Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2[C:10]([OH:9])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1O
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccccc1-c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
1-Bromo-4-iodobenzene (Aldrich, 2 g, 7.07 mmol), (2-hydroxyphenyl)boronic acid (Aldrich, 1.073 g, 7.78 mmol), Pd(Ph3P)4 (0.204 g, 0.177 mmol) were dissolved in 1,4-dioxane (30 mL) and water (10 mL), K3PO4 (2.251 g, 10.60 mmol) was added. The reaction mixture was stirred at 100° C. overnight. Solvents were removed under reduced pressure and DCM was added, mixture was washed with water, dried over anhydrous sodium sulfate. Then solvent was removed under reduced pressure to give the title product 4′-bromo-2-biphenylol (1.85 g, 6.54 mmol, 92% yield) as brown oil. LCMS: (M+H)+=247-249; Rt=3.52 min.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([CH2:21][OH:22])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7].[CH2:27]([C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1)[CH3:28].Cl.O1CCOCC1>C1COCC1.CN(C1C=CN=CC=1)C.CO>[ClH:1].[CH2:27]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:37])[O:22][CH2:21][C:8]2([C:6](=[O:7])[NH:5][CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[Cl:1])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:31][CH:30]=1)[CH3:28]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(C(=O)NCc2ccccc2Cl)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCc1ccc(NC(=O)OCC2(C(=O)NCc3ccccc3Cl)CCNCC2)cc1
Reaction time: 1 h
Yield: 151.9 %

Procedure:
To a solution of tert-butyl 4-(2-chlorobenzylcarbamoyl)-4-(hydroxymethyl)piperidine-1-carboxylate (1.8 g, 4.8 mmol) in THF were added DMAP (118 mg, 0.9 mmol, 0.1 equiv.) and 4-ethylphenylisocyanate (1.1 mL, 7.3 mmol, 1.5 equiv.) at r. t. The reaction mixture was stirred for 1 h. The reaction mixture was concentrated to dryness. To a solution of the above product in CH3OH was added 4M HCl in dioxane (3.6 mL, 3 equiv.), which was stirred overnight. The white solid was filtered and dried to give (4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate hydrochloride (1.7 g, 81%). LRMS (M-Boc+H+) m/z 430.1.
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]C)=[O:9])=[O:3].[CH:12]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[CH:12]1([CH2:18][CH2:19][NH:20][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NCCC1CCCCC1
Reactant: COC(=O)CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCCCC(=O)NCCC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 5-[chloroformyl]pentanoate (4.2 g) in dry dichloromethane (20 ml) was added dropwise to a stirred solution of 2-cyclohexylethylamine (3 g) and triethylamine (3.3 ml) in dry dichloromethane (40 ml) under a N2 atmosphere. The mixture was stirred at room temperature for 16 hours and heated under reflux for 1.5 hours.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][O:21][CH3:22])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[H-].[Na+].[CH3:25][OH:26]>>[CH3:25][O:26][C:2]1[N:3]=[C:4]([NH:20][O:21][CH3:22])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: CONc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: CONc1nc(OC)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-N-methoxyadenosine (Example 8) (0.20 g, 0.60 mmol) was added to a mixture of sodium hydride (40 % oil dispersion) (0.12 g, 3.0 mmol) methanol (0.24 ml) amd DMF (5 ml) which had been stirred under nitrogen at room temperature for 1 h. The reaction mixture was heated at 80° C. for 16 h, cooled and evaporated. Flash chromatography provided the title 2,N-dimethoxyadenosine, still however containing some starting 2-chloro-N-methoxyadenosine. 1H NMR (DMSO-d6)γ 3.52-3.59 (1H, m, H-5'a), 3.63-3.70 (1H, m, H-5'b), 3.77 (3H, s, --OCH3), 3.97 (1H, q, H-4'), 4.14 (1H, q, H-3'), 4.60 (1H, q, H-2'), 5.09 (1H, t, 5'-OH), 5.18, 5.44 (2H, 2d, 2' - and 3'-OH), 5.83 (1H, d, H-1'), 8.24 (1H, s, H-8), 11.04 (1H, s, N-H) (desired product only quoted).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:11])[C:8]=1[O:9][CH3:10])[NH2:5].C(N(CC)CC)C.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23]>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:22](=[O:23])[CH2:21][O:20][CH3:19])[CH:6]=[C:7]([CH3:11])[C:8]=1[O:9][CH3:10]
Reactant: COCC(=O)Cl
Reactant: COc1c(C)cc(N)cc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1cc(C)c(OC)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
To a solution of 5.00 g (33 mmol) of 3,5-dimethyl-4-methoxyaniline and 7.1 ml of triethylamine in 50 ml of dichloromethane was dropwise added a solution of 4.31 g (40 mmol) of methoxyacetylchloride in 20 ml of dichloromethane under chilling with ice for a period of 30 min. The resulting mixture was stirred for 30 min. at room temperature. The reaction mixture was washed sequentially with 5 aqueous sodium carbonate and 3 N hydrochloric acid, and then dried over anhydrous sodium sulfate. Dichloromethane was distilled off. The residue was crystallized from ether hexane to obtain 6.70 g of the desired compound as a white crystal. (Yield: 90.7 %)
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][CH:11]([OH:16])[CH2:12]2.[I-].[Na+].[CH3:21]I>O1CCCC1>[CH3:21][O:16][CH:11]1[CH2:10][CH:9]2[CH:13]([CH2:14][CH2:15][CH:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:17][CH3:18])[CH2:12]1
Reactant: CCC(CCCCC1CCC2CC(O)CC12)OC
Reactant: CI
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CCCCC1CCC2CC(OC)CC12)OC
Temperature: 50 °C

Procedure:
The starting material, 2-(5-methoxyhept-1-yl)bicyclo[3.3.0]7 octanol {octahydro-4-(5-methoxyheptyl)-2-pentalenol} (1.0 g, 3.9 mmoles) is added to a reaction vessel containing sodium iodide (0.12 g, 4.9 mmoles) and tetrahydrofuran (12 ml). The solution is stirred while methyl iodide (0.84 g, 5.9 mmoles) is rapidly added. The reaction is heated in a 50° C. water bath for 4 hours. The water bath is removed and the reaction neutralized with the addition of water (5 ml). The organic phase is separated and the aqueous phase extracted with ether (2×50 ml). The ether extracts are combined and washed with brine (50 ml). The solution is dried over anhydrous magnesium sulfate and the solvent removed under vacuum leaving a clear yellow oil. The product is then kugelrohred under reduced pressure leaving a pale yellow oil (0.8 g, 3.1 mmoles).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.FC1C(O)=C(F)C(F)=C(F)C=1F.C(N=C=NC(C)C)(C)C.Cl.[OH:33][CH:34]1[O:42][C@H:41]([CH2:43][OH:44])[C@@H:39]([OH:40])[C@H:37]([OH:38])[C@H:35]1[NH2:36].CCN(CC)CC>CN(C=O)C.CN(C=O)C.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:34]2([O:42][C@H:41]([CH2:43][OH:44])[C@@H:39]([OH:40])[C@H:37]([OH:38])[C@H:35]2[NH2:36])[OH:33])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1(O)C(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-iodobenzoic acid (1 mmol) in DMF (2 mL) was added pentafluorophenol (2 mmol) and diisopropylcarbodiimide (1.2 mmol). The solution was stirred at room temperature for 6 hours and then added to a solution of glucosamine hydrochloride (1 mmol) and NEt3 (2 mmol) in DMF/H2O (1 mL, 1:10 v/v). The reaction was stirred for 16 hours and then crystallized from hot water to yield 4-iodobenzoyl glucosamine, compound TP010. The structure of TP010 is shown below (R is I).
Reaction SMILES: [NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1.C(N(CC)CC)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.CN(C)C=O>[NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:41])=[O:40])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNS(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
4-Amino-N-(1-(4-aminobutyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.00 g) was dissolved in a mixed solvent of dichloromethane (20 ml) and dimethylformamide (15 ml). Triethylamine (0.57 ml) was added, and a solution of benzenesulfonyl chloride (0.35 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature. Insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.57 g of 4-amino-N-(1-(4-benzenesulfonylaminobutyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([OH:17])=O)[CH:8]=2)[CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(C)=CC=CC=1.O>[OH:1][C:2]1[C:11]([C:12]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:17])[CH:8]=2)[CH:3]=1
Reactant: O=C(O)c1ccc2cc(O)c(C(=O)O)cc2c1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=C(Nc1ccccc1)c1ccc2cc(O)c(C(=O)Nc3ccccc3)cc2c1
Temperature: 90 °C
Yield: 45.8 %

Procedure:
2-Hydroxy-3,6-dihydroxycarbonylnaphthalene (4.64 g) and aniline (4.10 g) were dispersed in xylene (92.8 g), followed by heating to 90° C. Phosphorous trichloride (2.4 g) was added dropwise at 90° to 100° C., and then the mixture was reacted at 140° C. for 3 hours. After the completion of the reaction, water (92.8 g) was added and the reaction solution was neutralized with sodium carbonate at 90° C. The solution was filtered at room temperature and washed in turn with xylene (46.4 g) and water (46.4 g). The resultant crystal was subjected to reflux washing using acetone (80 g) and then filtered. This operation was repeated three times, followed by drying to obtain 3.5 g of 2-hydroxy-3,6-diphenylaminocarbonylnaphthalene as a white powdered crystal (melting point: 314°-317° C.).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20]Cl)=[CH:9][CH:8]=1)[CH3:6].O.[CH3:23][N:24](C)C=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:1]([CH:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][C:23]#[N:24])=[CH:9][CH:8]=1)[CH3:6])#[N:2]
Reactant: CN(C)C=O
Reactant: CC(Cl)c1ccc(Cc2ccccc2CCl)cc1
Reactant: [C-]#N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C#N)c1ccc(Cc2ccccc2CC#N)cc1
Reaction time: 20 h

Procedure:
Sodium cyanide (2.4 g) and 0.8 g of benzyl triethyl ammonium chloride were added to 30 ml of dimethyl formamide, and with stirring, a solution of 5.6 g of (1-chloroethyl)-4-(2-chloromethylbenzyl)benzene in 10 ml of dimethyl formamide was added. The mixture was stirred at 40° C. for 1 hour and then at 70° C. for 20 hours. After the reaction, the reaction mixture was cooled, and 70 ml of water was added. The mixture was extracted with ether. The ethereal layer was washed with water, dried over anhydrous magnesium sulfate and distilled off to remove the ether. The resulting pale yellow oily substance was chromatographed on a silica gel column using benzene as an eluent. From the eluate, 3.4 g of (1-cyanoethyl)-4-(2-cyanomethylbenzyl)benzene was obtained as a colorless liquid. This compound crystallized by stimulating the reactor wall through addition of n-hexane. Recrystallization from a mixture of ether and n-hexane afforded colorless needle-like crystals having a melting point of 61° to 64° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11]/[N:12]=[C:13]2\[NH:14][C:15](=[O:27])[C:16]3[NH:17][CH:18]=[N:19][C:20]=3[N:21]\2[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=O)[CH:5]=[CH:6][CH:7]=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][C:9]1[N:14]2[C:15](=[O:27])[C:16]3[NH:17][CH:18]=[N:19][C:20]=3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:13]2=[N:12][N:11]=1
Reactant: CCCCCn1/c(=N/NC(=O)Cc2cccc(Br)c2)[nH]c(=O)c2[nH]cnc21
Solvent: c1ccccc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(Cc3cccc(Br)c3)nnc12
Yield: 86 %

Procedure:
The mixture of 2-(3-bromophenyl)-N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]acetohydrazide (1.8 g, 4.2 mmol) in benzene (100 mL) was refluxed overnight. The reaction mixture was concentrated to give the desired product 1.5 g. LCMS calculated for C18H20BrN6O (M+H): 415.1. Found: 415.1.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:15]([CH3:18])([CH3:17])[CH3:16].O>[N+](C)([O-])=O.[Cl-].[Zn+2].[Cl-]>[C:15]([C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][C:8]([C:5]([CH3:6])([CH3:13])[CH3:4])=[CH:9][CH:10]=3)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)Cl
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CC(C)(C)c1ccc2[nH]c3ccc(C(C)(C)C)cc3c2c1
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To a solution of carbazole (6.6 g, 39.5 mmol) and zinc (II) chloride (16.2 g, 118.8 mmol) in nitromethane (100.0 ml) was added dropwise 2-chloro-2-methylpropane (11.1 g, 120.0 mmol) under nitrogen atmosphere and stirring. The addition of 2-chloro-2-methylpropane was carried out over a 15 minute period. The mixture was stirred at room temperature for 24 hours. Water (100.0 ml) was then added. The product was extracted with dichloromethane (3×60.0 ml). The organic layer was washed with water (3×100.0 ml), and then dried with MgSO4, and dichloromethane was evaporated under vacuum. The product was purified by recrystallization from hot hexane to afford a white product crystal in the amount of 5.0 g (in 45.0% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:4][N:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.ClC(Cl)(O[C:33](=[O:39])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.Cl.[CH3:49][NH:50][OH:51]>O1CCCC1>[F:1][C:2]1[C:3]([C:22]2([OH:28])[CH2:23][CH2:24][N:25]([C:33](=[O:39])[N:50]([OH:51])[CH3:49])[CH2:26][CH2:27]2)=[N:4][N:5]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1
Reactant: COc1ccc(-n2nc(C3(O)CCNCC3)c(F)c2-c2ccc(C)cc2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C3(O)CCN(C(=O)N(C)O)CC3)c(F)c2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 172.2 %

Procedure:
To a solution of 4-(4-fluoro-1-(4-methoxyphenyl)-5-(4-tolyl)-1H-pyrazol-3-yl)-4-piperidinol (3.61 g, 9.46 mmol) in tetrahydrofuran (946 mL), triphosgene (1.12 g, 3.78 mmol) and triethylamine (1.65 mL, 11.8 mmol) were added at 0° C., and the obtained solution was stirred at the same temperature for 40 minutes. To the reaction solution, N-methylhydroxylamine hydrochloride (988 mg, 11.8 mmol) and triethylamine (3.43 mL, 24.6 mmol) were added, and the obtained mixture was stirred at 80° C. for 3 hours. The reaction solution was cooled to room temperature, and distilled water was added to the reaction solution. The resulting solution was extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by recrystallization (n-hexane/ethyl acetate, 80° C.) to obtain the title compound (2.96 g, 6.51 mmol, 68%) as a pale yellow solid.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1([CH2:31][O:32]C2CCCCO2)[N:13]([CH2:14][C:15]#[N:16])[C:12](=[O:17])[N:11]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=2)[C:10]1=[O:30].Cl.O>CO.C(Cl)Cl>[OH:32][CH2:31][C:9]1([CH2:8][OH:7])[N:13]([CH2:14][C:15]#[N:16])[C:12](=[O:17])[N:11]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([C:26]([F:29])([F:27])[F:28])[CH:19]=2)[C:10]1=[O:30]
Reactant: N#CCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(COC1CCCCO1)COC1CCCCO1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: N#CCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CO)CO
Temperature: 0 °C
Yield: 70.4 %

Procedure:
4.68 g of the product obtained in Stage 1 above in solution in 50 ml of methanol and 8.8 ml of hydrochloric acid are introduced and the whole is taken to reflux for 30 minutes. 60 ml of ice-cooled water is added, extraction is carried out with ether, the ethereal phase is washed with a saturated solution of sodium chloride and dried. After purification on silica, eluting with methylene chloride-acetone: 85-15 then 8-2, the crystals obtained are taken up in 10 ml of methylene chloride, separated out and dried. In this way 2.26 g of expected product (white crystals) is obtained. M.p.=157-158° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[N+:8]([O-:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:21]1(/[CH:27]=[CH:28]/[CH:29]=[CH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[N:1]1([CH2:6][C:7]2([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)[CH2:30][CH:29](/[CH:28]=[CH:27]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:10][N:8]2[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C[N+]([O-])=C(Cn1ccnc1)c1ccc2ccccc2c1
Reactant: C=C/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN1OC(/C=C/c2ccccc2)CC1(Cn1ccnc1)c1ccc2ccccc2c1
Temperature: 85 °C
Reaction time: 72 h

Procedure:
A mixture of compound 2 (11.02 g, 0.042 mol) and trans-1-phenyl-1,3-butadiene (8.0 g, 0.062 mol) in 500 ml of toluene is heated to 85° C. and held there for 72 hours, cooled and evaporated to dryness. The oil that remained is purified by flash chromatography on silica gel (eluent comprised of 98% CHCl3 and 2% MeOH by volume). The resulting semisolid is dissolved in chloroform, decolorized with carbon, and filtered through a bed of celite. The solvent is evaporated and the resulting tan solid recrystallized from ethyl acetate/hexane, m.p. 166°-169° C. (Found: C, 78.68; H, 6.39; N, 10.60. C26H25N3O requires: C, 78.96; H, 6.37; N, 10.62).
Reaction SMILES: CO[C:3](=[O:15])[NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].N1C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:32][NH:31][N:30]=2)=[CH:25][CH:24]=1>O1CCOCC1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:32][N:31]([C:3]([NH:4][S:5]([C:8]3[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=3)(=[O:6])=[O:7])=[O:15])[N:30]=2)=[CH:27][CH:28]=1
Reactant: COC(=O)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Temperature: 100 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
Part A: To a solution of N-((4-chlorophenyl)sulfonyl)carbamic acid methyl ester (CAS: 34543-04-9) (2.99 gram, 12.0 mmol) and pyridine (4 mL) in 1,4-dioxane (20 mL) is added 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (3.39 gram, 13.2 mmol) and the resulting mixture is stirred for 4 hours at 100° C. After concentration in vacuo the residue is dissolved in dichloromethane, successively washed with water, 1 N HCl and water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to a volume of 20 mL. Methyl-tert-butyl ether (60 mL) is added and the resulting solution is concentrated to a volume of 20 mL. The formed crystals are collected by filtration and recrystallised from methyl-tert-butyl ether to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (4.75 gram, 76% yield) Melting point: 211-214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[NH2:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=O>>[Cl:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18](=[O:20])[N:12]([S:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[C:13](=[O:14])[NH:15]2)=[CH:21][CH:22]=1
Reactant: O=C=NS(=O)(=O)c1c(Cl)cccc1Cl
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1S(=O)(=O)c1c(Cl)cccc1Cl
Yield: 40.4 %

Procedure:
1.12 g (4.42 mmol) of 2,6-dichlorobenzenesulfonylisocyanate and 882 mg (4.42 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 725 mg of the above-identified compound (yield 40.5%). Properties: colorless crystal, Melting point: 260°-261° C., PMR (δppm, DMSO-d6):7.18 (1H,s), 7.22 (1H,br), 7.63 (3H,br), 7.88 (1H,d), 11.83 (1H,br).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][CH2:19][CH:20]1[CH2:24][CH2:23][CH:22]([CH2:25][OH:26])[CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.Cl>[Si:11]([O:18][CH2:19][CH:20]1[CH2:24][CH2:23][CH:22]([CH:25]=[O:26])[CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(CO)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CCC(C=O)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
To a solution of oxalyl chloride (3.44 mL, 39.3 mmol) in dichloromethane (200 mL) at −78° C. was added, dropwise, dry DMSO (4.36 mL, 61.4 mmol). After 10 min at −78° C., a solution of (3-((tert-butyldimethylsilyloxy)methyl)cyclopentyl)methanol (6.0 g, 24.56 mmol) in CH2Cl2 (180 mL) was slowly added and the mixture stirred at −78° C. After 1 h, triethylamine (17.11 mL, 122.8 mmol) was added and stirring continued at −78° C. for 10 min after which the mixture was allowed to warm to 23° C. The reaction mixture was diluted with HCl 1N (pH˜6) and the phases separated. The organic fraction was dried (MgSO4), filtered and concentrated in vacuo to give 5.81 g (97% yield) of the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 9.62 (1 H, d, J=2.5 Hz), 3.54 (2 H, ddd, J=12.0, 10.0, 6.3 Hz), 2.73-2.82 (1 H, m), 2.14-2.24 (1 H, m), 1.89-2.00 (2 H, m), 1.74-1.85 (2 H, m), 1.57 (1 H, dt, J=13.1, 8.6 Hz), 1.33-1.44 (1 H, m), 0.91 (9 H, s), 0.06 (6 H, s).