Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([C:24]4[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[C:28]([CH:32]=4)[C:29](O)=[O:30])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:36]1[CH:41]=[CH:40][CH:39]=[N:38][C:37]=1[C:42]1([NH2:46])[CH2:45][O:44][CH2:43]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([C:24]4[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[C:28]([C:29](=[O:30])[NH:46][C:42]5([C:37]6[N:36]=[CH:41][CH:40]=[CH:39][N:38]=6)[CH2:45][O:44][CH2:43]5)[CH:32]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3ccc(OC)c(C(=O)O)c3)cc12
Reactant: NC1(c2ncccn2)COC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3ccc(OC)c(C(=O)NC4(c5ncccn5)COC4)c3)cc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl)-2-methoxy-benzoic acid (150 mg, 0.323 mmol) and 3-(pyrimidin-2-yl)oxetan-3-amine hydrochloride (77 mg, 0.42 mmol) in DMF at room temperature under a nitrogen atmosphere (7.5 mL) was added triethylamine (0.225 mL, 1.615 mmol). The mixture was cooled to 0° C. and then added with BOP (214 mg, 0.484 mmol) at the same temperature. The reaction mixture was warmed to rt and stirred at rt overnight. The reaction mixture was then diluted with water and stirred for 5 min. The solid obtained was filtered and dried under suction. Yield: 0.180 g (93%).
Reaction SMILES: [I:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:32])=O>>[I:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([Cl:32])=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(I)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C(=O)OCC)=C(Cl)c1ccc(I)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 28.3 g of diethyl 4-iodobenzoylmalonate, 14.6 g of diisopropylethylamine and 20 ml of phosphorus oxychloride was stirred at 100° C. for 2 hours and then poured over ice. The reaction mixture was extracted with diethyl ether, and the extract was dried over magnesium sulfate, treated with activated carbon, filtered and then concentrated at atmospheric pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 20.14 g of the title compound as a pale yellow liquid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[S:6][C:7]=1S(C)(=O)=O)#[N:2].O.[NH2:20][NH2:21]>CO.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[S:6][C:7]=1[NH:20][NH2:21])#[N:2]
Reactant: CC(C)(C)OC(=O)c1cc(C#N)c(S(C)(=O)=O)s1
Reactant: NN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc(C#N)c(NN)s1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (2.0 g, 7.0 mmol) and hydrazine hydrate (1.7 mL) in methyl alcohol (30 mL) was stirred at 60° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water. Organic layer was separated, dried over anhydrous sodium sulfate and evaporated. Through chromatography purification (n-hexane/ethyl acetate 3:2), 1 g of the title compound was thus obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]1[CH2:12][C:13]([O:15]C)=[O:14].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)Cn1c(=O)ccc2cnccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)Cn1c(=O)ccc2cnccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2-(2-oxo-1,6-naphthyridin-1(2H)-yl)acetate (1.51 g, 6.92 mmol) in THF (10 mL) was added sodium hydroxide (4 mL of a 3 N aqueous solution, 13.8 mmol) and the reaction mixture was stirred at room temperature for 18 h. The resulting solution was diluted with ethyl acetate and washed with water. The aqueous phase was separated, adjusted to pH 2 with aqueous HCl and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), filtered and concentrated under vacuum to give 2-(2-oxo-1,6-naphthyridin-1(2H)-yl)acetic acid. Retention time (min)=0.368, method [3], MS (ESI) 205.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:13](=[O:15])[NH2:14])[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:16](OC)(=O)C>C([O-])([O-])OCC>[OH:15][C:13]1[N:3]2[N:4]=[CH:5][C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:2]2[N:1]=[CH:16][N:14]=1
Reactant: NC(=O)n1ncc(-c2ccccc2)c1N
Reactant: COC(C)=O
Agent: CCOC([O-])[O-]
Product: Oc1ncnc2c(-c3ccccc3)cnn12
Reaction time: 13 h

Procedure:
A mixture of 3-amino-2-carbamoyl-4-phenylpyrazole (4.8 g) and ethyl orthoformate (30 ml) is stirred at 100°-110° C. for 13 hours, and thereto is added methanol acetate. The precipitate is separated by filtration, washed with methanol or ethyl acetate, and dried to give the title compound (2.08 g).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:24][C:23]=2[O:22]1>>[Br:1][CH:30]([C:25]1[CH:26]=[CH:27][C:28]2[O:29][CH2:21][O:22][C:23]=2[CH:24]=1)[C:31]([O:33][CH3:34])=[O:32]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: COC(=O)C(Br)c1ccc2c(c1)OCO2

Procedure:
N-Bromosuccinimide (3.95 g, 22.2 mMol) and AIBN (0.098 g, 0.06 mMol) were added to a solution of methyl (3,4-methylenedioxyphenyl)acetate (3.9 g, 21.2 mMol) and the mixture was refluxed for 2.5 h. The reaction was cooled and filtered. The filtrate was concentrated in vacuo and the residue obtained was purified by flash chromatography on silica-gel using 10% ethyl acetate-hexane. Yield 2.6 g (oil).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[N:25]1([CH2:34][C:35](O)=[O:36])[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]1=[O:27]>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:16][N:17]=1)(=[O:12])=[O:11])[C:35](=[O:36])[CH2:34][N:25]1[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]1=[O:27])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccccc2)s1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccccc2)s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O

Procedure:
The title compound was synthesized by the reaction of N-[2-(5-phenyl-1,3,4-thiadiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester with (thymin-1-yl)-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 11.28 (s, 0.6H), 11.26 (s, 0.4H), 9.08 (brs, 1H), 8.05 (d, 2H), 7.66–7.57 (m, 3H), 7.32 (s, 0.6H), 7.24 (s, 0.4H), 4.65 (s, 1.2H), 4.47 (s, 0.8H), 4.32 (s, 0.8H), 4.16 (q, 0.8H), 4.06 (q, 1.2H), 4.04 (s, 1.2H), 3.56 (t, 1.2H), 3.43–3.38 (m, 2H), 3.24 (t, 0.8H), 1.73 (s, 3H), 1.21 (t, 1.2H), 1.16 (t, 1.8H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19]C(=O)OC(C)(C)C)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][NH2:19])[CH2:16][CH2:17]2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[F:30][C:29]([F:32])([F:31])[C:27]([O-:33])=[O:28]
Reactant: CC(C)(C)OC(=O)NCC1CCN(C(=O)[C@@H]2C[C@H]2c2ccccc2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CCN(C(=O)[C@@H]2C[C@H]2c2ccccc2)CC1
Product: O=C([O-])C(F)(F)F

Procedure:
A solution of tert-butyl (1-{[(1R,2R)-2-phenylcyclopropyl]carbonyl}piperidin-4-yl)methylcarbamate (1.00 g, 2.79 mmol) in TFA (3 mL) and CH2Cl2 (3 mL) was stirred at R.T. for 0.5 h. The reaction mixture was then concentrated to give the title compound as a trifluoroacetate salt.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([CH2:17]Cl)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][N:20]1[C:28]2[N:27]=[C:26](Br)[N:25]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[C:24]=2[C:23](=[O:38])[NH:22][C:21]1=[O:39].[C:40]([O:44][C:45]([NH:47][C@@H:48]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([CH2:17][N:22]3[C:23](=[O:38])[C:24]4[N:25]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[Cl:37])[C:26]([N:50]5[CH2:51][CH2:52][CH2:53][C@@H:48]([NH:47][C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:46])[CH2:49]5)=[N:27][C:28]=4[N:20]([CH3:19])[C:21]3=[O:39])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCc1nc(-c2ccccc2)c2ccccc2n1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Product: Cn1c(=O)n(Cc2nc(-c3ccccc3)c3ccccc3n2)c(=O)c2c1nc(N1CCC[C@@H](NC(=O)OC(C)(C)C)C1)n2Cc1ccccc1Cl

Procedure:
Prepared by reacting (4-phenyl-quinazolin-2-yl)-methylchloride and 3-methyl-7-(2-chlorobenzyl)-8-bromo-xanthine and subsequently reacting with (R)-3-(tert.-butyloxycarbonylamino)-piperidine
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][N:19]1[CH2:35][C:36](O)=[O:37].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][NH:10][C:36](=[O:37])[CH2:35][N:19]2[CH2:20][CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:18]2=[O:17])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,3-diphenylpropan-1-amine (0.0.21 g, 1.00 mmol) in dichloromethane (20 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.61 mg, 0.005 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.01 (t, J=5.4 Hz, 1H), 7.12-7.35 (m, 20H), 3.98 (t, J=7.8 Hz, 1H), 3.89 (s, 2H), 3.35 (t, J=6.5 Hz, 2H), 2.94-3.01 (m, 2H), 2.72 (t, J=6.4 Hz, 2H), 2.13-2.21 (m, 2H); MS (DCI+) m/z 489 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][CH:4]=1.[C:10]1([CH3:19])[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:18])[CH3:17])[CH:11]=1.P>C1(C)C=CC=CC=1.C(Cl)C=CC1C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:17][C:16]([C:12]2[CH:11]=[C:10]([CH3:19])[CH:15]=[CH:14][CH:13]=2)=[O:18])=[CH:5][CH:4]=1
Reactant: CC(=O)c1cccc(C)c1
Reactant: COc1ccc(Cl)cc1
Agent: [Pd]
Agent: ClCC=Cc1ccccc1
Agent: P
Solvent: Cc1ccccc1
Product: COc1ccc(CC(=O)c2cccc(C)c2)cc1
Yield: 73.4 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are p-methoxyphenyl chloride (141.7 mg, 1.0 mmol), 1-(m-tolyl)ethanone (336.2 mg, 2.5 mmol), palladium cinnamyl chloride (7.8 mg, 0.015 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyldicyclohexyl)phosphine (18.4 mg, 0.045 mmol), K3PO43H2O (664.9 mg, 2.5 mmol) in 3 mL dry toluene at 110° C. for 23 h. 2-(4′-Methoxyphenyl)-1-(m-tolyl)-1-ethanone (176.4 mg) was obtained with a yield of 74% as solid. m.p.: 56.7-57.8° C. (n-hexane); 1H NMR (300 MHz, CDCl3) δ 7.82-7.75 (m, 2H, ArH), 7.36-7.27 (m, 2H, ArH), 7.20-7.10 (m, 2H, ArH), 6.88-6.79 (m, 2H, ArH), 4.18 (s, 2H, CH2), 3.73 (s, 3H, OCH3), 2.37 (s, 3H, ArCH3); 13C NMR (75 MHz, CDCl3) δ 198.0, 158.3, 138.2, 136.4, 133.7, 130.3, 128.9, 128.3, 126.4, 125.7, 113.9, 55.0, 44.4, 21.2; IR (KBr) v (cm−1) 3034, 2999, 2933, 2835, 1694, 1682, 1614, 1585, 1515, 1463, 1301, 1282, 1246, 1178, 1156, 1107, 1035, 1000; MS (70 eV, EI) m/z (%): 241 (M++1, 1.89), 240 (M+, 10.02), 119 (100); Anal. Calcd. for C16H16O2: C, 79.97; H, 6.71. Found: C, 79.71; H, 6.69.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([N:22]3[CH:26]=[C:25]([CH:27]=[O:28])[N:24]=[N:23]3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].Br[Mg][CH3:31].CCOCC.[NH4+].[Cl-]>C1COCC1>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([N:22]3[CH:26]=[C:25]([CH:27]([OH:28])[CH3:31])[N:24]=[N:23]3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-n3cc(C=O)nn3)cc(-c3ccccn3)c2s1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCNC(=O)Nc1nc2cc(-n3cc(C(C)O)nn3)cc(-c3ccccn3)c2s1
Temperature: 40 °C
Yield: 4 %

Procedure:
To a suspension of iv (40 mg, 0.1 mmol) in THF (0.7 mL) was added bromo(methyl)magnesium 3M in Et2O (0.250 mL, 0.1 mmol) and the mixture heated at 40° C. for 1 h. NH4Cl (sat. aq.) was added and the mixture extracted with DCM:IPA (5:1). The organic layers were washed with brine and then concentrated in vacuo to give a crude product that was purified by reverse phase SP4 (ACN gradient in H2O) affording Compound 9 (1.9 mg, 4%).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:20][C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(Cl)Cl>[Cl:20][C:21]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)Cl
Temperature: 12.5 °C
Yield: 84.3 %

Procedure:
Stearyl alcohol (2.7 g, 0.01 mol), and triphosgene (0.99 g, 0.0067 mol) were dissolved in 20 ml methylene chloride, stirred and cooled to 10-15° C. Anhydrous pyridine (0.8 g of, 0.02 mol) was added dropwise into the pre-cooled solution over a 1 hr period. The reaction mixture was stirred for an additional 1 h, then heated in a water bath at 65° C. for 15 min until all the methylene chloride evaporated. The residue was washed 3 times with cold water, dried over Na2SO4 and evaporated to give stearyl chloroformate (1.88 g, 83% yield), also known as octadecyl chloroformate.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH2:19][NH:18][CH2:17][CH2:16]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([S:36]([N:18]2[CH2:17][CH2:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[CH:14]=3)[CH2:19]2)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CCNC2
Agent: Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)N1CCc2cc(OCCCN3CCCCC3)ccc2C1

Procedure:
2-Benzenesulfonyl-6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline is prepared from 6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (330 mg, 0.95 mmol), NEt3 (0.48 mL, 3.5 mmol), and benzenesulfonyl chloride (0.15 mL, 1.17 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the product as a white solid (250 mg, 63% yld). MS(ES+) 415.3(M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[N:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21].N12CCN(CC1)CC2.[Cl:37]CCl>O1CCCC1.CCCCCCC>[Cl:37][C:4]1[N:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:20](=[O:21])[N:19]([CH3:18])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][CH:12]=2)=[O:9])=[CH:2][CH:3]=1
Reactant: O=C(Nc1ccc(O)nc1)c1cnccc1Cl
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: ClCCl
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CN(C(=O)Oc1ccc(NC(=O)c2ccc(Cl)nc2)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
A mixture of 4-chloro-N-(6-hydroxy-pyridin-3-yl)-nicotinamide (0.56 g, 2.25 mmol), N-methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.67 g, 6.00 mmol) in dry tetrahydrofuran (15 mL) was stirred at room temperature for 1 hour. Dichloromethane was added and the solution was extracted twice with water. The organic layer was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 70:30) followed by crystallised from ethyl acetate:heptane, yielding the title compound (44 mg, 5% yield) HPLC-MS (Method A): m/z=383 (M+H)+; Rt=3.40 min.
Reaction SMILES: C[C:2]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH:3]1[CH3:5].[OH-].[K+].BrC[C:15]1[CH:20]=[CH:19][CH:18]=C[C:16]=1[C:21](=[CH:26][O:27][CH3:28])[C:22]([O:24][CH3:25])=[O:23].[CH2:29](O)C>>[CH3:29][CH:9]([O:8][C:6]([CH:2]1[CH2:4][CH:3]1[CH3:5])=[O:7])[C:10]1[CH:18]=[CH:19][CH:20]=[CH:15][C:16]=1[C:21](=[CH:26][O:27][CH3:28])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: CCO
Reactant: CCOC(=O)C1(C)CC1C
Agent: [K+]
Agent: [OH-]
Product: COC=C(C(=O)OC)c1ccccc1C(C)OC(=O)C1CC1C
Yield: 69 %

Procedure:
A stirred solution of 3.8 g (27 mmol) of ethyl 1,2-dimethylcyclopropanecarboxylate and 1.6 g (29 mmol) of potassium hydroxide in 50 ml of ethanol was refluxed for 8 hours and then evaporated down. The solution was covered with a layer of diethyl ether, after which the resulting precipitate was separated off and washed with diethyl ether. Subsequent reaction of the resulting potassium salt of dimethylcyclopropanecarboxylic acid in 60 ml of N-methylpyrrolidone, at 100° C., with 4.2 g (15 mmol) of methyl alpha-(2-bromomethylphenyl)-beta-methoxyacrylate and purification of the end product were carried out similarly to Example 1. Yield: 69%; colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]1[NH:30][CH:31]=[CH:32][CH:33]=1)=[O:28])=[N+:22]=[N-:23]>>[NH:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:27]([NH:26][CH2:25][CH2:24][N:21]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]2[N:6]=[C:2]([NH2:1])[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=2)[N:23]=[N:22]1)=[O:28]
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: [N-]=[N+]=NCCNC(=O)c1ccc[nH]1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3ccc[nH]3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.097 g, 0.349 mmol) was reacted with N-(2-azidoethyl)-1H-pyrrole-2-carboxamide (0.063 g, 0.349 mmol) following the general click procedure to give tert-butyl 4-(5-(1-(2-(1H-pyrrole-2-carboxamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-2-amino-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 8.18 (s, 1H), δ 7.36 (d, J=5.7 Hz, 2H), δ 7.24 (s, 1H), δ 6.84 (t, J=8.1 Hz, 1H), δ 6.43 (s, 1H), δ 6.04 (s, 2H), 4.49 (s, 2H), δ 3.89 (s, 2H), δ 2.53 (s, 2H), δ 2.09 (s, 2H), δ 1.44 (m, 13H), δ 1.24 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 165.9, 164.8, 164.6, 161.5, 137.5, 122.3, 111.0, 110.7, 107.5, 107.1, 106.8, 85.1, 49.4, 40.5, 29.3, 28.9, 28.2, 25.5 ppm; HRMS (ESI) calcd for C22H32N3O3 (M+) 456.2597. found 456.2590, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-1H-pyrrole-2-carboxamide hydrochloride (0.129 g, 94% yield). 1H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), δ 7.41 (s, 2H), δ 7.17 (s, 1H), δ 6.50 (s, 1H), δ 4.74 (s, 2H), δ 3.98 (s, 2H), δ 2.88 (s, 2H), δ 2.49 (s, 2H), δ 1.78 (m, 4H), δ 1.44 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 166.3, 164.5, 162.0, 161.9, 137.4, 110.6, 110.3, 110.2, 108.5, 17.1, 106.8, 59.3, 52.4, 39.5, 36.5, 27.9, 27.8, 27.6, 24.1, 23.5, 23.3 ppm; HRMS (ESI) calcd for C17H24N8O (M+) 356.2073. found 356.2080.
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][NH:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C=O.[C:46](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[CH3:46][N:22]1[CH2:23][C@@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C@H:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:21]1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CNC[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(C)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.4 %

Procedure:
Compound 1 (4.00 g, 6.67 mmol) obtained in Example 1 was dissolved in 1,2-dichloroethane (50 mL) and methanol (50 mL), and stirred at room temperature for 1 hour after adding formaldehyde (4.96 mL, 66.7 mmol) and sodium triacetoxyborohydride (Acros Organics; 7.06 g, 33.3 mmol). The reaction mixture was further stirred at room temperature for 2.5 hours after adding sodium triacetoxyborohydride (Acros Organics; 7.06 g, 33.3 mmol). The aqueous layer was extracted with ethyl acetate after adding a saturated sodium bicarbonate aqueous solution to the reaction solution. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5) to give compound 10 (3.99 g, 97.4%).
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:15][C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[O:8]1)(=O)=O.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][NH:22][C:21]1=[O:28]>>[O:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:15][CH:7]1[CH2:6][NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][C:24]([CH3:26])([CH3:27])[CH2:23][NH:22][C:21]1=[O:28]
Reactant: CS(=O)(=O)OCC1Oc2cccnc2O1
Reactant: CC1(C)CNC(=O)N(CCCN)C1
Product: CC1(C)CNC(=O)N(CCCNCC2Oc3cccnc3O2)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
A mixture of intermediate (6) (0.0092 mol) and intermediate (13) (0.0183 mol) was stirred for 2 hours at 100° C. The crude reaction mixture was purified by open column chromatography over silica gel (eluent: CH2Cl2/CH3OH 90/10). The desired fractions were collected and the solvent was evaporated. The residue was washed with DIPE, then dried, yielding 1.48 g of (±)-1-[3-[(1,3-dioxolo[4,5-b]pyridin-2-ylmethyl)amino]-propyl]tetrahydro-5,5-dimethyl-2(1H)-pyrimidinone (compound 10).