Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([NH2:11])[CH:5]=1.CCN(CC)CC.[Cl:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([NH:11][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][Cl:20])[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)c1cc(N)cc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)cc(NC(=O)CCCCl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
To a solution of 3-amino-5-bromo-benzoic acid methyl ester (D12) (460 mg, 2.0 mmol, 1 equiv) in CH2Cl2 (10 ml) at room temperature was added NEt3 (306 μl, 2.2 mmol, 1.1 equiv) then 4-chlorobutyrylchloride (247 μl, 2.2 mmol, 1.1 equiv). The resulting mixture was stirred at room temperature for 16 h and then diluted with AcOEt. The organic phase was washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo to give 3-bromo-5-(4-chloro-butanoylamino)-benzoic acid methyl ester (D13) (530 mg, 79%) as a pale yellow oil. RT=2.88 s
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]Cl>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: CN(C)CCCl
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)CCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 53 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (374 mg, 2.7 mmol) and 2-dimethylaminoethyl chloride hydrochloride. (46 mg, 0.32 mmol) in N,N-dimethylformamide (1 mL) were heated in a sealed vial at 150° C. for 5 minutes. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using a gradient of 1% methanol in dichloromethane to 5% methanol in dichloromethane afforded 24 mg (53%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-dimethylaminoethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3): δ −8.86 (d, 1H), 8.23 (d, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.91 (t, 1H), 7.49 (m, 1H), 7.43 (s, 1H), 4.20 (t, 2H), 2.80 (t, 2H), 2.37 (s, 6H).
Reaction SMILES: [NH:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[C:2]([NH2:4])=[NH:3].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH:22]=[CH:23]N(C)C)=[CH:17][N:16]=1>CC(O)C>[N:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[NH:6][C:5]=1[NH:1][C:2]1[N:4]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[N:16][CH:17]=2)[CH:22]=[CH:23][N:3]=1
Reactant: CN(C)C=CC(=O)c1ccc(Cl)nc1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Solvent: CC(C)O
Product: Clc1ccc(-c2ccnc(Nc3nc4ccccc4[nH]3)n2)cn1
Temperature: 25 °C
Yield: 13.4 %

Procedure:
A solution of 2-guanidinobenzimidazole (0.83 g, 4.75 mmol) and 1-(2-chloropyrid-5-yl)-3-dimethylamino-2-propen-1-one (1.00 g, 4.75 mmol) in propan-2-ol (10 ml) was refluxed for 18 h. The solid which formed on cooling to room temperature was collected and washed with cold propan-2-ol to afford the title compound (205 mg) as a white solid m.p. 308-311°. δH (d6DMSO) 7.06 (2H, m), 7.45 (2H, m), 7.69 (1H, d, J 5.3 Hz), 7.74 (1H, d, J 8.4 Hz), 8.59 (1H, dd, J 2.5, 8.4 Hz), 8.75 (1H, d, J 5.2 Hz), 9.21 (1H, d, J 1.9 Hz) and 11.30 (1H, br s).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:28]I>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([N:19]([C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:28])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)c3ccccc3)ccc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccc1)c1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
Sodium hydride (60 mg, 1.5 eq.) was added to a mixture of 5-benzoylamino-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (570 mg, 1.68 mmol) and methyl iodide (0.42 mL, 4.0 eq.) in DMF (10 mL) at 0° C. and the resulting mixture was stirred for 20 min. After concentration, the residue from reaction mixture was diluted with sat. NaHCO3 and extracted with 3×EtOAc. The combined extracts were dried over Na2SO4, filtered, concentrated and the product was purified by chromatography (30% EtOAc-hexanes) to give 5-(benzoyl-methyl-amino)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (547 mg, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1.[CH3:23][NH2:24]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([NH:24][CH3:23])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(C)cccc3c21
Reactant: CN
Product: CNc1nc2c(C)cccc2c2c1ccn2-c1ccccc1C

Procedure:
1-(2-Methylphenyl)-4-chloro-6-methylpyrrolo[3,2-c]quinoline (1.5 g, 4.9 mmol) and methylamine (33% in ethanol, 50 ml) were heated to 150° C. in a pressure vessel for 16 hours, then the solvent evaporated. Chromatography (silica gel, 2% methanolic ammonia in dichloromethane) and recrystallisation from aqueous ethanol yielded 1-(2-methylphenyl)-4-methylamino-6-methylpyrrolo[3,2-c]quinoline (0.62 g),m.p. 129°-130°.
Reaction SMILES: [ClH:1].Cl.Cl.C1([NH:7][C:8]([C:10]2[C:18]3[CH:17]=[C:16]([C:19]4[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[N:20]=4)[S:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])CC1.[Cl:37]C1N=C(C2SC3C=CC=C([C:53](O)=[O:54])C=3C=2)C(Cl)=CN=1>>[ClH:25].[ClH:37].[ClH:1].[CH3:53][O:54][NH:7][C:8]([C:10]1[C:18]2[CH:17]=[C:16]([C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[N:20]=3)[S:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reactant: O=C(O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Agent: Cl
Product: CONC(=O)c1cccc2sc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)cc12

Procedure:
Using the method of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide tri-hydrochloride, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid and isolated as a yellow solid. ES+(m/z) 475 (35Cl) and 477 (37Cl) [M(free base)+H].
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.C(O[C@H:14]1[O:26][C@@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]1[O:16][C:17](=[O:19])[CH3:18])(=O)C>[N+](C1C=CC(OP([O-])(OC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1)([O-])=O.O>[C:17]([O:16][C@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:26][C@@H:14]1[N:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1)(=[O:19])[CH3:18]
Reactant: COC(=O)c1nc[nH]n1
Reactant: CC(=O)OC[C@@H]1O[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=[N+]([O-])c1ccc(OP(=O)([O-])Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: O
Product: COC(=O)c1ncn([C@H]2O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Reaction time: 0.42 h
Yield: 66 %

Procedure:
A mixture of methyl 1,2,4-triazole-3-carboxylate (0.64 g, 5 mmol), 1,2,3,5-tetra-O-acetyl-β-L-ribofuranose (2) (1.5 g, 4.72 mmol) and bis(p-nitrophenyl)-phosphate (20 mg) were placed in a pear shaped flask and placed in a preheated oil bath at (160-165° C.). The flask was connected to a water aspirator and kept at 160-165° C. (oil bath temperature) under reduced pressure with stirring for 25 min. The reaction mixture was removed, cooled and diluted with EtOAc (150 mL) and sat. NaHCO3 (100 mL). The product was extracted in EtOAc. The organic extract was washed with water (100 mL) and brine (50 mL), dried and evaporated to dryness. The residue that obtained was purified by flash column of silica gel using CHCl3→EtOAc as the eluent. The pure fractions were collected and evaporated to dryness to give 1.2 g (66%) of pure product: 1H NMR (CDCl3) δ2.10 (3s, 9H, 3 COCH3), 3.98 (s, 3H, OCH3), 4.22 (m, 1H), 4.46 (m, 2H), 5.54 (t, 1H), 5.76 (m, 1H), 6.04 (d, 1H, C1′H), and 8.38 (s, 1H, C3H). Anal. Calc. for C15H19N3O9 (385.22): C, 46.75; H, 4.97; N,10.91. Found: C, 46.82; H, 4.57; N=10.71.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([C@@H:15]2[CH2:17][C@H:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26][CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[C:31]([NH:30][CH:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([C@@H:15]3[CH2:17][C@H:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:25][CH2:26]1)(=[O:33])[CH3:32]
Reactant: CC(=O)NC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)[C@@H]3C[C@H]3c3ccccc3)cc(Cl)n2n1
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CO
Product: CC(=O)NC1CCN(c2cc(NC(=O)[C@@H]3C[C@H]3c3ccccc3)nc3cc(C)nn23)CC1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
The title compound was prepared by combining (1R,2R)—N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropane carboxamide (8D, 0.1 g, 0.306 mmol) and the N-(piperidin-4-yl)acetamide (0.087 g, 0.612 mmol) in NMP (Volume: 1.020 ml) and heating the mixture at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by 45-65% preparatory HPLC (MeCN/MeOH)/H2O+0.01% TFA). Lyophilization of the combined fractions gave 87 mg (66%) of the titled compound as a white solid. Melting point (190.2-231.1° C.). 1H NMR (DMSO-d6) δ: 10.95 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.23-7.37 (m, 3H), 7.12-7.24 (m, 3H), 6.08 (s, 1H), 4.30 (d, J=12.9 Hz, 2H), 3.88 (br. s., 1H), 3.16 (dd, J=24.3, 11.6 Hz, 2H), 2.39-2.47 (m, 1H), 2.25-2.38 (m, 4H), 1.89 (d, J=13.6 Hz, 2H), 1.82 (s, 3H), 1.46-1.62 (m, 3H), 1.40 (ddd, J=8.2, 6.4, 4.0 Hz, 1H); [α]D20=+218° (C=0.6917, MeOH). ESI-MS: m/z 433.0 (M+H)+. Melting point (190.2-231.1° C.).
Reaction SMILES: [BH4-].[Na+].Cl.[CH3:4][O:5][C:6]([C:8]1[CH2:9][N:10]([CH2:15][CH2:16][CH:17]2[O:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[O:19][CH2:18]2)[CH2:11][CH2:12][C:13]=1[OH:14])=[O:7].Cl.COC(C1C(=O)CCN(CCC2OC3C=CC=CC=3OC2)C1)=O>CO>[CH3:4][O:5][C:6]([C@H:8]1[C@H:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH:17]2[O:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[O:19][CH2:18]2)[CH2:9]1)=[O:7]
Reactant: COC(=O)C1=C(O)CCN(CCC2COc3ccccc3O2)C1
Agent: COC(=O)C1CN(CCC2COc3ccccc3O2)CCC1=O
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: COC(=O)[C@@H]1CN(CCC2COc3ccccc3O2)CC[C@H]1O
Reaction time: 4 h
Yield: 48.1 %

Procedure:
At -15° and while stirring, 2.65 g (70 mmol) of sodium borohydride are added in portions over a period of one hour to a suspension of 12.45 g (35 mmol) of 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride or 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-oxopiperidine-3-carboxylic acid methyl ester hydrochloride, respectively, in 250 ml of methanol. Stirring is continued for a further 4 hours at -10° and then the reaction mixture is concentrated by evaporation in vacuo and taken up in water/ethyl acetate. The ethyl acetate extracts are washed with water, dried over sodium sulphate and concentrated by evaporation. 11.2 g (100%) of crude product are obtained which are chromatographed on 560 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 5.41 g (48.2%) of trans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylic acid methyl ester are obtained in the form of a pale yellow oil. The trans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylic acid methyl ester fumarate produced therefrom using fumaric acid crystallises from methanol/diethyl ether in the form of the hemihydrate having a melting point of 150°-152°.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>>[CH:16]1([CH2:15][O:8][C:6]2[CH:7]=[C:2]([F:1])[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=2)[CH2:18][CH2:17]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1ncc(O)cc1F
Product: CCOC(=O)c1ncc(OCC2CC2)cc1F

Procedure:
Using ethyl 3-fluoro-5-hydroxypyridine-2-carboxylate and (bromomethyl)cyclopropane, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C@@H:4]([C:5]#[C:6][C:7]([O:9][C:10]([CH2:13][CH3:14])([CH3:12])[CH3:11])=[O:8])[C@H:3]1[C:15]([O:17][C@H:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16].N1C2C(=CC=CC=2)C=CC=1>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[CH3:34][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][C:10]([CH2:13][CH3:14])([CH3:11])[CH3:12])=[O:8])[C@H:3]1[C:15]([O:17][C@H:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1)=[O:16]
Reactant: CCC(C)(C)OC(=O)C#C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CCC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A mixture of 1.34 g of the product of Step A, 220 mg of 10% palladium hydroxide on barium sulfate, 20 ml of ethyl acetate and 0.25 ml of quinoline was hydrogenated for 30 minutes and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 9:1 cyclohexane-ethyl acetate mixture yielded 1.05 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-(tert.-amyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+63.5°±2.5° (c=0.7% in chloroform).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>CN(C)C=O>[Si:21]([O:20][CH2:19][CH2:18][O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OCCO[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.5 %

Procedure:
5.00 g (24.8 mmol) of tert-butyl 4-hydroxy-1-piperidine carboxylate was dissolved in 100 mL of dimethylformamide and 1.08 g (24.8 mmol) of sodium hydride (55% or more, oily) was added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 4 hours. Thereafter, 20 mL of a solution of 6.54 g (27.3 mmol) of (2-bromoethoxy)-tert-butyldimethylsilane in dimethylformamide was added dropwise to the reaction mixture under ice-cooling and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate, followed by washing successively with water and a saturated NaCl solution and drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel chromatography (eluting solvent: hexane/ethyl acetate=100/0-90/10) to obtain 1.65 g (yield: 18%) of the title compound as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[N:17]=[C:5]2[N:6]=[C:7](Cl)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.ClCCl.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]>[Br:1][C:2]1[N:17]=[C:5]2[N:6]=[C:7]([C:23]3[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Clc1nc2nc(Br)nn2cc1-c1ccccc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(-c2nc3nc(Br)nn3cc2-c2ccccc2)cc1
Temperature: 100 °C

Procedure:
To a mixture of 1.0 g 2-bromo-5-chloro-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine and 0.48 g 4-formylphenylboronic acid in 10 ml 1,2-dimethoxyethane are added 6.2 ml of a 10% w/w sodium carbonate solution and 118 mg dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) and the resulting mixture is heated to 100° C. by microwave irradiation under a inert gas atmosphere for 50 min. The work up is performed by diluting the reaction mixture with water and dichloromethane, separating the phases and extraction of the aqueous phase with dichloromethane. The combined organic layers are dried over Na2SO4 and the solvent is evaporated. The crude product is purified by chromatography on silica gel (dichloromethane/ethyl acetate) to yield the desired product.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Cl:12][C:13]1[CH:14]=[C:15](/[CH:19]=[CH:20]/[C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:21](=[O:22])/[CH:20]=[CH:19]/[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1cccc(Cl)c1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(3-chlorophenyl)propenoic acid; the compound was purified by chromatography on silica gel using amrnmoniated methanol/chloroform mixtures as the eluent; MS (ES+) 291, 293 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:17]([NH2:18])=[N:16][NH:15][C:12]2=[CH:13][N:14]=1.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21]>N1C=CC=CC=1.CO.ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:17]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])=[N:16][NH:15][C:12]2=[CH:13][N:14]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1n[nH]c2cnc(-c3cccc(F)c3F)cc12
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)C(=O)Nc1n[nH]c2cnc(-c3cccc(F)c3F)cc12

Procedure:
5-(2,3-Difluorophenyl)-1H-pyrazolo[3,4-c]pyridin-3-ylamine (Description 3; 100 mg, 0.41 mmol) was reacted with isobutyryl chloride (43 uL, 0.41 mmol) in pyridine (0.5 mL) in a manner analogous to that described in Example 1. Chromatography on silica gel using 4% v/v methanol in dichloromethane as eluent afforded the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13]Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([NH:23][CH:24]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:19]=[CH:20][C:21]=1[F:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][N:28]2[CH2:29][CH2:30][CH:25]([CH:24]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[NH:23][C:18]3[CH:19]=[CH:20][C:21]([F:22])=[C:16]([F:15])[CH:17]=3)[CH2:26][CH2:27]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCCCl)c1ccc(Cl)cc1
Reactant: Fc1ccc(C(Nc2ccc(F)c(F)c2)C2CCNCC2)cc1
Product: O=S(=O)(CCCN1CCC(C(Nc2ccc(F)c(F)c2)c2ccc(F)cc2)CC1)c1ccc(Cl)cc1

Procedure:
Following the procedure of Example 2, the title compound is prepared from 1-chloro-4-[(3-chloropropyl)sulfonyl]benzene and N-(3,4-difluorophenyl)-α-(4-fluorophenyl)-4-piperidinemethanamine.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)(=[O:12])[CH3:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:44]=[C:45]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:46][NH:47][C:48]([C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)=[O:49]>CN(C=O)C.O>[C:10]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([N:65]1[CH2:64][CH2:63][N:62]([C:45](=[O:44])[CH2:46][NH:47][C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:52][CH:51]=2)=[O:49])[CH2:67][CH2:66]1)=[O:17])(=[O:12])[CH3:11]
Reactant: CC(=O)c1ccccc1C(=O)O
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
DIPEA (179.8 mg, 1.39 mmol) was added to the stirred solution of 2-acetyl-benzoic acid (50.75 mg, 0.31 mmol) in DMF (3 mL), HOBt (45.95 mg, 0.34 mmol) and EDCI.HCl (148.14 mg, 0.77 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (120 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 30 mg (20.6% yield) of biphenyl-4-carboxylicacid {2-[4-(2-acetyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 95.52%, 1H NMR: (DMSO) δ 8.64 (s, 1H), 8.0 (dd, 3H), 7.84-7.72 (q, 4H), 7.7-7.64 (t, 1H), 7.6 (t, 1H), 7.5 (t, 2H), 7.44-7.32 (m, 2H), 4.26-4.1 (dd, 2H), 3.76-3.62 (d, 4H), 3.46 (s, 2H), 3.3 (d, 2H), 2.6 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13](=O)[NH:12][C:11](=[O:15])[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[NH:22][C:23]=1[CH3:24])=[O:5])[CH3:2].CN(C)C=O.O=P(Cl)(Cl)[Cl:38].C([O-])(=O)C.[K+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13]([Cl:38])=[N:12][C:11](=[O:15])[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[NH:22][C:23]=1[CH3:24])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C1=C(C)Nc2c(c(=O)[nH]c(=O)n2-c2ccccc2)C1c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2c(c(Cl)nc(=O)n2-c2ccccc2)C1c1ccccc1
Temperature: 25 °C
Yield: 72 %

Procedure:
The compound from step 5 (11 g, 27.3 mmol) was taken in 100 ml dry chloroform and then charged with DMF (dimethylformamide) (2 ml, 27 mmol). POCl3 (14 ml) was dissolved in advance in 26 ml chloroform and was added under stirring in an argon atmosphere. The reaction mixture was then stirred at 70 C for 6 h. The reaction was monitored by LC-MS. The reaction mixture was cooled down to room temperature and poured into 25% ice cold solution of potassium acetate (150 ml) under vigorous stirring, organic phase was separated, aqueous phase was extracted with DCM (dichloromethane) (2×100 ml) and the combined organic solution was dried over magnesium sulfate and then the solvent was evaporated under vacuum yielding yellow solids (8.3 g, 19.7 mmol, 72%).