Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:19]([O:21][CH2:22][CH2:23][CH3:24])[CH3:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].Cl>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:19]([O:21][CH2:22][CH2:23][CH3:24])[CH3:20])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: CCCOC(C)CCc1ccc(-c2ccc(OC(C)=O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOC(C)CCc1ccc(-c2ccc(O)cc2)cc1
Yield: 101.5 %

Procedure:
2.6 g (8 mM) of the thus-obtained (-)-4-acetoxy-4'-(3-propoxybutyl)biphenyl was dissolved in 50 ml of methanol, added thereto with 10 ml of 20% NaOH aqueous solution, and then stirred at room temperature for 2 hrs. After completion of the reaction, the reaction mixture was made to pH 2-3 by adding 1N hydrochloric acid, and then further added thereto with 100 ml of ethyl acetate, and thereafter subjected to extraction treatment. The resulting organic layer was water-washed, and then concentrated under a reduced pressure to obtain 2.3 g of 4-hydroxy-4'-(3-propoxybutyl)biphenyl (V-47) with 100% yield [[α]D20 =-9.4° (C=1, CHCl3), nD20 =1.3462.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.CN(C)CCCN=C=NCC.ON1C(=O)CCC1=O.[CH2:31]([NH:34][CH2:35][CH2:36][CH3:37])[CH2:32][CH3:33].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:34]([CH2:35][CH2:36][CH3:37])[CH2:31][CH2:32][CH3:33])=[O:7]
Reactant: CCCNCCC
Reactant: O=C(O)c1ccc(F)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1ccc(F)c(Br)c1

Procedure:
Combine 3-bromo-4-fluorobenzoic acid (5.0 g, 22.8 mmol) with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (4.4 g, 22.8 mmol) and N-hydroxy-succinimide (2.6 g, 22.8 mmol) in dichloromethane (75 mL) and stir at room temperature for 30 min. Add N,N-dipropylamine (4.7 mL, 34.3 mmol) and triethylamine (8.0 mL, 57.1 mol) and stir at room temperature overnight. Dilute with ethyl acetate and wash with 1 N HCl, saturated aqueous potassium carbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].S(OCC)(O[CH2:13][CH3:14])(=O)=O>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:13][CH3:14]
Reactant: Oc1ccccc1Br
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccccc1Br
Temperature: 25 °C

Procedure:
A mixture of 17.5 g of 2-bromophenol, 66 ml of diethyl sulphate and 170 ml of 10% NaOH solution is refluxed for 2 hours. After cooling the reaction mixture to RT, it is extracted with EtOAc, the organic phase is washed with 2N NaOH solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. 19.6 g of the expected product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].CI.[C:21](O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]([CH3:21])[C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)O
Reactant: COc1cccc(C2CCCCNC2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(C2C=CC=CN(C)C2=O)c1
Temperature: 5 °C

Procedure:
Hexahydro-3-(3-methoxyphenyl)-2H-azepin-2-one (2.2 g) in dry toluene (40 ml) was added dropwise to a stirred suspension of sodium hydride (0.62 g, 0.015 mole of 50% dispension in oil, pre-washed with dry light petroleum (b.p. 40°-60°). After stirring and heating at 60° for 1 hour the reaction was cooled to 5° C. and methyl iodide (1.9 ml, 2.5 g, 0.02 mole) was added rapidly. After stirring at ambient temperature for 20 hours acetic acid and water were added. The aqueous layer was separated and washed with toluene. Toluene extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated to an oil. Oil was recrystallised from ethylacetate light petroleum (b.p. 60°-80°) affording 1.95 g (83%) of hexahydro-(3-(3-methoxyphenyl)-1-methyl-2H-azepin-2-one, in several crops, m.p. 74°-5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][CH:9]2[C:20](=[O:21])[NH:19][CH2:18][CH2:17][NH:16][C:15](=[O:22])[CH2:14][N:13](C(=O)C(F)(F)F)[C:12](=[O:29])[CH2:11][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+]>>[N+:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][CH:9]2[C:20](=[O:21])[NH:19][CH2:18][CH2:17][NH:16][C:15](=[O:22])[CH2:14][NH:13][C:12](=[O:29])[CH2:11][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CN(C(=O)C(F)(F)F)C(=O)CNC(Cc2ccc([N+](=O)[O-])cc2)C(=O)NCCN1
Agent: [Na+]
Agent: [OH-]
Product: O=C1CNC(=O)CNC(Cc2ccc([N+](=O)[O-])cc2)C(=O)NCCN1

Procedure:
The aforementioned free amino acylation affords 3-(4-nitrophenyl)-2-hydroxy-N-(trifluoroacetylglycylglycyl-2-aminoethyl)propionamide. The hydroxyl group of 3-(4-nitrophenyl)-2-hydroxy-N-(trifluoroacetylglycylglycyl-2-aminoethyl)propionamide is tosylated with TsCl in pyridine to give 3-(4-nitrophenyl)-2-(p-toluenesulfonyl)-oxy-N-(trifluoroacetylglycylglycyl-2-aminoethyl)-propionamide. The trifluoroacetylamide group of 3-(5-nitrophenyl)-2-(p-toluenesulfonyl)-oxy-N-(trifluoroacetylglycylglycyl-2-aminoethyl)-propionamide is deprotonated with sodium hydride and cyclized to give 2-(4-nitrobenzyl)-3,8,11-trioxo-N-trifluoroacetyl-1,4,7,10-tetraazadodecane. The trifluoroacetyl group of 2-(4-nitrobenzyl)-3,8,11-trioxo-N-trifluoroacetyl-1,4,7,10-tetraazacyclododecane is cleaved with sodium hydroxide to afford a triamide product, 2-(4-nitrobenzyl)-3,8,11-trioxo-1,4,7,10-tetraazacyclododecane. The triamide is reduced with borane to give 2-(p-nitrophenyl)-1,4,7,10-tetraazacyclododecane. Conversion of this product to nitro-benzyl-DOTA is accomplished via the procedure discussed in the Renn et al. article referenced above or as discussed in subsections A and C set forth above.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([N:13]([CH2:18][CH3:19])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][N:10]2[N:20]=[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:22]([C:23](=[O:26])[NH:24][CH3:25])=[C:9]2[CH:8]=1)(=O)=O.[CH3:36][C:37]1[CH:54]=[CH:53][C:40]([C:41]([NH:43][C:44]2([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[CH2:46][CH2:45]2)=[O:42])=[CH:39][C:38]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH2:18]([N:13]([C:12]1[C:7]([C:38]2[CH:39]=[C:40]([C:41](=[O:42])[NH:43][C:44]3([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=4)[CH2:45][CH2:46]3)[CH:53]=[CH:54][C:37]=2[CH3:36])=[CH:8][C:9]2[N:10]([N:20]=[C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:22]=2[C:23]([NH:24][CH3:25])=[O:26])[CH:11]=1)[S:14]([CH3:17])(=[O:15])=[O:16])[CH3:19]
Reactant: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1OS(=O)(=O)C(F)(F)F)S(C)(=O)=O
Reactant: Cc1ccc(C(=O)NC2(c3ccccn3)CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1-c1cc(C(=O)NC2(c3ccccn3)CC2)ccc1C)S(C)(=O)=O
Temperature: 90 °C

Procedure:
6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl trifluoromethanesulfonate (0.07 g, 0.13 mmol, 1 eq), 4-methyl-N-(1-(pyridin-2-yl)cyclopropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.054 g, 0.14 mmol, 1.1 eq), tetrakistriphenylphosphine palladium (0.0045 g, 0.0039 mmol, 0.03 eq) and cesium carbonate (0.12 g, 0.39 mmol, 3 eq) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). Nitrogen gas was passed through the solution and the reaction was heated at 90° C. for 14 h. The solution was filtered through celite. Water was added to the filtrate which was then extracted with ethyl acetate. The organic layer was concentrated and the residue obtained purified by Preparative HPLC. Yield: 22 mg (26%). 1HNMR (400 MHz, CD3OD): δ 1.12 (broad s, 3H), 1.35 (s, 2H), 1.66 (s, 2H), 2.34 (s, 3H), 2.85 (s, 3H), 3.00-3.32 (br, 3H), 3.51 (br, 2H), 7.13 (m, 1H), 7.24 (m, 2H), 7.46 (m, 2H), 7.68 (m, 1H), 7.97 (m, 4H), 8.0 (s, 1H), 8.41-8.42 (d, J=4 Hz, 1H), 8.92 (s, 1H). LCMS: (ES+) m/z=641.2 (M+H) Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm); Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH; Mphase B: 98% MeCN—2% H2O-10 mM NH4COOH Flow: 1 mL/Min; RT min: 1.796; Wavelength: 220 nm. HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron; Buffer: 0.05% TFA in water pH 2.5; Mobile Phase A: Buffer:MeCN (95:5); Mobile Phase B: MeCN:Buffer (95:5); FLOW: 1 ml/min; Wavelength: 254 nm, RT min: 8 675; Purity: 96.6%.
Reaction SMILES: [OH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29](Cl)=[O:30].CC#N>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29]([O:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19])=[O:30]
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)=NC1O
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: ClCCl
Product: O=C(OC1N=C(c2ccccc2)c2ccccc2NC1=O)c1cc2ccccc2[nH]1
Reaction time: 16 h
Yield: 63.5 %

Procedure:
1,3-Dihydro-3-(RS)-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one (100 mg, 0.398 mmol) was dissolved in CH2Cl2 (10 ml), treated with indole-2-carbonyl chloride (78.6 mg, 0.438 mmol) and 4-dimethylaminopyridine (DMAP, 53.5 mg, 0.438 mmol) and stirred 16 hrs. at 25° C. A second portion of indole-2-carbonylchloride (78.6 mg, 0.438 mmol and DMAP (53.5 mg, 0.438 mmol) was added and the reaction stirred an additional 24 hrs. Chromatography of the reaction mixture on silica gel (1% MeOH in CH2Cl2) gave the title compound (100 mg) as a white solid from MeCN: (m.p. 271°-273°).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1.Cl.[CH3:28][NH:29][CH3:30].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[C:21]([C:24]([N:29]([CH3:30])[CH3:28])=[O:25])[CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1
Reactant: CNC
Reactant: O=C(O)c1ccc2c(c1)CCCN(c1cc(Cl)c3cc(Cl)ccc3n1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc2c(c1)CCCN(c1cc(Cl)c3cc(Cl)ccc3n1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
The mixture of 2-(4,6-dichloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine-7-carboxylic acid (135 mg, 0.35 mmol), dimethylamine hydrochloride (34.2 mg, 0.42 mmol), triethylamine (105 mg, 1.05 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (159 mg, 0.42 mmol) and 5 mL of dichloromethane was stirred at room temperature overnight under nitrogen. The reaction was diluted with ethyl acetate (20 mL), washed with water and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography to give 133 mg of product as a white solid. (yield was 92%). MS obsd. (ESI+) [(M+H)+] 414.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:30]3[CH2:35][CH2:34][CH:33]([O:36][C:37]4[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=4[F:45])[CH2:32][CH2:31]3)=[C:20]([NH:25][CH:26]3[CH2:29][CH2:28][CH2:27]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[CH:26]1([NH:25][C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]3=[N:18][C:19]=2[N:30]2[CH2:31][CH2:32][CH:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=3[F:45])[CH2:34][CH2:35]2)[CH2:29][CH2:28][CH2:27]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CCN(Cc3ccccc3)C4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CCNC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-benzyl-N-cyclobutyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (85.2 mg, 0.135 mmol) and Pd(OH)2 on carbon (10 mg, 0.071 mmol) in THF (674 μL) was stirred at rt under an atmosphere of hydrogen gas (balloon). After 4 h, the mixture was filtered, washing with MeOH, and concentrated to afford the title compound as its TFA salt (73 mg, 100%) as a yellow solid, which was used without further purification. ESI-MS m/z [M+H]+ 428.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[OH:25][CH:26]1[CH:31]([CH2:32][CH2:33][OH:34])[C:30]2[CH:35]=[CH:36][C:37]([C:39]([CH3:47])([CH3:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:38][C:29]=2[O:28][C:27]1([CH3:49])[CH3:48].C(N(CC)CC)C.[C:57](OC(=O)C)(=[O:59])[CH3:58]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[C:57]([O:25][CH:26]1[CH:31]([CH2:32][CH2:33][OH:34])[C:30]2[CH:35]=[CH:36][C:37]([C:39]([CH3:47])([CH3:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:38][C:29]=2[O:28][C:27]1([CH3:48])[CH3:49])(=[O:59])[CH3:58]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCC(C)(C)c1ccc2c(c1)OC(C)(C)C(O)C2CCO
Agent: CN(C)c1ccncc1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(C)(C)c1ccc2c(c1)OC(C)(C)C(OC(C)=O)C2CCO
Temperature: 0 °C

Procedure:
A solution of 3.48 g (0.01 mole) dl-5-hydroxy-4-(2-hydroxyethyl)-2,2-dimethyl-7-(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran in 50 ml methylene chloride and containing 1.01 g (0.01 mole) triethylamine is cooled to 0° C. while stirring in a nitrogen atmosphere. To this is added a solution of 1.22 g (0.01 mole) 4-dimethylaminopyridine in 5 ml of methylene chloride followed by 1.02 g (0.01 mole) acetic anhydride. After stirring at 0°-5° C. for one hour, the mixture is allowed to warm to room temperature, extracted with methylene chloride and the extracts washed with sodium bicarbonate. After drying over anhydrous magnesium sulfate and evaporation of solvent, the desired product is obtained. It can be purified by column chromatography on silica gel if desired.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C@H:6]([OH:8])[C@@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[O:12]=[C:13]1[CH:18]([C:19](OCC)=[O:20])[CH2:17][CH2:16][CH2:15][NH:14]1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[O:12]=[C:13]1[CH:18]([C:19]([O:8][C@H:6]2[CH2:7][C@@H:2]([CH3:1])[CH2:3][CH2:4][C@@H:5]2[CH:9]([CH3:11])[CH3:10])=[O:20])[CH2:17][CH2:16][CH2:15][NH:14]1
Reactant: CCOC(=O)C1CCCNC1=O
Reactant: CC1CC[C@H](C(C)C)[C@@H](O)C1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)[C@H]1CC[C@H](C)C[C@@H]1OC(=O)C1CCCNC1=O
Temperature: 25 °C

Procedure:
4-Dimethylaminopyridine (0.35 wt), (+)-menthol (0.95 wt) and ethyl 2-oxo-3-piperidinecarboxylate (1 wt) are dissolved/suspended in toluene (10 vol). The mixture is heated to reflux and stirred for seven days with periodic distillation of solvent and replenishment with fresh toluene. The reaction mixture is cooled to 25° C. and washed with two portions of 5% w/w aqueous HCl (4 vol) and then water (4 vol). The organic phase is concentrated under reduced pressure to give the title compound as a colourless oil.
Reaction SMILES: [CH2:1]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][N:19]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].S(Cl)([Cl:29])=O>>[CH2:1]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[CH:22][C:21]([C:24]([Cl:29])=[O:26])=[CH:20][N:19]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1ccc(-c2ncc(C(=O)O)cn2)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCCc1ccc(-c2ncc(C(=O)Cl)cn2)cc1

Procedure:
2-(4-n-Undecylphenyl)pyrimidine-5-yl-carboxylic acid (1.7 g) was heated together with excess thionyl chloride for 4 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 2-(4-n-undecylphenyl)pyrimidine-5-yl-carboxylic acid chloride.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11](/[C:13](=[N:17]/[O:18][CH3:19])/[C:14]([OH:16])=O)[N:12]=1)=[O:6])[CH:2]=[CH2:3].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[Cl-].[CH2:39]([O:46][C:47]([C:49]1[CH2:56][N:55]2[N:51]([C:52](=[O:58])[CH:53]([NH2:57])[CH2:54]2)[C:50]=1[C:59]([O:61][CH2:62][CH:63]=[CH2:64])=[O:60])=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl.C(OCC)(=O)C>[CH2:39]([O:46][C:47]([C:49]1[CH2:56][N:55]2[N:51]([C:52](=[O:58])[CH:53]([NH:57][C:14](=[O:16])/[C:13](/[C:11]3[N:12]=[C:8]([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[S:9][CH:10]=3)=[N:17]\[O:18][CH3:19])[CH2:54]2)[C:50]=1[C:59]([O:61][CH2:62][CH:63]=[CH2:64])=[O:60])=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C=CCOC(=O)Nc1nc(/C(=N/OC)C(=O)O)cs1
Reactant: C=CCOC(=O)C1=C(C(=O)OCc2ccccc2)CN2CC(N)C(=O)N12
Agent: COc1nc(Cl)nc(OC)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CCOC(=O)Nc1nc(/C(=N/OC)C(=O)NC2CN3CC(C(=O)OCc4ccccc4)=C(C(=O)OCC=C)N3C2=O)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
Under a nitrogen atmosphere, 2-[2-(allyloxycarbonylamino)thiazol-4-yl]-2-(Z)-methoxyiminoacetic acid (231 mg, 0.81 mmol) was suspended in methylene chloride (5 ml) and the suspension was cooled to 0° C. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (142 mg, 0.81 mmol) followed by N-methylmorpholine (0.09 ml, 0.81 mmol) were added and the solution was stirred at 0° C. for 30 minutes. A methylene chloride solution (10 ml) of allyl 3-(benzyloxycarbonyl)-7-(R,S)-amino-8-oxo-1,5-diazabicyclo[3.3.0]octa-2-ene-2-carboxylate chloride (0.81 mmol) followed by additional N-methylmorpholine (0.09 ml, 0.81 mmol) were added and the solution was stirred and allowed to warm gradually to room temperature over 1.5 hours. The methylene chloride was removed in vacuo and the resultant residue was flash chromatographed on silica gel eluted with 10% hexane:ethyl acetate to give 340 mg, 67% yield of the title compound: n.m.r. (90 MHz, CDCl3): δ 3.08 (dd, J=10.8 and 10.8, 1), 3.96 (s, 3), 3.99, 4.43 (ABq, J=12.6, 2), 3.88-4.28 (m, 2), 4.56-4.92 (m, 4), 5.16 (s, 2), 5.23 (d, J=9, 2), 5.42 (d, J=10.8, 2), 5.50-6.16 (m, 2), 7.10 (s, 1), 7.28 (br. s, 5), 8.09 (br. d, 1), 9.38 (br. s, 1); i.r. (CDCl3): 3025, 1731, 1704, 1557, 1386, 1369, 1277 cm-1 ; f.d.m.s. (m/e): M+ +1=625; u.v. (EtOH): εmax =264 (ε=10926), 338 (ε=6493); Anal. Calcd for C28H28N6O9S1 : Theory: C, 53.84; H, 4.52; N, 13.45; Found: C, 53.68; H, 4.59; N, 13.21.
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][CH2:9][CH:10]=[CH2:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.[Li]CCCC>C1(C)C=CC=CC=1.C1COCC1>[CH2:8]([C:3]1[C:2]([B:12]([OH:17])[OH:13])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCc1ncccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCCc1ncccc1B(O)O
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a stirring solution of 3-bromo-2-(but-3-en-1-yl)pyridine (Ref. Zhang, Z; Dwoskin, L. and Crooks, P. Tetrahedron Lett. 2011, 52, 2667-2669, 550 mg, 2.59 mmol) and triisopropyl borate (0.775 mL, 3.37 mmol) in toluene (4 mL) and THF (1 mL) cooled to −78° C. was added 2.5 M n-BuLi (1.349 mL, 3.37 mmol) over the course of 15 min. During this time period, the reaction color changed from yellow to orange. The reaction was stirred at −78° C. for 2 h then warmed to 0° C. for 15 min. It was then quenched with 2 N HCl (5 mL) and stirred for 10 min. The solution became a slurry (pH was found to be 3). It was then diluted with ether, the ether layer was discared. The aqueous layer was adjusted pH=7-8. A white cloud was formed. It was then extracted with EtOAc, the organic layer was dried over MgSO4, filtered and concentrated to obtain 450 mg (98%) of the desired product as a white foam. LCMS (M+1)=178.1.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[N:22][C:21]1=[O:27])[C@H:9]([O:11][Si](C(C)(C)C)(C)C)[CH3:10])(C)(C)C.CN(C=O)C.C(OC(=O)C)(=O)C>C(N(CC)CC)C>[NH2:26][C:23]1[CH:24]=[CH:25][N:20]([CH2:19][C@H:8]([C@H:9]([OH:11])[CH3:10])[CH2:7][OH:6])[C:21](=[O:27])[N:22]=1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1ccc(N)nc1=O
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](O)[C@H](CO)Cn1ccc(N)nc1=O
Reaction time: 24 h
Yield: 225.8 %

Procedure:
To a solution of 44 (1.2 g. 2.7 mmol) in 15 of anhydrous DMF was added triethylamine (0.45 ml) followed by 0.31 ml (3.3 mmol) of acetic anhydride. The reaction was kept at room temperature for 1 day, then 3 hrs at 50 C and concentrated. The oily residue was dried by co-evaporation with xylene and then re-dissolved in ethyl acetate. The solution was washed with saturated NaHCO3 (2×100 ml), saturated NaCl, dried over MgSO4. Concentration of the extract and drying in vacuo afforded 1.3 g (99%) of 45 as an off-white amorphous solid. 1H NMR (DMSO-d6): δ 10.79 (s, 1H), 7.94 (d, J=7 Hz, 1H), 7.12 (d, J=7 Hz, 1H), 4.01 (m, 1H), 3.87 (m, 1H), 3.69 (m, 1H), 3.56 (d, J=6 Hz, 2H), 2.14 (m, 1H), 2.08 (s, 3H), 1.14 (d, J=6 Hz, 3H), 0.84 (s, 9H), 0.82 (s, 9H), 0.02 (s, 6H), −0.02 (s, 3H), −0.03 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:48]1CCOC[CH2:49]1>>[S:8]1([C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:49](=[O:48])[NH:11]1)(=[O:10])=[O:9]
Reactant: C1COCCO1
Reactant: NS(=O)(=O)c1ccccc1Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1NS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 90 mL glass pressure tube was charged in a nitrogen dry box with 2 g (10.4 mmol) of 2-chlorobenzenesulfonamide, 2.35 g (20.8 mmol) of triethylamine, 30 mg (0.067 mmol) of Pd(CH3CN)4 (BF4)2, 30 mg (0.073 mmol) of 1,3-bis(diphenyl-phosphino)propane (dppp) and 6 mL of dioxane. The resulting suspension was stirred at room temperature for 30 min, cooled to -80° C., evacuated and charged with 70 psia of CO. After stirring at room temperature for 30 min, the tube was heated with stirring at 120° C. for 48 hours (hrs). Upon cooling to room temperature, the pressure was 38 psia and much solid formed. The pressure was released, 20 mL of dioxane were added to the reaction mixture to redissolve the solid, and the precipitate was isolated by filtration and washed with 5 mL of dioxane, three times, to yield 0.95 g of HNEt3+Cl-. The reaction of Example 2 to this point can be also illustrated by the general formula provided in Example 1. The filtrate was combined with the washings and the solvent was removed in a vacuum to yield 2.84 g of almost pure saccharin salt A with [HN(C2H5)3 ]+ and Cl-. To this material were added 60 mL of water followed by 1.6 g of NaOH. The resulting solution was filtered, concentrated under vacuum, and 4 g of HCl 38% by weight of the solution were added. A copious white precipitate was formed, and isolated by filtration and washed with a small amount of cold water. 1.73 g (91.4% of the calculated amount of saccharin expected based on the measured amounts of the ingredients) of pure saccharin was obtained after vacuum drying. This reaction step from the saccharin salt to saccharin is illustrated by the following general formula: ##STR6##