Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[H][H].[F:17]N(CC(C)(C)C)S(C1C=CC(C)=CC=1)(=O)=O>O1CCCC1.C1(C)C=CC=CC=1.CCOCC>[F:17][C:2]([CH3:1])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)N(F)CC(C)(C)C)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(F)C(=O)OCC
Reaction time: 0.08 h
Yield: 53.3 %

Procedure:
Diethyl 2-methylmalonate (870 mg, 860 μL, 5 mmole) was dissolved in anhydrous tetrahydrofuran (10 mL) under nitrogen. Sodium hydride (250 mg as a 60% oil dispersion, 6 mmole) was added and the mixture was stirred until hydrogen evolution ceased (about 15 minutes). The reaction mixture was diluted with toluene (20 mL) and transferred dropwise to a solution of N-fluoro-N-neopentyl-p-toluenesulfonamide (1.295 g, 5 mmole) in anhydrous toluene (10 mL) over 5 minutes. A precipitate formed during addition and the reaction temperature rose from 23° to 36°. After stirring an additional 5 minutes under nitrogen, the reaction mixture was diluted with ether (100 mL), washed with aqueous 1N oxalic acid (30 mL), 10% aqueous potassium bicarbonate (30 mL), and saturated aqueous sodium chloride (30 mL) solutions, and then dried over anhydrous magnesium sulfate. Filtration, removal of solvent under reduced pressure, and purification by flash column chromatography (silica, 1:1 methylene chloride-hexane) yielded diethyl 2-fluoro-2-methylmalonate (512 mg, 53% yield) as a colorless liquid. This material, and additional samples prepared by this procedure, were analyzed and provided the following results: IR (liquid film) γmax (cm-1) 2940 (m), 1750 (s, ester), 1440 (m), 1370 (m), 1290 (s); 1H NMR (80 MHz, CDCl3) δ1.33 (t, J=8 Hz, 6H, CH2CHHD 3), 1.81 (d, J=22.67 Hz, 3H, CH3), 4.30 (q, J=8 Hz, 4H, CH2); 19F NMR (94.1 MHz, CDCl3) -158.02 (q, J=22 Hz, 1F); HRMS (M--CH2CH3) calcd. for C6H8O3F: 147.0457; found: 147.0450; LRMS (CI) m/e 193.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([CH3:18])[C:16](I)=[C:12]3[N:11]=[C:10]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][OH:25])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>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.C(O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:16]2[C:15]([CH3:18])=[N:14][N:13]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[CH:9][C:10]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[CH2:24][OH:25])=[N:11][C:12]=23)=[CH:30][CH:29]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1nn2c(-c3cccc(Cl)c3)cc(N3CCC[C@H]3CO)nc2c1I
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: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(C)nn3c(-c4cccc(Cl)c4)cc(N4CCC[C@H]4CO)nc23)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
(S)-(1-(7-(3-Chlorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (30 mg), 4-methoxyphenylboronic acid (15 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (10 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred overnight at 90° C. under argon atmosphere. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield the target compound (21 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[NH4+]=[S:12]>CO.O>[F:1][C:2]1[C:3]([C:9](=[S:12])[NH2:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#Cc1ncc(F)cc1F
Solvent: CO
Solvent: O
Product: NC(=S)c1ncc(F)cc1F
Temperature: 0 °C
Reaction time: 14 h

Procedure:
3,5-Difluoropicolinonitrile (1.00 g) was partially dissolved in methanol (5 mL) and cooled to 0° C. A solution of ammonium sulfide in water (1.1 mL, 45% weight) was added slowly and the reaction was stirred 14 hours. The reaction was decanted and this solution was concentrated and then purified by column chromatography using dichloromethane as the eluant to obtain the title compound (0.17 g) having the following physical data.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:19]([F:22])([F:21])[F:20])[CH:10]([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Na+].[I-:24].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.O>[Si:1]([O:8][CH:9]([C:19]([F:22])([F:21])[F:20])[CH:10]([NH:14][C:15](=[O:18])[CH2:16][I:24])[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)C(NC(=O)CCl)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)C(NC(=O)CI)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 8 h
Yield: 91.9 %

Procedure:
N-(2-tert-Butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-chloroacetamide (15.56 g) was added to a solution of NaI (19.3 g) in acetone (130 mL). The mixture was stirred overnight and the yellow reaction mixture was diluted with water (180 mL). The resulting precipitate was filtered; washed with water and saturated aqueous sodium thiosulfate; and dried under vacuum at 40° C. overnight. After spectral data indicated the presence of starting material, the product was subjected to another iteration of the above reaction conditions. The subsequent work-up was identical except that no sodium thiosulfate wash was performed. Purification by chromatography, eluting with hexane:ethyl acetate (gradient, 80:20 and 50:50), and drying under vacuum afforded N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-iodoacetamide (17.91 g); TLC: Rf =0.30, hexane:ethyl acetate (9:1); MS: m/z=454(M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([CH3:41])=[CH:33][CH:34]=[C:35]([C:38](O)=[O:39])[N+:36]=2[O-:37])=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:38]([C:35]5[N+:36]([O-:37])=[C:31]([C:28]6[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=6)[C:32]([CH3:41])=[CH:33][CH:34]=5)=[O:39])=[CH:3][CH:4]=4)=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(=O)O)[n+]([O-])c1-c1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cc2)[n+]([O-])c1-c1ccc(F)cc1
Yield: 72.8 %

Procedure:
Using N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.649 mmol), 6-(4-fluorophenyl)-5-methylpyridine-2-carboxylic acid 1-oxide (192.5 mg, 0.779 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (224 μL, 1.30 mmol) and HATU (296 mg, 0.779 mmol) and in the same manner as in Example 58, the title compound (254 mg, 73%) was obtained as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[N+]([CH:26]=[CH:27][C:28]1[CH:36]=[CH:35][C:31]2[O:32][CH2:33][O:34][C:30]=2[CH:29]=1)([O-])=O>>[O:32]1[C:31]2[CH:35]=[CH:36][C:28]([C:27]3[C:12]4[CH2:13][NH:8][CH2:9][CH2:10][C:11]=4[N:22]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:26]=3)=[CH:29][C:30]=2[O:34][CH2:33]1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])C=Cc1ccc2c(c1)OCO2
Product: c1ccc(Cn2cc(-c3ccc4c(c3)OCO4)c3c2CCNC3)cc1

Procedure:
The title compound (306.0 mg) was prepared from 0.49 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 268 μL of benzylamine, and 0.48 g of 5-(2-nitro-vinyl)-benzo[1,3]dioxole. MS (ESI): exact mass calculated for C21H20N2O2, 332.15. found, m/z 333.2 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.36-7.30 (m, 2H), 7.29-7.24 (m, 1H), 7.18-7.14 (m, 2H), 7.01 (s, 1H), 6.85-6.75 (m, 3H), 5.93 (s, 2H), 5.12 (s, 2H), 4.31 (s, 2H), 3.49 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54].Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][O:41][S:53]([CH3:52])(=[O:55])=[O:54])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOS(C)(=O)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole (2.21 g) in dichloromethane (35 mL) were added triethylamine (0.65 mL) and methanesulfonyl chloride (0.33 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]phenyl)methyl}-1H-pyrazole. This material was dissolved in N,N-dimethylformamide (20 mL). To the solution was added sodium azide (0.46 g), and the mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water three times, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate 1/1-1/3) to give the title compound (1.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([Cl:15])=[C:10]([CH3:16])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:24][CH:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26](Cl)=[O:27]>C1COCC1>[Cl:24][CH:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([Cl:15])=[C:10]([CH3:16])[N:9]=2)=[CH:4][CH:3]=1)=[O:27]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(NC(=O)C(Cl)c3ccccc3)cn2)nc(O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of compound of example 16 (0.10 g, 0.42 mmol) in THF (10 mL), was added triethylamine (0.064 g, 0.63 mmol) and 2-chloro-2-phenyl acetyl chloride (0.119 g, 0.63 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5 methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: ClC1C=C(CC[CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]2[O:40][CH:39]=[C:38]([CH2:41][CH2:42]C(O)=O)[C:37]=2[CH:46]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]2[O:40][CH:39]=[C:38]([CH2:41][CH2:42][CH2:10][N:11]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]3)[C:12](=[O:24])[NH:13][C:14]3[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=3)[C:37]=2[CH:46]=1
Reactant: O=C(O)CCc1coc2ccc(Cl)cc12
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCc2coc3ccc(Cl)cc23)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(5-chloro-benzofuran-3-yl)-propionic acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH:5]=[O:6].[CH3:14][Al](C)C.O>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH:5]([OH:6])[CH3:14]
Reactant: COc1ccc([N+](=O)[O-])cc1C=O
Reactant: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1ccc([N+](=O)[O-])cc1C(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 2-methoxy-5-nitrobenzaldehyde (450 mg) in toluene (30 ml), a solution of trimethylaluminum in hexane (3.0 ml) was added dropwise under ice cooling. After stirring at room temperature for 1 h, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1) to give 385 mg of the titled compound (yield, 79%).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:13]([CH:23]([CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:24]=[O:25])[CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>O1CCCC1>[CH2:13]([CH:23]([CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:24]([OH:25])[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC/C=C\CCCBr
Reactant: CCCCC/C=C\CCCC(C=O)CCC/C=C\CCCCC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC/C=C\CCCC(O)C(CCC/C=C\CCCCC)CCC/C=C\CCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a suspension of magnesium turnings (0.6 g, 23.9 mmol) in tetrahydrofuran (5 mL) was slowly added a solution of (Z)-1-bromodec-4-ene 3 (4.5 g, 20.5 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred for 30 minutes at room temperature then a solution of (Z)-2-((Z)-dec-4-enyl)dodec-6-enal 7 in tetrahydrofuran (5 mL) was added. The solution was stirred for 15 minutes at room temperature then poured into 5% hydrochloric acid (50 mL) and ice (100 mL). The solution was extracted with ether (2×150 mL). The combine ether extracts were dried on magnesium sulfate, filtered, and concentrated in vacuo to dryness. The residue was purified by column chromatography (1% ethyl acetate in hexanes) to afford (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-ol 8 as a colorless oil (4.8 g, 76%). Rf 0.45 (10% EtOAc-Hexanes).
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[NH:38])SC)=[CH:31][CH:30]=1)=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[C@@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][NH2:40]>ClCCl.CO>[CH2:1]([S:8]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:39][NH2:40])=[NH:38])=[CH:31][CH:30]=1)=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=[O:18])[C@@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)NCc1ccc(C(=N)SC)cc1
Reactant: NN
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)NCc1ccc(C(=N)NN)cc1
Reaction time: 18 h
Yield: 60.7 %

Procedure:
N-(Benzylsulfonyl)-D-isoleucyl-N1-{4-[imino-(methylthio)methyl]benzyl}-L-methioninamide (49 mg, 0.084 mmol) was dissolved in dichloromethane (2 ml) and methanol (2 ml), to which hydrazine (0.020 ml, 0.624 mmol) was then added and stirred for 18 hours. The solvent was distilled off under reduced pressure and the residue was purified by preparative HPLC to give N-(benzylsulfonyl)-D-isoleucyl-N1-{4-[hydrazino(imino)methyl]benzyl}-L-methioninamide (29 mg, 0.051 mmol; yield 61%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[CH:16][CH:17]=2)[S:27]([CH3:26])(=[O:29])=[O:28])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncc(Br)cc1CNc1ccc(Oc2ccc(C)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ncc(Br)cc1CN(c1ccc(Oc2ccc(C)cc2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5-bromo-2-methoxy-pyridin-3-ylmethyl)-(4-p-tolyloxy-phenyl)-amine (0.73 g, 1.82 mmol) from Step A in CH2Cl2/pyridine (6 mL/3 mL) was dropwise added methylsulfonyl chloride (0.17 mL, 2.2 mmol) at 0° C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction was then diluted with CH2Cl2 and washed with aqueous HCl (3N) to remove pyridine. The organic layer was then brought to the usual work-up. The crude product was purified by chromatography (silica gel, 30% EtOAc/hexanes). MS (EI) 477, 479 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH:17](OCC)(OCC)OCC.C(O)C.[BH4-].[Na+]>C(OCC)(=O)C>[CH3:17][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: Nc1ccc2ccn3cccc3c(=O)c2c1
Reactant: CCOC(OCC)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1ccc2ccn3cccc3c(=O)c2c1
Reaction time: 2 h

Procedure:
A solution of 9-amino-11H-pyrrolo[2,1-b] [3]-benzazepin-11-one in triethyl orthoformate (2.17 g., 10 mmoles in 80 ml.) is refluxed for 5 hrs. The volatiles are removed under vacuum and the residue, dissolved in 100 ml. absolute ethanol is stirred in an ice bath as sodium borohydride (0.88 g., 0.024 moles) is added over a period of 10 minutes. The mixture is stirred for a period of 2 hrs. After concentration of the ethanol, the residue is dissolved in ethyl acetate, washed with water, dried over Na2SO4 and concentrated to dryness to yield 9-methylamino-11H-pyrrolo[2,1-b] [3]benzazepin-11-one as a brown amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:16](OCC)(=[O:22])[C:17](OCC)=[O:18]>>[Cl:15][C:13]1[CH:14]=[C:2]2[C:3](=[CH:11][CH:12]=1)[N:4]([CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)[C:17](=[O:18])[C:16](=[O:22])[NH:1]2
Reactant: Nc1cc(Cl)ccc1NC1CCCCC1
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cc(Cl)ccc2n(C2CCCCC2)c1=O
Yield: 63 %

Procedure:
34.5 g (0.15 mol) of 2-amino-4-chloro-N-cyclohexylaniline were refluxed in 500 ml of diethyl oxalate for 4 h. After cooling, the precipitate was filtered off with suction, washed with n-pentane and dried. 26.8 g (63%) of the product were obtained. Melting point 265°-266° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][OH:24])=[CH:20][CH:19]=1.Cl.O1CCOCC1.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=[C:2]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][OH:24])=[CH:20][CH:19]=3)[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: CCc1nc(Cl)cc(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCc1nc(Nc2ccc(CCO)cc2)cc(-c2cccc(Cl)c2)n1
Yield: 19.6 %

Procedure:
A solution of 4-chloro-6-(3-chlorophenyl)-2-ethylpyrimidine (0.100 g, 0.39 mmol), 4-aminophenethyl alcohol (0.081 g, 0.59 mmol) and HCl in dioxane (4.0 M, 0.023 mL, 0.59 mmol) in ethanol (2 mL) was heated to 85° C. for 3 h. After this time, the reaction was cooled, neutralized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.027 g, 27%) as a light yellow solid. MW=353.85. 1H NMR (DMSO-d6, 500 MHz) δ 8.01 (t, J=1.8 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.69-7.57 (m, 4H), 7.25 (d, J=8.3 Hz, 2H), 7.04 (s, 1H), 3.61 (t, J=7.0 Hz, 2H), 2.87 (q, J=7.6 Hz, 2H), 2.72 (t, J=7.0 Hz, 2H), 1.33 (t, J=7.6 Hz, 3H); APCI MS m/z 354 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[C:6](O)=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:4]1(=[O:17])=[O:16])[CH3:2].CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>C(Cl)Cl>[Cl:26][C:6]1[C:7](=[O:8])[N:3]([CH2:1][CH3:2])[S:4](=[O:17])(=[O:16])[C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Temperature: 0 °C
Yield: 292.4 %

Procedure:
2-Ethyl-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (5 g, 19.76 mmol) was dissolved in dry DCM (250 mL) and cooled to 0° C. under N2. Dry DMF (15 mL) was added, followed by oxalyl chloride (3 mL, 34.4 mmol). The ice-bath was removed and the mixture was refluxed at 50° C. under N2 for 4 h. The reaction mixture was evaporated and the residue was diluted with EtOAc, washed with water (3×25 mL) and brine, dried over Na2SO4 and evaporated. Another (16 g, 63.24 mmol) of 2-ethyl-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide was dissolved in dry DCM (500 mL) and cooled to 0° C. under N2. Dry DMF (20 mL) was added followed by oxalyl chloride (9 mL, 103.2 mmol). The ice-bath was removed and the mixture was refluxed at 50° C. under N2 for 4 h. The reaction mixture was evaporated and the residue was diluted with EtOAc, washed with water (3×50 mL) and brine, dried over Na2SO4 and evaporated where by red solid was obtained. The crude material from both batches were combined and purified by column chromatography on silica gel using 2.5-3% ethyl acetate in petroleum ether as eluant, and recrystallised from methanol to give the title compound (15.7 g, 70%) as a white solid; 1H NMR (400 MHz, CD3OD) δ 1.42 (t, 3H, J=7.3 Hz), 3.84 (q, 2H, J=7.3 Hz), 7.6-7.7 (m, 3H), 7.9-8.0 (m, 2H); Mass Spectrum: M+H+ 272.