Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO[C:4]1[N:12](CC2C=CC(C3C=CC=CC=3C3N=C(O)ON=3)=CC=2)[C:11]2[C:10](C(O)=O)=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1.N1C2C=CC=CC=2NC=1.[CH2:44]([O:46][C:47]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[NH:48])[CH3:45].[CH2:61]([O:63][C:64](Cl)=[O:65])C.CC1C=CC=C(C)N=1>>[N:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[NH:12][CH:4]=1.[CH3:61][O:63][C:64]([N:48]=[C:47]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[O:46][CH2:44][CH3:45])=[O:65]
Reactant: CCOC(=N)c1ccccc1-c1ccccc1
Reactant: CCOC(=O)Cl
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2noc(O)n2)cc1
Agent: c1ccc2[nH]cnc2c1
Solvent: Cc1cccc(C)n1
Product: CCOC(=NC(=O)OC)c1ccccc1-c1ccccc1

Procedure:
According to another method disclosed in U.S. '054 for the preparation of azilsartan (Scheme 2), ethoxycarboimidoyl biphenyl benzimidazole derivative of compound of formula (6) reacts with ethylchloroformate in presence of 2,6-dimethylpyridine as base gives N-methoxycarbonyl ethoxycarboimidoylbiphenyl benzimidazole derivative of compound of formula (7). The resulting N-methoxycarbonyl ethoxycarboimidoyl biphenyl benzimidazole compound of formula (7) can be converted to 1,2,4-oxadiazol derivative compound of formula (4) by either of the two ways: (i) by treating the compound of formula (7) with hydroxylamine hydrochloride in presence of sodium methoxide; (ii) by reacting compound of formula (7) with methyl chloroformate in presence of 2,4,6-trimethylpyridine to obtain a residue, which on further addition to a mixture of hydroxylamine hydrochloride and sodium methoxide under reflux yielded compound of formula (4). 1,2,4-Oxadiazol derivative compound of formula (4) thus obtained is further hydrolyzed in presence of a base to obtain azilsartan (5).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([CH:8]([CH2:21][CH3:22])[C@H:9]([NH:12][C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[C:10]#[N:11])[CH3:7].[NH4+].[OH-:24]>>[CH2:21]([CH:8]([CH2:6][CH3:7])[C@@H:9]([C:10]([NH2:11])=[O:24])[NH:12][C@H:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])[CH3:22]
Reactant: [OH-]
Reactant: CCC(CC)[C@@H](C#N)N[C@@H](C)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CCC(CC)[C@H](N[C@@H](C)c1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
To 25 mL of sulfuric acid at 0° C. was added (S)-3-ethyl-2-{[(S)-1-phenylethyl]amino}pentanenitrile (2.7 g, 11.6 mmol) portionwise. The mixture was warmed to 25° C. After 2 days, the reaction mixture was poured over about 100 g of crushed ice. Concentrated NH4OH was added to neutralize the acid. This mixture was extracted with EtOAc (3×100 mL), dried over Na2SO4, filtered and concentrated to give 3-ethyl-N2-[(S)-1-phenylethyl]-L-norvalinamide (2.6 g, 90%), which was used in the next step without purification. Mass Spectrum (+ESI): 249 (M+H)+. Anal. Calc'd for C15H24N2O: C, 72.54; H, 9.74; N, 11.28. Found: C, 72.24; H, 10.04; N, 11.01
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58]>O1CCCC1.C(OCC)(=O)C>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 78.1 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (1.0 g, 1.84 mmol), sodium hydride (60% in oil, 220 mg, 5.50 mmol), 15-crown-5 (400 mg, 1.82 mmol) and t-butyl bromoacetate (0.55 ml, 3.69 mmol) in tetrahydrofuran (20 ml) was refluxed under heating for 1 hour and 15 min. The reaction solution was diluted with ethyl acetate and filtered with CELITE. Under cooling with ice, water was added dropwise to the filtrate which was then washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent and the thus obtained residue was purified by column chromatography (hexane:ethyl acetate=20:1) to give the titled compound (946.6 mg, 78%) as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[C:11]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=O)[CH3:12].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>CC(C)=O>[CH3:12][C:11]1[O:18][C:16](=[O:17])[C:15](=[CH:1][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[N:14]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: CC1=NC(=Cc2ccc(C#N)cc2)C(=O)O1
Temperature: 50 °C

Procedure:
Acetone (80.0 l) was introduced into a mixture of 4-formylbenzonitrile (15.0 kg, 114.5 mol), N-acetylglycine (19.2 kg, 162.4 mol) and anhydrous sodium acetate (9.4 kg, 114.5 mol) followed by introduction, with stirring, of acetic anhydride (35.0 l, 370.5 mol). The reaction mixture was stirred under reflux for 1 h. The resulting thin yellow suspension was cooled to 50° C. and ice-water (200 l) was added as quickly as possible, with stirring and cooling. The mixture was stirred at 20° C. for another 1 h. To isolate the product, the yellow suspension was pressed onto a centrifuge and washed with deionized water (75 l), isopropanol (40 l) and methyl-tert-butylether (75 l). The product was dried under reduced pressure at 40° C. Yield 18.17 kg (85.7 mol, 75.2% of theory). M.p.: 192–193° C.; MS (DCl): m/z=213 [M+H+]; 1H-NMR (DMSO-d6): δ=2.42 (s, 3H), 7.30 (s, 1H), 7.96 (d, 2H), 8.33 (d, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]=[O:28])[CH2:23][CH2:22]3)[N:18]=[C:17]([O:29][CH2:30][CH2:31][C:32]([OH:34])=O)[C:16]=2[O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH3:43])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:44]([C:47]1[CH:53]=[CH:52][CH:51]=[CH:50][C:48]=1[NH2:49])([CH3:46])[CH3:45]>>[CH:44]([C:47]1[CH:53]=[CH:52][CH:51]=[CH:50][C:48]=1[NH:49][C:32](=[O:34])[CH2:31][CH2:30][O:29][C:17]1[C:16]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH3:43])=[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=2)(=[O:12])=[O:13])[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]=[O:28])[CH2:25][CH2:26]2)[N:18]=1)([CH3:46])[CH3:45]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(C=O)CC2)nc1OCCC(=O)O
Reactant: CC(C)c1ccccc1N
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(C=O)CC2)nc1OCCC(=O)Nc1ccccc1C(C)C

Procedure:
The procedure described in Example 2 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-2-(4-formylpiperazinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyloxy]propionic acid and 2-isopropylaniline, to thereby obtain the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](S(O)(=O)=O)=[CH:6][CH:7]=1.O.[CH2:13]([NH:20][C:21]1[C:22]([NH2:28])=[CH:23][C:24]([Br:27])=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.COC(OC)(OC)C1C=CC=CC=1>C(Cl)Cl>[CH2:1]([N:20]1[C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=2[N:28]=[C:13]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cc(Br)ccc1NCc1ccccc1
Agent: COC(OC)(OC)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: Brc1ccc2c(c1)nc(-c1ccccc1)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
p-TsOH.H2O (311.7 mg, 1.606 mmol) was added to a DCM (50 ml) solution of N1-benzyl-4-bromobenzene-1,2-diamine (4451 mg, 16.06 mmol) and trimethyl orthobenzoate (3096 μl, 17.66 mmol) and the resulting mixture was stirred at rt under an atmosphere of Nitrogen for 40 h. The reaction mixture was then concentrated in vacuo to give a yellow solid which was triturated with 40% MeOH/water (375 mL), filtered, washed with saturated NaHCO3 (20 ml)+H2O (80 ml) twice and 40% MeOH/H2O (2×50 ml), and dried to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm=5.44 (s, 2H, 7.05-7.08 (m, 3H), 7.30-7.36 (m, 4H), 7.44-7.50 (m, 3H), 7.66-7.68 (m, 2H) and 7.99 (dd, 1H, J=0.4 & 1.6 Hz). MS (ES+): m/z 363.20 and 365.26 [MH+].
Reaction SMILES: [P:1]([O:13][CH2:14]Cl)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[I-:16].[Na+].CC(C)=O>C(#N)C>[P:1]([O:13][CH2:14][I:16])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [I-]
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC#N
Product: CC(C)(C)OP(=O)(OCI)OC(C)(C)C

Procedure:
The title compound was prepared by halogen exchange reaction of di-tert-butyl chloromethyl phosphate (Intermediate 1) with sodium iodide in suitable solvent such as dry acetone or acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@:13]([F:15])([CH3:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]1([F:26])[CH2:22][CH:21]1[C:23](O)=[O:24]>>[NH2:16][C:10]1[O:11][CH2:12][C@@:13]([F:15])([CH3:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:23]([CH:21]3[CH2:22][C:20]3([F:26])[F:19])=[O:24])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)C1CC1(F)F
Reactant: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(N)ccc1F
Product: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(NC(=O)C2CC2(F)F)ccc1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.3) and 2,2-difluoro-cyclopropanecarboxylic acid (CAS 107873-03-0) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=360.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([OH:18])=[O:17])[CH2:14][NH:13][C:12]1=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](O)([CH3:23])([CH3:22])[CH3:21].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17])[CH2:14][NH:13][C:12]1=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Reactant: CC(C)(C)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
5.1 g of (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylic acid (Liebich's Annalen der Chemie 529 (1937), page 1) are dissolved in 20 ml of pyridine, and 50 ml of tert.-butanol are added thereto. The solution is cooled to a temperature below -5° C., and 3.5 g of phosphorous oxychloride are added dropwise thereto. The mixture is stirred at the same temperature for about 30 minutes and then at room temperature for 3 hours. The reaction mixture is poured into 200 ml of ice-water, and extracted with ethyl acetate. The extract is washed with 1% hydrochloric acid, an aqueous sodium bicarbonate solution and water, successively. Then, the extract is dried and evaporated to remove solvent. The residue obtained is crystallized with a mixture of ether and n-hexane. 5.5 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals. Yield: 89.0%
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:46][C:47]1[C:51]([CH3:52])=[N:50][O:49][N:48]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:46][C:47]3[C:51]([CH3:52])=[N:50][O:49][N:48]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1nonc1CBr
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: Cc1nonc1Cn1nnc2c(N3CC(F)(F)C(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole and isolated as light-yellow gum. MS(m/e): 415.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46](O)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]>C(Cl)Cl>[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)c2cc(CC3=C(C)C(=O)C(OC)=C(OC)C3=O)ccc2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.1 %

Procedure:
Ethyl 4-aminobenzoate (0.265 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.165 g, 0.316 mmol, 59%).
Reaction SMILES: CN(C=O)C.S(Cl)([Cl:8])=O.N1C=CC=CC=1.[CH2:16]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:33]=1)[CH2:29]O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>ClCCl>[CH2:16]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:33]=1)[CH2:29][Cl:8])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCOc1cc(CO)cc(OCCCCCCCCC)c1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCC)c1
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
A 1 L RBF was prepared containing 5 mL dry dichloromethane, a stir bar, a septum, an out-vent line and a nitrogen gas line. DMF (3.3 ml, 40.3 mmol) was added and the reaction mixture was cooled in an ice bath. Thionyl chloride (2.7 ml, 40.3 mmol) was added and the reaction mixture was stirred for 10 minutes. The ice bath was then removed and the reaction mixture was allowed to stir for an additional 10 minutes. The RBF was placed in an ice bath and a mixture of pyridine (2.72 ml, 33.6 mmol) and 3,5-dinonoxybenzylalcohol (13.2 g, 33.6 mmol) were added and dissolved in about 50 mL dichloromethane, drop-wise through the septum. After 15 minutes, the RBF was removed from the ice bath and the reaction was stirred for 2 hours after which the reaction mixture was placed in the refrigerator overnight. The solvent was removed by rotary evaporation. To the remaining organic matter, 100 mL of 50% ether/hexanes was added to dissolve the desired compound. A solid orange precipitate formed, the remaining liquid was decanted off and the precipitate was washed with an additional 100 mL of 50% ether/hexanes. The combined organic layers were vacuum filtered through a silica gel into a RBF and the solvent was removed under reduced pressure. The trace solvent was removed by high vacuum overnight. There was a 10.0 g yield or a 72.2% yield of the derivative. The NMR characterization data for this derivative is as follows. 1H NMR (300 MHz, CDCl3): 0.88 (t, J=6.3, 6H, CH2CH3), 1.1-1.55 (m, 28H, CH2(CH2)6), 1.76 (p, J=6.6, 4H, OCH2CH2), 3.93 (t, J=6.6, 4H,), 4.50 (d, J=5.8, 2H, CH2Cl), 6.39 (t, J=2.2, 1H, ArH), 6.51 (d, J=2.2, 2H, ArH).
Reaction SMILES: [CH2:1]([S:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9])[CH2:2][CH3:3].[F:10][C:11]1[C:12](=[O:18])[NH:13][C:14](=[O:17])[NH:15][CH:16]=1>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:1]([S:4][CH2:5][CH2:6][NH:7][C:8]([N:15]1[CH:16]=[C:11]([F:10])[C:12](=[O:18])[NH:13][C:14]1=[O:17])=[O:9])[CH2:2][CH3:3]
Reactant: CCCSCCN=C=O
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCSCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 8 h

Procedure:
To the above solution of 2-propylthioethyl isocyanate was added a solution of 5-fluorouracil (2.60 g.) in N,N-dimethylacetamide (20 ml.) at 80° C. and stirred for further 8 hours at the same temperature. The resultant mixture was diluted with ethyl acetate (200 ml.), washed with water (each 30 ml., 3 times), dried over magnesium sulfate, treated with activated charcoal, filtered and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 1-[N-(2-propylthioethyl)carbamoyl]-5-fluorouracil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.CN(C(ON1N=[N:28][C:23]2[CH:24]=[CH:25][CH:26]=[N:27][C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.CN1CC[C@@H](N)C1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:28][C@@H:23]2[CH2:24][CH2:25][N:27]([CH3:26])[CH2:22]2)=[O:8])=[C:4]([F:12])[CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1cc(F)c(C(=O)O)cc1Cl
Agent: CN1CC[C@@H](N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CC[C@@H](NC(=O)c2cc(Cl)c(N)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
4-amino-5-chloro-2-fluorobenzoic acid (Intermediate 176; 300 mg, 1.58 mmol), HATU (903 mg, 2.37 mmol) and (3R)-1-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 325 mg, 2.37 mmol) were stirred in DMF (5 mL) and diisopropylethylamine (1.2 mL, 7.12 mmol) added. The mixture was stirred for 2 hours at room temperature and then absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (5% ammonia in methanol/DCM) to yield the title compound as a pale orange solid (333 mg, 77%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[I].[K].[I:13]I.[NH:15]1[CH2:20][CH2:19][CH2:18][N:17]=[C:16]1[SH:21]>CO.O>[IH:13].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:21][C:16]1[NH:17][CH2:18][CH2:19][CH2:20][N:15]=1
Reactant: SC1=NCCCN1
Reactant: II
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [I]
Agent: [K]
Solvent: CO
Solvent: O
Product: Brc1ccc2[nH]cc(SC3=NCCCN3)c2c1
Product: I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 19.6 g of 5-bromo-indole in 50 ml of methanol is added to a stirred solution of 50 g potassium iodine and 25.4 g of iodine in 150 ml of water at room temperature. The mixture is further treated with a solution of 11.6 g of 1,4,5,6-tetrahydro-2-pyrimidinethiol in 270 ml of warm methanol. The reaction mixture is then stirred at room temperature for 2 hours, filtered and the filtrate is concentrated to one-fifth of the original volume and cooled. A crystalline precipitate is formed. This is filtered and recrystallised from a mixture of methanol, ethylacetate and ether to yield 5-bromo-3-(1,4,5,6-tetrahydro-2-pyrimidinylthio)-indole hydriodide which melts at 241°-242°.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12][C:13](=[O:24])[O:14][CH2:15][CH:16]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:25][CH3:26]>CCOC(C)=O>[I-:25].[CH3:26][N+:18]12[CH2:19][CH2:20][CH:21]([CH2:22][CH2:23]1)[CH:16]([CH2:15][O:14][C:13](=[O:24])[NH:12][C:11]1[CH:10]=[CH:9][S:8][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:17]2
Reactant: O=C(Nc1ccsc1-c1ccccc1)OCC1CN2CCC1CC2
Reactant: CI
Solvent: CCOC(C)=O
Product: C[N+]12CCC(CC1)C(COC(=O)Nc1ccsc1-c1ccccc1)C2
Product: [I-]
Reaction time: 8 h

Procedure:
To a solution of 1-azabicyclo[2.2.2]oct-3-ylmethyl (2-phenyl-3-thienyl)carbamate (100 mg) in EtOAc (2 mL) was added iodomethane (36 μL) at room temperature, followed by stirring for overnight. The reaction mixture was filtered, then concentrated under reduced pressure, and freeze-dried to obtain 1-methyl-3-({[(2-phenyl-3-thienyl)carbamoyl]oxy}methyl)-1-azoniabicyclo[2.2.2]octane iodide (88 mg) as a yellow amorphous substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:31])[CH:21]=[CH:22][C:23]1[CH:28]=[C:27](Br)[CH:26]=[C:25](Br)[CH:24]=1.Cl>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:18][O:19][C:20](=[O:31])/[CH:21]=[CH:22]/[C:23]1[CH:28]=[C:27]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH:26]=[C:25]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH:24]=1
Reactant: COC(=O)C=Cc1cc(Br)cc(Br)c1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)/C=C/c1cc(-c2ccc(OCc3ccccc3)cc2)cc(-c2ccc(OCc3ccccc3)cc2)c1
Reaction time: 8 h

Procedure:
4.00 g (14.4 mmol) sodium metaborate-octahydrate and 250 mg (0.349 mmol) bis(triphenylphosphine)palladium(II)chloride are stirred for 15 min in 50 ml THF and 50 ml water, and 5.00 g (21.3 mmol) 4-benzyloxybenzene boronic acid, 3.00 g (9.37 mmol) 3,5-dibromo cinnamic acid methyl ester are added and the mixture is stirred overnight at reflux. The mixture is acidified with 2 M hydrochloric acid, the precipitated product is filtered off, suspended in hot ethanol, filtered off and used in the next step without further purification.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:10]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:11]=2[S:12][C:13]=1[C:14]([NH2:16])=[O:15].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C=O)C.C(OCC)(=O)C>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:11]2[S:12][C:13]([C:14]([NH2:16])=[O:15])=[C:9]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]=2[CH:20]=1
Reactant: Sc1ccccc1
Reactant: COc1ccc2sc(C(N)=O)c(Cl)c2c1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2sc(C(N)=O)c(Sc3ccccc3)c2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Thiophenol (116 μL, 1.13 mmol) is added to a suspension of 3-chloro-5-methoxybenzo[b]thiophene-2-carboxamide (250 mg, 1.03 mmol) in 2 mL of DMF. Diazabicycloundecene (DBU) (169 μL, 1.13 mmol) is added and the mixture is warmed to 80° C. After 2 hours, the reaction mixture is allowed to cool and is diluted with ethyl acetate and washed with 1N NaOH, 1N HCl, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane gives 5-methoxy-3-(phenylthio)benzo[b]thiophene-2-carboxamide in 84% yield; mp 194°-196° C.