbonyldiimidazole (491 mg, 3.03 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. N-hydroxy-4-hydroxymethyl-benzamidine (420 mg, 2.53 mmol) was added to the reaction mixture, stirred at room temperature for 18 hours and diluted with ethyl acetate. The reaction mixture was washed with aqueous sodium hydroxide (0.25 N), water and brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was treated with a solution of tetrabutylammonium fluoride (1.0 M in THF, 2.78 mL) and THF (6 mL) and stirred at room temperature for 12 hours. The reaction mixture was quenched with brine and extracted with ethyl acetate. The combined organic layers were concentrated in vacuo. Purification by flash chromatography (silica, 1:9 to 2:3 EtOAc:hexanes) provided the title compound (193 mg, 29% yield) as a solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:55][CH2:56][CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62]>CN(C)C=O.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:25][CH2:26][CH:27]([C:30]([NH:55][CH2:56][CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:63])([CH3:62])[CH3:64])=[O:31])[CH2:28][CH2:29]4)[N:20]=3)[CH2:17][CH2:18]2)=[O:12])=[N:2]1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)C1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCNC(=O)C1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Yield: 84.5 %

Procedure:
A solution of 1-(5-{4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazin-1-yl}-1,2,4-thiadiazol-3-yl)piperidine-4-carboxylic acid (100 mg, 0.219 mmol), 1-hydroxybenzotriazole (29.6 mg, 0.219 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84.0 mg, 0.438 mmol) and tert-butyl N-(2-aminoethyl)carbamate (35.0 mg, 0.219 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 12 hours. The reaction mixture was poured to water, and a solid was separated by filtration, which was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to give 111 mg (84.7%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[N:4]1)[CH3:2].Br[C:11]1[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=[C:15]([Br:17])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(OCC)(=O)C.O>[Br:17][C:15]1[CH:16]=[C:11]([NH:9][C:5]2[CH:6]=[C:7]([CH3:8])[N:3]([CH2:1][CH3:2])[N:4]=2)[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CCn1nc(N)cc1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCn1nc(Nc2cc(Br)cn(C)c2=O)cc1C
Temperature: 100 °C
Yield: 39.9 %

Procedure:
A sealed tube was equipped with a magnetic stirrer and charged with 1-ethyl-5-methyl-1H-pyrazol-3-amine (870 mg, 7 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.9 g, 7 mmol) and cesium carbonate (5 g, 15 mmol) in 1,4-dioxane (69 mL). After bubbling nitrogen through the solution for 30 min, Xantphos (480 mg, 0.8 mmol) and tris(dibenzylideneacetone) dipalladium(0) (450 mg, 0.5 mmol) were added, and the reaction mixture was heated to 100° C. for 16 h. After this time, water (50 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate. The mixture was concentrated under reduced pressure to near dryness when the desired product crashed out and was filtered. Washing with diethyl ether (10 mL) afforded a 40% yield (870 mg) of 302a.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:26])[CH2:13][CH2:12]1.N>O>[O:26]=[C:18]1[NH:19][C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]2[N:17]1[CH:14]1[CH2:15][CH2:16][N:11]([C:2]2[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:13]1
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: N
Solvent: O
Product: O=C(O)c1ccnc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c1
Reaction time: 0.17 h

Procedure:
0.50 g (2.4 mmol) 2-bromopyridine-4-carboxylic acid and 1.1 g (5.0 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one were mixed and melted for 10 min using the hot air blower. The reaction mixture was cooled, mixed with water and made basic with ammonia. It was extracted with EtOAc. The aqueous phase was concentrated and purified by HPLC. The product-containing fractions were combined and concentrated to dryness by rotary evaporation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][NH:7][CH2:8][CH:9](OC)OC.[CH:19]1[C:24]([CH:25]=O)=[CH:23][C:22]2[O:27][CH2:28][O:29][C:21]=2[CH:20]=1.[ClH:30]>>[ClH:30].[CH3:18][O:17][C:16]1[CH2:15][C:14]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]=[N:7][C:8]1=[C:9]3[C:19](=[CH:24][C:25]=21)[CH:20]=[C:21]1[O:29][CH2:28][O:27][C:22]1=[CH:23]3
Reactant: COc1ccc(CNCC(OC)OC)cc1OC
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cl
Product: COC1=C(OC)Cc2c3c(ncc2=C1)=c1cc2c(cc1=C3)OCO2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Concentrated HCl (20 mL) was added to a mixture of amine 12a (2.17 g, 8.51 mmol) and piperonal (10b, 3.0 g, 0.020 mol). The reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was then cooled and washed with ether (50 mL×3). Then it was brought to a basic pH with NH4OH. The mixture was extracted with chloroform (50 mL×4), washed with water (100 mL), dried (Na2SO4) and concentrated. The residue was dissolved in a mixture of organic solvents (50 mL diethyl ether, 100 mL dichloromethane, 100 mL chloroform). The mixture was filtered and HCl (2 M in ether, 40 mL) was added to the filtrate. The yellow precipitate that formed (0.806 g, 26%) was collected by filtration, mp 238-240° C. 1H NMR (300 MHz D2O) δ 8.30 (s, 1H), 6.91 (s, 1H), 6.69 (s, 1H), 6.44 (s, 1H), 6.39 (s, 1H), 5.94 (s, 2H), 3.78 (s, 3H), 3.77 (s, 3H), 3.00 (s, 2H); low resolution ESIMS m/z (rel intensity) 322 (100, M+); IR (KBr) 3429, 3032, 2611, 1623, 1551, 1504, 1489, 1430, 1413, 1379, 1331, 1296, 1273, 1226, 1206, 1172, 1036, 977, 933, 837, 776, 724 cm−1. Anal. Calcd for C19H16NO4Cl(H2O)0.85: C, 61.17; H, 4.78; N, 3.75. Found: C, 61.19; H, 4.77; N, 3.56.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:19]=[C:18](Br)[O:17][CH:16]=2)=[O:14])=[CH:8][CH:7]=1)[CH3:2].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:17][CH:16]=2)=[O:14])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2coc(Br)c2)cc1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(NC(=O)c2coc(-c3ccccc3)c2)cc1
Yield: 26.6 %

Procedure:
A solution of {4-[(5-bromo-furan-3-carbonyl)-amino]-phenyl}-acetic acid ethyl ester (8) (200 mg, 0.57 mmoles), phenyl boronic acid (69.2 mg, 0.57 mmoles), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg, 0.06 mmoles) and 2M aqueous cesium carbonate (1.2 ml, 2.4 mmoles) in toluene (20 ml) was refluxed for 16 hours. The solvent was evaporated, the residue diluted with water (20 ml) and then extracted with ethyl acetate (3×20 ml). The combined organic layers were concentrated in vacuo. The residue was was purified by flash chromatography (gradient elution with 90% cyclohexane/10% ethyl acetate to 50% cyclohexane/50% ethyl acetate) to afford {4-[(5-phenyl-furan-3-carbonyl)-amino]-phenyl}-acetic acid ethyl ester (9) (53 mg). LC/MS System A; Rt=3.84 mins, m/z (ES+)=(M+H for C21H19NO4).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:8]=2)[NH:3]1.O.[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>C(O)C>[O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][C:13]([O:15][CH2:17][CH3:18])=[O:14])[CH:8]=2)[NH:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)C(=O)N2
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1ccc2c(c1)C(=O)C(=O)N2
Temperature: 80 °C
Reaction time: 12 h
Yield: 1114.7 %

Procedure:
4 g of (2,3-dioxo-2,3-dihydro-1H-indol-5-yl)acetic acid are dissolved in 100 ml of ethanol, and 300 mg of toluene-4-sulfonic acid monohydrate are added. The mixture is heated at 80° C. for 1 h, and the solvent is subsequently removed in vacuo. The residue is taken up in 100 ml of water and 100 ml of ethyl acetate and stirred at 60° C. for a further 12 h. The mixture is neutralised using sodium hydrogencarbonate, and the organic phase is separated off. The aqueous phase is washed a further twice with 100 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness in vacuo, giving 4.1 g of ethyl 2-(2,3-dioxoindolin-5-yl)acetate;
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a stirred solution of 0.50 g (1.32 mmol) of [1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (the preparation of which has been described in example 31) in CH2Cl2 (10 ml), were added 2 ml of TFA. The mixture was stirred 2 hours, then poured onto an aqueous solution of sat. NaHCO3 and then extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo, to afford 0.25 g (68%) of (4-amino-piperidin-1-yl)-(6-chloro-1H-indol-3-yl)-methanone as a light brown solid.
Reaction SMILES: [C:1]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].NN.[OH-].[K+].C(O)COCCOCCO>O>[CH2:1]([C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCC(=O)c1ccncc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: CCCCCCCCCCCc1ccncc1
Reaction time: 4 h
Yield: 80.7 %

Procedure:
A mixture of 8.50 g (34 mmol) of 4-n-undecanoylpyridine, 5.55 g (0.11 mol) of hydrazine.monohydrate, 4.41 g (74 mmol) of potassium hydroxide, and 30 ml of triethylene glycol was heated at 110° to 125° C. for one hour, and further, at 180° to 185° C. for 4 hours. After cooling, 50 ml of water was added, and the mixture was extracted with diethyl ether, washed with water and then dried over anhydrous potassium carbonate. After concentration under a reduced pressure, the residue was purified by distillation under a reduced pressure to give 6.40 g of the desired product (yield 79.8%).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([N:18]1[CH2:28][CH2:27][CH2:26][C@H:19]1[C:20]([NH:22][CH2:23][CH2:24][OH:25])=[O:21])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:9]([C:16]([N:18]1[CH2:28][CH2:27][CH2:26][C@H:19]1[C:20]([NH:22][CH2:23][CH2:24][OH:25])=[O:21])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NCCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NCCO
Reaction time: 2.5 h

Procedure:
In 25 ml of methylene chloride was dissolved 790 mg of compound (51) and then 20 ml of trifluoroacetic acid was added dropwise to the solution at 0° C. to 5° C. After stirring the mixture for 2.5 hours in an icebath, the reaction mixture was concentrated to dryness under reduced pressure. Furthermore, the product was azeotropically dried several times using toluene and the residue was triturated with dry ether to provide powder of L-histidyl-N-(2-hydroxyethyl)-L-prolinamide.2-trifluoroacetate with a quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])n[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)n[nH]1
Yield: 111.6 %

Procedure:
A suspension of methyl 3-nitro-1H-pyrazole-5-carboxylate (10 g, 58.4 mmol) and 10% Pd on charcoal (1.2 g) in methanol (150 Ml) was stirred under 50 psi pressure of hydrogen gas for 16 h. The reaction mixture was filtered over a bed of Celite and the filtrate was concentrated to give 9.2 g of methyl 3-amino-1H-pyrazole-5-carboxylate which was used as such in the next reaction. MS (ESI) m/z 142.3 (M+H).
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][C:11](=[O:16])[CH:12](O)[CH:13]=[CH2:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:9][O:10][C:11](=[O:16])[CH:12]=[CH:13][CH2:14][C:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(O)C(=O)OC
Reactant: O=CC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C=CCC1(C=O)CCCCC1
Temperature: 25 °C

Procedure:
To a solution of cyclohexanecarbaldehyde (6.3 mL) and 2-hydroxy-3-butenoic acid methyl ester (5 mL) in toluene (40 mL) was added para-toluenesulfonic acid monohydrate (20 mg), and the reaction mixture was heated under reflux by using a Dean-Stark apparatus for 16.5 hours. After cooling down to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate (volume ratio)=50:1 to 10:1) to give 4-(1-formyl-cyclohexyl)-but-2-enoic acid methyl ester (3.7 g).
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.F[B-](F)(F)F.[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[N+]#N.N1C(C)=CC=CC=1C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O.C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[CH:3]1[CH:4]=[CH:5][N:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2]1
Reactant: N#[N+]c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: CC(C)(C)OC(=O)N1C=CC(c2cc(F)ccc2F)C1
Temperature: 10 °C

Procedure:
Palladium(II) acetate (67 mg, 0.30 mmol, 0.020 equiv) was added to a vigorously stirred, deoxygenated mixture of tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate (2.59 mL, 15.0 mmol, 1 equiv) and 2,5-difluorobenzenediazonium tetrafluoroborate (2-1, 3.42 g, 15.0 mmol, 1.00 equiv) in water and carbon tetrachloride (1:1, 150 mL) at 23° C., and the resulting mixture was stirred for 20 h. The reaction mixture was concentrated, and the residue partitioned between ethyl acetate (300 mL) and saturated aqueous sodium bicarbonate solution (75 mL). The organic layer was washed with brine, then dried over sodium sulfate and concentrated. The residue was dissolved in toluene (200 mL), and the resulting solution concentrated in vacuo to facilitate azeotropic removal of residual water. 2,6-Lutidine (3.50 mL, 30.0 mmol, 2.00 equiv) and trifluoroacetic anhydride (1.48 mL, 10.5 mmol, 0.700 equiv) were then sequentially added to a solution of the residue in toluene (100 mL) at −10° C. The resulting mixture was allowed to warm to 10° C. over 16 h, then heated at reflux for 1 h. The reaction mixture was allowed to cool to 23° C., then concentrated. The residue was partitioned between ethyl acetate (300 mL) and saturated aqueous sodium bicarbonate solution (150 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to 20% EtOAc in hexanes) to give tert-butyl 3-(2,5-difluorophenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (2-2) as a red oil. 1H NMR (500 MHz, CDCl3) major rotamer: δ 7.03-6.84 (m, 3H), 6.70 (br s, 1H), 5.01 (br s, 1H), 4.42 (m, 1H), 4.13 (rn, 1H), 3.60 (m, 1H), 1.50 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[C:44]([CH3:46])[N:43]=[C:42]([CH3:47])[CH:41]=2)[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:41]=[C:42]([CH3:47])[N:43]=[C:44]([CH3:46])[CH:45]=2)[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(2-methoxy-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J32) (263 mg, 0.75 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (337 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([N:6]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20](=[O:23])[CH2:21][CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.C(=O)([O-])[O-].[K+].[K+].CCCCCC>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[C:14]([C:20](=[O:23])[C:21]=1[CH3:22])=[CH:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)=[O:24]
Reactant: CCC(=O)c1ccc(Cl)cc1N(C(=O)C(=O)OC)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 80 °C
Yield: 73.6 %

Procedure:
To a stirred suspension of N-(5-chloro-2-propionyl-phenyl)-N-phenyl-oxalamic acid methyl ester (15.0 g, 43.5 mmol) in methanol (200 mL) was added potassium carbonate (35.0 g, 253 mmol) at room temperature. The mixture was heated at 80° C. for 1 hr. Completion of the reaction was monitored by silica TLC (mobile phase; hexane:ethyl acetate=7:3; Rf=0.6). The reaction mixture was cooled to room temperature. The reaction mixture was filtered through a sintered glass funnel and the solids were washed with MeOH (2×50 mL). The combined filtrates were concentrated under reduced pressure. The residue obtained was taken up in ethyl acetate (500 mL), washed with water (2×200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified by washing with a mixture of hexane-ether to afford 7-chloro-3-methyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (10.5 g, 73.4% yield). 1H NMR (DMSO-d6) δ 8.24 (d, J=8.7 Hz, 1H) 7.28-7.78 (m, 6H) 6.69 (d, J=1.7 Hz, 1H) 3.49 (s, 3H) 1.97 (s, 3H); MS calcd. for C18H14ClNO3 [(M+H)+] 328.0, obsd. 327.9.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=2[C:4]#[N:5])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1c(F)ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc(F)c2C#N)CC1
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
To 1.0 g (6.36 mmol) of 2,3,6-trifluorobenzonitrile dissolved in 10 mL DMF was added 1.05 g (1.2 eq., 7.63 mmol) potassium carbonate and 1.18 g (1 eq., 6.36 mmol) piperazine-1-carboxylic acid tert-butyl ester. The mixture was stirred 30 minutes to completion, partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated under reduce d pressure. Column chromatography, eluting with ethyl acetate/hexanes provided 665 mg of 4-(2-cyano-3,6-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:24]([CH:27]=[C:28]3[CH2:31][N:30]([CH:32]([C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=4)[C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[CH2:29]3)(=[O:26])=[O:25])[CH:18]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C>C(O)=O>[NH2:7][CH2:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:24]([CH:27]=[C:28]3[CH2:29][N:30]([CH:32]([C:40]4[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=4)[C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[CH2:31]3)(=[O:26])=[O:25])[CH:18]=2)[CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Solvent: O=CO
Product: NCC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Yield: 78.3 %

Procedure:
A solution of 76 mg of (2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)carbamic acid tert-butyl ester in 2.5 cm3 of formic acid is stirred for 1 hour at a temperature close to 45° C. The reaction medium is concentrated to dryness under reduced pressure (5 kPa) at a temperature close to 30° C., taken up in 10 cm3 of ethyl acetate and alkalinized with 10 cm3 of a saturated aqueous sodium bicarbonate solution. After separating after settling out, the organic phase is washed with 10 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 51 mg of 2-amino-1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}ethanone are thus obtained in the form of a beige lacquer [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): from 1.95 to 2.25 (broad unresolved complex, 2H), 2.77 (s, 3H), from 3.10 to 3.30 (mt, 4H), from 3.50 to 3.60 (mt, 2H), 3.56 (broad s, 2H), from 3.75 to 3.90 (mt, 4H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (broad d, J=8 Hz, 1H), 6.91 (dd, J=8 and 2 Hz, 1H), 7.01 (mt, 1H), from 7.20 to 7.40 (mt, 9H)].