Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[NH:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:16][Si](C)(C)C.C1C([N+]([O-])=O)=CC=C([Cl-][C:31]([O-])=[O:32])C=1.[O:34]=[C:35]1[N:39]([CH:40]2[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][CH2:48][CH2:49][NH2:50])[CH2:42][CH2:41]2)[C:38]2[CH:51]=[CH:52][CH:53]=[CH:54][C:37]=2[NH:36]1.C(N(CC)CC)C>O1CCCC1.ClCCl>[ClH:16].[O:34]=[C:35]1[N:39]([CH:40]2[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][CH2:48][CH2:49][NH:50][C:31]([N:14]3[CH:9]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:10][CH2:11][CH2:12][C:13]3=[O:15])=[O:32])[CH2:42][CH2:41]2)[C:38]2[CH:51]=[CH:52][CH:53]=[CH:54][C:37]=2[NH:36]1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCCC(c2ccccc2)N1
Reactant: NCCCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cl
Product: O=C1CCCC(c2ccccc2)N1C(=O)NCCCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride in mineral oil (60mg of a 60% suspension, 1.50 mmol) was suspended in 3 mL of tetrahydrofuran. To this suspension was added a solution of 6-phenylpiperidin-2-one (134 mg, 0.765 mmol) in tetrahydrofuran (2 mL). The resulting solution was stirred at ambient temperature for 30 minutes, then transferred via syringe to a solution of chorotrimethylsilane (500 mL, 3.94 mmol) in tetrahydrofuran (3 mL) which had already been chilled to −78° C. The reaction mixture was stirred at −78° C. for 2 hours, and then evaporated to dryness. The resulting residue was dissolved in 2 mL of tetrahydrofuran and added to a 3 mL solution of 4-nitrophenylchloroformate (154 mg, 0.764 mmol) in tetrahydrofuran which had already been chilled to 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and then at ambient temperature for 30 minutes. The mixture was evaporated to dryness, and half of the resulting residue (160 mg, 0.470 mmol) was dissolved in 5 mL of dichloromethane. To this solution was added 4-(2-keto-1-benzimidazolinyl)-piperidine butylamine (139 mg, 0.482 mmol) and triethylamine (139 mL, 0.997 mmol). The yellow reaction mixture was stirred at ambient temperature for 18 hours, and then evaporated to dryness. The resulting residue was purified by “flash” chromatography (98:2 dichloromethane:methanol). The product fractions were evaporated to an oil which was treated with HCl-saturated ethyl acetate, evaporated to dryness, and reconcentrated from diethyl ether twice to give the title compound as a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([C:12](O)([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:2]#[C:3][CH3:4].FC1(F)N(C)CCN1C.O>C(#N)C>[N:9]1[CH:8]=[CH:7][CH:6]=[N:11][CH:10]=1.[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH2:19])[N:9]=[CH:10][N:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1cc(C(C)(O)c2ccccc2)ncn1
Agent: CN1CCN(C)C1(F)F
Solvent: CC#N
Solvent: O
Product: C=C(c1ccccc1)c1cc(OCC#CC)ncn1
Product: c1cncnc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.5 %

Procedure:
To a solution of 0.33 g of 6-(2-butynyloxy)-4-(α-hydroxy-α-methylbenzyl)pyrimidine in 4 ml of acetonitrile was added dropwise a solution of 0.2 g of 2,2-difluoro-1,3-dimethylimidazolidine in 2 ml of acetonitrile, followed by stirring at room temperature for 6 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined and washed with a saturated aqueous sodium chloride solution, and the combined organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.20 g of 4-(2-butynyloxy)-6-α-fluoro-α-methylbenzyl)pyrimidine (the present compound (154)) and 0.09 g of 4-(2-butynyloxy)-6-(1-phenylvinyl)pyrimidine (the present compound (155)).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[N:14][NH:15][C:3]=12.[CH3:16]N(C)C=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[C:4](=[CH:13][N:14]([CH3:16])[N:15]=2)[N:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cnc2cn[nH]c2c1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2cn(C)nc2c1Cl

Procedure:
Ethyl 7-chloro-1H pyrazolo[4,3-b]pyridine-6-carboxylate (4.5 g, 0.02 mole) and dimethyl formamide demethylacetal2 (10 ml, 0.04 mole) in dry toluene (200 ml) were heated together under reflux for 1 h. The solvent and excess of reagent were distilled off under reduced pressure to give a brown oil containing two isomers. The 1-methyl3 and 2-methyl isomers were separated by column chromatography on silica gel with ethyl acetate as eluant to give the title compound as a white crystalline solid m.p. 118°-120° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:7][CH2:6]1)=[O:4].[CH3:14][Mg]Br.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[F:13][C:2]([F:1])([F:12])[C:3]([C:5]1([S:8]([NH2:11])(=[O:9])=[O:10])[CH2:7][CH2:6]1)([OH:4])[CH3:14]
Reactant: C[Mg]Br
Reactant: NS(=O)(=O)C1(C(=O)C(F)(F)F)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)(C(F)(F)F)C1(S(N)(=O)=O)CC1
Reaction time: 4 h

Procedure:
Under inert gas, 250 mg 1-(2,2,2-trifluoroacetyl)cyclopropanesulfonamide were initially charged in 6 ml of THF and then, at a temperature of −78° C., 1.15 ml of a 3.0 N methylmagnesium bromide solution in diethyl ether were added dropwise and the mixture was stirred at constant temperature for 4 hours. The reaction solution was admixed with 5 ml of a saturated aqueous ammonium chloride solution and allowed to come to room temperature while stirring. After adjustment to pH 5 with 2 N aqueous hydrochloric acid, the mixture was extracted with 10 ml of ethyl acetate, and the organic phase was dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (208 mg) with a molecular weight of 233.2 g/mol (C6H10F3NO3S); MS (ESI): m/e=234 (M+H+).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][CH:12]=[C:11]([CH2:14]O)[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:11]1[CH:10]=[C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)[S:13][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cc(CO)cs2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2cc(CCl)cs2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-3-yl]-methanol (460 mg, 2.30 mmol) in dry CH2Cl2 (4.6 mL) was treated at 0° C. with Et3N (0.42 mL, 2.99 mmol) followed by DMAP (28 mg, 0.23 mmol) and Ms-Cl (0.21 mL, 2.76 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (20 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a pale yellow oil. TLC:rf (1:4 EA-Hept)=0.35.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[C:4]([F:11])[CH:3]=1.[OH2:12].[CH2:13]([OH:15])[CH3:14]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:15][CH2:13][CH3:14])=[O:12])=[C:4]([F:11])[CH:3]=1
Reactant: CCO
Reactant: N#CCc1ccc(Cl)cc1F
Reactant: O
Product: CCOC(=O)Cc1ccc(Cl)cc1F

Procedure:
Then, 15.1 g of 4-chloro-2-fluorophenylacetonitrile was dissolved in 150 ml of ethanol, to which 10 ml of suiliric acid was added, and the mixture was heated under reflux for 65 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 17.8 g of ethyl 4-chloro-2-fluorophenylacetate.
Reaction SMILES: [NH:1]([CH2:8][C:9]([O:11][CH:12]1[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:29])[NH:24][CH2:25][C:26](O)=[O:27])[CH:19]=[CH:20][CH:21]=1.S(Cl)(Cl)=O.[C:34](=O)([O-])O.[Na+]>ClCCCl.C(Cl)Cl>[CH3:15][C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:29])[NH:24][CH2:25][C:26]([N:1]([CH2:8][C:9]([O:11][CH2:12][CH:14]2[CH2:13][CH2:34]2)=[O:10])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:27])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(CNc1ccccc1)OC1CC1
Reactant: O=C([O-])O
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OCC2CC2)c2ccccc2)c1

Procedure:
A suspension of cyclopropyl 2-anilinoacetate (2.9 g) and 2-[3-(3-methylphenyl)ureido]acetic acid in anhydrous 1,2-dichloroethane (50 cc) is heated to reflux. Thionyl chloride (1.0 cc) is then added, refluxing being maintained until the gaseous evolution has ceased. The reaction mixture is then poured into saturated aqueous sodium hydrogen carbonate solution (30 cc) and thereafter methylene chloride (50 cc) is added. The organic phase is washed with distilled water (50 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in acetonitrile, cyclopropylmethyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate (1.6 g), m.p. 158° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[C-:11]#[N:12].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: [C-]#N
Reactant: ClCc1cccc(Cl)c1Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,3-Dichlorobenzylchloride (5.0 g, 25.5 mmol) was dissolved in 100 ml DMSO. 9.2 g NaCN (188 mmol) were added and the mixture stirred at room temperature for 16 hours. The reaction mixture was diluted with water, and the product extracted with ether. The organic layers were washed with water (2×) and brine, then dried over magnesium sulfate, filtered and concentrated. The product was used as. Crude yield˜quantitative. An analytical sample was purified by column chromatography on silica, using a gradient from 10% to 75% dichloromethane in hexanes as eluent. The combined aqueous layers and wash liquids were treated with 100 ml bleach to oxidize the excess cyanide to less toxic materials.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[N:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:16]1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3ccccc23)C1
Temperature: 100 °C
Yield: 52.5 %

Procedure:
To a 5 mL microwave vial containing 4-chloro-3-nitroquinoline (Ark Pharm, 312.9 mg, 1.500 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 358.9 mg, 1.792 mmol), 1-butanol (3.00 mL) was added followed by DIPEA (405.1 mg, 3.134 mmol). The reaction mixture was heated at 100° C. under microwave irradiation for 2 h. The reaction was then concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a yellow oil (293.5 mg, 53%). LCMS calc. for C19H25N4O4 (M+H)+: m/z=373.2. found 373.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9][CH3:10])=[CH:4][N:3]=1.OO.[OH2:13].C(O)(=[O:16])C>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([CH3:10])(=[O:16])=[O:13])=[CH:4][N:3]=1
Reactant: CSc1cnc(Cl)c(Cl)c1
Reactant: O
Reactant: CC(=O)O
Agent: OO
Product: CS(=O)(=O)c1cnc(Cl)c(Cl)c1
Temperature: 45 °C

Procedure:
6.2 g (0.02 mol) of Na2WO4.2H2O were added to a solution of 73.7 g (0.38 mol) of 2,3-dichloro-5-methylthiopyridine in 380 ml of glacial acetic acid. After the mixture had been heated to 40-50° C., 95 g of hydrogen peroxide (30% strength) were added carefully. Stirring was subsequently continued for a further hour at approximately 20° C. The mixture was then poured into 300 ml of water. The product was separated off from the resulting suspension, washed with water and n-pentane and dried under reduced pressure. Yield: 60 g (70%) as a brown powder; m.p.: 129-130° C.; 1H-NMR (in d6 dimethyl sulfoxide): δ [ppm]=3.4 (s, CH3); 8.7 and 8.9 (2×d, pyr H).
Reaction SMILES: [CH2:1]([C:8]1[S:14][CH:13]2[CH:10]([C:11](=[O:27])[N:12]2[C:15](=[C:24](O)[CH3:25])[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(C1SC2C(C(=O)[N:44]2[C:47](=C(OS(C)(=O)=O)C)[C:48]([O:50][CH2:51][C:52](Cl)(Cl)Cl)=O)N=1)C1C=CC=CC=1.N1CCOCC1>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([C:8]1[S:14][CH:13]2[CH:10]([C:11](=[O:27])[N:12]2[C:15](=[C:24]([N:44]2[CH2:47][CH2:48][O:50][CH2:51][CH2:52]2)[CH3:25])[C:16]([O:18][CH2:19][C:20]([Cl:21])([Cl:22])[Cl:23])=[O:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)=C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C2N=C(Cc3ccccc3)SC21
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCN1
Product: CC(=C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C2N=C(Cc3ccccc3)SC21)N1CCOCC1
Reaction time: 0.67 h

Procedure:
To a solution of 2,2,2-trichloroethyl α-[3-benzyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)-acetate (450 mg) in methylene chloride (7 ml) are added methanesulfonyl chloride (0.093 ml) and triethylamine (0.48 ml) at -25° C., and the mixture is kept at the same temperature for 40 minutes. To the produced solution of 2,2,2-trichloroethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate is added dropwise morpholine (0.112 ml), and the mixture is stirred for 1.3 hours. The reaction mixture is washed with water, dried, and evaporated to give residue which is purified by chromatography over silica gel containing 10% water to give 2,2,2-trichloroethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate (205 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([C@@H:42]5[CH2:46][CH2:45][CH2:44][N:43]5[CH3:47])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([C@@H:42]5[CH2:46][CH2:45][CH2:44][N:43]5[CH3:47])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][O:17][S:58]([CH3:57])(=[O:60])=[O:59])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CO)c4)c4ccccc43)cn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
A solution of Intermediate 149a (200 mg, 0.32 mmol) and DIPEA (164 μL, 0.95 mmol) in DCM (4 mL) was treated with methanesulfonyl chloride (32 μL, 0.41 mmol) and the reaction mixture was stirred at RT for 0.5 h. The mixture was diluted with DCM (5 mL) and washed with water (10 mL) and brine (10 mL). The layers were separated and the organic layer was passed through a phase separator and concentrated in vacuo to afford the title compound as a pale yellow solid (208 mg, 92%). LCMS (Method 3): Rt 3.02 min, m/z 713 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].[C:16]([C:18]1[CH:19]=[C:20]([S:25]([N:28](CC2C=CC(OC)=CC=2OC)[C:29]2[S:33][N:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1F)#[N:17].Cl>CN(C)C(=O)C.O1CCOCC1.CS(C)=O>[C:16]([C:18]1[CH:19]=[C:20]([S:25]([NH:28][C:29]2[S:33][N:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[S:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)#[N:17]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: Fc1ccc(S)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Sc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3,4-Difluorothiophenol (0.101 g, 0.690 mmol) and potassium carbonate (0.200 g, 1.45 mmol) were stirred in N,N-dimethylacetamide (3 mL). After 5 minutes, 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 1, 0.300 g, 0.690 mmol) was added to the reaction mixture and the mixture stirred at ambient temperature overnight. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with a 1M aqueous solution of sodium hydroxide, followed by brine, then dried over MgSO4, filtered and concentrated in vacuo to give a white solid. The solid was then dissolved in 1,4-dioxane and a 4M solution of hydrogen chloride in 1,4-dioxane (3 mL) added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo to give a residue. The residue was solubilised in dimethylsulfoxide (1 mL) and purified by the B-HPLC method to afford the title compound.
Reaction SMILES: C([Al:5]([CH2:10][CH:11]([CH3:13])[CH3:12])CC(C)C)C(C)C.[C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:20]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][Al:5]([O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Product: CC(C)C[Al](Oc1ccccc1-c1ccccc1)Oc1ccccc1-c1ccccc1

Procedure:
In a manner analogous to that described in Example 1, 17.5 g of triisobutylaluminum and 30 g of 2-phenyl-phenol are reacted to give bis(2-biphenylyloxy)isobutylaluminum and this is then reacted with 11.2 g of pyridine-N-oxide-2-thiol to give the title compound. The isolation of the product is carried out in an analogous manner. The yield of bis-(2-biphenylyloxy)(2-pyridinethiolato)aluminum N-oxide is 30.25 g, about 69.9% of theory, of a white finely granular powder with a melting point of 219°-221° C.
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]([OH:13])=O)[N:6]=[C:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:3].C(N(CC)CC)C.[NH2:27][CH:28]1[CH2:34][CH2:33][NH:32][C:30](=[O:31])[CH2:29]1.C(=O)(O)[O-].[Na+]>S(Cl)(Cl)=O.O1CCCC1>[CH2:2]([N:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]([NH:27][CH:28]2[CH2:34][CH2:33][NH:32][C:30](=[O:31])[CH2:29]2)=[O:13])[N:6]=[C:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:3]
Reactant: CCn1cc(C=CC(=O)O)nc1-c1ccccc1
Reactant: NC1CCNC(=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCn1cc(C=CC(=O)NC2CCNC(=O)C2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 422.2 %

Procedure:
β-(1-Ethyl-2-phenylimidazole-4-yl)acrylate hydrochloride (5.49 g, 20.3 mmole) was heated with stirring in thionyl chloride (50 ml) for 50 minutes. After excessive thionyl chloride was completely distilled off under reduced pressure, tetrahydrofuran (50 ml) and triethylamine (4.12 g, 40.7 mmole) were added and then 3-amino-δ-valerolactam (2.79 g, 24.4 mmole) was added to the mixture with cooling, followed by stirring at room temperature overnight. A sodium bicarbonate solution was added to the reaction mixture which was extracted with a chlorofolm-methanol mixed solvent. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel flash chromatography to obtain the titled compound (29 g, 62.3%).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[C:11](Cl)(=[N:13][OH:14])[CH3:12].[O:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[O:16]([C:23]1[CH:24]=[CH:25][C:26]([CH2:12][C:11]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=3)[O:14][N:13]=2)=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CC(Cl)=NO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 3-ethynyl-pyridin-2,6-diamine (170 mg, 28 mmol) described in Manufacturing Example 13-1-3 in anhydrous tetrahydrofuran (10 mL) was added (4-phenoxy-benzene)-acetohydroximoyl chloride (652 mg, 2.49 mmol) described in Manufacturing Example 17-1-4 under nitrogen atmosphere at room temperature. Triethylamine (714 μL, 5.12 mmol) was then added dropwise, and stirred for 1 hour at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:2 then 2:1) to obtain the title compound (314 mg, 68%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].[C:17](Cl)([Cl:19])=[O:18].O>C1(C)C=CC=CC=1>[Cl:19][C:17]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11])=[O:18]
Reactant: O=C(Cl)Cl
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CO
Solvent: Cc1ccccc1
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1COC(=O)Cl
Reaction time: 3 h
Yield: 13 %

Procedure:
A solution of (E)-methyl 2-[2-(hydroxymethyl)phenyl]-3-methoxypropenoate (1 g) in toluene (10 ml) was added slowly to a solution of phosgene in toluene (12.5% w/w, 6.5 ml). After stirring for 3 hours, water (70 ml) was added and the resulting mixture was extracted with diethyl ether. The diethyl ether extract was washed with brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to leave an oil. The oil was purified by chromatography on silica gel, eluting with 30% ethyl acetate/hexane to give (E)-methyl 2-[2-(chloroformyloxymethyl)phenyl]-3-methoxypropenoate (0.163 g, 13%). 1H NMR (CDCl3): 3.7(s,3H), 3.8(s,3H), 4.5(s,2H), 7.1-7.5(m,4H), 7.6(s,1H) ppm. IR (film): 1631, 1707, 1774 cm-1.
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:10]=2[NH2:11])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[S:19][CH:20]=[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:22]=1.[CH2:29]([O:31]C(=O)C)C>>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:21]1[N:22]=[C:18]([NH:17][C:29]([NH:11][C:10]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=2[S:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])=[O:31])[S:19][CH:20]=1)[CH3:28]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(N)c(S(=O)(=O)C2CCCC2)c1
Product: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2S(=O)(=O)C2CCCC2)n1

Procedure:
{2-[3-(2-Cyclopentanesulfonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl{-acetic acid ethyl ester (305 mg, 68%) was prepared from 2-cyclopentanesulfonyl-4-methyl-aniline (239 mg, 1.0 mmol) and ethyl 2-amino-4-thiazolylacetate (186 mg, 1.0 mmol) following the general procedure D.