Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[Br:15][C:16]1[C:17]([CH3:23])=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[C:16]([Br:15])[C:17]=1[CH3:23])=[O:6]
Reactant: Nc1ccccc1C(=O)O
Reactant: Cc1c(N)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1c(Br)cccc1NC(=O)c1ccccc1N
Reaction time: 0.25 h
Yield: 42.2 %

Procedure:
A solution of 2-aminobenzoic acid (5.00 g, 36.5 mmol) and thionyl chloride (8.68 g, 72.9 mmol) in toluene (50 mL) was heated at reflux for 60 min. The mixture was concentrated in vacuo, and the residue was suspended in THF (50 mL), cooled in an ice-water bath and treated with 3-bromo-2-methylaniline (20.35 g, 109 mmol). The resulting suspension was heated at reflux for 2 h. The cooled mixture was treated with 10% aqueous K2CO3 (50 mL), stirred vigorously for 15 min, and extracted with EtOAc. The organic phase was dried and concentrated. The residue was purified by column chromatography on silica gel to give 2-amino-N-(3-bromo-2-methylphenyl)benzamide as a light yellow solid (4.70 g, 42% yield). Mass spectrum m/z 305, 307 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 7.72 (d, J=7.9 Hz, 1H), 7.67 (br. s., 1H), 7.54 (dd, J=8.3, 1.2 Hz, 1H), 7.48 (dd, J=7.9, 0.9 Hz, 1H), 7.36-7.31 (m, 1H), 7.15 (t, J=8.0 Hz, 1H), 6.81-6.73 (m, 2H), 5.59 (br. s., 2H), 2.45 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36](O)[CH2:37][CH3:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Cl:29])[CH2:37][CH3:38])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Reactant: CCC(O)c1ccccc1Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(=O)OC)c1ccccc1Cl

Procedure:
In a similar manner as described for example B31, 3.0 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 1.83 g of 1-(2-chlorophenyl)propan-1-ol, 4.76 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 3.29 g of di-tert-butyl azodicarboxylate in 85 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:18])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:18])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:30])[CH3:6])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(C)c(Br)cc21
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1C(=S)COc2cc(C)c(Br)cc21
Yield: 80.9 %

Procedure:
To a solution of 2-(6-bromo-7-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (23.6 g, 69 mmol) in toluene (300 mL) was added Lawesson's reagent (30.7 g, 76 mmol) and the reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature water (300 mL) was added. The organic phase was separated and the aqueous portion was extracted with EtOAc (3×100 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5% EtOAc in petroleum ether) to give 2-(6-bromo-7-methyl-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as solid (20.0 g, 81%). 1H NMR (DMSO-d6, 400 MHz): δ 7.41 (s, 1H), 7.16 (s, 1H), 6.03 (m, 1H), 4.90 (s, 2H), 4.14 (m, 2H), 2.29 (s, 3H), 1.61 (d, J=6.8 Hz, 3H), 1.08 (t, J=7.2 Hz, 3H).
Reaction SMILES: [SH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].C=O.O.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=C(C)C=C(C)C=1>[S:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:8])[NH:9][CH2:13]1
Reactant: NC(=O)c1sccc1S
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: O
Solvent: Cc1cc(C)cc(C)c1
Product: O=C1NCSc2ccsc21

Procedure:
aad) 11.1 g of 3mercapto-thiophene-2-carboxamide, 2.2 g of 95 percent paraformaldehyde and 13.3 g of p-toluene-sulfonic acid monohydrate were heated together under reflux with 300 ml of mesitylene. After the reaction finished, the mixture was left to cool and the solvent was removed in vacuo. After chromatography of the residue on silica gel and recrystallization from ethyl acetate, there was obtained 2,3-dihydro-4H-thieno[2,3-e][1,3]thiazin-4-one as yellowish crystals of m.p. 153°-155°.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]([CH:14]=O)=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]([CH:14]=[N:17][OH:18])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccc(-n2c(Cl)ccc2C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-n2c(Cl)ccc2C=NO)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 115.4 %

Procedure:
A mixture of 5-chloro-1-(4-methylphenyl)pyrrole-2-carbaldehyde (365 mg), hydroxylamine hydrochloride (173 mg), and sodium acetate (204 mg) in 60% aqueous ethanol (6 ml) was stirred at 60° C. for one hour. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate. The mixture was washed with water, dried, and concentrated in vacuo to give a residue (450 mg) of 5-chloro-1-(4-methylphenyl)pyrrole-2-carbaldehyde oxime. A mixture of the residue and sodium acetate (30 mg) in acetic anhydride (5 ml) was stirred at 160° C. for one and half hours under nitrogen atmosphere. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted by ethyl acetate:n-hexane =1/15) to yield 5-chloro-1-(4-methylphenyl)pyrrole-2-carbonitrile (325 mg) as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[OH:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(#N)C>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:17][C:15]2[CH:14]=[CH:13][NH:12][C:11](=[O:10])[CH:16]=2)=[CH:4][CH:5]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Oc1ccnc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.40 g (7.41 mmol) 1-bromomethyl-4-fluoro-benzene in 20 mL acetonitrile is added 822 mg (7.40 mmol) 2,4-dihydroxy pyridine and 2.05 g (14.8 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT. 5 mL of DMF is added and the reaction is stirred overnight. After filtration and evaporation of the solvent, is the residue purified by HPLC (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]1[C:29]2[CH:30]=[C:31]([NH2:34])[CH:32]=[CH:33][C:28]=2[N:27]=[CH:26]1>CCCCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:34][C:31]4[CH:32]=[CH:33][C:28]5[N:27]=[CH:26][N:25]([CH3:24])[C:29]=5[CH:30]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cnc2ccc(N)cc21
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Solvent: CCCCO
Product: Cn1cnc2ccc(Nc3ncnc4[nH]c(C5=CCN(C(=O)OC(C)(C)C)CC5)cc34)cc21
Temperature: 120 °C

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (134 mg, 0.400 mmol) and 3-methyl-3H-benzoimidazol-5-ylamine (70.6 mg, 0.480 mmol) in n-BuOH (3 mL) in a sealed tube was heated at 120° C. for 17 h and concentrated in vacuo to obtain a brown solid that was purified using the mass-directed purification system to yield the title compound as beige solid. 1H NMR (CD3OD, 400 MHz): δ=1.52 (s, 9H), 2.57 (brs, 2H), 3.68 (brs, 2H), 3.93 (s, 3H), 4.12 (brs, 2H), 6.31 (brs, 1H), 6.65 (brs, 1H), 7.46 (dd, 1H, J=2.0 & 8.4 Hz), 7.66 (d, 1H, J=8.8 Hz), 8.14-8.15 (m, 2H), 8.23 (s, 1H), 8.24 (brs, 1H). MS (ES+): m/z 464.12 (100) [MH+]. HPLC: tR=2.18 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].F[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:17]1[CH:22]=[N:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1
Reactant: COc1cc2nccc(O)c2cc1OC
Reactant: O=[N+]([O-])c1ccc(F)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])nc3)c2cc1OC
Temperature: 80 °C

Procedure:
A mixture of 6,7-dimethoxyquinolin-4-ol (2.02 g, 9.8 mmol, 1.0 eq.), 5-fluoro-2-nitro-pyridine (1.96 g, 13.78 mmol, 1.4 eq.) and cesium carbonate (4.8 g, 14.7 mmol, 1.5 eq.) in dry DMF (10 mL) was heated for 1 h at 80° C. in a microwave oven. After cooling to RT the mixture was diluted with water and extracted with DCM. The combined organic phase was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (DCM/MeOH=100:0 to 10:1) to yield the desired product W1 (1.28 g, 40%) as a yellow solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 3.88 (s, 3H), 3.94 (s, 3H), 6.92 (d, J=5.2 Hz, 1H), 7.41 (s, 1H), 7.45 (s, 1H), 7.98 (dd, J=2.7 Hz, J=9.0 Hz, 1H), 8.40 (d, J=9.0 Hz, 1H), 8.60 (d, J=5.2 Hz, 1H), 8.66 (d, J=2.7 Hz, 1H). MS (ES) C16H13N3O5 requires: 327. Found: 328 (M+H)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH3:14].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C1COCC1>[Si:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:17]([CH3:19])([CH3:18])[C:16]([O:15][CH2:13][CH3:14])=[O:20])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CCOC(=O)C(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCCCCO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (32.8 mL) was added to a solution of diisopropylamine (1M in toluene, 11.64 mL) in THF (60 mL) at 0° C. to 5° C. over 15 minutes, and this mixture was stirred for 30 minutes. The reaction mixture was cooled to −78° C. then isobutyric acid ethyl ester (10 mL) was added dropwise over 15 minutes. The mixture was stirred at −78° C. for 1 hour, then (6-bromohexyloxy)-tert-butyldimethylsilane (23 mL) was added dropwise and the reaction mixture was stirred at −78° C. for a further 60 minutes. The cooling bath was removed and the mixture stirred at room temperature overnight before being poured onto a saturated aqueous solution of ammonium chloride (300 mL) and extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with water (250 mL), dried over magnesium sulfate, filtered and evaporated to give the crude product. Purification was by silica gel chromatography eluting with 0-40% ethyl acetate in cyclohexane to afford the subtitled compound as a pale amber liquid. Yield 20 g.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][CH2:29][CH:30]([PH:32](=[O:34])[OH:33])[CH3:31])=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1.[CH3:39][C:40]1([CH3:56])[C:44]([CH3:46])([CH3:45])[O:43][B:42]([C:47]2[CH:48]=[N:49][N:50]([CH2:52][CH2:53][CH2:54]O)[CH:51]=2)[O:41]1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][CH2:29][CH:30]([PH:32](=[O:33])[O:34][CH2:54][CH2:53][CH2:52][N:50]4[CH:51]=[C:47]([B:42]5[O:43][C:44]([CH3:46])([CH3:45])[C:40]([CH3:39])([CH3:56])[O:41]5)[CH:48]=[N:49]4)[CH3:31])=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC(C)[PH](=O)O)cc2OC)ncc1C(F)(F)F
Reactant: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC(C)[PH](=O)OCCCn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A suspension of (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)propan-2-ylphosphinic acid (Compound 68B, 0.240 g, 0.389 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 97.9 g, 0.388 mmol) in 1,2-dichloroethane (8.53 mL) and DIPEA (0.812 mL, 4.66 mmol) was charged with (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (1.21 g, 2.33 mmol). The reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with DCM (20 mL). The organic layer was washed with NaHCO3 (10 mL), washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a brown oil. The crude material was purified using a Teledyne ISCO Combiflash® Rf system using 1:1 DCM-EtOAc/MeOH (100:0→90:10) as eluent to afford the title compound as an off-white foam. MS (ESI): m/z 851.84/853.82 [M+H]+. UPLC: tR=1.57 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH2:9]I)([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21](=[O:24])[CH2:22][SH:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:19][O:20][C:21](=[O:24])[CH2:22][S:23][CH2:9][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NC(CI)c1ccc(F)cc1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CSCC(NC(=O)OC(C)(C)C)c1ccc(F)cc1
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
A mixture of [1-(4-fluoro-phenyl)-2-iodo-ethyl]-carbamic acid tert-butyl ester (3.88 g, 10.6 mmol), mercapto-acetic acid methyl ester (1.24 g, 11.7 mmol) and potassium carbonate (12.21 g, 18 mmol) in acetone (100 mL) was heated to reflux with stirring for 90 minutes. The mixture was then cooled and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, and the organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was recrystallized from hexanes to give 3.34 g of [2-tert-Butoxycarbonylamino-2-(4-fluoro-phenyl)-ethylsulfanyl]-acetic acid methyl ester, MP=61-62° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13](/[CH:16]=[C:17]2\[CH2:18][N:19]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:21][CH:22]\2O)=[N:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:43]([OH:46])(=[S:45])[CH3:44].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:43]([S:45][CH:22]1[CH2:21][CH2:20][N:19]([C:24]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:18]/[C:17]/1=[CH:16]\[C:13]1[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[N:12]=1)(=[O:46])[CH3:44]
Reactant: CC(O)=S
Reactant: CC(C)(C)OC(=O)NCCn1ccc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)n1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)SC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccn(CCNC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-3-({1-[2-(t-butoxycarbonylamino)ethyl]-1H-pyrazol-3-yl}methylidene)-1-(triphenylmethyl)piperidin-4-ol (3.67 g) in N,N-dimethylformamide (50 ml) were added thioacetic acid (4.6 ml) and N,N-dimethylformamide dineopentylacetal (18 ml). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride successively, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel using a mixture of ethyl acetate and hexane (1:9 to 1:1) as the eluent to afford crude (E)-4-(acetylsulfanyl)-3-({1-[2-(t-butoxycarbonylamino)ethyl]-1H-pyrazol-3-yl}methylidene)-1-(triphenylmethyl)piperidine (4.29 g) as a brown oil. To a solution of the above oil in dichloromethane (50 ml) was added trifluoroacetic acid (1.5 ml) at 0° C. The resulting mixture was stirred at room temperature for 30 minutes, and the solvent was removed in vacuo. The residue was purified twice by chromatography on silica gel using a mixture of methanol and dichloromethane (1:99 to 7:93) as the eluent to afford the title compound as a brown oil (1.46 g, overall yield: 37%).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)[CH2:5][CH2:6]C)[CH2:2]C.BrCC#N.C([N:22]([CH2:26][CH:27]1[CH2:32][CH2:31]CCN1CC#N)CCC)CC>ClCCl.C(OCC)(=O)C>[CH2:1]([N:4]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:31][CH2:32][CH2:27][C:26]#[N:22])[CH2:5][CH3:6])[CH3:2]
Reactant: CCCN(CCC)CC1CCCCN1CC#N
Reactant: CCCN(CCC)CC1CCCCN1
Agent: N#CCBr
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN(CC)CC1CCCCN1CCCC#N

Procedure:
from 2-[(dipropylamino)methyl]piperidine and 2-bromoacetonitrile, (±)-2-[2-[(dipropylamino)methyl]piperidin-1-yl]acetonitrile, RF 0.9 (Macherey-Nagel, PolygramRSIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/ethyl acetate 50:50 v/v).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([CH2:32][CH:33]=O)=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28])([O-:21])=[O:20]>>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([CH2:32][CH2:33][N:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:13](=[O:18])[CH2:14]2)=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28])([O-:21])=[O:20]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1CC=O
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1CCN1CCN(CCc2ccc([N+](=O)[O-])cc2)C(=O)C1

Procedure:
The title compound was prepared from 1-[2-(4-Nitrophenyl)ethyl]piperazin-2-one and Methyl 5-nitro-2-(2-oxoethyl)benzoate following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 457 [M+1]+.
Reaction SMILES: [CH:1]([C:3]1[O:7][CH:6]=[C:5](B(O)O)[CH:4]=1)=[O:2].C(=O)([O-])[O-].[Na+].[Na+].Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=1>C(O)C.[Pd]>[CH:1]([C:3]1[O:7][C:6]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:27])([F:29])[F:28])[CH:19]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1cc(B(O)O)co1
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(C=O)o2)cc1C(F)(F)F
Temperature: 25 °C
Yield: 396.9 %

Procedure:
To the stirred solution of 5-formylfuran-3-boronic acid (0.31 g, 2.2 mmol), palladium (10%) in carbon (0.090 g) and sodium carbonate (0.85 g, 8.0 mmol) in ethanol (10 ml) was added a solution of 4-bromo-2-(trifluoromethyl)benzonitrile (0.50 g, 0.19 mmol) in ethanol (10 ml) under nitrogen atmosphere. The reaction mixture was refluxed for two hours, and then cooled to RT and diluted with ethanol. The mixture was filtered through a pad of Celite, washed with ethanol and the filtrate was evaporated to dryness. Combiflash purification using heptane/ethyl acetate as eluent system afforded 0.20 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 7.73 (d, 1H), 7.76 (d, 1H), 8.31 (m, 1H), 8.33 (m, 1H), 8.39 (m, 1H), 9.71 (s, 1H).
Reaction SMILES: [C:1]([OH:20])(=O)[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][CH2:16][CH2:17][CH3:18].[NH2:21][C@H:22]([C:28]([OH:30])=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][NH2:27].O>C1(C)C(C)=CC=CC=1>[C:1]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]([C:28]([OH:30])=[O:29])[NH2:21])(=[O:20])[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][CH2:16][CH2:17][CH3:18]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Yield: 85.9 %

Procedure:
Lysine stearate (35.0 g) was suspended in 300 ml of xylene using a 600-milliliter reaction vessel. The suspension was boiled through heating, and water formed through azeotropic distillation was removed outside the system. After it was identified that a stoichiometric amount of water was removed (reaction time 3 hours), the residue was cooled. Crystals precipitated were separated through filtration, and washed with 100 ml of a 50% ethanol solution. The crystals were recrystallized from a sulfuric acid aqueous solution to obtain 28.8 g of Nε -stearoyl lysine (yield 85.9%). This is designated Derivative A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17](O)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[F:26][C:27]([F:33])([F:32])[S:28]([NH2:31])(=[O:30])=[O:29]>>[F:26][C:27]([F:33])([F:32])[S:28]([NH:31][C:17]([C:14]1[N:15]=[N:16][C:11]([N:8]([CH2:7][C:6]2[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH2:9][CH3:10])=[CH:12][CH:13]=1)=[O:18])(=[O:30])=[O:29]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: CCN(Cc1cc(Cl)ccc1OCC1CC1)c1ccc(C(=O)O)nn1
Product: CCN(Cc1cc(Cl)ccc1OCC1CC1)c1ccc(C(=O)NS(=O)(=O)C(F)(F)F)nn1
Yield: 18 %

Procedure:
The title compound was prepared from 6-[N-(5-chloro-2-cyclopropylmethoxybenzyl)-N-ethylamino]pyridazine-3-carboxylic acid (example 22) and trifluoromethanesulphonamide using a similar method to that of example 7. (Yield 18%). m.p. 150°-dec.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH2:10]([O:12][C:13](=[O:20])[CH:14]=[C:15]([NH2:19])[O:16][CH2:17][CH3:18])[CH3:11]>C(O)(C)C>[CH2:10]([O:12][C:13]([C:14]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[CH:14]([C:13]([O:12][CH2:10][CH3:11])=[O:20])[C:15]([O:16][CH2:17][CH3:18])=[N:19][C:15]=1[NH2:19])=[O:20])[CH3:11]
Reactant: CCOC(=O)C=C(N)OCC
Reactant: O=Cc1cccc(Cl)c1
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1cccc(Cl)c1
Yield: 76 %

Procedure:
Upon boiling a solution of 7.1 g of 3-chlorobenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 40 ml of isopropanol for 8 hours, 2-amino-4-(3-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 121° C is obtained. Yield: 76% of theory.