Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[CH:4]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][C:12]=2[O:21][CH3:22])[CH:3]1C(OC)=O.[Cl-].[Na+].O>CN1CCCC1=O>[O:1]=[C:2]1[NH:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[CH:4]([C:11]2[C:12]([O:21][CH3:22])=[CH:13][C:14]([O:19][CH3:20])=[CH:15][C:16]=2[O:17][CH3:18])[CH2:3]1
Reactant: COC(=O)C1NC(=O)C(C(=O)OC)C1c1c(OC)cc(OC)cc1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)C1NC(=O)CC1c1c(OC)cc(OC)cc1OC
Temperature: 170 °C

Procedure:
(+)-Dimethyl 5-oxo-3-(2,4,6-trimethoxyphenyl)pyrrolidine-2,4-dicarboxylate (4.0 g, 0.0109 mol) was dissolved in N-methylpyrrolidone (15 mL). Sodium chloride (0.631 g, 0.0109 mol) and water (0.196 mL, 0.0109 mol) were added and the reaction mixture was heated to 170° C. for 5 hours. The reaction mixture was poured on ice (50 g) and the solid was filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH:44]([N:47]([CH:51]([CH3:53])[CH3:52])[CH2:48][CH2:49][NH2:50])([CH3:46])[CH3:45]>C(Cl)(Cl)Cl.O>[CH:44]([N:47]([CH:51]([CH3:53])[CH3:52])[CH2:48][CH2:49][NH:50][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[O:23][CH3:24])=[O:42])([CH3:46])[CH3:45]
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Reactant: CC(C)N(CCN)C(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1NC(=O)NCCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diisopropyl-1,2-ethanediamine (68 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (50 mg, yield 32%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](=[N:35]O)[NH2:34]>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[N:35]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:34]=1
Reactant: NC(=NO)c1ccccc1Cl
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4Cl)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 38 mg (0.22 mmol, 1.1 eq.) of 2-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 49 mg (51% of theory)
Reaction SMILES: OC1C=CC(CC(C2C=NC=CC=2)C[NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=CC=1.C(N(CC)CC)C.C(Cl)(=O)OCC.O>C(Cl)Cl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([NH2:11])(=[O:13])=[O:14])=[CH:20][CH:19]=1
Reactant: O=S(=O)(NCC(Cc1ccc(O)cc1)c1cccnc1)c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
N-[3-(4-hydroxyphenyl)-2-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide (54.5 mg) and 15.1 mg of triethylamine were dissolved in 3 ml of methylene chloride, followed by addition of 16.2 mg of ethyl chlorocarbonate dissolved in 1 ml of methylene chloride, and stirred at room temperature for 15 hours. To the reaction mixture was added water, and the organic phase was separated which was then extracted with methylene chloride. The organic phases were combined and washed in water, followed by drying over magnesium sulfate, to distill off the solvent. The obtained residue was subjected to chromatography on a silica gel column, and from a fraction eluted with methanol-methylene chloride (5:95 v/v) was obtained 47.4 mg of N-[3-(4-ethoxycarbonylphenyl)-2-(3-pyridyl)}propyl]-4-chlorobenzene sulfonamide. The spectrometric data supports the structure of [35] as follows.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]2[N:25]([CH3:41])[N:26]=[C:27]([C:28]3[N:32]([C:33]4[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=4)[CH:31]=[N:30][CH:29]=3)[C:20]=12>C(#N)C>[CH2:39]([C:36]1[CH:37]=[CH:38][C:33]([N:32]2[C:28]([C:27]3[C:20]4[C:21](=[N:22][CH:23]=[N:24][C:19]=4[N:5]4[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]4)[N:25]([CH3:41])[N:26]=3)=[CH:29][N:30]=[CH:31]2)=[CH:34][CH:35]=1)[CH3:40]
Reactant: CN(C)[C@@H]1CCNC1
Reactant: CCc1ccc(-n2cncc2-c2nn(C)c3ncnc(Cl)c23)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(-n2cncc2-c2nn(C)c3ncnc(N4CC[C@@H](N(C)C)C4)c23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3R)—N,N-Dimethylpyrrolidin-3-amine (12.4 mg, 0.109 mmol) and N,N-diisopropylethylamine (14.5 mg, 0.109 mmol) were added to a solution of 4-chloro-3-[1-(4-ethylphenyl)-1H-imidazol-5-yl]-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (C22) (37 mg, 0.11 mmol) in acetonitrile (1 mL), and the reaction mixture was stirred at room temperature for 2 hours. After removal of volatiles in vacuo, the residue was chromatographed on silica gel (Gradient: 0% to 15% ethyl acetate in methanol) to afford the product as a glass. Yield: 13 mg, 0.031 mmol, 28%. LCMS m/z 417.1 (M+1). 1H NMR (500 MHz, CDCl3), characteristic peaks: δ 1.17 (t, J=7.6 Hz, 3H), 2.49-2.65 (m, 8H), 3.51-3.61 (br m, 1H), 3.72-3.81 (br m, 1H), 4.08 (s, 3H), 7.10 (br d, J=8.3 Hz, 2H), 7.22-7.29 (m, 2H, assumed; partially obscured by solvent peak), 7.40 (br s, 1H), 7.90 (br s, 1H), 8.29 (s, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[N:6][N:5](C2CCCCO2)[C:4](=[O:14])[CH:3]=1.[Cl:15][C:16]1[C:17]([F:23])=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.C[O:25][C:26](=[O:35])[CH:27](Br)[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[Cl:15][C:16]1[C:17]([F:23])=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][C:2]1[CH:7]=[N:6][N:5]([CH:27]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:26]([OH:25])=[O:35])[C:4](=[O:14])[CH:3]=1
Reactant: O=c1cc(I)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: Oc1cccc(Cl)c1F
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(Cl)c2F)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 70, starting from 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (Intermediate 70 step 2) and 3-chloro-2-fluoro-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 2-[4-(3-chloro-2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid as a white solid (4.4 g, 73% for the final step); LC-MS: tR=4.80 min, 381 (M+H)+. HPLC: tR=8.83 min, 95.66% (214 nm), 95.56% (254 nm). 1H NMR (300 MHz, DMSO-d6): δ 13.06 (broad, 1H), 8.21 (d, 1H, J=2.7 Hz), 7.63-7.58 (m, 1H), 7.54-7.49 (m, 1H), 7.38-7.33 (m, 1H), 6.07 (d, 1H, J=2.7 Hz), 5.33 (dd, 1H, J=11.0 Hz, J=4.2 Hz), 2.40-2.10 (m, 1H), 1.99-1.90 (m, 1H), 1.68-1.43 (m, 7H), 1.13-1.04 (m, 2H).
Reaction SMILES: [H-].[Na+].[N:3]1[NH:4][C:5]([SH:8])=[N:6][CH:7]=1.Br[CH2:10][CH:11]([C:34]1[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=1)[CH2:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[N:15]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:14]=1>CN(C)C=O>[Cl:25][C:20]1[CH:19]=[C:18]([C:16]2[N:15]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[N:14]=[C:13]([CH2:12][CH:11]([C:34]3[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=3)[CH2:10][S:8][C:5]3[NH:4][N:3]=[CH:7][N:6]=3)[CH:17]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: COc1ccc(-n2nc(CC(CBr)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reactant: Sc1ncn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(CC(CSc3ncn[nH]3)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a suspension of sodium hydride (4.0 mg, 60% dispersion in oil) in N,N-dimethylformamide (1.0 mL) at 0° C. was added a solution of 2H-[1,2,4]triazole-3-thiol (10.0 mg, 0.1 mmol, 1.1 equiv) in N,N-dimethylformamide (1.0 mL). The mixture was stirred at 0° C. for 30 min then a solution of 3-(3-bromo-2-m-tolyl-propyl)-5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole (48 mg, 0.09 mmol, 1.0 equiv) in N,N-dimethylformamide (1.0 mL) was added. The reaction mixture was brought to room temperature then was stirred for 2 h. The reaction was quenched with satd aq ammonium chloride (1.0 mL), and the resulting mixture was diluted with water (10.0 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (10 mL) then brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by reversed-phase HPLC to yield the title compound (39 mg, 80%). HPLC: Rt=3.26 (Method B). MS (ESI): mass calculated for C28H25Cl2N5OS, 549.12; m/z found, 550.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.32 (br s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H), 7.07-7.04 (m, 5H), 6.95 (dd, J=8.4, 21. HZ, 2H), 6.89 (d, J=9.0 Hz, 2H), 6.31 (s, 1H), 3.70 (s, 3H), 3.48 (dd, J=12.9, 6.3 Hz, 1H), 3.36 (dd, J=12.7, 8.2 Hz, 1H), 3.26 (m, 1H), 3.07 (dd, J=14.9, 6.4 Hz, 1H), 2.91 (dd, J=14.9, 8.2 Hz, 1H), 2.21 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]>CCOC(C)=O.[Pd]>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cccc(Oc2ccc(N)cc2)c1
Yield: 25.8 %

Procedure:
A slurry of 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.30 g) and 10% Pd/C (0.030 g) in EtOAc (20 mL) was stirred under an H2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(N-methylsulfamoyl)phenyloxy)aniline (0.070 g).
Reaction SMILES: Br[C:2](Br)=[CH:3][CH2:4][CH:5]([N:8]1[CH:12]=[C:11]([C:13]2[C:14]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH:10]=[N:9]1)[CH2:6][CH3:7].C1COCC1.C([Li])CCC.O.Cl>CCCCCC>[CH2:6]([CH:5]([N:8]1[CH:12]=[C:11]([C:13]2[C:14]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:29])[CH3:27])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH:10]=[N:9]1)[CH2:4][C:3]#[CH:2])[CH3:7]
Reactant: CCC(CC=C(Br)Br)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CCC(CC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
A solution of 4-[1-(4,4-dibromo-1-ethylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (20 mg, 0.00004 mol) (from Example 503 Step 1) in THF (1 mL, 0.01 mol) at −78° C. was treated with 2.5 M n-butyllithium in hexane (0.032 mL). The mixture was stirred at −78° C. for 1 h and then at room temperature for 1 h. The reaction was quenched with water (1 mL, 0.06 mol) and 1N HCl. The reaction was partitioned between water and ethyl acetate. The organic extract was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 4-[1-(1-ethylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine as a semisolid (12 mg, 80%). LC/MS (M+H)+: m/z=396.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[C:25]1([C:31]2([C:37](=[O:39])[CH3:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl.C(O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:6]2[C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[N:34]2[CH2:35][CH2:36][C:31]([C:37](=[O:39])[CH3:38])([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:32][CH2:33]2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CC(=O)C1(c2ccccc2)CCNCC1
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)C1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of 6-Chloro-9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purine I-(4A-7)c (68 mg, 0.18 mmol) in 1:1 methylene chloride/ethanol (2 ml) was added 1-(4-phenylpiperidin-4-yl)-ethanone (48 mg, 0.2 mmol) and triethylamine (70 μl, 0.5 mmol). The mixture was stirred overnight, concentrated under reduced pressure, and then purified on a Biotage™ Flash 12S column using 5–10% methanol in methylene chloride as eluant to give title compound 29A-1 (77 mg, 78%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([NH:6][C:7]([CH3:12])([C:9]#[C:10][CH3:11])[CH3:8])=[O:5].[Cl:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:13][CH:3]([S:2][CH3:1])[C:4]([NH:6][C:7]([CH3:12])([C:9]#[C:10][CH3:11])[CH3:8])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC#CC(C)(C)NC(=O)CSC
Solvent: ClC(Cl)(Cl)Cl
Product: CC#CC(C)(C)NC(=O)C(Cl)SC
Temperature: 0 °C
Reaction time: 2 h
Yield: 143.3 %

Procedure:
The product of Step 1 (0.824 g) was dissolved in carbon tetrachloride (15 ml) with warming. The solution was then cooled to 0° C. and N-chlorosuccinimide (NCS, 0.653 g) was then gradually added and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was filtered to remove succinimide and the resulting liquid was evaporated to give 2-(chloro)-2-(methylthio)-N-(2-methylpent-3-yn-2-yl) acetamide as a clear oil (1.4 g), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[NH:9])[NH:7][OH:8])=[C:4]([F:12])[CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[NH:9])[NH:7][O:8][CH:15]=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([F:12])[CH:3]=1
Reactant: C#CC(=O)OCC
Reactant: N=C(NO)c1ccc(Cl)cc1F
Product: CCOC(=O)C=CONC(=N)c1ccc(Cl)cc1F

Procedure:
Scheme 15 shows the synthesis of 5-(2-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)-1-isopropyl-3-methyl-1H-1,2,4-triazole 44 from 4-chloro-2-fluorobenzonitrile 38. Addition of hydroxylamine to the nitrile of 38 gave 4-chloro-2-fluoro-N-hydroxybenzimidamide 39. Michael addition of 39 to ethyl propiolate gave ethyl 3-(4-chloro-2-fluorobenzimidamidooxy)acrylate 40. Heating 40 in diphenyl oxide gave cyclized imidazole, ethyl 2-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carboxylate 41. Saponification of the ester of 41 with aqueous sodium hydroxide in tetrahydrofuran gave 2-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carboxylic acid 42. Reaction of 42 with N′-isopropylacetohydrazonamide 6 and coupling reagent HBTU in DMF gives intermediate, 2-(4-chloro-2-fluorophenyl)-N-(1-(2-isopropylhydrazinyl)ethylidene)-1H-imidazole-4-carboxamide 43 which cyclizes upon heating to give 44.
Reaction SMILES: S([O-])(O)=O.[Na+].C=O.[CH2:8]([N:10]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]1)[CH2:11][CH3:12])[CH3:9].[C-]#[N:21].[Na+].[CH2:23]1[CH2:28]CCCC1>O>[CH2:8]([N:10]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:28][C:23]#[N:21])[CH2:11][CH3:12])[CH3:9]
Reactant: CCN(CC)CC1CCCCN1
Reactant: C1CCCCC1
Reactant: [C-]#N
Agent: C=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CCN(CC)CC1CCCCN1CC#N
Temperature: 60 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of 236.5 ml (about 1.1 mol) of a 37% aqueous sodium hydrogen sulphite solution and 110 ml (about 1.1 mol) of a 40% formalin solution was heated to 60° C. for 30 minutes. It was allowed to cool to 30° C., a solution of 170.3 g (1.0 mol) of 2-[(diethylamino)methyl]piperidine in 70 ml of water was added dropwise thereto, whereupon the mixture spontaneously heated up to 40° C., and was then stirred for a further 2 hours without any external heating. The solution of 53.9 g (1.1 mol) of sodium cyanide in 172 ml of water was then added and the resulting mixture was stirred for 2 hours at ambient temperature. The upper organic layer was taken up in 500 ml of cyclohexane and the aqueous phase was extracted four times, each time with 125 ml of cyclohexane. The combined extracts were dried over sodium sulphate, concentrated by evaporation and distilled in vacuo. The desired 2-[2-[(diethylamino)methyl]-piperidin-1-yl]acetonitrile was obtained as a colourless oil, B.p.19 mm Hg 155°-156° C. in a yield of 172.0 g (82% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:5]2.O[CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1C=CC=CC=1.O>[C:17]([C:16]1[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[O:13][C:12]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([O:1][CH:28]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:11]=[CH:10]2)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=O)c1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Reactant: CCOC(=O)C(O)Cc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCC(=O)c1c(-c2ccc3cc(OC(Cc4ccccc4)C(=O)OCC)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To an ice-cooled mixture of 1-[2-(6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (0.620 g, 1.80 mmol), ethyl 2-hydroxy-3-phenylpropanoate (0.528 g, 2.72 mmol), triphenylphosphine (0.710 g, 2.71 mmol) in benzene (30 mL) was added, dropwise, diisopropyl azodicarboxylate (0.53 mL, 2.7 mmol) in benzene (5 mL). The mixture was stirred at room temperature for 45 minutes, poured into excess water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (Biotage apparatus) using 100% hexane and 2-3.5% ethyl acetate in hexane as eluants. The title compound was obtained as a thick yellow oil (0.670 g). Mass spectrum (+ESI, [M+H]+) m/z 521.5; 1HNMR (500 MHz, DMSO-d6): δ8.35 (s, 1H), 8.0 (t, 2H, J=7.8 Hz), 7.95 (d, 1H, J=8.6 Hz), 7.8 (dd, 1H, J=8.6 Hz and 1.7 Hz), 7.7 (d, 1H, J=8.1 Hz), 7.25-7.45 (m, 9H), 5.35 (t, 2H, J=6.5 Hz), 4.05-4.15 (m, 3H), 2.7 (t, 2H, J=7.3 Hz), 1.5-1.55 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.C(Cl)CCl.C1[CH:14]=[CH:15][C:16]2N(O)N=[N:19][C:17]=2C=1.C(N(C(C)C)C(C)C)C.[CH2:32](N)[CH2:33][CH2:34][CH3:35]>CN(C=O)C>[CH2:32]([N:19]([CH2:17][CH2:16][CH2:15][CH3:14])[C:6]([C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[O:8])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCN
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc[nH]n1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CCCC)C(=O)c1cc[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
To 1H-pyrazole-3-carboxylic acid (Matrix, 350 mg, 3.12 mmol) in DMF (8.7 mL) were added EDC (658 mg, 3.43 mmol), HOBT (622 mg, 4.06 mmol), i-Pr2EtN (1.6 mL, 9.37 mmol) and n-butylamine (550 μL, 3.28 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was then quenched with sat. aq. NH4Cl solution, washed with 1N aq. HCl solution and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified using flash column chromatography (gradient from 0% to 5% (MeOH/CH2Cl2) to give the title compound (530 mg, 76%) as a colorless crystalline solid. 1H NMR (CD3OD, 1.5:1 mixture of amide rotamers) δ 7.74 (br s, 1H), 6.67 (br s, 1H), 6.38 (br s, 1H), 3.70-3.39 (m, 4H), 1.64 (quin, J=7.6 Hz, 4H), 1.36 (dt, J=14.4, 7.0 Hz, 4H), 1.04-0.88 (m, 6H); MS(ESI+) m/z 224.3 (M+H)+.
Reaction SMILES: [NH:1]([C:17]([O:19]C(C)(C)C)=O)[C@H:2]([C:4]([NH:6][C@@H:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[OH:11])=[O:5])[CH3:3].C[Si]([CH:28]([Si](C)(C)C)[C:29](N)=O)(C)C.C(Cl)(=O)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].O>C(Cl)Cl>[NH:1]([C:17]([CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH3:37])=[O:19])[C@H:2]([C:4]([NH:6][C@@H:7]([C:13]([O:15][CH2:16][C:29]1[CH:28]=[CH:9][CH:8]=[CH:7][CH:13]=1)=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[OH:11])=[O:5])[CH3:3]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: COC(=O)[C@@H](CCC(=O)O)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)O)C(=O)OCc1ccccc1
Yield: 196.4 %

Procedure:
L-Ala-D-Glu(OH)OBzl (1) (942 mg) was suspended in methylene chloride (40 ml), and bis(trimethylsilyl)acetamide (1.20 g) was added to the suspension under stirring. The resulting solution was treated with stearoyl chloride (900 mg) at ambient temperature and left for an hour. Evaporation of the solvent gave an oily residue which was treated with water to give white solids. The solids were collected by filtration, washed with water and dried over magnesium sulfate to give stearoyl-L-Ala-D-Glu(OH)OBzl (2) (1.60 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][C:8]#[N:9])=[CH:4][CH:3]=1.C(O)C.[NH:15]([C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)[NH2:16].OCC[N+](C)(C)C>CO>[NH2:9][C:8]1[CH2:7][CH:6]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[N:15]([C:17]2[S:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[N:16]=1
Reactant: N#CC=Cc1ccc(Cl)cc1
Reactant: NNc1nc2ccccc2s1
Agent: C[N+](C)(C)CCO
Solvent: CO
Solvent: CCO
Product: NC1=NN(c2nc3ccccc3s2)C(c2ccc(Cl)cc2)C1

Procedure:
A mixture of 3.28 g. of p-chlorocinnamonitrile, 50 ml. of absolute ethanol, 3.1 g. of 2-hydrazinobenzothiazole and 1.0 g. of 50% w/v choline in methanol is refluxed on a steam bath for 16 hours. The reaction mixture is cooled and the precipitate is collected by filtration. The solid is washed with ethanol to yield 3.2 g. of crude product. This material is recrystallized from acetone to give 1.65 g. of the product of the Example as yellow crystals, m.p. 273°-275° C.