Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]([F:16])[CH:14]=[CH2:15])[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]CC.CCOCC.CCCCCC>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]([F:16])[CH:14]=[CH:15][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCCCCCCCCCCCC
Reactant: C=CC(F)[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCCCCCCCC=CC(F)[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 36 h

Procedure:
tert-Butyl-(4S)-4-(1-fluoroprop-2-en-1-yl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (0.036 g, 0.14 mmol) and 1-pentadecene (0.2 ml, 5 eq) were solubilised in anhydrous CH2Cl2 (2.5 ml) under an atmosphere of nitrogen, in a sealed tube. Grubbs 2nd Generation catalyst (0.006 g, 2 mol %) was added as a solid, and the reaction mixture was allowed to stir for 36 hours at 100° C., with the reaction monitored by t.l.c. (ether:hexane, 1:19). The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. Purification by flash chromatography (ether:hexane, 1:19) afforded the product (0.062 g, quantitative yield) and a mixture of compounds of varying alkyl chain length. Tentative analysis of this compound describes a mixture of products. m/z: HRMS required for C26H48FNO3 mass is 441.3600, found 441.3618 as major compound, also found 413.3164, 427.3433, 455.3875 and 469.3886 as minor products; IR (film) νmax (cm−1) 2926, 1704, 1386; 1H NMR (CDCl3, 400 Mhz) δ=5.81 (m, 1H, H8), 5.51 (m, 1H, H7), 5.10 and 4.94 (2 m, H6erythreo, threo), 4.08 (m, 1H, H4), 3.94 (m, 2H, H5,5′), 2.04 (m, 2H, H9,9′), 1.48 (m, 15H, NCOOC(CH3)3 and —OC(CH3)2N—), 1.25 (br s, 22H, (CH2)11), 0.88 (t, J=7.0, 3H, CH3, H21); 13C-NMR (CDCl3, 100.6 MHz) δ=152.4 (—NCOO—), 136.9 (CH, C8), 125.2 (CH, C7), 94.4 (CH, C6), 93.9 (OC(CH3)2N), 80.4 (OC(CH3)3), 63.4 (CH, C4), 60.4 (CH2, C5), 31.6, 31.9, 29.7, 22.7, 21.0 (12C, CH2, (CH2)12), 28.4 (CH3, OC(CH3)3), 26.9 and 24.7 (CH3, —OC(CH3)2N—), 14.1 (CH3, (CH2)12CH3)); 19F-NMR (CDCl3, 400 MHz) δ=major compounds −183.0, −186.0, minor compounds −175.6, −177.7, −192.6, −194.6;
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[C:11](=[CH:16][CH:17]=1)[C:12]([O:14][CH3:15])=[O:13].C[O:23][C:24]1[CH:25]=[C:26](CC(O)=O)[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32].CCN(CC)CC.C[CH2:53][O:54][C:55]([CH3:57])=O>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:57]=[C:28]([CH:29]([NH:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])=[O:32])[C:24]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][O:7][C:8]2[CH:9]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[C:11](=[CH:16][CH:17]=2)[C:12]([O:14][CH3:15])=[O:13])=[O:23])[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2)cc1C(=O)OC
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)C(NC(=O)Nc2ccccc2C)c2cccc(OC)c2)cc1C(=O)OC
Reaction time: 8 h
Yield: 97 %

Procedure:
To a stirred solution of dimethyl (S)-4-(2-pyrrolidinylmethoxy)phthalate (212 mg, 0.72 mmol) in DMF (8 mL) was added pentafluorophenyl ester of the 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (346 mg, 0.72 mmol) and Et3N (120 ml, 0.86 mmol), and the mixture was stirred overnight. The resulting mixture was diluted with EtOAc, washed with 1 N HCl, sat. NaHCO3, brine, and dried over MgSO4. The solvent was evaporated off in vacuo to give 413 mg (97%) dimethyl (S)-4-[1-[3-methoxy-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]phthalate as an oil. 1H-NMR (CDCl3) δ1.92-2.12 (m, 4 H), 2.29 (br s, 3 H), 3.51-3.64 (m, 7 H), 3.87 (s, 3 H), 3.89 (s, 3 H), 4.10-4.19 (m, 2 H), 4.44 (m, 1 H), 6.73-8.02 (series of m, total 12 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][N:14]=1)(=[O:11])=[O:10].[CH3:21][C:22](N=C(N(C)C)N(C)C)([CH3:24])[CH3:23].BrCC(C)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][N:14]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])(=[O:10])=[O:11]
Reactant: Cc1cnc(NS(=O)(=O)c2ccc(F)cc2Cl)c(C)c1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Solvent: CC(C)CBr
Product: Cc1cnc(N(CC(C)C)S(=O)(=O)c2ccc(F)cc2Cl)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.1 %

Procedure:
To a solution of 2-chloro-N-(3,5-dimethylpyridin-2-yl)-4-fluorobenzenesulfonamide (117 mg, 0.372 mmol) in acetonitrile (4 mL) stirred at room temperature, was added N″-(1,1-dimethylethyl)-N,N,N′,N′-tetramethylguanidine (127 mg, 0.743 mmol). The reaction mixture was stirred at room temperature for 1 hour, then 1-bromo-2-methylpropane (0.081 mL, 0.743 mmol) was added. The reaction vessel was sealed and heated under microwaves at 150° C. for 30 minutes. The solvent was evaporated in vacuo and the crude was purified by mass directed autoprep (ammonium carbonate modifier) to give the title compound (8.4 mg). LCMS (2 min, High pH) Rt 1.45 min, m/z (ES+) 371 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.C(N(CC)CC)C.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:20](=[O:21])C1.Cl.[C:37]12([CH2:47][CH2:48][NH:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]3)[CH2:38]1)[CH2:44]2>C(#N)C.C(Cl)Cl>[C:37]12([CH2:47][CH2:48][N:49]([CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:20](=[O:21])[O:10][CH2:9][CH2:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:44][CH:43]3[CH2:42][CH:41]([CH2:40][CH:39]([CH2:45]3)[CH2:38]1)[CH2:46]2
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: OCCCc1ccncc1
Reactant: CCCCCNCCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)OCCCc1ccncc1
Reaction time: 2.5 h
Yield: 96.9 %

Procedure:
4-Pyridinepropanol (528 mg, 3.85 mmol) was dissolved in acetonitrile (20 ml) at room temperature, and then triethylamine (1.61 ml, 11.6 mmol) was added to the solution. Further, N,N′-disuccinimidyl carbonate (1.48 g, 5.87 mmol) was added to the mixture, and the whole was stirred for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (100 ml) and a saturated aqueous sodium hydrogencarbonate solution (50 ml) were added to the residue. After separation, the organic layer was washed with a saturated aqueous sodium chloride solution (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dried under reduced pressure and dissolved in anhydrous methylene chloride (10 ml). Next, a solution of 2-(1adamantyl)-N-pentylethylamine hydrochloride (Intermediate No. 1-1, 1.32 g, 4.62 mmol) and triethylamine (0.80 ml, 5.7 mmol) in methylene chloride (90 ml) was added thereto, and the mixture was stirred for 1.5 hours. The reaction mixture was washed with a saturated aqueous sodium hydrogencarbonate solution (50 ml) and a saturated aqueous sodium chloride solution (50 ml) successively and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the target compound (1.54 g, 97%) as an oily matter.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:28])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:18][C:19]([CH:22]=O)=[CH:20][CH:21]=3)[CH:15]=2)[N:10]([C:24](=[O:26])[CH3:25])[C@@H:9]([CH3:27])[CH2:8]1)[CH3:3].C(O)(=O)C.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[O:18][C:19]([CH2:22][N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:28])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:27])(=[O:26])[CH3:25]
Reactant: C1CCNCC1
Reactant: CC(=O)N1c2ccc(-c3ccc(C=O)o3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)o3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 0.5 h

Procedure:
1-Methylethyl[(cis)-1-acetyl-6-(5-formyl-2-furanyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 21) (18 mg, 0.047 mmol) was dissolved in dichloromethane (DCM) (1 mL), mixed with acetic acid (8.04 μL, 0.140 mmol) and piperidine (9.27 μL, 0.094 mmol) and stirred under nitrogen for 30 minutes. sodium triacetoxyborohydride (12.90 mg, 0.061 mmol) was added and the reaction was stirred again under nitrogen. After 17 hours reaction time a second quantity of sodium triacetoxyborohydride (12.90 mg, 0.061 mmol) was added. 1 hour after this another sample of sodium triacetoxyborohydride (12.90 mg, 0.061 mmol) was added. After 2 further hours the reaction was loaded onto a 2 g Flash SCX-column, eluting with MeOH (60 mL) followed by 2M MeOH/NH3 (60 mL). The product-containing fraction was evaporated to dryness to give a brown solid which was purified by MDAP. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (3 mg).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:13]2[C:14]([CH2:22][CH3:23])=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.FC1C([I:31])=C(F)C(F)=C(F)C=1F.O.C1COCC1>O1CCCC1>[CH:1]1([CH2:4][N:5]([C:13]2[C:14]([CH2:22][CH3:23])=[N:15][N:16]3[C:21]([I:31])=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: Fc1c(F)c(F)c(I)c(F)c1F
Reactant: CCc1nn2ccccc2c1N(CC1CCOCC1)CC1CC1
Solvent: C1CCOC1
Solvent: O
Product: CCc1nn2c(I)cccc2c1N(CC1CCOCC1)CC1CC1
Reaction time: 0.33 h
Yield: 87.2 %

Procedure:
A solution of N-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2H-4-pyranylmethylamine (180 g, 574 mmol) in tetrahydrofuran (1620 mL) was cooled with dry ice-ethanol bath. A 1.6M n-butyllithium-hexane solution (538 mL, 854 mmol) was added dropwise to the solution at an internal temperature of from −73° C. to −64.5° C. After stirring the reaction mixture for 1 hour at the same temperature, pentafluoroiodobenzene (115 mL, 861 mmol) was added dropwise. The reaction-mixture was additionally stirred for 1 hour and 20 minutes, and then water/THF (1/1, v/v, 360 mL) was added thereto. Cooling was terminated, and then water (3600 mL) and heptane (3600 mL) were added to the reaction mixture, the aqueous layer was removed and the organic extract was washed with water (3600 mL). A 5N aqueous hydrochloric acid solution (1800 mL) was then added to the organic layer and the aqueous layer was separated off. After cooling the aqueous layer in an ice bath and adding a 5N aqueous sodium hydroxide solution (1620 mL), toluene (3600 mL) was further added to the reaction mixture and the organic layer was separated off. The aqueous layer was extracted with toluene (3600 mL), and both organic extracts were combined and concentrated to afford 220 g of the title compound as a dark green oil (87.3% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][CH:46]([NH2:50])[CH:47]([CH3:49])[CH3:48]>CN(C=O)C>[CH3:45][CH:46]([NH:50][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:15][CH:16]=1)=[O:21])[CH:47]([CH3:49])[CH3:48]
Reactant: CC(C)C(C)N
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC(C)C(C)C)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 1,2-dimethylpropylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(1,2-dimethylpropyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][C:27]=4[C:32]([O:34][CH3:35])=[O:33])[CH2:22][CH2:21]3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:35][O:34][C:32]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:26]=1[N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][O:18][C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9]3)=[CH:14][CH:13]=2)[CH2:25][CH2:24]1)=[O:33]
Reactant: COC(=O)c1cnccc1N1CCC(COc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cnccc1N1CCC(COc2ccc3c(c2)CNCC3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
To a solution of 7-[1-(3-methoxycarbonylpyridin-4-yl)piperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (37 mg) in chloroform (0.5 ml) was added trifluoroacetic acid (0.15 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated. To the obtained residue was added aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and dried under reduced pressure to give the title compound (30 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:11]([C@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:28](Cl)([Cl:30])=[O:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C:11]([C@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:28]([Cl:30])=[O:29])=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: Clc1ccc(Cn2ncnc2[C@H]2CCCN2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cl)N1CCC[C@@H]1c1ncnn1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 75.8 %

Procedure:
A solution of (R)-1-(4-chlorobenzyl)-5-(pyrrolidin-2-yl)-1H-1,2,4-triazole (216 mg, 0.82 mmol) and DIEA (233 mg, 1.90 mmol) in 5 mL of dry DCM was cooled to −20° C. under Ar, and a solution of phosgene (0.89 mL of 20% solution in toluene, 0.89 mmol) was added. The reaction mixture was stirred at RT for 2.5 days and the solvent was evaporated in vacuo. The residue was purified by chromatography (silica gel, hexane:EtOAc (1:1)) to give 202 mg of the desired product.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([O:10][CH2:11][CH2:12][N:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[N:15]=[C:14]1[NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1)[CH3:9].Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O>[CH2:8]([O:10][CH2:11][CH2:12][N:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[N:15]=[C:14]1[N:22]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1)[CH3:9]
Reactant: BrCc1ccccc1
Reactant: CCOCCn1c(NC2CCN(C(=O)OCC)CC2)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1c(N(Cc2ccccc2)C2CCN(C(=O)OCC)CC2)nc2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
A mixture of 2.7 parts of a sodium hydride dispersion 50% and 282 parts of N,N-dimethylformamide was stirred at room temperature under nitrogen atmosphere. 18.8 Parts of ethyl 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate were added portionwise to the previous mixture. Upon complete addition, stirring for continued for 1 hour at room temperature. 10 Parts of (bromomethyl)benzene were added dropwise and upon completion, stirring was continued for 1 hour. The reaction mixture was decomposed with water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and ethanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.2 parts (13.6%) of ethyl 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b] pyridin-2-yl](phenylmethyl)amino]-1-piperidinecarboxylate; mp. 115.0° C. (compound 177).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.ClCCl.[N:23]1([C:29]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:30]=2[NH2:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>O>[N:23]1([C:29]2[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:32][C:30]=2[NH:31][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
4-Nitrobenzoyl chloride (64.2 mg, 0.345 mmol, commercially available product) and triethylamine (120 μl, 0.859 mmol) were sequentially added at 0° C. to a dichloromethane (2 ml) solution of 2-(1-piperidinyl)-5-(trifluoromethyl)aniline (51.2 mg, 0.209 mmol), obtained as described in Referential Example 1-2. The resulting mixture was warmed to room temperature and stirred for 60 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=8/1-6/1). Thus, N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]-4-nitrobenzamide (GIF-0345) (46.3 mg, 56.3%) was yielded as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C([C:24]([O:26][CH2:27][CH3:28])=[O:25])#N>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C#N
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
To a solution of ethyl 2-(4-bromophenyl)acetate (5.0 g, 21 mmol) in dry THF (40 mL) at −78° C. was added a 2.0M solution of lithium diisopropylamide in THF (11 mL, 22 mmol). After stirring for 30 minutes at −78° C., ethyl cyanoformate (2.0 mL, 21 mmol) was added and the mixture was allowed to warm to room temperature. After stirring for 48 h at room temperature, the mixture was quenched with water (10 mL). The reaction was partitioned between 1 N HCl (50 mL) and dichloromethane (50 mL), and the organic layer was separated. The organic layer was washed with 1 N HCl (50 mL), dried over Na2SO4 and evaporated. The crude material was purified by silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes to give diethyl 2-(4-bromophenyl)malonate (2.6 g, 41%) 1H NMR (400 MHz, DMSO-d6) δ 7.60-7.58 (m, 2H), 7.36-7.34 (m, 2H), 5.03 (s, 1H), 4.21-4.09 (m, 4H), 1.20-1.16 (m, 6H).
Reaction SMILES: C(OC(=O)C(CS(N1CCN(C2C=CC(Br)=CC=2)CC1)(=O)=O)C(C)C)(C)(C)C.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[CH:37][CH:36]=2)[CH:30]=1.[CH3:47][O:48][C:49]([C:51]1([CH2:57][S:58](Cl)(=[O:60])=[O:59])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)=[O:50]>>[CH3:47][O:48][C:49]([C:51]1([CH2:57][S:58]([N:44]2[CH2:45][CH2:46][N:41]([C:38]3[CH:37]=[CH:36][C:35]([C:31]4[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=4)=[CH:40][CH:39]=3)[CH2:42][CH2:43]2)(=[O:60])=[O:59])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)=[O:50]
Reactant: COC(=O)C1(CS(=O)(=O)Cl)CCOCC1
Reactant: c1cncc(-c2ccc(N3CCNCC3)cc2)c1
Agent: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)OC(C)(C)C
Product: COC(=O)C1(CS(=O)(=O)N2CCN(c3ccc(-c4cccnc4)cc3)CC2)CCOCC1
Yield: 55 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-bromophenyl)piperazine-1-sulfonylmethyl]-3-methyl-butyric acid ter-butyl ester, from 1-(4-pyridin-3-yl-phenyl)piperazine (0.18 g) and 4-chlorosulfonylmethyl tetrahydropyran-4-carboxylic acid methyl ester (0.23 g), to yield the title compound as a white solid (0.19 g, 55%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]([C:31]2[CH:36]=[N:35][CH:34]=[C:33](Cl)[N:32]=2)[C:28](=[O:30])[OH:29])=[CH:23][CH:22]=1.[Cl-].[Li+].[C:40]1([CH3:46])[CH:45]=CC=C[CH:41]=1>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>[C:40]([O:29][C:28](=[O:30])[N:27]([C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1)[C:31]1[CH:36]=[N:35][CH:34]=[C:33]([C:6]2[N:7]=[CH:8][CH:9]=[CH:10][N:11]=2)[N:32]=1)([CH3:46])([CH3:45])[CH3:41]
Reactant: O=C(O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(-c2ncccn2)n1
Yield: 10 %

Procedure:
Bis(triphenylphosphine)palladium(II) dichloride (95 mg, 0.13 mmol) and 2-(tributylstannyl)-pyrimidine (493 mg, 1.34 mmol) were added to a degassed solution of (4-chloro-phenyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tent-butyl ester (500 mg, 1.47 mmol) and lithium chloride (170 mg, 4.00 mmol) in toluene (5 mL) and the mixture was heated to reflux over night. The reaction was quenched with aqueous sodium hydrogen carbonate and brine. The aqueous phase was extracted with ethyl acetate (4×15 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulphate, filtrated and evaporated. The crude product was purified by column chromatography (ethyl acetate/heptane as eluent) to give (4-chloro-phenyl)-(6-pyrimidin-2-yl-pyrazin-2-yl)-carbamic acid tert-butyl ester (53 mg, 10%) as a white solid.