Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:15][CH:14]=3)[CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:39][CH2:38]1>CCOC(C)=O>[CH3:36][N:37]1[CH2:38][CH2:39][N:40]([C:43]2[CH:48]=[CH:47][C:46]([NH:49][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][C:13]5[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]6[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=6)=[O:21])=[CH:17][CH:18]=5)[CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:45][CH:44]=2)[CH2:41][CH2:42]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(Cc2ccc3c(c2)C(=CO)C(=O)N3)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1nc(C)cc1C(=O)Nc1ccc(Cc2ccc3c(c2)C(=CNc2ccc(N4CCN(C)CC4)cc2)C(=O)N3)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl)-phenyl]-amide (prepared below, 70 mg, 0.175 mmol) and THF (1 mL). To the resulting solution was added 4-(4-Methyl-piperazin-1-yl)-phenylamine (66.8 mg, 0.349 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and then diluted with EtOAc (2 mL). The solution was washed with water (2 mL) and the water layer was re-washed with additional EtOAc (2 mL). The combined organic layers were then concentrated in vacuo affording the crude product. The crude product was further purified by silica gel column chromatography with 5% methanol in chloroform as eluant to give the desired product as a solid in 55% yield (55 mg, 0.96 mmol).
Reaction SMILES: [ClH:1].O1CCOC[CH2:3]1.C(OC([NH:15][C@H:16]1[CH2:24][O:23][C@H:19]([C:20]([OH:22])=[O:21])[CH2:18][CH2:17]1)=O)(C)(C)C>CO>[ClH:1].[NH2:15][C@H:16]1[CH2:24][O:23][C@H:19]([C:20]([O:22][CH3:3])=[O:21])[CH2:18][CH2:17]1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(=O)O)OC1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1CC[C@@H](N)CO1
Reaction time: 20 h
Yield: 100 %

Procedure:
4N hydrochloric acid/1,4-dioxane solution (20 ml) was added to a methanol (5 ml) solution of 2,6-anhydro-5-[(tert-butoxycarbonyl)amino]-3,4,5-trideoxy-L-erythro-hexonic acid (Eur. J. Org. Chem., 2003, 2418-2427) (1.00 g, 4.08 mmol) at room temperature and the resulting mixture was stirred for 20 hours. The reaction mixture was concentrated under reduced pressure to give 0.80 g (100%) of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH:16]=C[C:18](=O)[NH:19]2)[C@@H:14]2[C@@H:3]1[C@H:4]1[C@:11]([CH3:24])([CH2:12][CH2:13]2)[C@@H:7]([C:8](=[O:10])[CH3:9])[CH2:6][CH2:5]1.[CH3:25][Li].CI.[Cl-].[NH4+].CC[O:33][CH2:34][CH3:35]>O1CCCC1>[CH3:18][N:19]1[C:34](=[O:33])[CH:35]=[CH:16][C@@:15]2([CH3:23])[C@H:20]1[CH2:21][C@H:2]([CH3:1])[C@@H:3]1[C@@H:14]2[CH2:13][CH2:12][C@@:11]2([CH3:24])[C@H:4]1[CH2:5][CH2:6][C@@H:7]2[C:8]([CH3:25])([OH:10])[CH3:9]
Reactant: CCOCC
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@H]1C[C@H]2N(C)C(=O)C=C[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)(C)O)CC[C@H]3[C@H]12
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of 73 mg (0.22 mmol) 7β-methyl-5α-4-azapregn-1-ene-3,20-dione in 7 ml dry tetrahydrofuran at -40° C. under N2 was added 3 eq methyllithium (0.7 mmol) in ether. The reaction was stirred and monitored by TLC. After three hours a second (0.5 eq) portion of methyllithium was added. After two hours 10 eq methyl iodide (2.2 mmol) was added and the reaction was allowed to warm to room temperature over 18 hrs. Aqueous ammonium chloride (5 ml) was added and the solvents were evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. The product was purified via HPLC on a 19×300 mm 8 micron silica column using a 5 to 15% isopropanol/hexane gradient at 20 ml/min to yield 34 mg (0.095 mmol, 43% yield) of the title compound.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F:10][C:11]([F:33])([F:32])[C:12]1[N:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][CH:24]([CH2:27][O:28][CH2:29][CH2:30]O)[CH2:23][CH2:22]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1>C(Cl)Cl>[F:7][CH2:30][CH2:29][O:28][CH2:27][CH:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([C:12]([C:11]([F:33])([F:32])[F:10])=[N:13][N:14]=3)[N:17]=2)[CH2:22][CH2:23]1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCCOCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Solvent: ClCCl
Product: FCCOCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.1 %

Procedure:
(Diethylamino)sulfur trifluoride (0.059 mL, 0.45 mmol) was added dropwise to a stirred solution of 2-[[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl)methoxy]ethanol (104 mg, 0.3 mmol) in DCM (3 mL) at −70° C. The solution was allowed to warm to ambient temperature and stir for 18 hours. The solution was diluted with DCM and washed with 2M aqueous K2CO3. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-[(2-fluoroethoxy)methyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (22.0 mg, 21%) as a white solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH3:5].O([CH:14]1O[C@H](CO)[C@@H](O)[C@H:17](O)[C@@H:15]1O)S(C(F)(F)F)(=O)=O.[C:25](Cl)(Cl)(Cl)Cl>>[CH3:25][C:3]1[CH:4]=[CH:5][C:17]([CH:15]=[CH2:14])=[CH:1][CH:2]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCCCC
Reactant: O=S(=O)(OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)C(F)(F)F
Product: C=Cc1ccc(C)cc1

Procedure:
TLC Rf=0.70 (pentane); IR (CCl4) 3089 (m), 3048 (m), 3009 (s), 2962 (s), 2962 (s), 2926 (s), 2855 (s), 1628 (m), 1570 (s), 1513 (s); 1H NMR (200 MHz, CDCl3) δ2.32 (s, 3H), 2.59 (d, J=10.9, 1H), 2.56 (d, J=17.6, 1H), 6.67 (dd, J=17.5, 10.9, 1H), 7.12 (d, J=8.0, 2H), 7.29 (d, J=8.1, 2H); 13C NMR (CDCl3) δ21.2, 112.8, 126.1, 129.2, 134.8, 136.7, 137.6; LRMS (EI) 119((M+1), 11), 118 ((M+), 100), 117 (68), 91 (42); HRMS (EI) calculated for C9H10 118.0783 (M+), found 118.0777. The IR and 1H NMR matched spectral data reported by Hollywood, F. and Suschitzaky, H., Synthesis 662-665 (1982).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=S)[NH:10][C:4]=2[CH:3]=1.O.[NH2:21][NH2:22]>C1C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[N:21][NH2:22])[NH:10][C:4]=2[CH:3]=1
Reactant: S=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Reactant: NN
Solvent: O
Solvent: c1ccccc1
Product: NN=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Reaction time: 8 h
Yield: 59.5 %

Procedure:
9-Bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-thione (4 g), hydrazine hydrate (4 ml) and benzene (150 ml) were combined and refluxed overnight. The reaction mixture was concentrated to approximately 50 ml and, after standing overnight, the precipitate was filtered. Recrystallization of the filter cake from chloroform/ether gave 2.35 g (59.5%) of product, mp 260° C. (dec).
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CO>[O:8]1[C:4]([C:1](=[O:3])[CH:2]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]1=2
Reactant: CC(=O)c1cc2ccccc2o1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CO
Product: O=C(C=Cc1ccccc1)c1cc2ccccc2o1

Procedure:
8 g of 2-acetyl benzo[b]furan and 6 g of benzaldehyde are heated to boiling in 50 ml of methanol in the presence of 3 of concentrated hydrochloric acid. The batch is cooled after 10 h, and the precipitated yellow mass of crystals is filtered off by suction and rewashed with a small quantity of cold methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].C(O)(=O)C>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:22][N:23]3[C:24](=[O:33])[C:25]4=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]4[C:27]3=[O:28])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1CCl
Reactant: O=[N+]([O-])c1ccc(N=Nc2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1COc1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the red dye, 4-(4-nitro-phenylazo)phenol (0.5 g), in DMF was added sodium hydride (0.1 g of a 50% dispersion). After stirring for 5 minutes at room temperature, N-(chloromethyl)phthalimide (0.5 g) was added and stirring continued overnight. The solution was acidified with acetic acid and the product precipitated by pouring into ice water. The product recrystallized from ethyl acetate/cyclohexane, was obtained in 0.72 g yield, m.p. 182°-190° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13].Cl>O1CCCC1>[Cl:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: C1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(c1cccc(CCl)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86436.8 %

Procedure:
To an ice-cooled solution of piperidine (67.6 g, 0.793 mole) in tetrahydrofuran (1 L) was added dropwise a solution of 3-chloromethylbenzoyl chloride (100.0 g, 0.529 mmol). When the addition was complete, the reaction mixture was allowed to warm to ambient temperature and was left to stir overnight. The reaction mixture was poured into a solution of 1N hydrochloric acid. This solution was extracted with diethyl ether. The ether extracts were combined, washed with water, dried (MgSO4), and concentrated to afford 108.7 g (86%) of N-(3-(chloromethyl)benzoyl)piperidine (10) as a pale yellow oil whose 1H NMR in CDCl3 supported the structure.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:20][O:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:21]([O-])=O>CO.[Pd]>[NH2:21][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:18][O:19][CH2:20]3)[CH2:13][CH2:12]2)[C:2]=1[Cl:1])[C:6]#[N:7]
Reactant: N#Cc1cc(OC2CCN(C3COC3)CC2)c(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: N#Cc1cc(N)c(Cl)c(OC2CCN(C3COC3)CC2)c1
Reaction time: 1.5 h
Yield: 12.8 %

Procedure:
A mixture of 4-chloro-3-nitro-5-((1-(oxetan-3-yl)piperidin-4-yl)oxy)benzonitrile (430 mg, 1.272 mmol) and Pd/C (271 mg, 0.127 mmol) in methanol (20 mL) was hydrogenated at 20 PSI for 1.5 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g gold column, eluting with 1-5% 2 N ammonia in methanol/dichloromethane). 3-amino-4-chloro-5-((1-(oxetan-3-yl)piperidin-4-yl)oxy)benzonitrile (50 mg) was obtained as a foaming solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)[S:8][C:7]=3[C:6]=2[CH:23]=1.C[OH:25].C1[CH2:30][O:29][CH2:28]C1.N12CCCN=C1CCCCC2>ClCCl.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[CH3:28][O:29][C:30]([C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)[S:8][C:7]=3[C:6]=2[CH:23]=1)=[O:25]
Reactant: CO
Reactant: C1CCOC1
Reactant: CC(C)n1ncnc1-c1cc2c(s1)-c1cc(Br)ccc1OCC2
Agent: [Mo]
Agent: [C-]#[O+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc2c(c1)-c1sc(-c3ncnn3C(C)C)cc1CCO2
Temperature: 130 °C

Procedure:
A mixture of 5-(9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazole (290 mg), molybdenum hexacarbonyl (196 mg), Herman's catalyst (70 mg), tributyl phosphonic tetrafluoroborate (43 mg), methanol (3 mL), THF (3 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 ml) was heated in the microwave at 130° C. for 30 minutes. The reaction mixture was cooled, and then diluted with dichloromethane, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid methyl ester. This was hydrolyzed using sodium hydroxide in water/methanol/THF to yield the corresponding acid. Treatment with HATU, diisopropylethylamine and ammonium chloride in dry DMF yielded 419. NMR: (DMSO): 1.51 (6H, d), 3.25 (2H, t), 4.38 (2H, t), 5.09 (1H, septet), 7.02 (1H, d), 7.33 (1H, br, s), 7.51 (1H, s), 7.75 (1H, dd), 8.00 (1H, s), 8.04 (1H, s, br.), 8.18 (1H, s). MS. ESI+3396 (MH++MeCN)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[C:12]([CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:31]CCl>FC(F)(F)C(O)=O>[ClH:31].[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[C:12]([CH2:21][CH2:22][NH2:23])=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCl
Reactant: COc1ccc2c(c1)c(CCNC(=O)OC(C)(C)C)cn2S(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)c(CCN)cn2S(=O)(=O)c1ccccc1
Product: Cl
Reaction time: 3 h

Procedure:
A solution of the above protected tryptamine (2.1 g, in a mixture of dichloromethane and trifluoroacetic acid (1:1; 60 ml) was allowed to stand at room temperature for 3 h. The solvents were removed under vacuum and the residue was azeotroped with toluene-methanol (5:1; 100 ml). The residue was dissolved in 4N sodium hydroxide solution (50 ml) and extracted with ethyl acetate (3×100 ml). The combined organic solutions were washed with brine (1×50 ml), dried (Na2SO4) and concentrated. The hydrochloride salt was prepared and recrystallised from acetonitrile to give 1.53 g of the title compound; mp 117°-120° C.; δH (360 MHz, D2O) 7.81 (2H, d, J=7.5 Hz), 7.74 (1H, d, J=9.0 Hz), 7.56 (1H, s), 7.54 (1H, t, J=7.5 Hz), 7.41 (2H, t, J=8.1 Hz), 7.00 (1H, d, J=2.3 Hz), 6.89 (1H, dd, J=9.0 and 2.3 Hz), 6.89 (1H, dd, J=9.0 and 2.3 Hz), 3.78 (3H, s),3.29 (2H, t, J=7.6 Hz), 3.01 (2H, t, J=7.6 Hz); m/z (ES) 331 (M++1). (Found: C, 54.07; H, 5.39; N, 7.41. C17H18N2O3S.1.0HCl.0.6 H2O requires: C, 54.06; H, 5.39; N, 7.42%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].Cl.[C:12]1([CH:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][SH:29])[CH2:22][CH2:21]2)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[OH2:9].[OH2:9].[ClH:10].[ClH:10].[C:1]1([NH:7][C:8](=[SH:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:22][CH2:21][N:20]([CH:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:19])[CH2:25][CH2:24]2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1ccccc1)N1CCN(CCCS)CC1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(c1ccccc1)N1CCN(CCC[SH]=C(O)Nc2ccccc2)CC1
Product: O
Yield: 94.8 %

Procedure:
The procedure described in Example 2 was followed, using 1.6 g of phenyl isocyanate, 4.5 g of 3-[4-(1-phenylethyl)piperazin-1-yl]propanethiol dihydrochloride, 1.3 g of triethylamine and 50 ml of methylene chloride, to give 2.1 g (38% of theory) of N-phenyl-S-{3-[4-(1-phenylethyl)piperazin-1-yl]propyl}thiocarbamate dihydrochoride dihydrate as a white crystalline solid, M.p. 227°-229° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Cl[C:12]1[S:13][C:14]([C:17]#[N:18])=[CH:15][N:16]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:12]2[S:13][C:14]([C:17]#[N:18])=[CH:15][N:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2ccnc(Cl)n2)s1
Reaction time: 0.33 h

Procedure:
2-Chloropyrimidin-4-amine 49-1 (0.30 g, 2.32 mmol) and sodium hydride (0.093 g, 2.32 mmol) were suspended in dry THF and stirred for 20 minutes before adding 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.33 g, 2.32 mmol) and more sodium hydride (0.093 g, 2.32 mmol) simultaneously. This was refluxed for 1.5 hour and then quenched with methanol and water, and concentrated to dryness. The residue was partitioned between DCM, MeOH, and water. The aqueous layer was evaporated to dryness and then purified on a silica column. 1H-NMR (CD3OD): 8.50(d, 1H); 8.42(s, 1H); 7.11(d, 1H). By 1H-NMR this material is a mixture of the desired product and 2-chloropyrimidin-4-amine in a ratio of 5:8, which was used as is in the next step.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10](Cl)(=[O:13])[CH2:11][CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:3]1([CH2:2][CH2:1][NH:9][C:10](=[O:13])[CH2:11][CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCC(=O)Cl
Reactant: NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCCc1ccccc1

Procedure:
The title compound was prepared in a reaction between phenethylamine (12.1 g, 100 mmol), propionyl chloride (9.25 g, 100 mmol) and triethylamine (20 ml) in methylene chloride (200 ml). The product (10.1 g) was used without purification; MS [M+H]+ 178.
Reaction SMILES: [CH2:1]1[CH2:7][NH:6][C:4](=[O:5])[NH:3]C1.[CH2:8]([O:10][C:11](Cl)=[O:12])[CH3:9].[CH2:14](N(CC)CC)C>ClC(Cl)C>[CH2:8]([O:10][C:11]([CH2:14][CH:7]([NH:6][C:4]([NH2:3])=[O:5])[CH3:1])=[O:12])[CH3:9]
Reactant: O=C1NCCCN1
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCOC(=O)CC(C)NC(N)=O
Reaction time: 2 h

Procedure:
Propyleneurea of 30.0 g (0.3 mol), ethylchloroformate of 10.9 g (0.1 mol) and dichloroethane of 100 g were charged in a reaction vessel and refluxed at 85° to 88° C. A solution of triethylamine of 10.1 g (0.1 mol) in dichloroethane of 250 g was added drop by drop to the refluxed mixture in 2.5 hours followed by continuing for further 2 hours. The resulting solution was condensated and a crude product was refined by the column chromatography to obtain ethoxycarbonylpropyleneurea of 2.2 g (12.7%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:26])[C:12]([C:16]1[N:17]=[C:18]([NH:21]C(=O)CCl)[S:19][CH:20]=1)=[N:13][O:14][CH3:15])(=[O:3])[CH3:2].CSC(=S)N.[Na]>CN(C=O)C>[C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:26])[C:12]([C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1)=[N:13][O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N[C@H]1OC(C)=O)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na]
Solvent: CN(C)C=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@H]1OC(C)=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of 500 mg of (3S,4S)-4-acetoxy-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine (syn-isomer) in 10 ml of DMF is added 0.245 g of sodium monomethyldithiocarbamate and the mixture is stirred at room temperature for one hour. The solvent is distilled off under reduced pressure, the residue is washed three times with ethyl acetate and the insolubles are filtered off after addition of ethanol. The filtrate is concentrated under reduced pressure. Then, purifying the residue on a silica gel column (ethyl acetate:CHCl3 :CH3OH=2:2:1) yields 0.270 g of (3S,4S)-4-acetoxy-3-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine (syn-isomer).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]=O.[CH:9]1[C:14](=[O:15])[C:13]([OH:16])=[CH:12][O:11][C:10]=1[CH2:17][OH:18]>C(O)C>[O:4]1[CH2:5][CH2:6][N:1]([CH2:7][C:12]2[O:11][C:10]([CH2:17][OH:18])=[CH:9][C:14](=[O:15])[C:13]=2[OH:16])[CH2:2][CH2:3]1
Reactant: C=O
Reactant: C1COCCN1
Reactant: O=c1cc(CO)occ1O
Solvent: CCO
Product: O=c1cc(CO)oc(CN2CCOCC2)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 70 ml of ethanol were dissolved 7 g of morpholine and 6.4 ml of 35% formalin followed by stirring at room temperature for 30 minutes. Further, 8.3 g of kojic acid was added thereto and stirred for 30 minutes in the same temperature. The formed crystals were taken out by filtration, washed in succession with ethanol and ether and dried to give 11.5 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:25])[CH2:15][P:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])[OH:17])[CH3:3].[CH2:26](O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH3:12][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[C:5]=1[NH:13][C:14](=[O:25])[CH2:15][P:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:17])[O:18][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CP(=O)(O)c1ccccc1
Reactant: CCCCCCCCCCCCO
Product: CCCCCCCCCCCCOP(=O)(CC(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1

Procedure:
In a process analogous to Example 7, using (±)-[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phenyl phosphinic acid in place of (±)-[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic acid, ethyl ester and 1-dodecanol in place of 1-nonanol, the title compound is obtained as a sticky white solid; mp 66°-68° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[C:12]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])=[N:13][O:14][C:15]=2[CH:16]([CH3:18])[CH3:17])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:27]([O:38][CH3:39])(=[O:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32]([O-])=[O:33])=[CH:30][CH:29]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[C:12]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])=[N:13][O:14][C:15]=2[CH:16]([CH3:18])[CH3:17])[CH:6]=[CH:5][C:3]=1[NH:4][C:32]([C:31]1[CH:35]=[CH:36][C:28]([C:27]([O:38][CH3:39])=[O:37])=[CH:29][CH:30]=1)=[O:33]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(N)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Nc2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-chloro-4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}aniline (85 mg, 206 μmol), monomethyl terephthalate (37.2 mg, 206 μmol), 1-hydroxybenzotriazole (5.6 mg, 41 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (39.6 mg, 206 μmol) in dichloromethane (1 mL) was stirred at ambient temperature for 24 h. The reaction was partitioned with ethyl acetate and water. The organic layer was washed sequentially with saturated aqueous sodium hydrogensulfate and brine, then was dried over anhydrous sodium sulfate, filtered, and condensed to a residue which was chromatographed on silica gel eluting with 30% ethyl acetate/hexanes. Yield=65 mg, (55%) of methyl 4-{[(2-chloro-4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}phenyl)amino]carbonyl}-benzoate.