Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C:8](=[NH:10])[NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:12]N.[C:14]([NH:17][CH:18]([CH3:26])[C:19](=O)[C:20](OCC)=[O:21])(=[O:16])[CH3:15]>C(O)C>[O:21]=[C:20]1[C:19]([CH:18]([NH:17][C:14](=[O:16])[CH3:15])[CH3:26])=[N:12][N:9]=[C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:10]1
Reactant: CCOC(=O)C(=O)C(C)NC(C)=O
Reactant: NN
Reactant: N=C(N)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)NC(C)c1nnc(-c2ccccc2)[nH]c1=O
Temperature: 45 °C
Reaction time: 3 h

Procedure:
48 g (306 mmol) of benzenecarboximidamide hydrochloride were dissolved in 1.2 l ethanol, and 16.4 ml (337 mmol) of hydrazine hydrate were added. The mixture was stirred at 45° C. for 3 h. 86 g (459 mmol) of ethyl 3-acetamido-2-oxobutanoate (Example 13A), dissolved in 600 ml of ethanol, were added dropwise. The mixture was stirred at 80° C. for another 6 h and at RT for another 12 h. The reaction mixture was chromatographed on silica gel (mobile phase dichloromethane/methanol 20:1). This gave 23.2 g (26% of theory) of the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[NH2:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[CH2:30][OH:31])=[C:20]([O:34][CH3:35])[CH:19]=1>ClCCl.CO>[OH:31][CH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:25]1[CH2:24][CH2:23][O:22][C:21]1[CH:32]=[CH:33][C:18]([NH:17][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(N)ccc1OCCN1CCC[C@H]1CO
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN1CCC[C@H]1CO

Procedure:
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl)propynoic acid and {(S)-1-[2-(4-amino-2-methoxyphenoxy)ethyl]pyrrolidin-2-yl}methanol. Yield: 140 mg (58.9% of theory); melting point: decomposition at 300° C.; C24H24ClF3N2O4 (M=496.91); calc.: molecular ion peak (M+H)+: 497/499; found: molecular ion peak (M+H)+: 497/499; Rf value: 0.2 (silica gel, dichloromethane/methanol (9:1).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:22]([O:24][CH3:25])=[O:23])[CH:2]=C.[O:26]=[O+][O-]>C(Cl)Cl.CO>[CH2:15]([O:14][C:13]1[C:4]([CH2:1][CH:2]=[O:26])=[C:5]([C:22]([O:24][CH3:25])=[O:23])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCc1c(OCc2ccccc2)cc(C(=O)OC)cc1C(=O)OC
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(OCc2ccccc2)c(CC=O)c(C(=O)OC)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of dimethyl 4-allyl-5-(benzyloxy)isophthalate (3.5 g, 10.28 mmol) in CH2Cl2 and methanol was cooled to −78° C. and treated with ozone until the solution appeared blue (20 min). Nitrogen was bubbled through the solution until the blue color dissipated. Dimethylsulfide (1.0 mL) was added and the cold-bath was removed allowing the reaction mixture to warm to room temperature overnight. Concentration of the solution under vacuum provided an oil which was purified by column chromatography on silica gel eluted with 10-30% EtOAc in hexanes to afford the aldehyde (3.0g, 98%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.90 (s, 3 H) 3.95 (s, 3 H) 4.29 (s, 2 H) 5.14 (s, 2 H) 7.31-7.56 (m, 5 H) 7.81 (d, J=1.32 Hz, 1 H) 8.29 (d, J=1.51 Hz, 1 H) 9.75 (s, 1 H); MS (ESI, pos): 343.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[C:10](Cl)[S:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Na+].[CH3:18][N:19]([CH3:23])[C:20](=[S:22])[S-:21].[I-].[Na+]>C(O)C>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[C:10]([S:22][C:20](=[S:21])[N:19]([CH3:23])[CH3:18])[S:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=S)[S-]
Reactant: O=c1cc(Cl)sn1Cc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(C)C(=S)Sc1cc(=O)n(Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of 6.76 g. (0.03 mole) of 2-benzyl-5-chloro-4-isothiazolin-3-one in 25 ml of ethanol was added a solution of 5.37 g. (0.03 mole) of N,N-dimethyldithiocarbamic acid sodium salt dihydrate in 30 ml of ethanol followed by 0.1 g. of sodium iodide. A yellow solid separated spontaneously. The mixture was stirred at room temperature for 3 hours, then cooled and filtered. The solid was triturated with 50 ml of water and recrystallized from 250 ml of boiling EtOH to give 5.6 g. (60% yield) of the named product, mp 184°-186°.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1)#[N:20].[NH2:36][CH2:37][CH:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[OH:39]>>[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[CH:29][C:30]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:36][CH2:37][CH:38]([OH:39])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:18])=[O:7])=[CH:31][CH:32]=1)#[N:20]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(O)c1ccccc1
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3C#N)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-cyano[1,1′-biphenyl]-4-carboxylic acid, and (1RS)-2-amino-1-phenylethanol, the title compound was obtained in 86% purity by HPLC. MS(ESI+): m/z=483.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:8]([C:9](Br)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:17]1(B(O)O)[C:30]2[C:31]3=[C:32]4[C:27](=[CH:28][CH:29]=2)[CH:26]=[CH:25]C=C4[CH:22]=[CH:21][C:20]3=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:42][CH2:43]O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]([C:10]2[C:11]3[C:32]4=[C:31]5[C:20](=[CH:21][CH:22]=3)[CH:19]=[CH:18][CH:17]=[C:30]5[CH:29]=[CH:28][C:27]4=[CH:26][CH:25]=2)=[C:14]2[C:15]=1[CH:42]=[CH:43][CH:12]=[CH:13]2
Reactant: CCO
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1c2ccccc2c(-c2ccc3ccc4cccc5ccc2c3c45)c2ccccc12
Temperature: 90 °C
Yield: 43 %

Procedure:
A mixture of 15 g (44.6 mmol) of 9,10-dibromoanthracene, 11 g (44.6 mmol) of pyren-1-ylboronic acid, 0.52 g (0.446 mmol) of Tetrakis(triphenylphosphine)palladium, 33 ml of 2M Na2CO3, 60 ml of EtOH and 150 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product 8.8 g (43%) as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl.CCOCC>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: C1CCNCC1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=Cc1ccc(C(=O)N2CCCCC2)cc1
Reaction time: 0.08 h

Procedure:
Synthesis of these compounds was begun by suspending 4-carboxybenzaldehyde (34.5 mmol) in 50 mL CH2Cl2, adding 5 mL triethylamine and, after 5 minutes, 4.25 mL pivaloyl chloride. After 1.5 hours, 3.42 mL piperidine was added to the stirred reaction and, after 2 hours, the solution was diluted with ether and washed two times with 5% NaHCO3, three times with dilute HCl, and finally a saturated solution of NaCl. The organic solution was dried over Na2SO4 and the solvents were removed on a rotary evaporator to yield 7.38 g of 1-(4'-formylbenzoyl)piperidine.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:17]([O:19][C:20]([CH2:22][N:23]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:25](O)=[O:26])=[O:21])[CH3:18].CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH2:17]([O:19][C:20](=[O:21])[CH2:22][N:23]([C@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[C:25]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:16])=[O:26])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH3:18]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (L)-proline benzyl ester hydrochloride (0.49 g), N-Ethoxycarbonylmethyl-N-tert.-butoxycarbonyl-2-(R)-amino-3-(4-methoxyphenyl)-propionic acid (0.760 g), N-methyl morpholine (0.93 mL) and 0.65 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 10 mL of dry N,N-dimethyl formamide was stirred for 16 h at ambient temperature. The volatiles were pumped off and water was added followed by extraction with ethyl acetate and concentration of the organic layer. The remaining residue was purified by silica chromatography (isohexane/ethyl acetate 1/2). Yield: 0.99 g (86%); colorless oil; (+)-APCI-MS: 569 (MH+).
Reaction SMILES: [SH:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1.II>>[N:11]1([C:4]2[N:3]=[C:2]3[S:1][NH:10][C:8](=[O:9])[C:7]3=[CH:6][N:5]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NC(=O)c1cnc(N2CCCCC2)nc1S
Agent: II
Product: O=c1[nH]sc2nc(N3CCCCC3)ncc12
Yield: 69.6 %

Procedure:
Using the procedure of Example 20, 20.8 g (87.4 mmol) of 4-mercapto-2-piperidin-1-yl-pyrimidine-5-carboxylic acid amide were treated with 22.2 g (87.4 mmol) of iodine to give 14.37 g of the title compound after recrystallization from dimethyl-formamide, mp 268°-269° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:17])=[CH:9][C:8]=1[C:18](=[O:20])[CH3:19])(=O)=O.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[C:8]([C:18](=[O:20])[CH3:19])[CH:9]=1
Reactant: CC(=O)c1cc(Cl)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Cl)c2ccccc2c1-c1cccc(F)c1
Temperature: 100 °C
Yield: 66 %

Procedure:
To a mixture of 2-acetyl-4-chloro-1-naphthyl trifluoromethanesulfonate (0.100 g, 0.284 mmol, from Example 45, Step 2) and (3-fluorophenyl)boronic acid (0.048 g, 0.34 mmol) in 1,4-dioxane (1 mL) was added 1 N solution of sodium carbonate in water (0.43 mL, 0.43 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.016 g, 0.014 mmol). The mixture was heated at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0 to 40% ethyl acetate in hexane, to give the desired product (56 mg, 66%). LCMS calculated for C18H13ClFO (M+H)+: m/z=299.1; Found: 299.0.
Reaction SMILES: [Br-].[CH2:2]([C:4]1([O:9][C:10](=[O:34])[CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([S+:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]4[CH:29]=[CH:30][CH:31]=[CH:32][C:21]3=4)=[CH:15][C:14]=2[CH3:33])[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:3].[OH:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2.[Na].[C:47]([O:50][CH:51]([CH3:62])[C:52]([F:61])([F:60])[C:53]([F:59])([F:58])[S:54]([O-:57])(=[O:56])=[O:55])(=[O:49])[CH3:48].O>ClCCl>[OH:35][C:36]12[CH2:37][CH:38]3[CH2:44][CH:42]([CH2:41][C:40]([CH2:48][C:47]([O:50][CH:51]([CH3:62])[C:52]([F:61])([F:60])[C:53]([F:59])([F:58])[S:54]([O-:57])(=[O:56])=[O:55])=[O:49])([CH2:39]3)[CH2:45]1)[CH2:43]2.[CH2:2]([C:4]1([O:9][C:10](=[O:34])[CH2:11][O:12][C:13]2[C:14]([CH3:33])=[CH:15][C:16]([S+:20]3[C:21]4[CH:32]=[CH:31][CH:30]=[CH:29][C:22]=4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]3=4)=[CH:17][C:18]=2[CH3:19])[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:3]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)OC(C)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Agent: CCC1(OC(=O)COc2c(C)cc(-[s+]3c4ccccc4c4ccccc43)cc2C)CCCC1
Agent: [Br-]
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: CC(OC(=O)CC12CC3CC(CC(O)(C3)C1)C2)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Yield: 89.1 %

Procedure:
5-(4-(2-(1-ethylcyclopentyloxy)-2-oxoethoxy)-3,5-dimethylphenyl)-5H-dibenzo[b,d]thiophenium bromide (2.00 g, 3.71 mmol) and sodium 3-hydroxyadamantane-acetoxy-1,1,2,2-tetrafluorobutane-1-sulfonate (1.61 g, 3.78 mmol) were dissolved in dichloromethane (100 mL) and water (100 mL) and stirred at r.t. overnight. The dichloromethane layer was separated and the aqueous phase washed with dichloromethane (3×100 mL). The combined organic layers were washed with water (4×200 mL), concentrated in vacuo and residual water removed via azeotrope with acetonitrile (2×200 mL) to afford the title compound (2.90 g, 91%) as a white solid. 1H NMR (500 MHz, (CD3)2CO) δ: 8.52 (d, J=8 Hz, 2H), 8.34 (d, J=8.5 Hz, 2H), 8.01 (t, J=7.5 Hz, 2H), 7.08 (t, J=7.5 Hz, 2H), 7.51 (s, 2H), 4.55 (s, 2H), 4.32 (t, J=6.5 Hz, 2H), 3.60 (brs, OH), 2.72 (tt, J=14, 6.5 Hz, 2H), 2.29 (s, 6H), 2.12-2.20 (m, 2H), 2.00 (q, J=7 Hz, 2H), 1.50-1.82 (m, 12H), 0.84 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([C:6]1[CH:13]=[CH:12]C(C#N)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH:4]=[CH2:5].[OH-:14].[K+].Cl.C(O)CO[CH2:20][CH2:21][OH:22]>O>[CH2:1]([C:6]1[CH:13]=[CH:12][C:20]([C:21]([OH:22])=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: [OH-]
Reactant: C=CCCCc1ccc(C#N)cc1
Reactant: OCCOCCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: C=CCCCc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.9 g of p-(4-pentenyl)benzonitrile and a 10% solution of potassium hydroxide in diethylene glycol was boiled at 180° C. for 2 hours. The reaction mixture was then cooled to room temperature, adjusted to pH 3 with 23% hydrochloric acid, diluted with water and extracted four times with methylene chloride. The organic phases were washed twice with water, dried over magnesium sulphate, filtered and concentrated, whereby 2.12 g of p-(4-pentenyl)benzoic acid were isolated as brown crystals.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:25](N1C=CN=C1)([N:27]1[CH:31]=[CH:30]N=[CH:28]1)=O.CCOC(C)=O.CCCCCC.CN(CCO)C>CC#N.CN(C)C1C=CN=CC=1>[C:1]([O:24][CH2:30][CH2:31][N:27]([CH3:28])[CH3:25])(=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCO
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)OCCN(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a solution of docosahexaenoic acid (0.986 g, 3.0 mmol) in CH3CN (6.0 mL) was added carbonyldiimidazole (0.535 g, 3.3 mmol) in one portion at 0° C. The mixture was allowed to warm to room temperature and stirred at room temperature for 30 min. TLC showed a complete reaction (1:1 EtOAc/hexane). N,N-dimethylaminoethanol (0.89 g, 10.0 mmol) was added dropwise followed by addition of 4-dimethylaminopyridine (0.073 g, 0.60 mmol) The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation and the residue was purified on silica gel using 72% EtOAc/hexane, 80% EtOAC/hexane and 100% EtOAc with 0.5% MeOH each to provide the product, 2-dimethylaminoethyl docosahexaenoate (1.098 g, 92%), as a light yellow oil. The product was stored at -20° C. with small amount of β-carotene.
Reaction SMILES: [N+:1]([C:4]1[C:12]([CH2:13][CH2:14][CH:15]([CH3:43])[CH:16]([OH:42])[CH:17]([CH3:41])[C:18](=[O:40])[CH:19]([CH2:38][CH3:39])[CH:20]2[CH:24]([CH3:25])[CH2:23][C:22]([CH2:36][CH3:37])([CH:26]3[CH2:31][CH2:30][C:29]([CH2:33][CH3:34])([OH:32])[CH:28]([CH3:35])[O:27]3)[O:21]2)=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:44])=[C:6]([CH3:45])[CH:5]=1)([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[C:12]([CH2:13][CH2:14][CH:15]([CH3:43])[CH:16]([OH:42])[CH:17]([CH3:41])[C:18](=[O:40])[CH:19]([CH2:38][CH3:39])[CH:20]2[CH:24]([CH3:25])[CH2:23][C:22]([CH2:36][CH3:37])([CH:26]3[CH2:31][CH2:30][C:29]([CH2:33][CH3:34])([OH:32])[CH:28]([CH3:35])[O:27]3)[O:21]2)=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:44])=[C:6]([CH3:45])[CH:5]=1
Reactant: [H][H]
Reactant: CCC(C(=O)C(C)C(O)C(C)CCc1c([N+](=O)[O-])cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Agent: [Ni]
Solvent: CCO
Product: CCC(C(=O)C(C)C(O)C(C)CCc1c(N)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C

Procedure:
A solution of 5.0 g. (7.6 millimole) of 5-nitro-3-methyl-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]-heptyl}salicylic acid in ethanol (450 ml.) was hydrogenated over 2 g. of Raney-nickel with an uptake of 22.2 mm. of hydrogen. The reaction was filtered (over N2) and 17.2 ml. of N HCl was added. The solvent was removed under reduced pressure, and the residue was crystallized from aqueous acetone to give 5-amino-3-methyl-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]-heptyl}salicylic acid, m.p. 223°-225°[α]D25 +17.92° (1%, MeOH).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8](Cl)[CH3:9].[Na].[CH3:21][SH:22]>CO>[Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8]([S:22][CH3:21])[CH3:9]
Reactant: CC(Cl)c1ncnc(NC(C)c2ccccc2)c1Cl
Reactant: CS
Agent: [Na]
Solvent: CO
Product: CSC(C)c1ncnc(NC(C)c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 30 ml of methanol was dissolved 1.20 g of 5-chloro-6-(1-chloroethyl)-4-(1-phenylethylamino)pyrimidine, and to the mixture was added 2.89 g of a methanethiol sodium salt 15% aqueous solution. The mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[NH:6][C:7]([C:10]([C:12]2[C:13](Cl)=[N:14][CH:15]=[CH:16][CH:17]=2)=O)=[CH:8][CH:9]=1)=[O:4].O.[NH2:20][NH2:21]>C(O)C>[CH3:1][NH:2][C:3]([C:5]1[NH:6][C:7]([C:10]2[C:12]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:21][N:20]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: CNC(=O)c1ccc(C(=O)c2cccnc2Cl)[nH]1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CNC(=O)c1ccc(-c2n[nH]c3ncccc23)[nH]1
Temperature: 80 °C
Yield: 27 %

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid methylamide (320 mg, 1.2 mmol) and hydrazine hydrate (2 mL) in ethanol (20 mL). The mixture was heated to at 80° C. for 48 hours. The precipitate was collected by vacuum filtration, washed with ethanol and water, dried to give 80 mg (27%) of the titled compound.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[C@H:9]([NH:19][C:20]([O:22][CH:23]([CH3:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-:32].[Cs+].[Cs+].[N:37]1([CH:42](I)[C:43](N)=O)[CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C)C=O>[N:37]1([C:42]([CH2:43][N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][C@@H:9]([NH:19][C:20]([O:22][CH:23]([CH3:30])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[C:10]2=[O:18])=[O:32])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CC(OC(=O)N[C@@H]1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccccc1
Reactant: NC(=O)C(I)N1CCCC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(OC(=O)N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(=O)N2CCCC2)C1=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 85.4 %

Procedure:
1,3-Dihydro-5-phenyl-3(R)-{[(α-methyl)benzyloxycarbonyl]-amino}-2H-1,4-benzodiazepin-2-one (100 mg, 0.25 mmole) in 2 ml of dry N,N-dimethylformamide was stirred magnetically in an ice bath under an inert atmosphere. Cesium carbonate (106 mg, 0.325 mmole) and pyrrolidinyliodoacetamide (78 mg, 0.325 mmole) were added and the reaction mixture was stirred vigorously at 0° C. for 1.75 hours. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with brine. The crude product was chromatographed on three, 1 mm×20 cm×20 cm precoated silica gel plates (3:2 hexane-ethyl acetate elution) to give 109 mg of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])[CH:2]=1.S(Cl)([Cl:19])=O.[CH2:21](O)[CH3:22]>>[ClH:19].[ClH:19].[CH2:21]([O:15][C:14](=[O:16])[C@H:12]([CH2:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH2:13])[CH3:22]
Reactant: O=S(Cl)Cl
Reactant: N[C@@H](Cc1cnc2ccccc2c1)C(=O)O
Reactant: CCO
Product: CCOC(=O)[C@@H](N)Cc1cnc2ccccc2c1
Product: Cl
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A mixture of 0.45 g (2.08 mmol) of 3-(3-quinolyl)-alanine, 1 mL of thionyl chloride and 20 mL of ethanol was gently refluxed overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water and treated with active charcoal. Removal of the active charcoal by filtration afforded a filtrate which was evaporated to give a white solid. Crystallization from a mixture of ethanol and ethyl ether gave 0.598 g (90.6%) of the title compound, melting at 204°-205° C. with decomposition. NMR spectrum was consistent with the assigned structure: ##STR73##
Reaction SMILES: N(OCCC(C)C)=O.[CH3:9][C:10]1[N:11]=[C:12](N)[S:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[ClH:25]>CC#N.[Cu](Cl)Cl>[Cl:25][C:12]1[S:13][C:14]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[C:10]([CH3:9])[N:11]=1
Reactant: Cl
Reactant: Cc1nc(N)sc1-c1ccc([N+](=O)[O-])cc1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cc1nc(Cl)sc1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isoamyl nitrite (3.5 ml, 25 mmol) is added to a stirred suspension/solution of anhydrous copper (II) chloride (2.75 g, 20 mmol) in dry methylcyanide (50 ml). 4-Methyl-5-(4-nitro-phenyl)-thiazol-2-ylamine (25a) (4.0 g, 17 mmol) is then added over 30 minutes. The resulting slurry is stirred at room temperature for 1 hour then heated at 70° C. for 30 minutes. After cooling to room temperature the black solution is poured into 4M hydrochloric acid (200 ml). The product is extracted with ethyl acetate, dried (MgSO4) and the solvent removed to give the title compound as an orange powder (3.13 g). MH+ (TOF, ES+): 255.0