Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:33]=[CH:32][C:21]([O:22][CH2:23][C:24]3[CH:31]=[CH:30][C:27]([CH2:28][OH:29])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:33]=[CH:32][C:21]([O:22][CH2:23][C:24]3[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:16][CH2:17]1
Reactant: CN1CCN(c2ccc(OCc3ccc(CO)cc3)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(OCc3ccc(C=O)cc3)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of DMSO (2.6 equivalents) in dry DCM, cooled to −78° C. under N2 was added oxalyl chloride (1.1 equivalents) in DCM drop-wise. The solution was stirred at −78° C. for 5 minutes before a solution of 4-[4-(4-methylpiperazin-1-yl)phenoxymethyl]benzyl alcohol (1 equivalent) in DCM was added drop-wise, and allowed to stir at −78° C. for another 30 minutes. Triethylamine (2.5 equivalents) was slowly dripped in before allowing the solution to reach ambient temperatures. The solution was washed with aqueous NaHCO3 and brine, dried over MgSO4 and concentrated to provide the crude 4-[4-(4-methylpiperazin-1-yl)phenoxymethyl]benzaldehyde that was converted to thiosemicarbazones according to Scheme 7.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.O>C(Cl)(Cl)Cl>[Br:1][C:12]1[C:6]2[C:7](=[N:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[NH:10][CH:11]=1
Reactant: Clc1cnc2[nH]ccc2c1
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: Clc1cnc2[nH]cc(Br)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of bromine (3.5 ml) in chloroform (40 ml) was added dropwise to an ice-cold solution of the 5-chloro-1H-pyrrolo[2,3-b]pyridine (3) (10 g, 65 mM) in chloroform (260 ml). The reaction mixture was stirred for 60 minutes at 0° C. The reaction mixture was then hydrolysed with water and the pH of the solution was adjusted to 10. The resulting solid was removed by filtration, and the aqueous was extracted with dichloromethane. The organic was washed with water, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (10.5 g, 69%). 1H NMR (DMSO-d6) 7.8 (1H,$), 7.9 (1H, s), 8.3 (1H, s)
Reaction SMILES: [N:1]([CH2:4][C:5](Cl)=[O:6])=[N+:2]=[N-:3].C(N(CC)CC)C.[N:15]12[C:21](=[O:22])[CH2:20][CH:19]1[CH2:18][C:17](=[O:23])[CH:16]2[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[N:1]([CH2:4][C:5]([O:23][C:17]1[CH2:18][CH:19]2[N:15]([C:21](=[O:22])[CH2:20]2)[C:16]=1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:6])=[N+:2]=[N-:3]
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=NCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=NCC(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Azidoacetyl chloride (21 μl) is added by syringe in an ice-cold, stirring solution of triethylamine (42 μl) and benzyl 1-azabicyclo[3.2.0]heptane-3,7-dione-2-carboxylate (52 mg) in anhydrous methylene chloride (2 ml). After stirring 30 mins in the cold, the reaction mixture is diluted with methylene chloride (5 ml), washed with H2O (2 ml), pH 3 phosphate buffer (2 ml), and 5% NaHCO3 (2 ml), dried with MgSO4, filtered, and evaporated in vacuo. Chromatography of the residue on a silica gel GF plate gives benzyl 3-(α-azidoacetoxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[F:36][C:37]1[CH:38]=[C:39]([C:43]2[NH:44][C:45](=[O:53])[C:46]3[CH:52]=[CH:51][CH:50]=[N:49][C:47]=3[N:48]=2)[CH:40]=[CH:41][CH:42]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:51]4[CH:50]=[N:49][C:47]5[N:48]=[C:43]([C:39]6[CH:40]=[CH:41][CH:42]=[C:37]([F:36])[CH:38]=6)[NH:44][C:45](=[O:53])[C:46]=5[CH:52]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2cccc(F)c2)nc2ncccc12
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc4nc(-c5cccc(F)c5)[nH]c(=O)c4c3)cc12
Temperature: 80 °C
Reaction time: 5 h
Yield: 13.5 %

Procedure:
To a mixture of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (90 mg, 0.18 mmol), 2-(3-fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (63 mg, 0.19 mmol) and K3PO4.3H2O (143 mg, 0.54 mmol) in 1,4-dioxane/H2O (3 mL/0.3 mL), Pd2(dba)3 and X-Phos (10 mg/10 mg) were added under N2 protection. After being stirred at 80° C. for 5 h, the reaction mixture was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC give the product of 2-(4-fluorophenyl)-5-(2-(3-fluorophenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (15 mg, yield: 13%). 1H-NMR (DMSO-d6, 400 MHz) δ 12.97 (br s, 1H), 9.03 (d, J=2.4 Hz, 1H), 8.50˜8.60 (m, 2H), 8.16 (s, 1H), 8.12 (d, J=7.6 Hz, 1H), 8.00˜8.09 (m, 3H), 7.79 (s, 1H), 7.65 (dd, J=14.0, 8.0 Hz, 1H), 7.46˜7.52 (m, 1H), 7.43 (t, J=8.8 Hz, 2H), 3.26 (s, 3H), 3.02 (s, 3H), 2.85 (d, J=4.8 Hz, 3H). MS (M+H)+: 616.
Reaction SMILES: [F:1][C:2]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[Cl:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]3[O:32][C:33]([CH3:36])=[N:34][N:35]=3)[CH:29]=2)[N:24]=[CH:23][N:22]=1>>[ClH:20].[F:1][C:2]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[O:32][C:33]([CH3:36])=[N:34][N:35]=5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: Cc1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2F)c1
Product: Cc1nnc(-c2ccc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5F)c4)c3c2)o1
Product: Cl

Procedure:
The title compound was prepared according to Procedure A from 1-(2,3-difluorobenzyl)-1H-indazol-5-ylamine and 4-chloro-6-(5-methyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.90(1H, s), 9.47(1H, s), 8.91(1H, s), 8.60(1H, d), 8.25(1H, s), 8.15(2H, m), 7.89(1H, d), 7.72(1H, dd), 7.40(1H, m), 7.18(1H, m), 6.98(1H, m), 5.83(2H, s), 2.67(3H, s); m/z (M+1+) 470.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([CH3:17])[CH:11]=1.O>C(#N)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:12]([CH3:17])[CH:11]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1cc(Br)ccc1N
Solvent: CC#N
Solvent: O
Product: Cc1cc(Br)ccc1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
3,3-Dimethylbutanoyl chloride (724 mg, 0.75 mL, 5.4 mmol) was added to a solution of 4-Bromo-2-methyl-phenylamine (1.0 g, 5.4 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (830 mg, 56% yield).
Reaction SMILES: [C:1]([C:3]([CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[OH-:21].[Na+]>S(=O)(=O)(O)O.O>[C:1]([C:3]([CH:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:21])[NH2:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Temperature: 85 °C
Reaction time: 9 h

Procedure:
3-(R,S)-(1-Cyano-1,1-diphenylmethyl)pyrrolidine (30 g--see Preparation 7) was dissolved in 95% sulphuric acid (210 ml) and the mixture was heated, with stirring, at 85° C. for 9 hours and then at 100° C for 30 minutes. The mixture was allowed to cool to room temperature and poured onto ice (2 kg). The mixture was basified (pH 12) by addition, in portions with cooling in an ice bath, of a cold solution of sodium hydroxide (340 g) in water (500 ml). The resulting mixture was extracted with dichloromethane (3×300 ml) and the combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as a foam, yield 16.4 g.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[N:23][CH:24]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[N:23][CH:24]=2)[C:8]2[S:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)nc2)C2CCCCC2)sc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To a mixture of ethyl 3-{[(5-{[cyclohexyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}pyridin-2-yl)carbonyl](methyl)amino}propanoate (141 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (112 mg, 84%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:14][C:15]1[C:19]([CH2:20][N:21]2[CH:25]=[C:24]([NH2:26])[CH:23]=[N:22]2)=[C:18]([CH3:27])[O:17][N:16]=1>>[CH3:14][C:15]1[C:19]([CH2:20][N:21]2[CH:25]=[C:24]([NH:26][C:10]([C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][CH2:9]3)=[O:12])[CH:23]=[N:22]2)=[C:18]([CH3:27])[O:17][N:16]=1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)C2(c3ccccc3)CC2)cn1
Yield: 6 %

Procedure:
Prepared as in Example 4-8 from 1-phenylcyclopropanecarboxylic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 6%. MS M+H calculated 337.6, found 337.5.
Reaction SMILES: C1C(=O)N([O:8][C:9]([O:11][CH2:12][CH:13]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=O)C(=O)C1.[NH2:26][C@@H:27]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[CH2:36][C@H:37]([O:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][O:53]1)[CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C:28]([OH:30])=[O:29].C([O-])([O-])=O.[Na+].[Na+].Cl>CN(C=O)C>[CH2:44]([O:43][C:41]([NH:40][CH2:39][CH2:38][C@@H:37]([O:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][O:53]1)[CH2:36][N:35]([C:58]([O:60][CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)=[O:59])[CH2:34][CH2:33][CH2:32][CH2:31][C@H:27]([NH:26][C:9]([O:11][CH2:12][CH:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]2[C:25]1=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:8])[C:28]([OH:30])=[O:29])=[O:42])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: N[C@@H](CCCCN(C[C@@H](CCNC(=O)OCc1ccccc1)OC1CCCCO1)C(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCC[C@H](CN(CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)C(=O)OCc1ccccc1)OC1CCCCO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
A solution of 9-fluorenylmethyl N-succinimidyl carbonate (203 mg, 0.60 mmol) in DMF (3.0 mL) was added to a solution of 18a (219 mg, 0.37 mmol) in 9% Na2CO3 (803 mg, 0.68 mmol) at 0° C. and stirred overnight at room temperature. The pH was adjusted to 7.0 with 0.1 N HCl. The mixture was concentrated to an oil and purified by flash chromatography (CHCl3, then 95% CHCl3/MeOH) to give 11a (150 mg, 50%) as a colorless oil: 1H NMR δ 1.15-1.94 (m, 14H), 3.10-3.52 (m, 7H), 3.66-3.98 (m, 2H), 4.05-4.21 (m, 2H), 4.24-4.61 (m, 3H), 5.04 (s, 2H), 5.08 (s, 2H), 7.21-7.40 (m, 14H), 7.65 (dd, 2H, J=6.9, 4.2), 7.77 (d, 2H, J=7.2); 13C NMR δ 21.1, 21.7, 24.1, 26.4, 26.5, 28.2, 28.9, 32.1, 32.5, 32.6, 33.2, 34.3, 38.1, 38.5, 51.9, 52.4, 55.5, 64.1, 65.2, 67.4, 67.9, 68.3, 74.9, 79.5, 100.0, 101.5, 120.9, 126.3, 128.2, 128.80, 128.97, 129.10, 129.20, 129.48, 129.57, 129.62, 138.2, 138.5, 142.6, 145.2, 145.4, 158.1, 158.6, 176.8; HRMS m/z calcd for C46H54N3O10 808.3809, found 808.3833.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4](N)[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.[F:18][C:19]([F:24])([F:23])[C:20](O)=[O:21].[N:25]1C=CC=CC=1>>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[C:7]([NH2:25])[C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([C:20](=[O:21])[C:19]([F:24])([F:23])[F:18])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Reactant: O=C(O)C(F)(F)F
Reactant: c1ccncc1
Product: CC1(C)Oc2c(cc3nonc3c2N)C(C(=O)C(F)(F)F)C1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
A mixture of 300 mg (1.28 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole and 3 ml of pyridine were added with 180 μl (1.28 m mol) of anhydrous trifluoroacetic acid with stirring for 3 hours at 0° C., followed by further stirring for 3 hours at the room temperature. After the completion of the reaction, the mixture was washed thrice with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was subjected to a silica gel column chromatography using a developing solvent of ethyl acetate-methanol (10:1 (v/v)) to obtain 124 mg (yield: 29%) of the intended compound. A part of the obtained compound was recrystallized from ethanol to obtain the pure intended compound.
Reaction SMILES: FC1(F)CC1CN1CCN(C2SC(C(OCC)=O)=C(C)N=2)C1=O.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][C:43]([F:46])([F:45])[F:44])[C:36]2=[O:47])[S:28][C:29]=1[C:30]([O:32]CC)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][C:43]([F:44])([F:45])[F:46])[C:36]2=[O:47])[S:28][C:29]=1[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)c1sc(N2CCN(CCCC(F)(F)F)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(CC3CC3(F)F)C2=O)nc1C
Product: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)O
Yield: 87 %

Procedure:
Following the procedure as described in Preparation 14, making variations as required to replace ethyl 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate with ethyl 4-methyl-2-(2-oxo-3-(4,4,4-trifluorobutyl)imidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colourless solid in 87% yield: 1H NMR (300 MHz, DMSO-d6) δ 12.8 (s, 1H), 4.02-3.97 (m, 2H), 3.59-3.54 (m, 2H), 3.33-3.29 (m, 2H), 2.50 (s, 3H), 2.35-2.26 (m, 2H), 1.79-1.69 (m 2H); MS (ES+) m/z 338.1 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(CBr)cc1
Reaction time: 1 h

Procedure:
4-bromomethylbenzoic acid (25 g, 116.25 mmol) was dissolved in CH2Cl2 (200 ml) and treated with oxalyl chloride (12.2 ml, 139.5 mmol). DMF (0.45 ml) was added slowly then stirred for 1 h. The solvent was removed to give the 4-bromomethylbenzoyl chloride as a white solid.
Reaction SMILES: O[CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH3:7][C:8]1([CH3:15])[O:12][CH:11]([CH2:13][OH:14])[CH2:10][O:9]1.S(C1C=CC(C)=CC=1)(OC)(=O)=O.[OH-:28].[Na+]>O.CC(C)=O>[CH3:2][C:3]([CH2:5][OH:6])([OH:4])[C:8]([CH3:15])([CH3:7])[OH:28].[CH3:7][C:8]1([CH3:15])[O:12][CH:11]([CH2:13][OH:14])[CH2:10][O:9]1
Reactant: OCC(O)CO
Reactant: [OH-]
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC1(C)OCC(CO)O1
Solvent: O
Product: CC(C)(O)C(C)(O)CO

Procedure:
Trimethyl glycerol was prepared from glycerol through a ketal glecerol derivative, solketal (1,2-isopropylidene glycerol) as shown in FIG. 2. Solketal starting material was prepared by reacting 1 g glycerol with 2 ml acetone and 1 g Dowex 50W strong cation exchange resin (Dow Chemical Co., Midland, Mich.) at 60° C. for 1 hour. The resultant solketal (3 mmol) was reacted with 3 mmol methyl tosylate (as prepared in Example 1) in 3 mmol NaOH with mL water in a small scale vessel for 2 hours at 70° C., producing methyl solketal. Hydrolysis of the methyl solketal was effected by reaction with Dowex 50W strong cation exchange resin (½″) in 4 ml methanol for 2 hours at 70° C., producing 1-methyl glycerol. The 1-methyl glycerol produced from the hydrolysis was reacted with 2 molar equivalents of methyl tosylate in aqueous NaOH for 2 hours at 70° C., yielding 1,2,3-trimethoxy glycerol ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH2:11])=[CH:4][CH:3]=1.[N:16]([O-])=O.[Na+].[Cl:20][Sn]Cl.[OH-].[Na+]>Cl>[ClH:20].[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH:11][NH2:16])=[CH:6][CH:7]=1
Reactant: Nc1ccccc1Sc1ccc(F)cc1
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NNc1ccccc1Sc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
2-[(4-Fluorophenyl)sulfanyl]aniline (400 mg, 1.6 mmol) was stirred at 0° C. in conc. HCl (4.0 mL) and NaNO2 (130 mg, 1.8 mmol) was added slowly, maintaining 0° C. reaction temperature. After stirring for 1 hour at 0° C., a solution of SnCl2 (610 mg, 3.2 mmol) in 1.5 mL conc. HCl was added. The reaction was brought to rt and stirred for one h. Upon completion, the reaction was basified with 1N aqueous NaOH to pH 12. The reaction mixture was partition between water and CHCl3 and the aqueous layer extracted with CHCl3 (3×20 mL). The combined extracts were washed with brine (20 mL), H2O (20 mL) and dried (Na2SO4) and evaporated to a residue. The residue was taken up in a minimal amount of CHCl3 (10 mL) and 1N HCl-Ether (10 mL) was added. The solvent was evaporated affording 1-{2-[(4-fluorophenyl)sulfanyl]phenyl}hydrazine hydrochloride as a dark semi-solid (327 mg, 76%). 1H NMR (CD3OD, 300 MHz) δ 7.40-7.51 (m, 2H), 7.16-7.25 (m, 2H), 6.95-7.14 (m, 4H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[O:11][CH3:12].C(N(CC)CC)C.[C:21](O)(=[O:23])[CH3:22].C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:21](=[O:23])[CH3:22])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(N)cc1OC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(C)=O)cc1OC
Yield: 84 %

Procedure:
To a mixture of 29.0 g (0.16 mole) of methyl-4-amino-2-methoxybenzoate, 0.5 g of 4-dimethylaminopyridine, and 16.0 gm (0.16 mole) of triethylamine in 500 ml of dichloromethane was added in batches 22 ml (ca. 0.23 mole) of acetic acid. After two hours the reaction mixture was neutralized with sodium bicarbonate (in solution and as a solid). The organic phase was washed successively with aqueous sodium bicarbonate. The organic phase was washed successively with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from toluene gave 30 g of methyl-4-acetamido-2-methoxybenzoate. To 100 ml of fuming nitric acid, stirred at −40° C., was slowly added 22.3 g (0.10 mole)of the acetylated intermediate. After about twenty minutes the mixture was warmed to 0° C. and stirred for another twenty minutes. The mixture was poured onto one liter of ice and the resultant precipitate was collected. Recrystallization from toluene/ethanol gave 14.2 g of the nitrated and deacetylated compound, methyl-4-amino-2-methoxy-5-nitrobenzoate. (Under similar conditions in which the acetyl group is not removed, saponification with methanolic sodium hydroxide gives the same product.) Hydrogenation of the nitro intermediate in tetrahydrofuran using Raney nickel as catalyst gave methyl-4,5-diamino-2-methoxybenzoate. A mixture of 4.83 g (24.6 mmole) of the diamine and 7.08 g (49.2 mmole) of potassium ethylxanthate was heated at reflux under argon in 40 ml of water. The resultant product mixture was chromatographed on silica gel to give 1.5 g of methyl-2-mercapto-5-methoxy-1H-benzimidazole-6-carboxylate. (Analysis. Calc'd. for C10H10N2O3S: C, 50.41; H, 4.23; N, 11.76; S, 13.46. Found: C, 50.30; H, 4.19; N, 11.71; S, 13.12.) The title compound was then prepared by the method of Example 1 using 1.19 g (5.0 mmole) of methyl-2-mercapto-5-methoxy-1H-benzimidazole-6-carboxylate instead of 2-mercaptobenzimidazole and 0.97 g (5.5 mmole)of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Analysis. Calc'd. for C17H17N3O3S*2HCl: C, 49.05; H,4.60; N, 10.09; S, 7.70; C1, 17.03. Found: C, 49.37; H, 4.77; N, 9.72; S, 7.43; C1, 16.77.
Reaction SMILES: C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:27]1([CH2:33][CH:34]([OH:38])[CH2:35][CH:36]=[CH2:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.I[C:40]1[CH:49]=[CH:48][CH:47]=[CH:46][C:41]=1[C:42]([O:44][CH3:45])=[O:43]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(=O)OCC>[OH:38][CH:34]([CH2:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:35]/[CH:36]=[CH:37]/[C:40]1[CH:49]=[CH:48][CH:47]=[CH:46][C:41]=1[C:42]([O:44][CH3:45])=[O:43]
Reactant: C=CCC(O)Cc1ccccc1
Reactant: COC(=O)c1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1/C=C/CC(O)Cc1ccccc1
Yield: 56 %

Procedure:
A mixture of triethylamine (7.6 mL, 54.7 mmol), triphenylphosphine (0.778 g, 2.97 mmol) and palladium acetate (0.35 g, 1.56 mmol) in 1,4-dioxane (50 mL) was refluxed to form a homogeneous dark-red solution. The reaction temperature was then reduced to just below reflux. Compound 30b (4.56 g, 28 mmol), methyl 2-iodobenzoate (4.10 g, 15.6 mmol) and triethylamine (2.88 mL, 10.2 mmol) were added subsequently with stirring. The reaction mixture was then refluxed for about 30 min until TLC showed the SM had disappeared. The reaction mixture was filtered hot through celite, which was washed with 1,4-dioxane. The combined filtrate and washings were evaporated in vacuo to a small volume and purified by CC using PE:EA=5:1 as mobile phase to give the desired product (2.59 g, 56% yield).