Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1.[OH-].[K+].[CH3:11]I.O>C(O)C>[CH3:11][N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1
Reactant: CI
Reactant: OCCc1cn[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(CCO)cn1

Procedure:
To a solution cooled (0° C.) of 2-(1H-pyrazol-4-yl)ethanol (93 g, 0.83 mol) and potassium hydroxide (48.8 g, 0.87 mol) in absolute ethanol (9.25 L) was added methyl iodide (178 g, 1.25 mol) dropwise. The mixture was allowed to react for 30 min, at which time it was poured into water (400 mL) and extracted with diethyl ether (4×100 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo, and purified by vacuum distillation to afford the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]2[CH2:10][CH2:9]2)[S:6][CH:7]=1.CS(C)=[O:13]>CCOC(C)=O.O=[Mn]=O>[CH:8]1([C:5]2[S:6][CH:7]=[C:3]([CH:2]=[O:13])[N:4]=2)[CH2:10][CH2:9]1
Reactant: ClCc1csc(C2CC2)n1
Reactant: CS(C)=O
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: O=Cc1csc(C2CC2)n1
Temperature: 100 °C
Yield: 38 %

Procedure:
To a solution of 4-(chloromethyl)-2-cyclopropylthiazole (3.0 g, 17.2 mmol) in DMSO (10 mL) was charged MnO2 (1.5 g, 17.2 mmol). The mixture was heated to 100° C. overnight, cooled to room temperature and diluted with EtOAc (30 mL). The mixture was filtered through Celite and washed with EtOAc (3×30 mL). The combined organic layer was washed with brine (3×40 mL) and concentrated. The residue was purified by silica gel chromatography using 2 to 5% EtOAc in hexane to afford the title compound (1.0 g, 38%) as a light brown oil, which solidified upon standing in a refrigerator overnight. 1H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 7.93 (s, 1H), 2.36 (m, 1H), 1.20 (m, 2H), 1.16 (m, 2H). MS (ES) m/z 154.1 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3C2CCCCO2)[CH3:11])[CH:5]=[C:6]([F:9])[C:7]=1[CH3:8].[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].Cl>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.O1CCOCC1.O>[F:9][C:6]1[CH:5]=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][NH:17]3)[CH3:11])[C:3]([O:28][CH3:29])=[C:2]([C:37]2[CH:38]=[CH:39][C:34]([S:31]([CH3:30])(=[O:33])=[O:32])=[CH:35][CH:36]=2)[C:7]=1[CH3:8]
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(F)c(C)c1Br
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(F)c(C)c1-c1ccc(S(C)(=O)=O)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
N-[1-(3-bromo-5-fluoro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (21 mg, 0.044 mmol), [4-(methylsulfonyl)phenyl]boronic acid (13 mg, 0.066 mmol), potassium carbonate (15 mg, 0.11 mmol), water (0.2 mL), and 1,4-dioxane (0.40 mL) were added to a microwave vial. The mixture was degassed under nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (5.1 mg, 4.4 μmol) was added to the mixture and the vial was then sealed and bubbled under nitrogen for 5 minutes. The mixture was heated at 80° C. overnight. The cooled reaction mixture was then treated with 4.0 M hydrogen chloride in water (0.5 mL, 2 mmol) and was stirred at room temperature for 30 minutes. Purification by preparative LCMS (pH 10) RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 60 mL/min) afforded N-{1-[5-Fluoro-2-methoxy-6-methyl-4′-(methylsulfonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine (13 mg, 66%). LCMS calculated for C22H23FN5O3S (M+H)+: m/z=456.1. Found: 456.0.
Reaction SMILES: C([O:8][C:9]([C:11]1([N:16]([CH:34]=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.O>[CH2:39]([O:38][C:36]([CH2:35][CH2:34][N:16]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[CH:24][CH:25]=1)(=[O:19])=[O:18])[C:11]1([C:9]([OH:10])=[O:8])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:37])[CH3:40]
Reactant: CCOC(=O)C=CN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: [H][H]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
A solution of 2.50 g (4.4 mmol) of 1-{(2-ethoxycarbonylvinyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid benzyl ester in 25 mL of ethanol was treated with 2.5 g of 50% water wet 10% palladium on carbon catalyst and shaken under 53 psi of hydrogen for 21 hours. The catalyst was removed by filtration and washed with ethanol (4×25 mL). The filtrate and washings were combined and concentrated under vacuum to 1.74 g (82%) of crude 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid as a viscous oil.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH2:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1)C(=O)OC.C[N:29](CCC1C=CC([N+]([O-])=O)=CC=1)C(=O)OC>>[CH3:1][NH:2][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:15][N:29]=[C:18]2[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20]
Reactant: COC(=O)N(C)CCc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)N(C)CCc1ccc([N+](=O)[O-])c(CS(=O)(=O)c2ccccc2)c1
Product: CNCCc1ccc2[nH]nc(S(=O)(=O)c3ccccc3)c2c1

Procedure:
Methyl methyl(2-{4-nitro-3-[(phenylsulfonyl)methyl]phenyl}ethyl)carbamate Using substantially the same manner as described in Example 171, step 1 and employing methyl methyl[2-(4-nitrophenyl)ethyl]carbamate (2.47 g, 10.38 mmol), the title compound was obtained as a white solid, (2.06 g, 51%). Mp: 42° C., MS (ES+): 393 (M+H)+. Step 4
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:15][N:16]([CH3:18])C)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1[S:21][CH:22]=[CH:23][N:24]=1.Cl.O>C(O)(C)C>[C:1]([NH:9][C:10](=[CH:15][NH:16][C:18]1[S:21][CH:22]=[CH:23][N:24]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=CN(C)C)NC(=O)c1ccccc1
Reactant: Nc1nccs1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COC(=O)C(=CNc1nccs1)NC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
10 g (39.5 mmol) of methyl 2-benzoylamino-3-dimethylaminoacrylate and 11.3 g (118 mmol) of 2-aminothiazole were dissolved at 40° C. in 200 ml of isopropanol. The solution was admixed with 3.96 ml (48 mmol) of concentrated hydrochloric acid within 5 minutes (min) and stirred for a further 60 min. 75 ml of deionized water were added, the suspension was cooled overnight and the crystallized product was filtered off.
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].COC1C=CC=C(OC)[C:27]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(B2OC(C)(C)C(C)(C)O2)=CCC1>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:29][C:28]1([CH3:27])[C:33]([C:2]2[C:3]([O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])=[CH:32][CH2:31][CH2:30]1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: COC(=O)c1cc(Br)c(OC2CCCCO2)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)CCC=C1B1OC(C)(C)C(C)(C)O1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C2=CCCC2(C)C)c(OC2CCCCO2)cc1F
Temperature: 75 °C
Reaction time: 21 h
Yield: 261.1 %

Procedure:
A stirred mixture of T31.3 (10.33 g, 31.0 mmol), ground S-Phos (2.55 g, 6.21 mmol), palladium acetate (0.70 g, 3.11 mmol), and potassium phosphate, tribasic (16.49 g, 77.7 mmol) in DMF (75 mL) and water (4 mL) was purged with argon and placed under vacuum and the process repeated three times. Before heating, 2-(5,5-dimethylcyclopent-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (T2.2) (8.96 g, 40.4 mmol) was added via syringe. The mixture was then heated at 75° C. After 21 hours, the reaction was cooled to room temperature, diluted with water, and extracted three times with EtOAc. The organic layers were combined and washed twice with brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to yield T31.4 (5.65 g, 52% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.63 (1H, d, J=8.6 Hz), 6.93 (1H, d, J=13.3 Hz), 5.55 (1H, t, J=2.3 Hz), 5.43 (1H, t, J=2.7 Hz), 3.90 (3H, s), 3.82 (1H, m), 3.67 (1H, m), 2.41 (2H, td, J=7.0, 2.3 Hz), 1.97 (5H, m), 1.79 (3H, m), 1.07 (6H, d, J=13.7 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[CH3:18][C@H:19]1[CH2:24][NH:23][CH2:22][C@@H:21]([CH3:25])[NH:20]1.C(N(C(C)C)CC)(C)C.Cl>C(#N)C.C(OCC)C>[CH3:18][C@H:19]1[NH:20][C@@H:21]([CH3:25])[CH2:22][N:23]([C:2]2[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:3]=2)[CH2:24]1
Reactant: FC(F)(F)c1nnc(Cl)cc1-c1ccccc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2cc(-c3ccccc3)c(C(F)(F)F)nn2)C[C@H](C)N1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
A mixture of 6-chloro-4-phenyl-3-trifluoromethyl-pyridazine (D3) (0.15 g, 0.58 mmol), 2,6-cis-dimethylpiperazine (0.097 g, 0.87 mmol) and diisopropylethylamine (0.202 ml, 1.16 mmol) in acetonitrile (3 ml) was stirred at 180° C. for 30 min., under microwave irradiation. The solvent was evaporated in vacuo and then dichloromethane and a saturated solution of ammonium chloride were added. The mixture was filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography (silica gel; 1-3% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. The product thus obtained was treated with a solution of hydrochloric acid in diethyl ether (2M) to yield the corresponding salt E4 (0.058 g, 27%; CIS) as a pale brown solid. C17H19F3N4.HCl; free base requires 336. Found 337 (MH+).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6](OO)/[CH:7]=[CH:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>B(O)([O-])[O-].B(O)(O)O.B(O)(O)O.B(O)(O)O.[Na+].[Na+]>[C:18]([OH:20])(=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8]/[CH:7]=[CH:6]\[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCC[C@@H](/C=C/C=C\CCCCCCCC(=O)O)OO
Agent: OB(O)O
Agent: [Na+]
Agent: [O-]B([O-])O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O

Procedure:
13-HPODE, which is a lipid hydroperoxide was produced by the peroxidation of linoleic acid by soybean lipoxygenase-1, in 100 mM di-sodium tetraborate buffer at pH 9.4. After purification by HPLC, the absorption spectrum of 13-HPODE (80 μM) was obtained (FIG. 31). This shows a peak at 234 nm where the conjugated diene absorbs.
Reaction SMILES: BrC1C=C(C)C(C(N2CCC(N3CCCC3)CC2)=O)=C(C)C=1.BrC1C=C(C)C(C(N2CCC(N3CCC[C@H]3CO)CC2)=O)=C(C)C=1.[CH3:47][C:48]1[C:53]([C:54](O)=[O:55])=[C:52]([CH3:57])[N:51]=[C:50]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=2)[N:49]=1.[NH:68]1[CH2:73][CH2:72][CH:71]([N:74]2[CH2:78][CH2:77][CH2:76][C@H:75]2[CH2:79][O:80][C:81](=[O:88])[C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[CH2:70][CH2:69]1>>[CH3:57][C:52]1[C:53]([C:54]([N:68]2[CH2:73][CH2:72][CH:71]([N:74]3[CH2:78][CH2:77][CH2:76][C@H:75]3[CH2:79][O:80][C:81](=[O:88])[C:82]3[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=3)[CH2:70][CH2:69]2)=[O:55])=[C:48]([CH3:47])[N:49]=[C:50]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=2)[N:51]=1
Reactant: O=C(OC[C@@H]1CCCN1C1CCNCC1)c1ccccc1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)nc(C)c1C(=O)O
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCC[C@H]2COC(=O)c2ccccc2)CC1

Procedure:
In analogy to the procedures described for intermediate 1 and for intermediate 4 B), 4,6-dimethyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (intermediate 5) was converted into its acid chloride and subsequently reacted with benzoic acid (S)-1-piperidin-4-yl-pyrrolidin-2-ylmethyl ester (intermediate 3) to give benzoic acid (S)-1-{1-[4,6-dimethyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-piperidin-4-yl}-pyrrolidin-2-ylmethyl ester, which was subsequently saponified to give the title compound as colorless solid. MS: 463.2 (MH+).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([CH:26]([OH:28])[CH3:27])[CH:22]=[CH:23][CH:24]=3)[C:19]([NH:29][S:30]([C:33]3[S:34][C:35]([Cl:38])=[CH:36][CH:37]=3)(=[O:32])=[O:31])=[N:18]2)[CH:13]=[CH:14][CH:15]=1.C([O:42][C:43]([CH3:48])([CH3:47])[C:44](Cl)=[O:45])(=O)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CS(C)=O.CO>[Cl:38][C:35]1[S:34][C:33]([S:30]([NH:29][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][C:21]=3[CH:26]([OH:28])[CH3:27])[N:17]([CH2:16][C:12]3[CH:11]=[C:10]([CH2:9][NH:8][C:44](=[O:45])[C:43]([OH:42])([CH3:48])[CH3:47])[CH:15]=[CH:14][CH:13]=3)[N:18]=2)(=[O:32])=[O:31])=[CH:37][CH:36]=1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CC(O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CO
Product: CC(O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
Triethylamine (0.021 mL, 0.151 mmol) was added to N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(1-hydroxyethyl)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 77) (24 mg, 0.050 mmol) in dichloromethane (1 mL). 2-Chloro-1,1-dimethyl-2-oxoethyl acetate (7.92 μL, 0.055 mmol) was added and the reaction mixture was stirred at room temp for 2 h. The reaction mixture was concentrated on the blowdown unit, potassium carbonate (69.5 mg, 0.503 mmol) and methanol (2 mL) was added and the mixture was stirred at room temp for 1 h. The mixture was concentrated, acidified with 2N HCl and extracted with EtOAc (2×15 mL). The combined organic layers were dried by passing through a hydrophobic frit and concentrated to afford the crude product. The residue was dissolved in DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A). The solvent was removed under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound (10.5 mg, 37%). LCMS (System A) RT=0.99 min, ES+ve m/z 563/565 (M+H)+.
Reaction SMILES: N[C@H:2](C(O)=O)CC1C=CC=CC=1.[NH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15][OH:16].[ClH:20]>CO>[ClH:20].[CH3:2][O:18][C:17](=[O:19])[C@H:14]([CH2:15][OH:16])[NH2:13]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N[C@@H](CO)C(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](N)CO
Yield: 83.8 %

Procedure:
The same esterification procedure as in Example 1 was followed with the exception that the L-phenylalanine was replaced with 105.6 g of L-serine and that 105.6 g of methanol and 50.5 g of hydrochloric acid were used. Following cooling to deposit the crystals, which were collected by filtration and then dried to obtain 134.4 g (83.8% yield) of L-serine methyl ester hydrochloride having a purity of 97.0% and containing 0.2% of water and 0.7% of L-serine.
Reaction SMILES: [CH3:1][C:2]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][Cl:27]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([C:2]([CH3:1])=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:11]1=[O:19]
Reactant: ClCCCCBr
Reactant: CC(=Cc1ccccc1)n1c(=O)[nH]c2ccccc21
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(=Cc1ccccc1)n1c(=O)n(CCCCCl)c2ccccc21
Temperature: 55 °C
Reaction time: 4 h

Procedure:
A mixture of 38.5 parts of 1,3-dihydro-1-(1-methyl-2-phenylethenyl)-2H-benzimidazol-2-one, 5 parts of N,N,N-triethylbenzenemethanaminium chloride and 225 parts of sodium hydroxide solution 60% is stirred and heated at 55° C. Then there are added dropwise 30.9 parts of 1-bromo-4-chlorobutane. Upon completion, stirring at 55° C is continued for 4 hours. The reaction mixture is cooled, water is added and the oily product is extracted with methylbenzene. The extract is dried, filtered and evaporated, yielding 53 parts of 1-(4-chlorobutyl)-1,3-dihydro-3-(1-methyl-2-phenylethenyl)-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [CH3:1][N:2]([CH2:8][CH2:9][S:10][CH:11]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:25]([NH:27][C:28](=[N:36][CH2:37][CH2:38][S:39][CH2:40][C:41]1[N:42]=[C:43]([NH:46][C:47]([NH2:49])=[NH:48])[S:44][CH:45]=1)OC1C=CC=CC=1)#[N:26]>>[C:25]([NH:27][C:28]([NH:36][CH2:37][CH2:38][S:39][CH2:40][C:41]1[N:42]=[C:43]([NH:46][C:47]([NH2:49])=[NH:48])[S:44][CH:45]=1)=[N:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH2:8][CH2:9][S:10][CH:11]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:1])#[N:26]
Reactant: Cc1ccc(C(SCCN(C)CCCCN)c2ccccc2)cc1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Product: Cc1ccc(C(SCCN(C)CCCCN=C(NC#N)NCCSCc2csc(NC(=N)N)n2)c2ccccc2)cc1

Procedure:
Preparation is effected analogously to Example 1, using 0.87 g (2.5 mmol) of N-methyl-N-[2-[[(4-methylphenyl)phenyl-methyl]thio]ethyl]-1,4-butanediamine and 0.95 g (2.5 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=624 ([M+H]+,6), 181 (100); IR (KBr): 2161 cm-1 (C≡N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: 134°-140° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2>>[NH:23]1[C:24]2[C:20](=[CH:19][C:18]([NH:17][C:10](=[O:12])/[CH:9]=[CH:8]/[C:7]3[C:2]([CH3:1])=[N:3][C:4]([C:13]([F:16])([F:15])[F:14])=[CH:5][CH:6]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: Cc1nc(C(F)(F)F)ccc1/C=C/C(=O)O
Reactant: Nc1ccc2[nH]ccc2c1
Product: Cc1nc(C(F)(F)F)ccc1/C=C/C(=O)Nc1ccc2[nH]ccc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[2-methyl-6-(trifluoromethyl)(3-pyridyl)]prop-2-enoic acid, Example 82(b), (120 mg, 0.50 mmol) and 5-aminoindole (66 mg, 0.50 mmol, Aldrich) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a yellow solid. MP 231° C. MS (ESI, pos. ion) m/z: 346 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[C:8](=[O:15])[NH:9][C:10](SC)=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][S:24][CH2:25][CH2:26][NH2:27].Cl>>[ClH:1].[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][S:24][CH2:25][CH2:26][NH:27][C:10]1[NH:9][C:8](=[O:15])[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=2)=[CH:12][N:11]=1
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Reactant: NCCSCc1nccs1
Agent: Cl
Product: O=c1[nH]c(NCCSCc2nccs2)ncc1Cc1ccc(Cl)cc1

Procedure:
An intimate mixture of 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (1.36 g) and 2-(2-thiazolylmethylthio)ethylamine (0.9 g) was heated at 130°-135° for 31/2 hours. After cooling the reaction mixture was treated with 2N hydrochloric acid. Evaporation to dryness followed by recrystallisation from isopropanol/methanol gave 2-[2-(2-thiazolyl-methylthio)-ethylamino]-5-(4-chlorobenzyl)-4-pyrimidone monohydrochloride, m.p. 172.5°-174.5°.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH:20]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=3)[C:21]([O:23]CC3C=CC=CC=3)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1>C1COCC1.[Pd]>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH:20]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=3)[C:21]([OH:23])=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(C(Oc2ccc3c(N)nccc3c2)C(=O)OCc2ccccc2)cc1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(Oc2ccc3c(N)nccc3c2)C(=O)O)cc1OC
Reaction time: 16 h
Yield: 110 %

Procedure:
6F (130 mg, 0.29 mmol) was dissolved in THF (8 mL). To this solution was added 10% Pd/C (cat.), and the mixture was hydrogenated at 50 psi for 16 h. The reaction was filtered and concentrated to provide 6G (113 mg, 10%). LC-MS: 355.19 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([OH:9])=O)[CH3:6])(=[O:3])[CH3:2].S(Cl)(Cl)=O.CN(C)C=O.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]([C:30]([OH:32])=[O:31])[C:23]2=[O:33].C(N(CC)CC)C.Cl[Si](C)(C)C>ClCCl>[C:1]([NH:4][CH:5]([CH3:6])[C:7]([NH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]([C:30]([OH:32])=[O:31])[C:23]2=[O:33])=[O:9])(=[O:3])[CH3:2]
Reactant: Nc1ccc2[nH]cc(C(=O)O)c(=O)c2c1
Reactant: CC(=O)N[C@@H](C)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)C(=O)Nc1ccc2[nH]cc(C(=O)O)c(=O)c2c1
Reaction time: 0.33 h
Yield: 68.3 %

Procedure:
A mixture of 1.73 g (13.2 mmol) of N-acetyl-L-alanine, 0.97 ml (13.2 mmol) of thionyl chloride, 1.02 ml (13.02 mmol) dimethylformamide, and 50 ml of dichloromethane is stirred at -20° to -30° for 20 minutes. A mixture of 2.45 g (12 mmol) of 6-amino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5.04 ml (36 mmol) triethylamine, 4.57 ml (36 mmol) chlorotrimethylsilane and 100 ml of dichloromethane is stirred at room temperature for 25 minutes and is cooled to -60°. The cold acid chloride solution is added to the cold silylated quinoline and is stirred for 2 hours while the temperature comes up to 10°. The reaction mixture is evaporated to dryness and the residue is treated with water to give 2.60 g of 6-[[2-(acetylamino)-1-oxopropyl]amino]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 196°-200° .
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: OCCSCc1ccncc1
Product: CC(=O)OCCSCc1ccncc1
Reaction time: 8 h

Procedure:
4-(2-Hydroxyethylthiomethyl)pyridine (1.0 g.) was refluxed with 10 ml. of acetic anhydride for 3 hours. After standing overnight at room temperature, the acetic anhydride was evaporated in vacuo, the residue diluted with 10 ml. of water, made basic with sodium bicarbonate, and the product extracted into chloroform (four times 50 ml.). The chloroform was carbon treted, dried and concentrated to an oil (1.47 g.). The oil was chromatographed on 60 g. of silica gel with 5% methanol/chloroform as eluant. Fractions containing only product (Rf 0.6 on thin layer silica gel chromatography eluted with 18:1 chloroform:methanol) were combined and concentrated to yield 4-(2-acetoxyethylthiomethyl)pyridine [300 mg. of oil; pnmr/CDCl3 /TMS/τ: 7.9 (s, 3H), 7.3 (t, 2H), 6.3 (s, 2H), 5.8 (t, 2H), 2.7 (d, 2H), 1.4 (d, 2H)].