Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:5]=[CH:4][N:3]=[CH:2]1.[Br-:26].O[CH2:28][CH2:29][CH2:30][P+:31]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br-:26].[N:1]1([CH:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:28][CH2:29][CH2:30][P+:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:19])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCC(CCCCCCCCCCCC(=O)O)n1ccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: [Br-]
Solvent: ClCCl
Product: CCCCCC(CCCCCCCCCCCC(=O)OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)n1ccnc1
Yield: 78.5 %

Procedure:
A stirred solution of 13-(1H-imidazol-1-yl)octadecanoic acid (365 mg, 1.041 mmol), (3-hydroxypropyl)triphenylphosphonium bromide (418 mg, 1.041 mmol) and DMAP (catalytic amount) in DCM (10 ml), was cooled to 0° C., to which was then added DCC (215 mg, 1.041 mmol) under N2 gas, and stirring continued overnight at room temperature. The reaction mixture was filtered and concentrated. The crude product was purified by silica gel column (5% MeOH in DCM) to give TPP-13-ISA as a gummy semi-solid (600 mg, 78%)
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][N:38]=1)[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[CH2:29]([NH:28][C:26](=[O:27])[C:25]1[CH:36]=[CH:37][N:38]=[C:23]([NH:22][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:24]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Agent: O=C(Cl)c1ccccc1F
Product: COc1ccc(C(=O)Nc2cc(C(=O)NCc3ccccc3)ccn2)cc1
Yield: 28 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 4-methoxybenzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(4-methoxybenzamido)isonicotinamide was obtained as a colorless solid in 28% yield: mp 165-166° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 8.65 (s, 1H), 8.38 (d, J=5.2 Hz, 1H), 7.91-7.86 (m, 2H), 7.58 (dd, J=5.2, 1.5 Hz, 1H), 7.34-7.25 (m, 5H), 6.99-6.94 (m, 2H), 6.77 (s, 1H), 4.64 (d, J=5.8 Hz, 2H), 3.86 (s, 3H); MS (ES+) m/z 362.5 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][Cl:6])[CH3:2].Cl.[CH2:10]([N:12]([CH2:16][CH3:17])[CH2:13][CH2:14][Cl:15])[CH3:11].[OH:18][C:19]1[CH:31]=[CH:30][C:29]2[C:28]3[C:23](=[CH:24][C:25]([OH:32])=[CH:26][CH:27]=3)[C:22](=[O:33])[C:21]=2[CH:20]=1.C[O-].[Na+]>C1(C)C=CC=CC=1>[ClH:6].[ClH:15].[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][O:18][C:19]1[CH:31]=[CH:30][C:29]2[C:28]3[C:23](=[CH:24][C:25]([O:32][CH2:14][CH2:13][N:12]([CH2:10][CH3:11])[CH2:16][CH3:17])=[CH:26][CH:27]=3)[C:22](=[O:33])[C:21]=2[CH:20]=1)[CH3:2]
Reactant: O=C1c2cc(O)ccc2-c2ccc(O)cc21
Reactant: CCN(CC)CCCl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN(CC)CCOc1ccc2c(c1)C(=O)c1cc(OCCN(CC)CC)ccc1-2
Reaction time: 3 h

Procedure:
A solution of 2-diethylaminoethyl chloride [obtained from 15.5 g (0.09 mole) of 2-diethylaminoethyl chloride hydrochloride] in 100 ml of toluene (dried over molecular sieves) is added to a mixture of 6.4 g (0.03 mole) of 2,7-dihydroxyfluoren-9-one and 3.3 g (0.06 mole) of sodium methoxide in 200 ml of toluene (dried over molecular sieves). This mixture is heated to reflux with stirring for three hours. Upon cooling, the mixture is filtered to remove the precipitated sodium chloride. The toluene solution is washed three times with water, then once with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. This mixture is filtered, and the filtrate acidified to Congo Red with ethereal hydrogen chloride. The solid which precipitates is filtered, recrystallized from butanone with enough methanol added to effect solution, and the product dried at 100°C for 24 hours under vacuum to give 2,7-bis(2-diethylaminoethoxy)fluoren-9-one dihydrochloride. M.P. 235°-237°C.
Reaction SMILES: [NH2:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:19]([OH:21])=[O:20])=[C:6]([CH2:9][S:10][C:11]3[N:12]=[N+:13]([O-:18])[C:14]([CH3:17])=[CH:15][CH:16]=3)[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+].O.[CH2:30]=[C:31]1[O:35][C:33](=[O:34])[CH2:32]1>CC(C)=O>[C:33]([NH:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:19]([OH:21])=[O:20])=[C:6]([CH2:9][S:10][C:11]3[N:12]=[N+:13]([O-:18])[C:14]([CH3:17])=[CH:15][CH:16]=3)[CH2:7][S:8][C@H:3]12)(=[O:34])[CH2:32][C:31]([CH3:30])=[O:35]
Reactant: C=C1CC(=O)O1
Reactant: Cc1ccc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n[n+]1[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3ccc(C)[n+]([O-])n3)CS[C@H]12

Procedure:
A mixture of 0.354 g. of 7-amino-3-(6-methyl-1-oxidopyridazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid, 0.42 g. of sodium hydrogen carbonate, 5 ml. of water and 5 ml. of acetone is cooled to 5° C and under stirring, 0.2 g. of diketene is added. The mixture is further stirred at room temperature for 30 minutes. The acetone is distilled off under reduced pressure and the residue is washed with ethyl acetate. The water layer is separated, brought to pH 2 with 50 % phosphoric acid, saturated with sodium chloride and extracted three times with ethyl acetate. The extracts are pooled, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated and allowed to stand under cooling with ice. The resultant crystals are loosened with the addition of ether and recovered by suction-filtration. The procedure gives 7-acetoacetamido-3-(6-methyl-1-oxidopyridazin-3-yl) thiomethyl-3-cephem-4-carboxylic acid as crystals melting at 85°-87° C(decomp.). Yield 0.13 g. (30 %).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH:20]([CH3:22])[CH3:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:36][OH:37]>O1CCCC1>[NH3:16].[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH:20]([CH3:22])[CH3:21])[N:16]=2)[CH2:11][C:12]([NH:36][OH:37])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Product: N
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-(3-isopropyl-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 47) (175 mg, 0.57 mmol) in anhydrous tetrahydrofuran (10 ml) was treated with 1,1′-carbonyldiimidazole (93 mg, 0.57 mmol) and the mixture stirred at room temperature under a nitrogen atmosphere for 1 hour. Hydroxylamine hydrochloride (40 mg, 0.57 mmol) was then added and the mixture stirred for 18 hours. The mixture was filtered and the solvent was removed from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (95:5:0.5) to afford the title compound as an oil (44 mg).
Reaction SMILES: [C:1]([NH:11][C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C1C=CC=CN=1)C.[CH3:27][C:28]1([CH3:36])[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH:29]1[NH2:35]>C(Cl)Cl>[CH3:27][C:28]1([CH3:36])[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH:29]1[NH:35][C:15]([C:12]1([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH2:13][CH2:14]1)=[O:17]
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Reactant: CC1(C)CCC(C)(C)C1N
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)C1NC(=O)C1(NC(=O)OCc2ccccc2)CC1
Reaction time: 48 h

Procedure:
To a stirred solution of N-Cbz-1-aminocyclopropanecarboxylic acid in dry CH2Cl2 containing dicyclohexycarbodiimide and dimethylaminopyridine (DMAP), all at 0° C., is added, via an addition funnel, 2,2,5,5-tetramethyl-1-cyclopentyl amine dissolved in CH2Cl2. After stirring for 48 hours, the mixture is filtered, and the filtrate is washed with 5% HCl (1×50 ml), saturated NaHCO3 (1×50 ml), and water (1×50 ml). The organic layer is separated, dried over MgSO4 and evaporated to yield N-Cbz-1-aminocyclopropanecarboxylic acid 2,2,5,5-tetramethylcyclopentyl amide.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:12])[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[C:10]([OH:12])[CH:9]=[CH:8][CH:7]=3)=[O:15])=[CH:21][CH:20]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2cccc(O)c2c1O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cccc(O)c2c1O
Temperature: 180 °C
Yield: 28.4 %

Procedure:
A mixture of 3-aminophenol (5.457 g) and diethyl ethoxymethylenemalonate (10.81 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The reaction is cooled to 80° C. and 50 ml of diphenyl ether is added. The mixture is heated to 250° C. for 30 min with removal of ethanol by a Dean-Stark trap. The solution is cooled to 80° C. and the resulting solid is collected and washed with hexanes. A portion of this solid is adsorbed onto silica and chromatographed, eluting with 5% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo to yield ethyl 4,5-dihydroxyquinoline-3-carboxylate as a gold solid. A mixture of this ester (0.125 g) and 4-chlorobenzylamine (0.379 g) are heated to 180° C. for 1 h. The solution is cooled to room temperature. The crude reaction is chromatographed on silica, eluting with 2% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo. The residue is sonicated with CH2Cl2 /hexanes. The resulting solid is collected and dried to yield 0.050 g of the desired product as a pale-yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][CH2:13][O:14][CH3:15])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CN(C)C=O>[C:4]([C:3]1[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][O:14][CH3:15])[CH:8]=[CH:9][C:2]=1[O:1][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:5]
Reactant: COCOCCc1ccc(O)c(C#N)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(CCOCOC)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-hydroxy-5-(2-methoxymethoxyethyl)benzonitrile (496 mg) in N,N-dimethylformamide (5 ml) were added potassium carbonate (435 mg) and ethyl bromoacetate (292 μl), and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, and removal of the solvent under reduced pressure gave ethyl 2-[2-cyano-4-(2-methoxymethoxyethyl)phenoxy]acetate (619 mg). To a solution of the obtained ethyl 2-[2-cyano-4-(2-methoxymethoxyethyl)phenoxy]acetate (522 mg) in ethanol (5 ml) was added concentrated hydrochloric acid (20 μl), and the mixture was stirred for 2 hours at 70° C. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, and removal of the solvent under reduced pressure gave ethyl 2-[2-cyano-4-(2-hydroxyethyl)phenoxy]acetate (449 mg).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[C:6]([N:15]([CH2:26][CH:27]=[CH2:28])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:5]=1.[Li+].[OH-]>CO.O.Cl.C(Cl)Cl>[CH2:26]([N:15]([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=1)[C:3]([OH:29])=[O:2])[CH:27]=[CH2:28]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cc(C(=O)OC)cc(-c2ncco2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: C=CCN(C(=O)OCc1ccccc1)c1cc(C(=O)O)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(Allyl-benzyloxycarbonyl-amino)-5-oxazol-2-yl-benzoic acid methyl ester (300 mg, 757 μmol, 1 eq) is dissolved in methanol (10 ml) and H2O (4 ml). LiOH*H2O (100 mg, 2.37 mmol, 3.13 eq) is added to the reaction mixture, which is stirred for 8 h at rt and then diluted with HCl (1N in H2O) and DCM. The combined organic solvents are separated and washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting crystals are washed with hexane and dried under vacuum to give the product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].I[CH2:9][CH2:10][CH2:11][Si:12]([O:17][CH3:18])([O:15][CH3:16])[O:13][CH3:14].ClCCl>O1CCCC1>[CH3:14][O:13][Si:12]([CH2:11][CH2:10][CH2:9][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)([O:17][CH3:18])[O:15][CH3:16]
Reactant: CO[Si](CCCI)(OC)OC
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[Si](CCCc1ncc[nH]1)(OC)OC
Reaction time: 4 h

Procedure:
5 g (73 mmol) of imidazole were dissolved in 100 ml of tetrahydrofurane and 1.73 g (73 mmol) of sodium hydride were added. The suspension was stirred for 4 hours, after which 10 ml of iodopropyltrimethoxy silane (52 mmol) were added and the reaction mixture was heated under reflux for 18 hours. 15 ml of dichloromethane were then added and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and the product was distilled off at 150-155° C. at 8 mbar. The yield was 8.2 g (60%).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:5]=1[C:6]([OH:8])=[O:7].[C:15](Cl)(Cl)=[O:16]>O.C1(C)C=CC=CC=1>[CH3:14][O:13][C:9]1[C:5]2[C:6](=[O:8])[O:7][C:15](=[O:16])[NH:3][C:4]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(N)c1C(=O)O
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2[nH]c(=O)oc(=O)c12
Temperature: 0 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A solution of NaOH (6.6 g, 165 mmol) in water (300 mL) was treated with 2-amino-6-methoxylbenzoic acid (10 g, 59.9 mmol); cooled to 0° C., treated dropwise with a 20% wt solution of phosgene in toluene (75 mL), stirred overnight at room temperature and filtered. The filter cake provided 10.5 g of the desired product (yield: 91.0%). 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 6.65 (d, 1H), 6.80 (d, 1H), 7.65 (t, 1H), 11.58 (br s, 1H); MS (ESI(−) m/e 192 (M−H)−.
Reaction SMILES: [Na].[C:2]([NH:10]O)(=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:13][C:14]([OH:16])=[O:15].Cl>C(O)C.O>[CH2:2]([NH:10][CH2:13][C:14]([OH:16])=[O:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CCl
Reactant: O=C(NO)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(O)CNCc1ccccc1
Reaction time: 3 h

Procedure:
9.2 Grams (0.4 moles) of metallic sodium was dissolved in 300 ml of absolute ethanol. To the resulting solution, a solution of 27 g (0.2 moles) of benzhydroxamic acid in 600 ml of absolute ethanol was added dropwise 20°-25° C. with stirring for 3 hours. Subsequently, a solution of 9.5 g (0.1 mole) of chloroacetic acid in 100 ml of absolute ethanol was added dropwise and the resulting mixture wa stirred at 50° C. for 8 hours. After cooling the mixture, water was added and the mixture was neutralized with concentrated HCl. Ethanol was distilled off under vacuum and the pH of the residue was adjusted to 1 by addition of concentrated HCl. The precipitating crystal was recovered by filtration and dried to obtain benzamidooxyacetic acid in an amount of 8.2 g (yield, 42 mol %).
Reaction SMILES: CS(C)=O.[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([CH2:20][OH:21])[CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>O>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[CH:20]=[O:21])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cc(CO)cc(OCc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C=O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A mixture of a sulfur trioxide-pyridine complex (2.113 g) and dimethyl sulfoxide (10 mL) was added dropwise to a mixture of (3-(benzyloxy)-5-methylphenyl)methanol (1.01 g), triethylamine (3.08 mL), and dimethyl sulfoxide (5 mL) at room temperature, and the obtained mixture was stirred overnight at room temperature. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with 1 M hydrochloric acid and brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (0.948 g).
Reaction SMILES: S1C2C=CC=CC=2N=C1.[CH3:10][CH2:11][N:12]1[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[S:21]/[C:22]/1=[CH:23]\C(C)=O.COC1C=CC2SC(C)=NC=2C=1.C([I:41])C>>[I-:41].[CH2:11]([N+:12]1[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[S:21][C:22]=1[CH3:23])[CH3:10]
Reactant: CCI
Reactant: CCN1/C(=C/C(C)=O)Sc2ccc(OC)cc21
Agent: COc1ccc2sc(C)nc2c1
Agent: c1ccc2scnc2c1
Product: CC[n+]1c(C)sc2ccc(OC)cc21
Product: [I-]
Yield: 71.9 %

Procedure:
A series of benzothiazole compounds including TG003 were synthesized according to the procedures reported by Gupta et al. (27). In the case of TG003, a mixture of commercially available 5-methoxy-2-methylbenzothiazole (202 mg, 1.12 mmol) and ethyl iodide (2.70 ml, 33.7 mmol) was refluxed for 24.5 h. The precipitate was filtrated, washed with ethyl acetate (20 ml) on a funnel, and dried under reduced pressure to afford 3-ethyl-5-methoxy-2-methylbenzothiazolium iodide (270 mg, 0.805 mmol, 71.9%) as a pale green solid. To a suspension of 3-ethyl-5-methoxy-2-methylbenzothiazolium iodide (502 mg, 1.49 mmol) in acetonitrile (2.0 ml), acetic anhydride (330 μl, 3.49 mmol) and triethylamine (490 μl, 3.51 mmol) were successively added at room temperature. After refluxing for 2 h, the mixture was cooled to room temperature and concentrated under reduced pressure. Water (50 ml) was added to the residue, and the mixture was extracted with ethyl acetate (three times with 15 ml). The combined organic extracts were washed with brine (30 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (18 g, CH2Cl2/ethyl acetate, 4:1) to afford (Z)-1-(3-ethyl-5-methoxy-2,3-dihydrobenzothiazol-2-ylidene) propan-2-one (TG003) (201 mg, 0.806 mmol, 54.1%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH:13](OS(C)(=O)=O)[CH3:14])[CH2:9]2)=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.ClC1C=CC(N2CCC(C(OS(C3C=CC(C)=CC=3)(=O)=O)C)C2)=C([N+]([O-])=O)C=1.[N-:51]=[N+:52]=[N-:53].[Na+]>CN(C)C=O.O>[N:51]([CH:13]([CH:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N+:20]([O-:22])=[O:21])[CH2:9]1)[CH3:14])=[N+:52]=[N-:53]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)C1CCN(c2ccc(Cl)cc2[N+](=O)[O-])C1
Agent: Cc1ccc(S(=O)(=O)OC(C)C2CCN(c3ccc(Cl)cc3[N+](=O)[O-])C2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(N=[N+]=[N-])C1CCN(c2ccc(Cl)cc2[N+](=O)[O-])C1
Temperature: 80 °C
Yield: 88.3 %

Procedure:
A mixture of methanesulfonic acid 1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethyl ester (285.9 mg), toluene-4-sulfonic acid 1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethyl ester (55.2 mg) and sodium azide (185 mg) in N,N-dimethylformamide (ca. 5 mL) was heated at 80° C. overnight. The reaction mixture was cooled, diluted with water and extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 90/10) to give 214 mg (76% yield) of 3-(1-azido-ethyl)-1-(4-chloro-2-nitro-phenyl)-pyrrolidine.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[F:26])=[C:16]([C:27](OCC)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[F:26])=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1cc(Cl)ccc1F
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 39.4 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(5-chloro-2-fluorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (1.82 g, 3.87 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (0.88 g, 4.89 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (0.92 g, 47%) was obtained.
Reaction SMILES: N1CCC[CH2:2]1.CC(=O)CC.[C-]#N.[K+].[CH3:14][C:15]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)([CH3:18])[C:16]#[N:17]>O>[CH3:14][C:15]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)([CH2:18][CH3:2])[C:16]#[N:17]
Reactant: C1CCNC1
Reactant: CC(C)(C#N)N1CCCC1
Agent: [C-]#N
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCC(C)(C#N)N1CCCC1
Yield: 63 %

Procedure:
The title compound (9.6 g, 63%) was prepared from pyrrolidine (8.35 ml, 0.1 mol), 2-butanone (8.96 g, 0.1 mol) and potassium cyanide (6.51 g, 0.1 mol) in water (50 ml) in a similar manner to that described in D4. 1H NMR (CDCl3) δ: 1.06 (3H, t, J=7.2 Hz), 1.45 (3H, s), 1.66-1.93 (6H, m), 2.70-2.75 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[CH3:11].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl>ClCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:22][O:23][CH3:24])[C:5]=1[CH3:11]
Reactant: COCCl
Reactant: COC(=O)c1cccc(O)c1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(C(=O)OC)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.5 %

Procedure:
3-Hydroxy-2-methylbenzoic acid methyl ester (0.5 g, 3.01 mmol) in dichloromethane (15 ml) and N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was cooled to 0° C. under nitrogen. Chloromethyl methyl ether (0.46 ml, 6.02 mmol) was added dropwise and the reaction allowed warming to room temperature over a period of 18 hours. The reaction was judged to be 50% complete by tlc (1:2 ethyl acetate/hexanes, 12) and therefore, N,N-diisopropylethylamine (1.57 ml, 9.03 mmol) was added, the reaction mixture cooled to 0° C. and chloromethyl methyl ether (0.46 ml, 6.02 mmol) added once more. The reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction was quenched with water and the layers separated. The aqueous layer was extracted once with dichloromethane and the organic layers combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (20% ethyl acetate/hexanes) affording 0.44 g (69%) of 3-methoxymethoxy-2-methyl-benzoic acid methyl ester as an oil.