Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:28](=[O:29])[NH:27][C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1
Reactant: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)cc1)OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reaction time: 3 h
Yield: 77.4 %

Procedure:
A solution of 0.17 g of 3,5-dichloro-4-(3-hydroxypropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.09 g of 4-chlorophenyl isocyanate and a catalytic amount of pyridine dissolved in 10 ml of toluene was heated at 60° to 70° C., while stirring, for 3 hours, and the reaction mixture was then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.19 g of 3,5-dichloro-4-(3-(N-(4-chlorophenyl)carbamoyloxy)propyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (77% yield), m.p., 54.3° C.
Reaction SMILES: C(O[CH:5]1[S:25][C@H:24]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.[NH:35]1[CH:42]=[CH:41][C:39]([NH2:40])=[N:38][C:36]1=[O:37].C(#N)C.C[Si](C)(C)N[Si](C)(C)C.Cl[Si](C)(C)C.C[Si](OS(C(F)(F)[F:69])(=O)=O)(C)C>>[CH2:8]([O:7][C@H:6]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:24]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:25][CH:5]1[N:35]1[CH:42]=[C:41]([F:69])[C:39]([NH2:40])=[N:38][C:36]1=[O:37])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)OC1S[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC#N
Product: Nc1nc(=O)n(C2S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-O-acetyl 2,3,5-tri-O-benzyl-4-thio-D-arabinofuranose (478 mg, 1 mmol) and cytosine (129.0 mg, 1 mmol) in anhydrosis acetonitrile (25 mmol) were added consecutively hexamethyldisilazane (HMDS, 162 mg, 1 mmol) and chlorotrimethylsilane (TMSCl, 434 mg, 4 mmol), and the mixture was stirred at room temperature for 0.5 hours. This solution was cooled to −78° C. Trimethylsilyltrifluoromethane sulfonate (267 mg, 1.2 mmol) was added and the resulting solution was stirred at −78° C. for another 2.5 h, after which time the reaction was essentially complete. The mixture was warmed to room temperature, concentrated to a small volume (5 mL), diluted with methylene chloride (50 mL) and then washed with water (20 mL) followed by saturated sodium bicarbonate and water. The organic layer was dried over MgSO4 and evaporated to dryness. The residue was purified by chromatography over silica gel (50 g. elution with CHCl3/MeOH 98:2) to afford 7 as 2:1α,β mixture (425.2 mg 80.0%) as a colorless syrup TLC (95:5 CHCl3/MeOH) Rf 0.65; MS z/e 553 (M+Li)+.
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[N:26]1([CH2:25][CH2:24][CH2:23][O:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[C:12]4[C:7]([N:6]=[C:5]5[C:14]=3[CH2:1][CH2:2][CH2:3][CH2:4]5)=[CH:8][CH:9]=[CH:10][CH:11]=4)=[CH:16][CH:17]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Oc1ccc(-c2c3c(nc4ccccc24)CCCC3)cc1
Reactant: ClCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: c1ccc2c(-c3ccc(OCCCN4CCCC4)cc3)c3c(nc2c1)CCCC3
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
The product from the previous step, 4-(1,2,3,4-Tetrahydro-acridin-9-yl)-phenol (22 mg, 0.08 mmol), 1-(3-Chloropropyl)-pyrrolidine (18 mg, 0.12 mmol), and K2CO3 (17 mg, 0.12 mmol) were mixed in NMP (267 uL) and stirred rapidly at 80° C. for 90 minutes in a sealed vial. The reaction mixture was cooled, partitioned between Et2O (50 mL) and H2O (10 mL). The organic layer was washed with H2O (3×10 mL), sat. aq. NaCl (10 mL), dried over Na2SO4, decanted and concentrated. The residue was purified using preparative LCMS to give product the desired product.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([CH:9]=[O:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:11]OS([O-])=O.[K+]>CO.O.C(Cl)Cl>[CH3:1][S:2]([C:3]1[C:4]([CH:9]=[O:10])=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:11]
Reactant: O=S([O-])OO
Reactant: CSc1cccnc1C=O
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CS(=O)c1cccnc1C=O
Reaction time: 5 h
Yield: 22.6 %

Procedure:
To a cold (0° C.), stirred solution of 3-methylsulfanyl-pyridine-2-carbaldehyde (prepared as described for AMD9574) (280 mg, 1.83 mmol) in a mixture of MeOH (20 mL) and water (2 mL) was added solid oxone (2.25 g, 3.66 mmol) and the resulting heterogeneous mixture was stirred for 5 h. At this point, the reaction mixture was diluted with CH2Cl2 (50 mL), and then filtered through celite, washed with CH2Cl2 (3×20 mL) and concentrated and dried in vacuo. Flash chromatography (silica gel, 4:1 hexanes-EtOAc) of the residue thus obtained afforded 70 mg (23%) of 3-methanesulfinyl-pyridine-2-carbaldehyde. 1H NMR (CDCl3) □ 2.86 (s, 3H), 7.81 (dd, 1H, J=8, 5 Hz), 8.66-8.69 (m, 1H), 8.90 (d, 1H, J=3 Hz), 10.12 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]([OH:34])=O)[CH2:27][CH2:26]3)=[CH:22][N:23]=1)=[CH:15]2)(=[O:8])=[O:7].[N:35]1(O)[C:39]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN>CN(C)C=O.C1COCC1.O>[CH3:39][NH:35][C:32](=[O:34])[CH2:31][N:28]1[CH2:29][CH2:30][N:25]([CH2:24][C:21]2[S:20][C:19]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][S:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)(=[O:8])=[O:7])=[N:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CN1CCN(Cc2cnc(-c3cc4cccc(NS(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)CN1CCN(Cc2cnc(-c3cc4cccc(NS(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a solution of {4-[(2-{7-[(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)methyl]piperazin-1-yl}acetic acid (0.230 g) in N,N-dimethylformamide (4 ml) were added 1H-1,2,3-benzotriazol-1-ol (0.066 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.093 g), and the mixture was stirred at 50° C. for 1 hr. A 2.0 mol/L solution of N-methylamine in THF (0.60 ml) was added to the reaction solution, and the mixture was stirred at 50° C. for 1 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol), and recrystallized from tetrahydrofuran-hexane to give the title compound (0.100 g, yield 42%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[C:8]([CH3:15])[CH:7]=1>C(Cl)Cl.[Pd]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[C:8]([CH3:15])[CH:7]=1
Reactant: COC(=O)C=Cc1cc(C)c(C=O)c(C)c1
Agent: [Pd]
Solvent: ClCCl
Product: COC(=O)CCc1cc(C)c(C=O)c(C)c1

Procedure:
To a solution of 3-(4-formyl-3,5-dimethylphenyl)-acrylic acid methyl ester (900 mg, 4.1 mmol) in CH2Cl2 (20 mL) was added 10% Pd/C (90 mg) and the mixture was hydrogenated at one atm overnight. The catalyst was filtered through Celite and was washed with CH2Cl2. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (5:1) to give 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].F[C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:12]=1[CH:13]=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[C:12]=1[CH:13]=[O:14]
Reactant: Oc1ccc(F)cc1Cl
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(Oc2ccc(F)cc2Cl)cccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 2-chloro-4-fluoro-phenol (20.97 g, 143.10 mmol) and 2-fluoro-6-(trifluoromethyl)benzaldehyde (25 g, 130.1 mmol) in DMF (125.0 mL) was added Cs2CO3 (46.62 g, 143.1 mmol) and the reaction mixture was stirred at 100° C. for 1 hour. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate (3×150 ml). The organics were combined, washed with water, brine (2×), dried over Na2SO4, filtered and evaporated to give a red oil which solidified after standing over night. The material was then triturated with hot hexanes and cooled to 25° C. The slurry was filtered and washed with cold hexanes to give 2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzaldehyde (32.7 g, 79%) as an off white solid. 1H NMR (400 MHz, DMSO) δ 10.61 (s, 1H), 7.84-7.70 (m, 2H), 7.66 (d, J=7.9 Hz, 1H), 7.47 (dd, J=9.0, 5.3 Hz, 1H), 7.42-7.32 (m, 1H), 7.12 (d, J=8.3 Hz, 1H) ppm.
Reaction SMILES: [C:1]1([C:7]23[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:11][NH:10][CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:1]1([C:7]23[CH2:15][CH2:14][CH2:13][CH:12]2[CH:11]([C:31](=[O:32])[CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:10][CH2:9][CH2:8]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: c1ccc(C23CCCC2CNCC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(Cc1ccccc1)C1NCCC2(c3ccccc3)CCCC12
Temperature: 25 °C

Procedure:
To a cold solution (0°-5° C.) of 3.0 g. of 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine in 47 ml. of methanol containing 14 ml. of water and 2.6 g. of potassium carbonate was added 2.6 g. of phenylacetyl chloride in one portion. The reaction mixture was stirred at 0°-5° C. for thirty minutes and then was warmed to 25° C., at which it was stirred for an additional one hour. The reaction mixture was concentrated under reduced pressure, leaving an oily residue. The oil was then dissolved in 500 ml. of diethyl ether and washed with dilute aqueous sodium bicarbonate solution and with water. After drying the ethereal solution, the solvent was evaporated under reduced pressure to afford 4a-phenyl-2-phenylacetyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine formed in the above acylation reaction as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C@H:9]1[O:13][C:12](=[O:14])[CH2:11][CH2:10]1.[CH3:15][CH2:16][Mg+].[Br-].CCOCC>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[OH:13][C@H:9]([CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:10][CH2:11][C:12]1([OH:14])[CH2:16][CH2:15]1
Reactant: CC[Mg+]
Reactant: O=C1CC[C@@H](COC2CCCCO2)O1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O[C@@H](CCC1(O)CC1)COC1CCCCO1
Temperature: 15 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a mixture of Ti(OiPr)4 (0.33 mL, 0.001 mol, Ardrich) and (5S)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-dihydrofuran-2(3H)-one (1.0 g, 0.005 mol) in 18.7 mL of THF was added a solution of 3M EtMgBr in Et2O (4.3 mL, 0.0125 mol, Aldrich) via a syringe over 3 hrs at 15° C. After stirring for additional one hour at 15° C., the reaction was quenched with 20 mL of saturated NH4Cl solution, filtered and extracted with EtOAc (50 mL×2). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography to afford 1-((S)-3-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)butyl)cyclopropanol as colorless oil (0.853 g, 74%)2.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[C:5]=1[CH2:14][CH2:15][CH3:16])[CH:2]=C.[O:17]=[O+][O-].CSC>CO>[O:11]=[C:8]1[C:7]2[CH:12]=[CH:13][C:4]([CH2:1][CH:2]=[O:17])=[C:5]([CH2:14][CH2:15][CH3:16])[C:6]=2[CH2:10][O:9]1
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc2c(c1CCC)COC2=O
Solvent: CSC
Solvent: CO
Product: CCCc1c(CC=O)ccc2c1COC2=O
Temperature: 25 °C

Procedure:
To the flask charged with 5-allyl-4-propyl-2-benzofuran-1(3H)-one (60 mg) was added methanol (10 mL). The solution was chilled to −78° C. before ozone was bubbled through. Ozone was stopped when the solution turned light blue. Excess ozone was removed by bubbling nitrogen through the solution, which was followed by addition of dimethyl sulfide (170 mg, 2.8 mmol). The mixture was allowed to warm to RT. The desired product, (1-oxo-4-propyl-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde, was purified by silica gel chromatography.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[S:5]([N:11]=C=O)([N:8]=[C:9]=[O:10])(=[O:7])=[O:6].[CH:14]1C=CC=CC=1>>[C:9]([NH:8][S:5]([NH:11][C:1](=[O:4])[CH3:2])(=[O:7])=[O:6])(=[O:10])[CH3:14]
Reactant: c1ccccc1
Reactant: CC(=O)O
Reactant: O=C=NS(=O)(=O)N=C=O
Product: CC(=O)NS(=O)(=O)NC(C)=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
12 g of anhydrous acetic acid are dissolved in 150 ml of absolute benzene and 14.8 g of sulfuryl diisocyanate (prepared in accordance with German Pat. No. 940,351) are added dropwise within 20 minutes at ambient temperature, accompanied by stirring. The temperature rises from 21° to 39° C. and CO2 evolution as well as a precipitation of a colorless precipitate occur. The reaction mixture is heated by means of an oil bath to 60° C. accompanied by stirring until the evolution of the gas is at an end, which takes 2 hours. The reaction mixture is cooled, the precipitate removed by suction filtering and dried at 60° C. 17.8 g of colorless crystals are obtained (98.8% of theory), m.p. 167°-169° C. (decomp.) which can be recrystallized from isopropanol and acetic acid.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[C:15]([CH:24]([CH3:26])[CH3:25])[CH:14]=1.CN(C)[CH:29]=[O:30]>>[CH2:20]([N:19]([CH2:22][CH3:23])[C:16]1[CH:17]=[CH:18][C:13]([CH:29]=[O:30])=[CH:14][C:15]=1[CH:24]([CH3:26])[CH3:25])[CH3:21]
Reactant: CN(C)C=O
Reactant: CCN(CC)c1ccc(Br)cc1C(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCN(CC)c1ccc(C=O)cc1C(C)C
Yield: 97.4 %

Procedure:
In a manner analogous to example 1 d, the process is carried out by a reaction of 1.8 ml (4.4 mmol) of 2.5M n-butyllithium/hexane with 1 g (3.7 mmol) of (4-bromo-2-isopropylphenyl)diethylamine and 0.35 ml (4.5 mmol) of dimethylformamide. 790 mg of 4-diethylamino-3-isopropylbenzaldehyde are obtained in the form of a yellow oil (yield=97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][N:12]=2)=[CH:6][CH:5]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[C:27]1[C:31]([CH2:32]O)=[C:30]([CH:34]([CH3:36])[CH3:35])[O:29][N:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[N:12]=[N:13][C:14]([O:17][CH2:32][C:31]3[C:27]([C:21]4[C:20]([Cl:19])=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:26])=[N:28][O:29][C:30]=3[CH:34]([CH3:36])[CH3:35])=[CH:15][CH:16]=2)=[CH:8][CH:9]=1.[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH2:32][C:31]3[C:27]([C:21]4[C:20]([Cl:19])=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:26])=[N:28][O:29][C:30]=3[CH:34]([CH3:36])[CH3:35])[N:12]=2)=[CH:8][CH:9]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Reactant: COC(=O)c1ccc(Oc2ccc(=O)[nH]n2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(Oc2ccc(=O)n(Cc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)n2)cc1
Product: COC(=O)c1ccc(Oc2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)nn2)cc1
Temperature: 25 °C
Reaction time: 27 h
Yield: 58 %
Yield: 9 %

Procedure:
To a mixture of 4-(6-oxo-1,6-dihydro-pyridazin-3-yloxy)-benzoic acid methyl ester (0.43 g, 1.75 mmol), [3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-yl]-methanol (0.50 g, 1.75 mmol) and triphenylphosphine (0.56 g, 2.1 mmol) in benzene (12 ml) was added dropwise 0.6 ml (2.9 mmol) of diisopropyl 1,2-diazenedicarboxylate (DIAD). The reaction mixture was stirred at room temperature for 27 h and the solvent was removed in vacuo. The residue was subjected to preparative HPLC purification eluting with acetonitrile/water 1:1 to provide 0.08 g (9%) of the desired 4-{6-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-pyridazin-3-yloxy}-benzoic acid methyl ester together with 0.52 g (58%) of 4-{1-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethyl]-6-oxo-1,6-dihydro-pyridazin-3-yloxy}-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[O:4].COCN[C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:21]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[O:4]
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Reactant: COCNC(=O)C1CCCC1
Product: COC(=O)c1sc(C(=O)C2CCCC2)cc1NC(=O)C(F)(F)F

Procedure:
3-(2,2,2-Trifluoroacetylamino)thiophene-2-carboxylic acid methyl ester and cyclopentanecarboxylic acid methoxymethylamide were reacted by method Z. The product with the molecular weight of 349.33 (C15H17F2NO4S) was obtained in this way; MS (ESI): 350 (M+H+).
Reaction SMILES: [ClH:1].Cl[C:3]([N:22]([CH3:24])[CH3:23])=[N:4][C:5]1[N:6]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[N:7]=[CH:8][C:9]=1[C:10]#[N:11]>ClCCCl>[Cl:1][C:10]1[N:11]=[C:3]([N:22]([CH3:24])[CH3:23])[N:4]=[C:5]2[N:6]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[N:7]=[CH:8][C:9]=12
Reactant: Cl
Reactant: CN(C)C(Cl)=Nc1c(C#N)cnn1-c1ccc(S(C)(=O)=O)cc1
Solvent: ClCCCl
Product: CN(C)c1nc(Cl)c2cnn(-c3ccc(S(C)(=O)=O)cc3)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stream of dry hydrogen chloride was passed through a solution of 1-chloro-N′-[4-cyano-2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-N,N-dimethyl-formamidine (0.600 g, 1.70 mmol) in 1,2-dichloroethane (20 mL) for 1 h. The solution was stirred at rt for 3 days. The solvent was removed under reduced pressure and the crude washed several times with dichloromethane. [4-Chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-dimethyl-amine recrystalized in dichloromethane and it was retrieved by filtration as an off-white solid (0.4 g, 67%). Exact mass calculated for C14H14ClN5O2S 351.06, found 352.20 (MH+, 100%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([CH2:27][C:28](N)=[O:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].BrCCO[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:24][N:25]([CH2:27][CH2:28][O:29][CH:35]6[CH2:40][CH2:39][CH2:38][CH2:37][O:36]6)[CH2:26]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: BrCCOC1CCCCO1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCOC4CCCCO4)C3)ccc1-2

Procedure:
The title compound was prepared by a similar method to 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide using 2-(2-bromoethoxy)tetrahydro-2H-pyran instead of 2-bromoacetamide and DMF instead of THF and performing the reaction at 60° C. The title compound was isolated as an amber gum (104 mg, 29%). LCMS: RT=3.24, 3.35 min, [M+H]+=496
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1.Cl[C:16](OC(Cl)(Cl)Cl)=[O:17]>C1(C)C=CC=CC=1>[CH3:12][C:8]1([CH3:11])[CH2:7][C:6]2[C:5]([O:13][CH3:14])=[CH:4][CH:3]=[C:2]([N:1]=[C:16]=[O:17])[C:10]=2[O:9]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(N)c2c1CC(C)(C)O2
Solvent: Cc1ccccc1
Product: COc1ccc(N=C=O)c2c1CC(C)(C)O2

Procedure:
By the method of Example 1, Step F, 3.70 g (0.0191 mole) of 7-amino-2,3-dihydro-2,2-dimethyl-4-methoxybenzofuran and 3.79 g (0.0191 mole) of trichloromethyl chloroformate were reacted in 100 mL of toluene, yielding 2,3-dihydro-2,2-dimethyl-4-methoxybenzofuran-7-yl isocyanate as a brownish-yellow, viscous oil. The IR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[N:15]=[C:14]3[C:17](=[O:26])[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH2:20][CH2:21][C:13]3=[C:12](Br)[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:28][CH2:29][CH2:30][CH3:31].[Na+]>>[CH2:1]([N:8]1[C:16]2[N:15]=[C:14]3[C:17](=[O:26])[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH2:20][CH2:21][C:13]3=[C:12]([O:28][CH2:29][CH2:30][CH3:31])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC[O-]
Reactant: O=C1c2ccccc2CCc2c1nc1c(cnn1Cc1ccccc1)c2Br
Agent: [Na+]
Product: CCCOc1c2c(nc3c1cnn3Cc1ccccc1)C(=O)c1ccccc1CC2

Procedure:
By treating the product of Example 11 according to the procedure of Example 3, replacing the sodium ethoxide with sodium propoxide, 1-benzyl-4-propoxy-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)one is obtained.
Reaction SMILES: C([CH2:3][C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])([OH:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)#N.[C:20](=[O:23])(O)[O-:21].[Na+]>S(=O)(=O)(O)O.O>[C:20]([CH2:3][C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])([OH:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)([OH:21])=[O:23]
Reactant: N#CCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
1-Cyano-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol (4 g, 13.9 mmole) was dissolved in 40% aqueous sulfuric acid (100 ml) and heated in an oil bath at 100°-110° C. for 18 hours. The solution was then cooled, diluted with water (200 ml), and rendered alkaline by the slow addition of solid sodium bicarbonate. The mixture was then extracted several times with ethyl acetate (3×100 ml) and the aqueous phase was rendered acidic (pH 3) by the addition of dilute orthophosphoric acid. The aqueous phase was then extracted with ethyl ether (3×150 ml), the combined ether extracts were washed once with water, and then dried over magnesium sulfate. Evaporation of the ether gave the title compound as a pale yellow solid, 2.7 g, (62%), m.p. 158°-159° C.