Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]3[O:20][CH2:21][O:22][C:15]=13)=[CH:10][C:9]([O:23][CH3:24])=[C:8]([O:25][CH2:26][C@@H:27]1[O:29][CH2:28]1)[CH:7]=2)#[N:2].[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:28][C@@H:27]([OH:29])[CH2:26][O:25][C:8]2[CH:7]=[C:6]3[C:11]([C:12]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]5[O:20][CH2:21][O:22][C:15]=45)=[C:3]([C:1]#[N:2])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:23][CH3:24])[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: COc1cc2c(Nc3cccc4c3OCO4)c(C#N)cnc2cc1OC[C@H]1CO1
Reactant: CC(=O)N1CCNCC1
Product: COc1cc2c(Nc3cccc4c3OCO4)c(C#N)cnc2cc1OC[C@H](O)CN1CCN(C(C)=O)CC1
Yield: 35 %

Procedure:
Using an analogous procedure to that described in Example 11, 3-cyano-7-[(2R)-2,3-epoxypropoxy]-6-methoxy-4-(2,3-methylenedioxyanilino)quinoline was reacted with 1-acetylpiperazine to give the title compound in 35% yield; NMR Spectrum: (DMSOd6) 1.96 (s, 3H), 2.34-2.54 (m, 6H), 3.35-3.45 (m, 4H), 3.94 (s, 3H), 4.0-4.1 (m, 2H), 4.13-4.21 (m, 1H), 4.94 (d, 1H), 5.97 (s, 2H), 6.80-6.92 (m, 3H), 7.23 (s, 1H), 7.76 (s, 1H), 8.4 (s, 1H), 9.49 (s, 1H); Mass Spectrum: M+H+ 520.
Reaction SMILES: [OH:1][C:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][S:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>C(#N)C.O>[CH3:20][N:21]([CH3:25])[C:22](=[O:23])[O:1][C:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][S:4][N:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: Oc1nsnc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C)C(=O)Oc1nsnc1Oc1ccccc1
Yield: 95.7 %

Procedure:
In acetonitrile were suspended 0.80 g of 3-hydroxy-4-phenoxy-1,2,5-thiadiazole and 0.46 g of potassium carbonate and after adding 0.36 g of dimethylcarbamoyl chloride to the suspension, the mixture was refluxed for 12 hours. After allowing to cool, the reaction mixture was poured in water and extracted with ether. The ether layer was washed twice each time with a diluted aqueous solution of sodium hydroxide, water, and then a saturated aqueous sodium chloride solution. The ether layer thus washed was dried with anhydrous magnesium sulfate, concentrated, and thereafter purified by silica gel column chromatography to provide 0.85 g of 3-phenoxy-1,2,5-thiadiazol-4-yl N,N-dimethylcarbamate.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][C:13](=[C:17]2[C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.O>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][CH:13]([CH:17]2[C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCC(=C2C(=O)Nc3cc(Cl)ccc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(C2C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Sodium borohydride (1.42 g, 37.5 mmol) (Aldrich) was added in small portions to a solution of rac-4-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-azepane-1-carboxylic acid tert-butyl ester (1.36 g, 3.75 mmol) (from Example 61a supra) in methanol (25 mL) and water (0.5 mL). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give rac-4-(6-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl)-azepane-1-carboxylic acid tert-butyl ester as a white solid (Yield 1.37 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([OH:30])=[CH:19][N:18]=3)=[N:9]2)=[CH:5][CH:4]=1.FC(F)(F)S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([O:30][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:19][N:18]=3)=[N:9]2)=[CH:31][CH:32]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1ccc(Cn2nc(-c3ncc(O)c(Nc4ccncc4)n3)c3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(-c3ncc(OCC(F)(F)F)c(Nc4ccncc4)n3)c3ccccc32)cc1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
143 mg of 2-[1-(4-methoxybenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol (3-2, 0.337 mmol, 1. eq.) were dissolved in 500 μl of dry DMF. Then 117 mg of 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.505 mmol, 1.5 eq.), 93.1 mg of potassium carbonate (0.674 mmol, 2 eq.) and 24 μl of acetonitrile were added. The resulting mixture was stirred at 150° C. for 30 minutes in a microwave. Then the mixture was partitioned between water and dichloromethane/isopropanol 4:1. The phases were separated and the aqueous layer was extracted twice with dichloromethane/isopropanol 4:1. The combined organic layers were washed with brine, dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography and preparative TLC to yield 7.7 mg (0.01 mmol, 3.9%) of the analytically pure target compound.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])[CH:22]=1>>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:35](=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCCCCCCc1cccnc1
Reactant: C(=C(c1ccccc1)c1ccccc1)C1CCNCC1
Product: O=C(CCCCCCCCc1cccnc1)N1CCC(C=C(c2ccccc2)c2ccccc2)CC1
Yield: 86 %

Procedure:
The title compound was prepared in a manner similar to that employed for the compound of Example 10 starting with 7.9 g of 4-(2,2-diphenylethenyl)piperidine and the acid chloride prepared from 8.24 g of 3-pyridinenonanoic acid. The toluene extracts were evaporated and the residue was crystallized from ether to give 12.4 g (73.7%) of 4-(2,2-diphenylethenyl)-1-[1-oxo-9-(3-pyridinyl)nonyl]piperidine, mp 82°-83° C. Analysis Calculated for C33H40N2O: C, 82.46; H, 8.39; N, 5.83. Found: C. 82.76; H. 8.33; N, 5.83.
Reaction SMILES: [NH2:1][CH:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C.[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36](Cl)=[O:37]>C(Cl)Cl>[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36]([NH:1][C@H:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][C@H:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:37]
Reactant: CCOC(=O)C1CN(c2ccccc2)C(=O)C1N
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.2 %

Procedure:
To a solution of the aminopyrrolidinone of Example S (1.54 g, 6.2 mmol) and triethylamine (1.3 ml, 9.3 mmol) in CH2Cl2 (10 ml) was added a solution of 2-naphthoyl chloride (1.18 g, 6.2 mmol) in CH2Cl2 (7 ml) dropwise via syringe. After stirring for 12 h at room temperature the reaction mixture was evaporated in vacuo to give a residue which was chromatographed on silica gel eluting with EtOH/CH2Cl2 (2%-5%) to give the title compound (2.5 g, 100%) as a colorless solid. Anal calcd for C24H22N2O4 : C, 71.63; H, 5.51; N, 6.96. Found C, 71.31; H, 5.45; N, 6.73. MS calcd for C24H22N2O4 402; found 402.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:21][C@H:22]1[NH:27][C@@H:26]([CH3:28])[CH2:25][N:24]([C:29]([C:31]2[C:32]([CH3:38])=[C:33]([CH:36]=O)[NH:34][CH:35]=2)=[O:30])[CH2:23]1>C(O)C.N1CCCCC1>[CH3:28][C@H:26]1[NH:27][C@@H:22]([CH3:21])[CH2:23][N:24]([C:29]([C:31]2[C:32]([CH3:38])=[C:33]([CH:36]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:34][CH:35]=2)=[O:30])[CH2:25]1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3cccc(C(F)(F)F)c3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 27 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-{4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (34.3 mg, 27%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:15](=[C:16]3[C:21]=1[CH:20]=[CH:19][CH:18]=[CH:17]3)[CH:14]=[CH:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=1)[CH3:2].C1C2C=CC3C(=CC([CH:40]=[O:41])=C4C=3C=CC=C4)C=2C=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:6](=[C:7]3[C:12](=[C:13]([CH:40]=[O:41])[CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c3ccccc3ccc2c2ccccc12
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Solvent: ClCCl
Product: CCOc1cc2c3ccccc3c(C=O)cc2c2ccccc12
Yield: 64 %

Procedure:
6-Ethoxychrysene (Cambridge Chemical, Inc., 48 g, 0.176 mol) was formylated according to the procedure outlined in 1A, except that CH2Cl2 (1 L) was used as the reaction solvent. After isolation, the crude material was chromatographed on a plug of SiO2 (500 g) using CH2Cl2 as the eluting solvent to give (after removal of solvent and drying) 33.7 g (64%) of 12-ethoxychrysene-6-carbaldehyde mp 173.5°-176°, (C, H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].[NH:26]1[CH:30]=[C:29]([CH:31]=O)[CH:28]=[N:27]1>C1COCC1>[NH:26]1[CH:30]=[C:29](/[CH:31]=[CH:6]/[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:28]=[N:27]1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cn[nH]c1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cn[nH]c1
Temperature: 70 °C

Procedure:
[(Ethoxycarbonyl)methylene]triphenylphosphorane (0.836 g, 2.4 mmol) was added to a solution of 1H-pyrazole-4-carbaldehyde (0.192 g, 2 mmol) in THF (6 mL) at room temperature. This solution was heated at 70° C. under a nitrogen atmosphere for 8 h.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH:13]=1.[O:14]1CCOCC1.I([O-])(=O)(=O)=O.[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:14])[CH2:10][CH2:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH:13]=1
Reactant: C1COCCO1
Reactant: OC1=CCCSc2ccc(Cl)cc21
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: O=S1CCC=C(O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material is prepared as follows: The solution of 6.4 g of 7-chloro-5-hydroxy-2,3-dihydro-1-benzothiepin in 65 ml of dry methanol and65 ml of dry dioxane is treated dropwise at 0° in 1 hour with the solution of 7.0 g of sodium metaperiodate in 65 ml water. The mixture is stirred at 0° for two hours after the addition period and then allowed to warm to room temperature for overnight. It is filtered and the solid rinsed with 30 ml of methanol. The combined filtrate and wash is concentrated to a smaller volume and treated with 40 ml of water. The mixture is extracted with chloroform, the extract separated, washed with water, dried and evaporated, to yield the 7-chloro-5-hydroxy-2,3-dihydro-1-benzothiepin-1-oxide boiling at 154-157/0.25 mmHg.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:29]([CH3:42])=[C:30]([CH3:41])[C:31]4[O:35][C:34]([CH3:37])([CH3:36])[CH:33](O)[C:32]=4[C:39]=3[CH3:40])[CH2:24][CH2:23]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>CCCCCC.CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]3[C:29]([CH3:42])=[C:30]([CH3:41])[C:31]4[O:35][C:34]([CH3:36])([CH3:37])[CH:33]([N:3]5[CH2:2][CH2:1][C:7]6[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=6[CH2:5][CH2:4]5)[C:32]=4[C:39]=3[CH3:40])[CH2:26][CH2:27]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1OC
Reactant: c1ccc2c(c1)CCNCC2
Solvent: CCCCCC
Solvent: CO
Product: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(N3CCc5ccccc5CC3)C(C)(C)O4)CC2)cc1OC
Yield: 54 %

Procedure:
Using 2,3,4,5-tetrahydro-1H-3-benzazepine and 5-(4-(3,4-dimethoxyphenyl)piperidino)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 19, the title compound was synthesized in the same manner as in Example 57. Yield 54%. mp. 136–138° C. (hexane-methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[C:4]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:5]=[CH:6][C:7]=2[O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:27]=[CH:31][CH:30]=[CH:29]1
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(N)c1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(-n2cccc2)c1
Reaction time: 2 h

Procedure:
5 g (0.016 mmol) of the compound from Example XXIX are dissolved in 70 ml of acetic acid, 2.78 g (0.02 mol) of 2,5-dimethoxytetrahydrofuran are added and the mixture is heated to boiling for 2 hours. After distilling off the acetic acid in vacuo, taking up the residue in 200 ml of dichloromethane, extracting with water, drying with sodium sulphate and concentrating in vacuo to a small volume, the brown oil which remains (6 g) is separated by column chromatography (silica gel 60, eluent: toluene/ethyl acetate=4:1).
Reaction SMILES: [OH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:13][O:14]/[C:15](/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Br)=[CH:16]/[C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C.C(=O)([O-])[O-].[Ag+2]>[CH3:13][O:14]/[C:15](/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][O:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1)=[CH:16]/[C:17]([O:19][CH3:20])=[O:18]
Reactant: Oc1nc(-c2ccccc2)cs1
Reactant: COC(=O)/C=C(/OC)c1ccccc1CBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)/C=C(/OC)c1ccccc1COc1nc(-c2ccccc2)cs1
Yield: 56.2 %

Procedure:
1.2 g (0.007 mol) of 2-hydroxy-4-phenylthiazole, 2.1 g (0.0077 mol) of silver carbonate and 2.1 g (0.0074 mol) of methyl (E)-β-methoxy-2-bromomethylcinnamate (see Example 2) are stirred in 15 ml of DMF at 60° C. for 8 hours. The precipitate is filtered off and the DMF solution is poured into 100 ml of water, and the mixture is extracted with methyl tert-butyl ether. Drying and concentration of the organic phase result in a brown oil which is chromatographed on silica gel with cyclohexane/acetone (95:5). 1.5 g (56% yield) of methyl (E)-β-methoxy-2-(4-phenyl-2-thiazolyloxymethyl)cinnamate as yellowish oil are isolated as the main fraction.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.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>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: OCc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCc1cncc(-c2ccc(F)cc2)c1
Temperature: 85 °C
Yield: 84.4 %

Procedure:
To a solution of 3-bromo-5-hydroxymethyl-pyridine (3.3 g, 17.5 mmol) in toluene (35 ml) was added Pd(PPh3)4 (0.6 g, 0.52 mmol), an aqueous solution of Na2CO3 (17.5 ml of a 2M solution) and p-fluorphenylboronic acid (2.65 g, 19 mmol, dissolved in 8.5 ml EtOH). The mixture was heated at 80-90° C. for 1 hr and vigorously stirred. After the reaction was completed, the biphasic reaction mixture was cooled, the organic layer was collected and washed with saturated NaCl. The aqueous layer was washed with EtOAc and the combined organic layers were dried on Na2SO4. The drying agent was removed by filtration and the solvent was evaporated in vacuo to give a dark oil which was purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH/NH4OH, 95/4.5/0.5) and yielded 3-(p-fluorophenyl)-5-hydroxymethyl-pyridine (3.0 g, 84%). The product was converted into its monohydrochloride salt; the residue was dissolved in Et2O and treated with 16.5 eq of ethanolic HCl. The product 3-(p-fluorophenyl)-5-hydroxymethyl-pyridinium hydrochloride Q4-OH.HCl precipitated as a white solid which was collected by filtration and subsequent drying.
Reaction SMILES: [Cl-].[CH2:2]([N+:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]2[C:18]([CH3:21])=[CH:19][S:20][C:10]=12)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:22][O-:23].[Na+]>CO>[CH2:2]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11](/[C:18](/[CH3:21])=[CH:19]\[S:20][CH3:10])[C:22]1=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[O-]
Reactant: Cc1csc2n1c1ccccc1[n+]2Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CS/C=C(/C)n1c(=O)n(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 94.4 %

Procedure:
200 mg of 9-benzyl-3-methyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium chloride (0.635 mmol) were solubilised in methanol (25 mL), then 137 mg of NaOMe (4 eq) were added and the solution stirred at room temperature. After 48 h the solvent was evaporated, water was added (20 mL) and the mixture extracted with CH2Cl2 (3×20 mL). The organic layer was dried with MgSO4 and evaporated under reduced pressure. The residue was then purified by chromatography on silica gel (eluent: CH2Cl2) to afford 1-benzyl-3-[(1Z)-1-(methylsulfanyl)prop-1-en-2-yl]-1,3-dihydro-2H-benzimidazol-2-one as a colourless oil (186 mg, 94% yield). 1H NMR (300 MHz, CDCl3) δH 2.18 (3H, d, J=1.1, CH3), 2.26 (3H, s, SCH3), 5.10 (3H, s, NCH2), 6.27 (1H, q, J=1.1, H5), 6.84-7.10 (4H, m, arom), 7.25-7.35 (5H, m, arom); 13C NMR (75 MHz, CDCl3) δC 16.90, 20.44, 44.79, 108.50, 109.00, 121.24, 121.48, 126.61, 127.37, 127.57 (2C), 127.65, 127.69, 128.69 (2C), 129.45, 136.22, 152.34; HRMS m/z calcd C18H19N2OS [M+H]+: 311.1212; found: 311.1211.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7]([OH:9])=[O:8].[C:15](Cl)(Cl)=[O:16]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[NH:14][C:15](=[O:16])[O:9][C:7](=[O:8])[C:6]2=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1cc2[nH]c(=O)oc(=O)c2cc1OC
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a mixture of 10.0 g (51.0 mmol) of 4,5-dimethoxyanthranilic acid in 80 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene in toluene, at room temperature. The mixture was stirred overnight. The mixture was concentrated to yield a residue which was triturated with ethyl acetate-hexane (1:4), filtered, washed with hexane and dried to afford 11.0 g (97.2%) of the 4,5-dimethoxyisatoic anhydride as a gray solid. MS (Cl mode) m/z 206 (M-18, 100%), 224 (M+H, 51%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[N:7]=[C:8]([C:12]([C:18]2[S:19][C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)([OH:17])[C:13]([F:16])([F:15])[F:14])[S:9][C:10]=1[CH3:11]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:17][C:12]([C:8]1[S:9][C:10]([CH3:11])=[C:6]([CH3:5])[N:7]=1)([C:18]1[S:19][C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=1)[C:13]([F:15])([F:16])[F:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1nc(C(O)(c2nc(C)c(C)s2)C(F)(F)F)sc1C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(c1nc(C)c(C)s1)(c1nc(C)c(C)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (0.68 ml) was added to a solution of 1,1-bis(4,5-dimethyl-2-thiazolyl)-2,2,2-trifluoroethanol (1.54 g) and 4-dimethylaminopyridine (2 g) in dry dichloromethane (70 ml). The mixture was stirred at room temperature overnight and was then washed with saturated aqueous sodium hydrogen carbonate solution. The organic phase was separated, dried and evaporated and the residue was purified by flash chromatography to give the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([CH:10]([F:12])[F:11])=[N:8][CH:9]=1.CCN(C(C)C)C(C)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>C(Cl)Cl>[F:11][CH:10]([F:12])[C:7]1[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][C:4]([CH2:3][NH:2][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:9][N:8]=1
Reactant: CCOC(=O)c1cc(CN)cnc1C(F)F
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(CNC(=O)C(C)C)cnc1C(F)F
Yield: 73.6 %

Procedure:
In a thermally controlled reactor stir a mixture of ethyl 5-(aminomethyl)-2-(difluoromethyl)pyridine-3-carboxylate hydrochloride (198 g, 742.4 mmol, 1.0 equiv), DCM (3040 mL), and DIPEA (520 mL, 2.98 mol, 4 equiv), then add a solution of isobutyryl chloride (95 mL, 903 mmol, 1.2 equiv) at such a rate so that the internal temperature is held between 18° C. and 22° C. Stir for 90 min. Extract the reaction mixture with NaHCO3 (sat., 1 L). Add water (1 L) and DCM (1 L), and filter the resulting suspension through diatomaceous earth. Combine all organic phases, and dry over MgSO4. Remove the solids by filtration, and concentrate the filtrate under reduced pressure. Purify the resulting material by slurrying with iso-hexane:Et2O [1:1, 1 L]. Collect the solids by filtration, wash with cold iso-hexanes (500 ml), and dry under vacuum at 50° C. to give the title compound as an off-white crystalline powder (164 g). MS (m/z) 301 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:17](O)(=[O:20])[CH:18]=[CH2:19]>CN(C)C=O>[C:17]([NH:9][C:7]([CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)=[O:8])(=[O:20])[CH:18]=[CH2:19]
Reactant: NC(=O)C1CCNCC1
Reactant: C=CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)NC(=O)C1CCNCC1

Procedure:
Into a liquid reaction mixture of 4-piperidinecarboxamide (5.0 mg) and triethylamine (5.3 ml) in dimethylformamide (70 ml), a solution of acrylic acid (3.2 ml) dissolved in dimethylformamide (20 ml) was dropped under ice-cooling over 3 hours. After the completion of the addition, the resultant mixture was stirred at room temperature for 1 hour and then filtered. From the filtrate thus obtained, the solvent was eliminated by using a rotary evaporator. After adding an acetone solution to the residue, the mixture was treated with a silica gel column to give N-acryloyl-4-piperidinecarboxamide (1.4 g).