Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[O:2]1[CH:7]=[CH:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=[O:9].[H][H]>CO.[Ni]>[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=[O:9]
Reactant: [H][H]
Reactant: O=C(O)C1CCC=CO1
Agent: [Ni]
Agent: [Na]
Solvent: CO
Product: O=C(O)C1CCCCO1

Procedure:
210 g. of the sodium salt of 3,4-dihydro-2H-pyran-2-carboxylic acid dissolved in 2 liters methanol and hydrogenated at 3 atmosphere pressure over 60 g. haney nickel catalyst. After hydrogen uptake was complete the catalyst was filtered and the solvents removed in vacuo. The residue was acidified with concentrated hydrochloric acid and extracted with chloroform. Distillation gave 143.8 g. product, b.p. 75°-80° C./0.4 mm ND25 =1.4633.
Reaction SMILES: C(OCC)(=O)C.[ClH:7].[CH2:8]([O:10][C:11]([C@@H:13]([NH:32][C@@H:33]1[C:39](=[O:40])[N:38]([CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[C:37]2[CH:49]=[CH:50][CH:51]=[CH:52][C:36]=2[O:35][CH2:34]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])=[O:12])[CH3:9]>>[ClH:7].[CH2:8]([O:10][C:11]([C@@H:13]([NH:32][C@@H:33]1[C:39](=[O:40])[N:38]([CH2:41][C:42]([OH:44])=[O:43])[C:37]2[CH:49]=[CH:50][CH:51]=[CH:52][C:36]=2[O:35][CH2:34]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])=[O:12])[CH3:9]
Reactant: CCOC(=O)[C@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Reaction time: 3 h

Procedure:
A mixture of 5N hydrogen chloride-ehtyl acetate solution (5 ml) and tert-butyl 3(S)-[1(S)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.1 g) is allowed to stand at room temperature for 3 hours. The mixture is diluted with petroleum ether (80 ml) to precipitate colorless powder, which is collected and dried in vacuo to give 3(S)-[1(S)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid.hydrochloride (0.067 g).
Reaction SMILES: [C:1]12([NH:11][C:12]3[CH:17]=[C:16]([NH:18][C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)[N:15]=[C:14](Cl)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[C:1]12([NH:11][C:12]3[CH:17]=[C:16]([NH:18][C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)[N:15]=[C:14]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C1CNCCN1
Reactant: Clc1nc(NC23CC4CC(CC(C4)C2)C3)cc(NC23CC4CC(CC(C4)C2)C3)n1
Product: c1c(NC23CC4CC(CC(C4)C2)C3)nc(N2CCNCC2)nc1NC12CC3CC(CC(C3)C1)C2
Yield: 94.4 %

Procedure:
4,6-bis(1-adamantylamino)-2-chloropyrimidine is reacted with piperazine according to the method of Example 4 to obtain the title compound in a yield of 94.4%, m.p.:210°-220° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:33]=[N:32][CH:31]=[CH:30][N:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1cnccn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cnccn5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-pyrazine following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.11 min; Mass spectrum (ESI+): m/z=437 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]2[C:15]=1I)=[O:4].[Li+].[CH3:20]CC[CH2-].CI>O1CCCC1>[F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]2[C:15]=1[CH3:20])=[O:4]
Reactant: O=C(Nc1nc2ccc(F)cn2c1I)C(F)(F)F
Reactant: [CH2-]CCC
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(NC(=O)C(F)(F)F)nc2ccc(F)cn12
Temperature: -78 °C

Procedure:
2,2,2-trifluoro-N-(6-fluoro-3-iodoimidazo[1,2-a]pyridin-2-yl)acetamide (0.500 g, 0.00134 mol) was dissolved in tetrahydrofuran (16 mL) and was cooled at −78° C. N-Butyllithium (2 molarin cyclohexane, 1.6 mL) was added and the reaction was warmed to −20 for 15 minutes then chilled to −78° C. Methyl iodide (110 uL, 0.0017 mol) was added and the reaction was allowed to warm to room temperature. The reaction was poured into ice water and extracted with ethyl acetate (3×50 mL). The combined organics were dried (magnesium sulfate) and solvent removed. Residue chromatographed on silica (50% ethyl acetate/hexanes) to give 2,2,2-trifluoro-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)acetamide 5 Rf 0.47, 50% ethyl acetate/hexanes; MS m/z 262 (M+H).
Reaction SMILES: [NH3:1].[C:2]1([C:8]2[C:9]3[S:32][CH:31]=[CH:30][C:10]=3[N:11]=[C:12](OP(N3CCOCC3)(N3CCOCC3)=O)[CH2:13][N:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>>[C:2]1([C:8]2[C:9]3[S:32][CH:31]=[CH:30][C:10]=3[N:11]=[C:12]([NH2:1])[CH2:13][N:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=P(OC1=Nc2ccsc2C(c2ccccc2)=NC1)(N1CCOCC1)N1CCOCC1
Product: NC1=Nc2ccsc2C(c2ccccc2)=NC1

Procedure:
Gaseous ammonia was conducted into a solution of 14.4 g of dimorpholin-4-yl-phosphinic acid (5-phenyl-3H-thieno[3,2-e][1,4]-diazepin-2-yl) ester at room temperature while stirring until the starting product had reacted completely. After removal of the solvent in a vacuum the residue was extracted with dichloromethane/water in the presence of a small amount of methanol. The aqueous phase was washed several times with dichloromethane, the dichloromethane extracts were dried with sodium sulphate, filtered and evaporated in a vacuum. The residue was suspended in dichloromethane and stirred for 0.5 h. There were obtained 2.9 g of crude 5-phenyl-3H-thieno[3,2-e][1,4]diazepin-2-ylamine which was used without further purification as the starting product for the step described below.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:22][CH2:23][N:24]([C:39]([CH:36]4[CH2:38][CH2:37]4)=[O:40])[CH2:25][CH2:26]3)[C@H:17]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:16]2)=[O:14])[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccc(F)cc2)C1
Reactant: O=C(Cl)C1CC1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(C(=O)C3CC3)CC2)[C@H](c2ccc(F)cc2)C1

Procedure:
The title compound, MS: m/e=572.1 (M+H+), was prepared in accordance with the general method of example 38 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3-(4-fluoro-phenyl)-4-piperazin-1-yl-piperidin-1-yl]-methanone and cyclopropane carboxylic acid chloride.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:8]([CH:9](Br)Br)=[N:7][CH:6]=[CH:5][N:4]=1.[C:13]([O:22][CH2:23][CH3:24])(=[O:21])/[CH:14]=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17].[Na+].[I-]>CN(C=O)C>[CH2:23]([O:22][C:13]([C:14]1[CH:2]=[C:3]2[C:8](=[CH:9][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]=[CH:6][CH:5]=[N:4]2)=[O:21])[CH3:24]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: BrC(Br)c1nccnc1C(Br)Br
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nccnc2cc1C(=O)OCC
Temperature: 80 °C
Yield: 36.9 %

Procedure:
To a solution of 38.0 g (90.0 mmol) 2,3-bis-dibromomethyl-pyrazine and 70.0 g (400 mmol) diethyl maleate in 450 ml DMF is added 40.0 g (270.0 mmol) NaI and the mixture is heated at a temperature of 80° C. during 20 hours. After evaporation of the solvent, the residue is dissolved in 1000 ml t-butyl-methyl ether and washed with a 5% sodium thiosulfate solution and water (5 times). Evaporation of the solvent and purification of the residue with flash-chromatography yielded 9.1 g dark oil (37%). 1H-NMR (CDCl3, 400 MHz): 1.45 ppm (t, 6H), 4.45 (q, 4H), 8.5 (s, 2H), 9.0 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:5]([O:7][CH3:8])=[O:6].[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>C(OCC)(=O)C>[CH3:22][C:21]([CH3:24])([CH3:23])[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:5]([O:7][CH3:8])=[O:6])=[O:25]
Reactant: COC(=O)c1ccc(NCC2CCOCC2)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NCC2CCOCC2)c(NC(=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 67.7 %

Procedure:
To a solution of methyl 3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]benzoate (step B, 527 mg, 1.93 mmol) in ethyl acetate (16 mL) was added pivaloyl chloride (256 mg, 2.12 mmol) at room temperature. After stirring for 14 h at room temperature, the mixture was quenched with saturated sodium hydrogencarbonate aqueous solution. The mixture was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound (455 mg, 71%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[C:1]1(/[CH:7]=[CH:8]/[CH2:11][C:12]([OH:14])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=CCc1ccccc1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
To a stirred solution of 2-phenylacetaldehyde (5.0 g, 32.3 mmol) and malonic acid (4.0 g, 38.8 mmol) in pyridine (25.0 mL) was added a catalytic amount of piperidine (0.64 mL, 6.46 mmol) then heated to reflux. After 3 h, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was slowly added 2N HCl. The white precipitate was filtered off and dried under vacuum to produce the title compound (3.5 g, 55˜80%)
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:20]=[C:21]([NH:25]C(=O)C)[CH:22]=[CH:23][CH:24]=4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=4)[NH2:25])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1cccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c1
Temperature: 100 °C

Procedure:
A stirred mixtureof N-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidiny]propoxyl]phenyl]acetamide (9.2 g, 22 mmol), prepared as described in the previous example, in 15% hydrochloric acid (110 ml) was heated at 100° C. for 2.5 hours until a homogeneous solution resulted. The reaction was cooled to 0° C. in an ice bath and basified with 50% NaOH. The product was extracted with ethyl acetate (3×200 ml). The ethyl acetate solution was washed with water, brine, then dried over Na2SO4. The solvent was removed. The crude product was purified on a flash chromatography column. The product thus obtained was a solid: 6.6 g (80%). Recrystallization from hot ethanol (50 ml) gave 3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-aniline as off-white crystals: 3.46 g, m.p.=115°-117° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N+:59]([C:62]1[CH:70]=[CH:69][C:65]([C:66](O)=[O:67])=[CH:64][CH:63]=1)([O-:61])=[O:60].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:66](=[O:67])[C:65]2[CH:64]=[CH:63][C:62]([N+:59]([O-:61])=[O:60])=[CH:70][CH:69]=2)[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:27][CH:28]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2OC(=O)c2ccc([N+](=O)[O-])cc2)cc1-c1ccc(OC2CCCCC2)cc1
Yield: 77.5 %

Procedure:
To a stirred mixture of (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (Example 43, 1.18 mmol, 0.64 g), PPh3 (1.43 mmol, 0.375 g) and p-nitrobenzoic acid (1.5 mmol, 0.251 g) in anhydrous THF (15 mL) at −60° C. was added DIAD (1.43 mmol. 0.289 mL) over 10 min. The stirring was continued and let the reaction slowly attain room temperature over 3 h. The reaction mixture was diluted with ether (300 mL), washed with water (100 mL) followed by saturated sodium bicarbonate (100 mL). The organic layer was dried, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel flash column chromatography by eluting with 20% ethyl acetate in hexanes to provide (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-(4-nitro-benzoyloxy)-piperidine-1-carboxylic acid tert-butyl ester (0.63 g).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:5]1)(=O)C.CCN(CC)CC>CO>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][N:13]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(=O)n1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2c[nH]c3ccccc23)CC1
Reaction time: 1 h

Procedure:
Into a 250 mL round bottom flask was placed a solution of tert-butyl 4-(1-acetyl-1H-indol-3-yl)piperazine-1-carboxylate (2.6 g, 7.58 mmol) in methanol (80 mL). To the mixture was added Et3N (2.3 g, 22.73 mmol). The resulting solution was allowed to react, with stirring, for 1 hour while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by LCMS and TLC (ethyl acetate/petroleum ether=1:1). The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was diluted with 200 mL of ethyl acetate. The resulting mixture was washed 3 times with 150 mL of NaCl(aq.). The residue was purified by eluting through a column with a 10:1 petroleum ether/ethyl acetate solvent system. This resulted in 2.1 g (89%) of tert-butyl 4-(1H-indol-3-yl)piperazine-1-carboxylate as a light pink solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13](Cl)=[CH:14][C:15]=3[Cl:19])[NH:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[H-].[Na+].Cl.C1C[O:29][CH2:28]C1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:29][CH3:28])=[CH:14][C:15]=3[Cl:19])[NH:10][C:9]2=[O:21])=[CH:4][CH:3]=1
Reactant: CC1(c2ccc(Br)cc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Reactant: C1CCOC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COc1cc(Cl)c2c(c1)NC(=O)C(C)(c1ccc(Br)cc1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of 3-(4-bromo-phenyl)-5,7-dichloro-3-methyl-1H-quinoline-2,4-dione (600 mg, 1.40 mmol) in dry THF (30 mL) was added NaH (140 mg, 3.50 mmol) at 0° C. and stirred for 1 hour at room temperature. The reactant was poured into a 0.5N HCl solution and extracted with ethyl acetate (100 mL×3). The organic layer was washed with brine (100 mL×2), dried over anhydrous MgSO4, and concentrated in vacuo. The pure objective compound (260 mg, 47%) was obtained as white solid by a flash column chromatography (n-hexane:EtOAc=5:1): 1H NMR (200 MHz, CDCl3) δ 1.73 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 6.48 (d, J=1.6 Hz, 1H, ArH), 6.60 (d, J=1.6 Hz, 1H, ArH), 7.11-7.44 (m, 4H, ArH), 8.62 (br s, 1H, NH); m.p. 239-240° C.; MS(EI) m/e 393 [M+], 210, 183; HRMS m/e cacld. for C17H13N1O3Br1Cl1 392.9767, found 392.9760.
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]([CH2:22][CH3:23])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:11]([F:21])[CH:10]=1)=[O:7])[CH3:4].[CH3:24][O:25][C:26](=[O:36])[CH:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:24][O:25][C:26](=[O:36])[CH:27]([N:18]1[CH2:17][CH2:16][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[CH:5]([CH2:3][CH3:4])[CH2:22][CH3:23])=[CH:10][C:11]=2[F:21])[CH2:20][CH2:19]1)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: COC(=O)C(Br)c1cccc(F)c1
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)OC)c3cccc(F)c3)CC2)c(F)c1
Reaction time: 20 h
Yield: 77.7 %

Procedure:
A mixture of 2-ethyl-N-(3-fluoro-4-piperazin-1-yl-phenyl)-butyramide dihydrochloride (0.26 g, 0.70 mmol), bromo-(3-fluoro-phenyl)-acetic acid methyl ester (0.23 g, 0.91 mmol), and anhydrous K2CO3 (0.34 g, 2.45 mmol) in DMF (10 mL) was stirred for 20 h. The mixture was diluted with water (100 mL) and extracted with DCM (2×30 mL). The combined organic layers were washed with water, dried (Na2SO4), and concentrated. The residue was purified (SiO2; acetone/DCM) to give the title compound (0.25 g, 78%). MS: mass calcd. for C25H31F2N3O3, 459.23. m/z found, 460.3 [M+H]+. 1H NMR (CDCl3): 7.48-7.43 (m, 1H), 7.35-7.28 (m, 1H), 7.25-7.20 (m, 2H), 7.17 (br s, 1H), 7.12-7.07 (m, 1H), 7.05-6.99 (m, 1H), 6.86 (t, J=9.0, 1H), 4.07 (s, 1H), 3.71 (s, 3H), 3.11-3.04 (m, 4H), 2.70-2.59 (m, 4H), 2.03-1.95 (m, 1H), 1.75-1.66 (m, 2H), 1.59-1.49 (m, 2H), 0.93 (t, J=7.4, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:32]>>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][C:31](=[O:32])[N:14]([C@@H:13]2[C@@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12]2)[CH3:15])=[CH:35][CH:36]=1
Reactant: CN[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(OC(=O)Cl)cc1
Product: COc1ccc(OC(=O)N(C)[C@H]2CN(C(=O)C3CCN(C(=O)C4(C)CC4)CC3)C[C@@H]2c2ccc(Cl)c(Cl)c2)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid p-methoxy-phenyl ester was prepared from rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using p-methoxyphenyl chloroformate instead of 4-fluorophenyl chloroformate and was obtained as a light brown foam. MS m/e: 588.2 [M]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][CH2:9][C:10](=[CH2:22])[CH:11]([OH:21])[CH:12]([NH:18][CH:19]=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:2].S(Br)([Br:25])=O>O>[Br:25][CH2:22][CH:10]([CH2:9][CH2:8][O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]([OH:21])[CH:12]([NH:18][CH:19]=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=S(Br)Br
Reactant: C=C(CCOCC(=O)OCC)C(O)C(NC=O)C(=O)OCC
Solvent: O
Product: CCOC(=O)COCCC(CBr)C(O)C(NC=O)C(=O)OCC
Reaction time: 0.17 h

Procedure:
7.5 g (23.6 mmol)of ethyl 6-ethoxycarbonylmethoxy-2-formylamino-3-hydroxy-4-methylene-hexanoate are dissolved in 75 ml of CH2C12 and 2.2 ml (28.3 mmol) of thionyl bromide are then added dropwise at room temperature to this solution. After 1 hour 50 ml of water are added and the reaction mixture is stirred vigorously for 10 minutes. The organic phase is separated and washed once with water, once with a 1N solution of KHCO3 and once with brine. The aqueous phases are extracted twice with CH2Cl2. The combined organic phases are dried over Na2SO4, filtered, and concentrated by evaporation giving ethyl 4-bromomethyl-6-ethoxycarbonylmethoxy-2-formylamino-3-hydroxy-hexanoate as a yellow oil which is further reacted without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O-])(=O)C.[Na+].[Br:20]Br.O>C(O)(=O)C>[Br:20][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:11][CH2:12][C:13]#[N:14]
Reactant: BrBr
Reactant: COc1ccc(CCC#N)cc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Br)c(CCC#N)cc1OC
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a mixture of 21 g of 3-(3,4-dimethoxyphenyl)propanenitrile, 10.3 g of sodium acetate and 400 mL of acetic acid there are added 20 g of dibromine in 50 mL of acetic acid. The resulting reaction mixture is stirred overnight and then poured into water and extracted with benzene. The organic phase is washed with aqueous sodium thiosulphate solution and then with water, dried over sodium sulphate and concentrated under reduced pressure. The crude reaction product is purified on a silica column (eluant: benzene), and the product obtained is recrystallised from ethanol to yield 19.3 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:12][CH3:13].[C:18](Cl)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:12]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:5][CH2:4][C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:18](=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:13]
Reactant: CCN1CCCCC1CCc1ccccc1N
Reactant: O=C(Cl)C=Cc1ccccc1
Product: CCN1CCCCC1CCc1ccccc1NC(=O)C=Cc1ccccc1

Procedure:
Reaction of 2-(2-aminophenethyl)-1-ethylpiperidine with cinnamoyl chloride according to the procedure of Example 25 provides 2'-[2-(1-ethyl-2-piperidyl)ethyl]cinnamanilide, m.p. 119.5° - 121.5° C. (corr.), from ethyl acetate and then acetonitrile.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10]Cl)[N:6]=1)[C:2]([CH3:4])=[O:3].C(N(CC)CC)C.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Cc1nc(CCl)no1
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Cc1nc(CN2CCCCC2)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.8 %

Procedure:
To a solution of 15.0 g of 5-acetonyl-3-chloromethyl-1,2,4-oxadiazole in 50 ml of THF were added dropwise 17.4 g of triethylamine and subsequently 11.0 g of piperidine. The mixture was stirred at room temperature for 24 hours and then heated under reflux for 6 hours. After cooling, the precipitated material was removed by filtration and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel using chloroform-methanol (20:1, v/v) as eluent to give 10.9 g of 5-acetonyl-3-piperidinomethyl-1,2,4-oxadiazole as a colorless solid, m.p. 66°-67° C.