Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]([NH:28][C@@H:29]([C:37](O)=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O.O.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[C:24]([O:23][C:21]([NH:28][C@H:29]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:37]([NH:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20])=[O:38])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CN1C(=O)C(N)N=C(C2CCCCC2)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C(NC(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)N=C(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
To a solution of 3(R,S)-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (4 g) in anhydrous dimethylformamide (35 ml), under an atmosphere of nitrogen, was added in succession Boc-D-phenyl-alanine (4.11 g), 1-hydroxybenzotriazole trihydrate (2.09 g) and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (2.97 g). Triethylamine (2.16 ml) was then added and the resulting suspension was stirred at ambient temperature for 20 min. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (50 ml) and 10% citric add solution (50 ml). The organic phase was separated and the aqueous phase extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with 10% sodium hydroxide solution (50ml), water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel, using 1:1 petrol:ethyl acetate as the eluant, to afford the product (7.26 g), mp 95°-98° C. 1H NMR (360 MHz, CDCl3) δ 0.99-1.11 (1H, m), 1.16-1.72 (7H, m), 1.40 (9H, s), 1.83-1.92 (1H, m), 1.98-2.06(1H, m), 2.73-2.83 (1H, m), 3.10-3.24) (2H, m), 3.38 (3H, s), 4.53 (1H, brs), 4.98 (1H, brs), 5.28-5.34 (2H, m), 7.19-7.32 (7H, m), 7.49-7.58 (2H, m).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:15]([C:16](=O)[CH:17]=[CH:18]N(C)C)=[C:9]3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:32]1([NH:37][C:38]([NH2:40])=[NH:39])[CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[C:14]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:40]=[C:38]([NH:37][CH:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[N:39]=4)=[C:9]3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2nn3ccc(NC4CCCC4)cc3c2C(=O)C=CN(C)C)cc1
Reactant: N=C(N)NC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nn3ccc(NC4CCCC4)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 1-[5-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (1.05 g, 2.60 mmol) in N,N-dimethylformamide (20 mL) was added N-cyclopentyl guanidine hydrochloride (1.27 g, 7.79 mmol; Prepared by modification of a procedure from Bannard, R. A. B. et al., Can. J. Chem. 1958, 36,1541–1549), followed by potassium carbonate (0.54 g, 3.89 mmol). The resulting solution was heated at reflux for 15 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (4:6 ethyl acetate:hexane) to give N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-pyrazolo[1,5-α]pyridin-5-amine (1.06 g, 87%) as a yellow solid. 1H NMR (CDCl3): δ 8.15 (d, 1H), 7.91 (d, 1H), 7.51 (d, 2H), 7.41 (d, 1H), 6.94 (d, 2H), 6.26 (d, 1H), 6.22 (dd, 1H). 5.11 (d, 1H), 4.42 (m, 1H), 4.09 (d, 1H), 3.88 (m, 1H), 3.85 (s, 3H), 2.10–2.01 (m, 4H), 1.76–1.52 (m, 12H); MS m/z 469 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.C1C[O:20][CH2:19]C1.CCCCCCC.C(C1C=CC=CC=1)C.CN(C=O)C>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH:19]=[O:20]
Reactant: C1CCOC1
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: O=Cc1c(Cl)ccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a solution of 2,4-dichloropyridine (2 g, 13.51 mmol) in tetrahydrofuran (20 mL) at −78° C., was added LDA, 2M in THF/heptane/ethylbenzene (8.11 mL, 16.22 mmol) and the solution was stirred for 30 min. DMF (10.46 mL, 135 mmol) was added and the solution was stirred for 1 h and then warmed RT. The reaction mixture was quenched with saturated NH4Cl solution and diluted with ethyl acetate (50 mL). The organic layer was washed with saturated NaHCO3 (2×10 mL), water (20 mL), dried over Na2SO4 and concentrated under reduced pressure to afford 2,4-dichloronicotinaldehyde (2 g, 11.36 mmol, 84% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.49 (s, 1H),), 8.44 (d, J=5.4 Hz, 1H), 7.43 (d, J=5.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24](O)=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:7]=1[C:8]#[CH:9].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:43]1([O:52][C:53](N(C)C)=[N+](C)C)[C:47]2C=CC=CC=2N=N1.Cl.CNOC.Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]([N:43]([O:52][CH3:53])[CH3:47])=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:7]=1[C:8]#[CH:9]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C#Cc1c(Cl)cc(C(=O)O)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#Cc1c(Cl)cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
A solution of 4-chloro-6-[(1E)-3,3-diethyltriaz-1-en-1-yl]-5-ethynyl-3′-fluorobiphenyl-2-carboxylic acid (2.7 g, 7.1 mmol) in N,N-dimethylformamide (14 mL) was treated with N,N-diisopropylethylamine (4.3 mL, 25 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.5 g, 9.3 mmol) and stirred at 20° C. for 5 minutes. The reaction mixture was treated with N,O-dimethylhydroxylamine hydrochloride (0.9 g, 9.3 mmol) and stirred at 20° C. for 1 hour. The reaction mixture was poured into 0.5 M hydrogen chloride in water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was washed with saturated sodium bicarbonate (50 mL), brine (25 mL), dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0% - 40%) gave the desired product (2.7 g, 92% for 2 steps). LCMS for C21H23ClFN4O2 (M+H)+: m/z=417.1; Found: 417.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][C:16]=2[N+:29]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O1CCCC1.O>CO.[Fe]>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:17][C:16]=2[NH2:29])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(OCc3ccccc3)cc2N)cc1
Yield: 84.2 %

Procedure:
A solution of the product of Example 214C (1.4 g, 3.09 mmol), iron powder (0.70 g, 12 mmol) and ammonium chloride (0.18 g, 3.41 mmol) in a methanol (10 mL), tetrahydrofuran (10 mL), and water (5 mL) solution was heated to reflux for 1.5 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (1.1 g, 90%).
Reaction SMILES: [ClH:1].S1[CH2:6][CH:5]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10]2)C2C=CC=CC1=2.S(OCCCC1[C:42]2[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:43]=2[O:44][CH:45]=1)(C1C=CC(C)=CC=1)(=O)=O.COC1C(N2CCNCC2)=NC=CC=1>>[ClH:1].[F:50][C:48]1[CH:49]=[CH:42][C:43]2[O:44][CH:45]=[C:6]([CH2:5][CH2:7][CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]4[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:11][CH2:10]3)[C:46]=2[CH:47]=1
Reactant: COc1cccnc1N1CCN(CCC2CSc3ccccc32)CC1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2coc3ccc(F)cc23)cc1
Agent: COc1cccnc1N1CCNCC1
Agent: Cl
Product: COc1cccnc1N1CCN(CCCc2coc3ccc(F)cc23)CC1

Procedure:
The title compound was prepared (0.93 g, 74%, mp 182°-184° C.) in a manner analogous to the preparation of 1-[2-(2,3-dihydrobenzo[b]thien-3-yl)ethyl]-4-(3-methoxy-2-pyridinyl)piperazine hydrochloride (Example 17) by the reaction of 5-fluoro-3-benzo[b]furanpropanol tosylate with 1-(3-methoxy-2-pyridinyl)piperazine.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH:10]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][O:8][CH2:7]1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+].O>CN(C)C=O>[N:20]([CH:6]1[CH2:7][O:8][CH2:9][CH:10]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11]1)=[N+:21]=[N-:22]
Reactant: CC(C)(C)OC(=O)NC1COCC(OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1COCC(N=[N+]=[N-])C1
Temperature: 25 °C
Yield: 137.6 %

Procedure:
A solution of 5-(tert-butoxycarbonylamino)-tetrahydro-2H-pyran-3-yl methanesulfonate (90 mg, 0.3 mmol) and sodium azide (30 mg, 0.5 mmol) in 10 mL of dry N,N-dimethylformamide was heated to 100° C. for 3 h. The reaction mixture was cooled to room temperature, 40 mL of water were added, product extracted with ethyl acetate (2×50 mL), organics combined dried with sodium sulfate, filtered and concentrated to give tert-butyl 5-azido-tetrahydro-2H-pyran-3-ylcarbamate (100 mg, crude) which was used directly in the next step without further purification.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[O-:15][C:16]#[N:17].[Na+]>O1CCCC1>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[N:17]=[C:16]=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: N#C[O-]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1N=C=O
Reaction time: 8 h
Yield: 90 %

Procedure:
In an argon atmosphere, 7.69 g (33.0 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 30 mL of tetrahydrofuran and after adding 2.58 g (purity: 90%, 35.7 mmol) of sodium cyanate, the mixture was stirred for 8 hours under heating and refluxing. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 85° C./3.3×102 Pa) to obtain 1,3-di-tert-butyl-2-isocyanato-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NCO) as a colorless liquid (yielded amount: 7.09 g, yield: 90%).
Reaction SMILES: [Na].[N+:2]([C:5]([CH3:13])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:4])=[O:3].[N+:14](C([N+]([O-])=O)([N+]([O-])=O)[N+]([O-])=O)([O-:16])=[O:15].[CH3:27][OH:28]>>[N+:2]([C:5]([N+:14]([O-:16])=[O:15])([CH3:13])[CH:6]([O:28][CH3:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])C([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Reactant: CC(=Cc1ccccc1)[N+](=O)[O-]
Reactant: CO
Agent: [Na]
Product: COC(c1ccccc1)C(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.15 g (0.05 mol) of sodium metal dissolved in 75 ml of methanol was added dropwise with cooling (0°-10° C.) a solution of 4.0 g (0.025 mol) of 2-nitro-1-phenyl-1-propene and 4.9 g (0.025 mol) of tetranitromethane in 25 ml of methanol. The resulting solution was stirred at room temperature for 1 hour. The product was isolated and purified as described in Example 1 above, except that acidification prior to workup was omitted. Ultimately there was obtained 2.5 g (42%) of analytically pure, white crystalline 2,2-dinitro-1-methoxy-1-phenylpropane, mp 53°-55° C. The same procedure was employed to prepare the 2-ethoxy and 2-propoxy derivatives with the exception that the appropriate alcohol was substituted for methanol.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]>C(Cl)(Cl)Cl>[BrH:1].[NH2:3][C:4]1[C:12]([F:13])=[CH:11][C:10]([Br:1])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Nc1c(F)cccc1C(=O)O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Br
Product: Nc1c(F)cc(Br)cc1C(=O)O
Reaction time: 12 h

Procedure:
Bromine (3.65 mL, 70.9 mmol) in Chloroform (250 mL) was added dropwise via an addition funnel to a suspension of 2-amino-3-fluorobenzoic acid (10 g, 64.5 mmol) in chloroform (400 mL) at RT. The solution was stirred for 12 hours at which point the resulting slurry was filtered. The solid was washed well with CH2Cl2 and dried under a stream of nitrogen to afford 2-amino-5-bromo-3-fluorobenzoic acid HBr.
Reaction SMILES: C([Cl:4])(=O)C.[CH3:5][O:6][C:7](=[O:39])[C@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32](=[O:34])[CH3:33])=[C:27]([O:35][C:36](=[O:38])[CH3:37])[CH:26]=1)[NH:9][C:10](=[O:23])[CH2:11][NH:12]C(OCC1C=CC=CC=1)=O>CO.C(O)(=O)C.Cl.CCOCC.[Pd]>[ClH:4].[CH3:5][O:6][C:7](=[O:39])[C@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32](=[O:34])[CH3:33])=[C:27]([O:35][C:36](=[O:38])[CH3:37])[CH:26]=1)[NH:9][C:10](=[O:23])[CH2:11][NH2:12]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)=O)c(OC(C)=O)c1)NC(=O)CNC(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(OC(C)=O)c(OC(C)=O)c1)NC(=O)CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
Next, 3.00 g (6.17 millimole) of the above isolated ester was dissolved in methanol (100 ml) and glacial acetic acid (5 ml). The solution was then shaken in a Parr apparatus for 16 hours over 10% Pd/C (0.4 g) under a hydrogen atmosphere (35 lbs). The solution was then filtered and concentrated in vacuo at room temperature. The residue obtained was dissolved in 10 ml of glacial acetic acid, saturated with hydrogen chloride and treated with 10 ml of acetyl chloride. The solution was stirred at room temperature overnight in a tightly sealed reaction flask and then diluted to 125 ml with ether to give a light brown gum. The ether was decanted and the residue was suspended in anhydrous ether (100 ml). The suspended solid was dispersed with a spatula and allowed to stir until it became homogeneous. It was then filtered and the residue was dried in a vacuum oven at 60°C to yield 0.58 g (m.p. 80°-100°C, 24% yield) of glycyl- 3,4-diacetyloxy-L-phenylalanine-methyl ester hydrochloride from carbobenzyloxyglycyl-3,4-diacetyloxy-L-phenylalanine-methyl ester. The nmr spectrum was consistent with the proposed structure of the compound obtained and upon analysis of the compound, the following data was obtained. Analysis Calculated for: C16H21O7N2Cl: C, 49.42; H, 5.44; and N, 7.21. Found: C, 49.65; H, 5.50; and N, 7.47.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](O)[CH:5]=[C:4]([CH3:9])[N:3]=1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1.Cl.C[N:22](C=O)C>>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([NH:22][C:6]2[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:9])[CH:5]=2)[CH:18]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(O)cc(C)n1
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(Nc2cc(Cl)ncn2)cc(C)n1
Reaction time: 0.25 h

Procedure:
0.12 g (0.97 mmol) 2,6-dimethyl-4-hydroxypyridine and 55 mg (1.26 mmol) sodium hydride (60% dispersion in mineral oil) were dissolved in 1.5 mL DMF and stirred for 15 min. 0.15 g (0.98 mmol) 4,6-dichloropyrimidine were added and the mixture was stirred overnight at RT. The reaction mixture was acidified with a 4M hydrochloric acid, filtered and purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: C[C:2]1(C)[CH2:7][CH2:6][CH2:5][C:4](C)(C)[NH:3]1.C([Li])CCC.C(#N)C1C=CN=CC=1.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[O:32]1CCC[CH2:33]1>C(Cl)(Cl)Cl.O>[C:25]1([CH:24]2[C:5]3[CH:4]=[N:3][CH:2]=[CH:7][C:6]=3[C:33](=[O:32])[O:31]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C1CCOC1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: O=Cc1ccccc1
Agent: N#Cc1ccncc1
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1OC(c2ccccc2)c2cnccc21
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, 14.35 g (105.5 mmol) of 2,2,6,6-tetramethylpiperidine was dissolved in tetrahydrofuran (200 ml) as a solvent, and the solution was cooled to −30° C. After that, 60 mL (1.6-mol/L solution, 96.1 mmol) of normal butyllithium was slowly dropped to the solution. After the dropping, the mixture was heated to 0° C., and was stirred for 15 minutes. After that, the mixture was cooled to −70° C. A solution (100 ml) of 5.00 g (48.0 mmol) of isonicotinonitrile in tetrahydrofuran was dropped over 15 minutes to the mixture at −70° C. After the mixture had been stirred at −70° C. for an additional 30 minutes, a solution (50 ml) of 10.2 g (96.1 mmol) of benzaldehyde in tetrahydrofuran was dropped over 5 minutes to the mixture. After having been stirred at −70° C. for an additional 30 minutes, the mixture was slowly heated to 0° C., and water was added to the mixture to stop the reaction. Chloroform was added to the mixture to separate an organic layer, and the layer was washed with water four times. After that, the solvent was removed by distillation, and chloroform (50 ml) and 35 g of silica gel were added to the resultant residue. The mixture was stirred under heat and reflux for 6 hours, and then stirred under heat and reflux for 3 hours with addition of acetic acid. After the mixture had been cooled to room temperature, the solvent was removed by distillation again. The resultant residue was purified by silica gel column chromatography (toluene:ethyl acetate=8:1), whereby 2.06 g of Intermediate Compound 3 were obtained.
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15]O)=[NH:5].Cl.N[N:19]1[CH2:23][CH2:22][N:21]=[C:20]1[NH2:24].CC1C=CC(S(O)(=O)=O)=CC=1.C=CC1C=CC=CC=1.C(C1C=CC=CC=1C=C)=C>C(O)(C)C>[ClH:1].[ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15][N:21]1[CH2:22][CH2:23][N:19]=[C:20]1[NH2:24])=[NH:5]
Reactant: NC1=NCCN1N
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Agent: C=Cc1ccccc1C=C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: C=Cc1ccccc1
Product: N=C(NO)c1cccc2c1CCC2=NN1CCN=C1N

Procedure:
0.5 ml of 32% hydrochloric acid (Merck, Darmstadt, Germany; p.a.) is added, with stirring, to a mixture of 0.51 g (0.0025 mol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 0.342 g (0.0025 mol) of 1,2-diamino-4,5-dihydro-imidazole hydrochloride [m.p. 245°-246° C.; prepared from the corresponding p-toluenesulfonate salt, see EP 0 327 919, Example 12, by ion exchange on ®Amberlite IRA-400 (anion exchanger based on a styrene/divinylbenzene polymer with quaternary ammonium groups in the Cl- form; Fluka, Buchs, Switzerland)] and 12 ml of isopropanol, and the reaction mixture is stirred at 80°-90° C. for 16 hours. The reaction mixture is filtered while hot and the filtration product is washed with isopropanol and recrystallized from hot water. In that manner there is obtained the title compound, m.p. >245° C., 1H-NMR (D2O): δ=8.08 (d, 1H); 7.72 (d, 1H); 7.56 (t, 1H); 4.14 (t, 2H); 3.81 (t, 2H); 3.3 (m, 2H); 3.15 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[NH:9]1[CH:13]=[N:12][C:11]([S:14]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:16])=[O:15])=[N:10]1.Cl>N1C=CC=CC=1.ClCCl>[CH:18]1([CH2:17][S:14]([C:11]2[N:12]=[CH:13][N:9]([C:4]([N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:5])[N:10]=2)(=[O:16])=[O:15])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=S(=O)(CC1CCCCC1)c1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)C(=O)n1cnc(S(=O)(=O)CC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
Diethylcarbamoyl chloride (1.2 ml; 9.4 mmol) was added to cyclohexylmethyl 1,2,4-triazol-3-yl sulfone (2.0 g; 8.7 mmol) in dry pyridine (10 ml) under dry nitrogen, and the solution stirred at room temperature overnight. The resulting mixture was poured into 2M hydrochloric acid (40 ml) at 2° C. and the cloudy solution extracted into ethyl acetate (3×60 ml). The extracts were combined, dried (Na2SO4), filtered and evaporated, to afford a colorless oil which was dissolved in 95% dichloromethane, 5% acetonitrile, and the solution filtered through silica. Evaporation afforded 3-(cyclohexylmethylsulfonyl)-N,N-diethyl-1,2,4-triazole-1-carboxamide (2.82 g; 98%) as white crystals, m.p. 40°-46° C. (Found, C: 51.04; H: 7.39; N: 17.01; S: 9.81. C14H24N4O3S requires C: 51.20; H: 7.37; N: 17.06; S: 9.76%). NMR - d(CDCl3 ; 90 MHz) 0.80-2.30 (17H, m), 3.31 (2H, d, J=6.1 Hz), 3.61 (4H, m) and 8.92 (1H, s).
Reaction SMILES: CC1C(N=C=O)=CC([N:8]=[C:9]=[O:10])=CC=1.C([C:18]1C=C(C)C=C(C(C)(C)C)[C:19]=1[OH:29])(C)(C)C.OCC[O:33][C:34](=[O:37])[CH:35]=[CH2:36].C1OC1.C1OC1CC>>[C:34]([OH:37])(=[O:33])[CH:35]=[CH2:36].[NH2:8][C:9]([O:29][CH2:19][CH3:18])=[O:10]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: C=CC(=O)OCCO
Agent: CCC1CO1
Solvent: C1CO1
Product: C=CC(=O)O
Product: CCOC(N)=O
Reaction time: 1 h

Procedure:
In a reaction vessel equipped with a stirrer, 109.8 gm of 2,4-tolylene diisocyanate, 1 gm of dibutyltindilaurate, and 0.3 gm of 2,6-di-t-butyl-4-methylphenol as a polymerization inhibitor were added. To this, 48.8 gm of hydroxyethylacrylate was added while controlling the temperature to 20° C. or lower. After the addition was completed the mixture was continuously stirred for an additional one hour at 10° to 20° C. Following this, 841.4 gm of a copolymerized diol of ethylene oxide and 1,2-butylene oxide [ethylene oxide:1,2-butylene oxide 1:9 (by weight)] of a number average molecular weight of 2,000 was added while maintaining the temperature in the 40° to 50° C. range, after which the mixture was continuously stirred for 5 hours at 50° to 60° C. to complete the reaction. A urethane acrylate [A-I] of a number average molecular weight of about 4,750 was obtained.