Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][C@H:3]([OH:5])[CH3:4].[C:7]([Si:11](Cl)([CH3:13])[CH3:12])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Si:11]([O:6][CH2:1][CH2:2][C@H:3]([OH:5])[CH3:4])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](O)CCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-Butane-1,3-diol (5.00 mL), tert-butylchlorodimethylsilane (8.82 g), N,N-dimethylpyridin-4-amine (0.34 g) and triethylamine (23.2 mL) were suspended in dichloromethane (60 mL) and stirred at room temperature overnight. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organics were dried over magnesium sulfate and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 5-10% ethyl acetate/hexane) to furnish to afford the title compound (8.33 g) having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][N:11]1[C:15]([CH3:16])=[C:14]([C:17](O)=[O:18])[C:13](=[O:20])[N:12]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.O>[F:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:17]([C:14]1[C:13](=[O:20])[N:12]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:11]([CH3:10])[C:15]=1[CH3:16])=[O:18]
Reactant: Nc1ccc(O)cc1F
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(O)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a suspension of 4-amino-3-fluorophenol (1.0 g, 7.87 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (2.19 g, 9.44 mmol) in CH2Cl2 (20 mL) were added EDCI (3.02 g, 15.7 mmol) and HOAT (0.21 g, 1.57 mmol). The reaction mixture was refluxed for 20 hours, and then cooled to rt. Water (10 mL) was added and the mixture stirred at rt overnight, then filtered and the filter cake was washed with water (5 mL), followed by purifying by a silica gel column chromatography (CH2Cl2/MeOH (v/v)=70/1) to give the title compound as a beige white solid (1.25 g, 46.6%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][Br:17])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[Br-:17].[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][P+:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCc1cccc(Oc2ccccc2)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: [Br-]
Product: c1ccc(Oc2cccc(CCC[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Yield: 75.9 %

Procedure:
Under nitrogen a mixture of 2.9 grams (0.01 mole) of 3-(3-phenoxyphenyl)propyl bromide and 2.9 grams (0.01 mole) of triphenylphosphine in 25 mL of acetonitrile was heated at reflux overnight. The solvent was evaporated under reduced pressure. Toluene was added to the residue, and this mixture was heated at reflux for 90 minutes during which a solid formed. Filtration yielded 4.2 grams of 3-(3-phenoxyphenyl)propyltriphenylphosphonium bromide, m.p. 198°-200° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:20][OH:21])[CH:15]2[C:6]([CH3:18])([C:7]3[C:12]([CH2:13][CH2:14]2)=[C:11]([O:16]C)[CH:10]=[CH:9][CH:8]=3)[CH2:5][CH2:4][C:3]1=[O:19].B(Br)(Br)Br.C(=O)([O-])[OH:27].[Na+]>ClCCl.CCCCCC>[OH:21][CH2:20][C:2]1([CH3:1])[CH:15]2[C:6]([CH3:18])([C:7]3[C:8](=[O:27])[CH:9]=[CH:10][C:11](=[O:16])[C:12]=3[CH2:13][CH2:14]2)[CH2:5][CH2:4][C:3]1=[O:19]
Reactant: COc1cccc2c1CCC1C(C)(CO)C(=O)CCC21C
Reactant: O=C([O-])O
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: CC1(CO)C(=O)CCC2(C)C3=C(CCC12)C(=O)C=CC3=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In 4 ml of dichloromethane was dissolved 150 mg of the compound obtained in Example 8, and under ice-cooling, 1.2 ml of a solution (1.0M) of boron tribromide in n-hexane was added. The mixture was stirred at 0° C. for 1.5 hours, and then it was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. In 10 ml of ethanol was dissolved 34 mg of the resulting crude crystals, and after addition of an aqueous solution (6.8 ml) containing 83 mg of potassium dinitrosulfonate and 34 mg of dipotassium hydrogen phosphate, the mixture was stirred at room temperature for 13 hours. The reaction mixture was then diluted with water and extracted with chloroform. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent=ethyl acetate:n-hexane=1:9) to provide 1 mg of the object compound.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:38])=[C:18]([CH:27]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1.O>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH3:38])=[C:18]([CH:27]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
Cyanuric chloride (from Aldrich, 1.22 g, 6.62 mmol) was weighed into a flask and N,N-dimethylformamide (0.512 mL, 6.62 mmol) was added. After stirring for a few minutes a solution of tert-butyl 3-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate (1.5 g, 4.2 mmol) in methylene chloride (30 mL) was added. The resulting mixture was stirred at room temperature overnight. Water was added, and then diluted with dichloromethane. The layers were separated and the organics were washed with sat. NaHCO3 solution, water, brine, dried over MgSO4, and concentrated. The resulting residue was purified on silica gel, eluting with 0-35% EtOAc in hexanes to give the desired product (1.36 g, 86%). LCMS calculated for C13H17ClNO (M—Cl—Boc+H)+: m/z=238.1; Found: 238.1. 1H NMR (400 MHz, CDCl3): δ 7.46 (s, 1H), 5.44, (q, 1H), 4.32 (m, 2H), 4.18-4.10 (m, 3H), 3.67 (s, 3H), 2.27 (s, 3H), 1.79 (d, 3H), 1.44 (s, 9H) ppm.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]1[C:20]([Cl:21])=[CH:19][C:8]([C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:10])=[C:7]([OH:22])[CH:6]=1.Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C>[NH2:4][C:5]1[C:20]([Cl:21])=[CH:19][C:8]([C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:15][CH3:16])[CH2:17][CH3:18])=[O:10])=[C:7]([O:22][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:6]=1
Reactant: COC(=O)CBr
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
To a stirred suspension of sodium hydride (420 mg of 0%, 10.5 mmoles) in DMF (10 ml) was added 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (1.612 g, mmoles) and the mixture stirred for 20 minutes, followed by cooling (ice water) and addition of methyl bromoacetate (832 mg, 5.44 mmoles). The mixture was stirred for 20 minutes in the cold and another 10 minutes at ambient temperature followed by pouring into 70 ml of ice-cold water. A separated solid was filtered and dried to give 1.58 g of crude product mp 92°-94°. This was recrystallized from methylene chloride-ether to give 1.21 g of the title compound as a white crystalline solid, mp 94°-95° (67.6% yield). The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ8.2 (s, 1H); 6.16 (s, 1H); 4.7 (s, 2H); 4.40 (bs, H); 3.86 (s, 3H); 3.54 (m, 2H); 2.6 (m, 6H); 1.04 (t, 6H).
Reaction SMILES: [IH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:16]2([CH2:20][CH2:19][C:18](SC)=[N:17]2)[CH:14]2[CH2:15][CH:11]1[CH2:12][CH2:13]2.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)C>[IH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:16]2([CH2:20][CH2:19][C:18]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:17]2)[CH:14]2[CH2:15][CH:11]1[CH2:12][CH2:13]2
Reactant: COc1ccccc1C1C2CCC(C2)C12CCC(SC)=N2
Reactant: C1CCNC1
Agent: I
Solvent: CCO
Product: COc1ccccc1C1C2CCC(C2)C12CCC(N1CCCC1)=N2

Procedure:
12 mmoles of 3-(2-methoxyphenyl)-5'-methylthio-spiro[bicyclo[2.2.1]-heptane-2,2'-5-pyrroline]hydriodide and 2 g of pyrrolidine in 50 ml of ethanol are refluxed. The solvent is stripped off and the residue obtained is recrystallized from isopropanol. Colorless crystals of melting point 228° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:29][C:30]([NH:32][C@@H:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@H:36]([O:43][C:44]3[CH:45]=[CH:46][C:47]4[N:48]([C:50]([N:53]5[CH2:58][CH2:57][CH2:56][CH2:55][C@@H:54]5[CH3:59])=[N:51][N:52]=4)[CH:49]=3)[CH2:35][CH2:34]2)=[O:31])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[C:12]([CH2:27]Cl)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:29][C:30]([NH:32][C@@H:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@H:36]([O:43][C:44]3[CH:45]=[CH:46][C:47]4[N:48]([C:50]([N:53]5[CH2:58][CH2:57][CH2:56][CH2:55][C@@H:54]5[CH3:59])=[N:51][N:52]=4)[CH:49]=3)[CH2:35][CH2:34]2)=[O:31])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[C:12]([CH2:27][N:64]3[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1CCl)(C(C)C)C(C)C
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1CN1CCN(C)CC1)(C(C)C)C(C)C
Temperature: 50 °C
Yield: 49.8 %

Procedure:
A solution of Intermediate 61f (31.0 mg, 0.04 mmol) in THF (0.4 mL) was treated with 1-methyl-piperazine (41 μL, 0.37 mmol) and the mixture was heated to 50° C. for 64 h. The mixture was evaporated in vacuo and the residue was partitioned between DCM and water. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with water (2×), dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM, to give the title compound as a colorless glass (18 mg, 55%). LCMS (Method 3): Rt 3.64 min, m/z 903.7 [MH+].
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH2:14][C:15](=[O:19])[NH:16]3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[N:20]1([CH2:25][CH2:26][NH:27][C:28]([C:30]2[C:34]([CH3:35])=[C:33]([CH:36]=O)[NH:32][C:31]=2[CH3:38])=[O:29])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH2:25][CH2:26][NH:27][C:28]([C:30]2[C:34]([CH3:35])=[C:33]([CH:36]=[C:14]3[C:13]4[C:17](=[CH:18][C:10]([C:6]5[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=5)=[CH:11][CH:12]=4)[NH:16][C:15]3=[O:19])[NH:32][C:31]=2[CH3:38])=[O:29])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)c1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4cccc(C(C)C)c4)ccc32)c(C)c1C(=O)NCCN1CCCC1
Yield: 62.6 %

Procedure:
6-(3-Isopropylphenyl)-1,3-dihydroindol-2-one (48 mg, 0.19 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (50 mg) to give 59 mg (63%) of the title compound as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:24][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)=[O:20])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: CN1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN1CCN(C(=O)CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (120.0 mg, 0.29 mmol) from example 210 and N-methyl-piperazine (35.3 mg, 0.35 mmol). The title compound was obtained as a solid (30.0 mg, 21% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.05 (1H, m), 8.99 (2H, m), 8.51 (1H, s), 4.07 (2H, m), 3.42 (2H, m), 3.32 (2H, m), 2.29 (2H, m), 2.24 (2H, m), 2.17 (3H, s). MS m/z: 488.13, 490.15 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[NH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:23]#[N:24])=[C:16]2[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=1>C(Cl)Cl.O1CCCC1>[Br:32][C:28]1[CH:27]=[C:26]([NH:25][C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([NH:12][C:8](=[O:10])[CH3:9])[CH:14]=3)[N:19]=[CH:18][C:17]=2[C:23]#[N:24])[CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)Cl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
Triethylamine (0.359 g, 3.55 mmol) and acetyl chloride (0.277 mg, 3.55 mmol) were added to an ice cold solution of 1.00 g (2.96 mmol) of 6-amino-4-[(3-bromophenyl)-amino]-3-quinolinecarbonitrile in 8 mL of methylene chloride and 6 mL of tetrahydrofuran under N2. After stirring overnight at 25° C., volatile material was removed, and the residue was slurried with water and collected. Recrystallization from ethanol gave 0.543 g of brown solid; mp 258-261° C.(dec).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:26]1([CH2:32][CH2:33][SH:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[Na+]>O1CCOCC1.O>[CH2:33]([S:34][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Reactant: SCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(SCCc3ccccc3)nn2)CC1
Temperature: 105 °C
Yield: 44.1 %

Procedure:
A mixture of [4-(6-chloro pyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.089 g, 0.240 mmol), 2-phenylethanethiol (0.049 g, 0.36 mmol) and sodium hydroxide (9.6 mg) in 5 mL 1,4-dioxane was heated at 100-110° C. overnight. The reaction mixture was cooled to room temperature, diluted with 20 mL of water, and then extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate, then concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid (50 mg, 43.7% yield). 1H NMR (400 MHz, CDCl3) δ 7.65, 7.52-7.55, 7.47-7.48, 7.27, 7.12-7.22, 7.03, 6.76, 3.89-3.94, 3.79-3.84, 3.54-3.61, 3.49-3.51, 3.45, 3.17-3.25, 2.97.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(N(CC)CC)C.CS(ON=C(C#N)C(OCC)=O)(=O)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C>[C:1]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:4])[CH3:2]
Reactant: CC(=O)O
Reactant: Nc1ccccc1
Agent: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1
Reaction time: 0.67 h
Yield: 88.9 %

Procedure:
Acetic acid (0.3 g) and triethylamine (0.7 ml) are dissolved in ethyl acetate (10 ml), and thereto is added ethyl 2-methanesulfonyloxyimino-2-cyanoacetate (1.1 g) and the mixture is stirred for 40 minutes. To the solution is added aniline (0.5 g) and the mixture is stirred for 2 hours. The reaction mixture is washed well with 1 N aqueous sodium hydrogen carbonate, water and 1 N hydrochloric acid in order and then dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off to give flasks of acetanilide (0.6 g), melting poit: 95°-105° C. The product recrystallized from water has a melting point of 104°-108° C.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@H:19]1[C@H:23]([OH:24])[CH2:22][CH2:21][O:20]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][CH3:16].Cl[P:26]1(=[O:31])[O:30][CH2:29][CH2:28][O:27]1.[CH:32]([N:35]([CH:38](C)C)[CH2:36]C)(C)C>ClCCCl>[P:26]([O-:27])([O:30][CH2:29][CH2:28][N+:35]([CH3:38])([CH3:36])[CH3:32])([O:24][C@@H:23]1[CH2:22][CH2:21][O:20][C@H:19]1[CH2:18][O:17][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][CH3:16])=[O:31]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=P1(Cl)OCCO1
Reactant: CCCCCCCCCCCCCCCCOC[C@@H]1OCC[C@H]1O
Solvent: ClCCCl
Product: CCCCCCCCCCCCCCCCOC[C@@H]1OCC[C@H]1OP(=O)([O-])OCC[N+](C)(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution containing 1.275 g of dl-trans-2-hexadecyloxymethyl-3-hydroxytetrahydrofuran (prepared as described in Preparation 14), 1.060 g of 2-chloro-2-oxo-1,3,2-dioxaphospholane and 1.30 ml of diisopropylethylamine in 20 ml of 1,2-dichloroethane was heated, with stirring, at 80° C. for 16 hours. The mixture was then cooled, and the solvent was removed by distillation under reduced pressure. The residue was then dissolved in 15 ml of acetonitrile. 3.0 g of trimethylamine gas were passed through and dissolved in the solution, and the resulting reaction mixture was heated in a sealed tube at 80° C. for 18 hours. It was then cooled, and the reaction mixture was evaporated to dryness. The residue was subjected to column chromatography using 50 g of silica gel. The crude substance obtained from the fraction eluted with a 60:35:5 by volume mixture of methylene chloride, methanol and water was further purified by chromatography through two silica gel Lobar B columns. The fraction eluted with the same solvent system as described above gave 1.257 g of the title compound as a white powder, melting at 213°-223° C.
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:5]=1.[CH3:19][O:20][C:21](=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](Cl)=[O:29])[CH:23]=1.[C:32]([O:36][C:37]([NH:39][NH2:40])=[O:38])([CH3:35])([CH3:34])[CH3:33].N1C=CC=CC=1>CCOCC.CCOC(C)=O>[C:32]([O:36][C:37](=[O:38])[CH2:19][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:5]=1)=[O:18])([CH3:35])([CH3:34])[CH3:33].[C:32]([O:36][C:37]([NH:39][NH:40][C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([OH:20])=[O:31])=[O:29])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: COC(=O)c1cccc(-c2nnc(C)c(C)n2)c1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NNC(=O)c1cccc(C(=O)O)c1
Product: Cc1nnc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound was prepared from 3-(5,6-dimethyl-[1,2,4]triazin-3-yl)-benzoic acid methyl ester [prepared by the following procedure: A solution of 3-chlorocarbonyl-benzoic acid methyl ester (31.6 g, 0.15 mol) in Et2O (0.15 l) was added over 15 min at 0-5° C. to a solution of hydrazinecarboxylic acid tert-butyl ester (19.9 g, 0.1 mol) and pyridine (13.3 ml, 0.165 mol) in Et2O (0.6 l). The mixture was stirred for 1 h at 0° C. and for 1 h at RT, diluted with AcOEt and washed successively with 1N HCl, sat. NaHCO3-sol. and brine. The organic layer was dried and evaporated to give 3-(N′-tert-butoxycarbonyl-hydrazinocarbonyl)-benzoic acid (31.5 g) as white solid. A sample of this material (29.4 g, 0.1 mol) was stirred in a mixture of MeOH (0.1 l) and 1 N KOH (0.2 l) for 18 h at RT The solution was concentrated in vacuum and then washed with AcOEt. The aqueous phase was acidified to pH 1 with 3N HCl and the precipitate formed was isolated by filtration, dried and then stirred with TFA (0.3 l) at RT for 40 min. The mixture was evaporated in vacuum and the residue was triturated with Et2O/EtOH (10:1) to give 3-hydrazinocarbonyl-benzoic acid as a white solid (16.2 g). A solution of this material (3.6 g, 20 mmol) and 1,3-butandione (1.89 g, 22 mmol) in MeOH (20 ml) was stirred at RT for 1 h. The mixture was evaporated in vacuum and the residue was heated in an autoclave in 5N NH3-MeOH (30 mL) at 150° C. for 3 h. The mixture was cooled and partitionned between AcOEt and sat. NaHCO3-solution. The aqueous phase was acidified to pH 3 with 3N HCl and extracted with AcOEt. The crude product obtained from the AcOEt extract was esterified by heating in 1N HCl-MeOH (80 mL) for 18 h at 50° C. The crude product was purified by chromatography (silica gel, AcOEt) to give the methyl ester as light yellow solid (1.21 g).] (1.21 g, 5 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as a light brown solid (1.78 g, crude product).
Reaction SMILES: [Cl-].ClC1N(C)CC[N+]=1C.[CH3:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.[CH2:22]([C:27]12[CH2:34][CH2:33][C:30]([C:35]([NH:37][NH2:38])=O)([CH2:31][CH2:32]1)[CH2:29][CH2:28]2)[CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][C:12]([C:13]2[O:15][C:35]([C:30]34[CH2:31][CH2:32][C:27]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH2:34][CH2:33]3)[CH2:28][CH2:29]4)=[N:37][N:38]=2)=[C:11]([CH3:10])[CH:19]=1
Reactant: CCCCCC12CCC(C(=O)NN)(CC1)CC2
Reactant: COc1ccc(C(=O)O)c(C)c1
Agent: CN1CC[N+](C)=C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC12CCC(c3nnc(-c4ccc(OC)cc4C)o3)(CC1)CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Chloro-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium chloride (5.07 g, 30.0 mmol) was added to a solution of 2-methyl-4-methoxybenzoic acid (2-D) (856 mg, 5.0 mmol) and 4-pentylbicyclo[2.2.2]octane-1-carbohydrazide (2-C) (1.25 g, 5.25 mmol) in methylene chloride (60 mL) followed by triethylamine (8.36 mL, 60 mmol) and the mixture stirred at room temperature for 48 h. The mixture was diluted with methylene chloride and washed with water, 1N HCl, 10% NaHCO3, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate, 9:1) to give 2-(4-methoxy-2-methylphenyl)-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole (2-E) Mass spectrum: 369 (M+1); 1H NMR (500 MHz, CDCl3): δ 0.93 (t, 3H); 1.27 (m, 8H); 1.56 (m, 6H); 2.03 (m, 6H); 2.70 (s, 3H); 3.89 (s, 3H); 6.86 (m, 2H); 7.89 (d, 1H) ppm.