Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:9][C:10]([C:12]1[S:16][CH:15]=[N:14][CH:13]=1)=[O:11])[CH2:7][CH3:8].[Cl:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][CH2:24]S(C2C=CC(Cl)=CC=2)(=O)=O)=[CH:20][CH:19]=1.C(OC(=O)C)C>CCCCCC.O1CCCC1>[CH2:6]([N:9]([CH2:24][CH2:23][O:22][C:21]1[CH:35]=[CH:36][C:18]([Cl:17])=[CH:19][CH:20]=1)[C:10]([C:12]1[S:16][CH:15]=[N:14][CH:13]=1)=[O:11])[CH2:7][CH3:8]
Reactant: CCCNC(=O)c1cncs1
Reactant: O=S(=O)(CCOc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCN(CCOc1ccc(Cl)cc1)C(=O)c1cncs1
Yield: 74.5 %

Procedure:
Butyl lithium (1.6 M, 7.5 ml) in hexane was added to a solution of the N-propyl thiazole-5-carboxamide (1.7 g, 10 mmol) obtained in A in tetrahydrofuran (80 ml) at -78° C. under an atmosphere of nitrogen. The resultant solution was stirred for 10 minutes and then allowed to warm to room temperature whereupon the 2-(4-chlorophenoxy)-1-(4-chlorophenylsulphonyl)ethane (5.20 g, 15 mmol) obtained in B dissolved in tetrahydrofuran (40 ml) was added. The resultant solution was then refluxed for 5 days. On cooling, the solvent was evaporated and the residue dissolved in 1:4 water: ethyl acetate (500 ml). The organic layer was washed with saturated sodium chloride solution, dried (MgSO4) and the solvent evaporated to leave an oil which, after flash chromatography on silica gel with 1:2 ethylacetate: petroleum ether as the eluant, yielded the desired product (2.42 g). Mass spectroscopy revealed the mass/charge ratio of the parent molecule ion, M+, to be 324 thereby confirming the molecular weight of the product to be 324.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][CH2:16][C@@H:15]([Br:18])[C:14]2=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1[CH:25]=[CH:24][C:23]([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Br-:18].[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][CH2:16][C@@H:15]([P+:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=3)[C:14]2=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1[C@H](Br)CCN1C1CCN(Cc2ccccc2)C1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1[C@H]([P+](c2ccccc2)(c2ccccc2)c2ccccc2)CCN1C1CCN(Cc2ccccc2)C1
Product: [Br-]
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A suspension of 800 mg of 1′-benzyl-3-bromo-[1,3′]bipyrrolidinyl-2-one in 1.0 ml toluene was treated with 1.95 g of Ph3P and stirred at 110° C. for 30 min whereupon TLC indicated the reaction was complete. The brown two phase mixture was diluted with 10 ml EtOAc and the organic phase was extracted with three portions of 10 ml of saturated NaBr solution. The combined aqueous phases were washed three times with 10 ml EtOAc (to remove Ph3P), and then extracted seven times with 15 ml CH2Cl2, the combined organic phases dried over MgSO4 and concentrated to give 1.13 g (78%) of (R)-(1′-benzyl-2-oxo-[1,3′]bipyrrolidinyl-3-yl)-triphenyl-phosphonium bromide as a light brown foam. 1H-NMR (250 MHz; CDCl3, ˜1:1 mixture of diastereomers): 7.32-8.04 (m, 5H), 7.50-7.82 (m, 10H), 7.19-7.40 (m, 5H), 6.44-6.64 (m, 1H), 4.39-4.50 (m, 1H), 3.10-3.88 (m, 5H), 2.85-3.00 (m, 0.5H), 2.62-2.80 (m, 1H), 2.32-2.5 (m, 0.5 H), 1.72-2.32 (m, 5H).
Reaction SMILES: C([N:11]1[CH2:18][C:17]([F:20])([F:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.[BrH:21].CCOCC>C(O)(=O)C>[BrH:21].[F:19][C:17]1([F:20])[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: O=C(O)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)[C@@H]1CC(F)(F)CN1

Procedure:
A mixture of 2.4 grams of N-carbobenzyloxy-4, 4-difluoro-L-proline and 12 ml. of hydrogen bromide in acetic acid (30-32%) is stirred for 30 minutes at room temperature and then 300 ml. of anhydrous ether is added. The mixture is cooled and the precipitated solid is filtered and dried under reduced pressure. The desired 4,4-difluoro-L-proline, hydrobromide melts at 163°-165° (s. 160°); [α]D26 -14° (c=1%; methanol).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([OH:14])=[C:9]([CH3:15])[N:8]=1.C[O-].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:36]=[CH:35][C:29]([O:30][CH2:31][CH2:32][CH2:33]Br)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>O1CCCC1>[ClH:19].[NH2:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([O:14][CH2:33][CH2:32][CH2:31][O:30][C:29]2[CH:35]=[CH:36][C:26]([C:23]3[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)=[CH:27][CH:28]=2)=[C:9]([CH3:15])[N:8]=1
Reactant: Clc1ccc(-c2ccc(OCCCBr)cc2)cc1
Reactant: Cc1nc(N)nc(N)c1O
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(N)nc(N)c1OCCCOc1ccc(-c2ccc(Cl)cc2)cc1
Product: Cl
Temperature: 40 °C
Yield: 146.4 %

Procedure:
2,4-Diamino-5-hydroxy-6-methylpyrimidine dihydrogen sulphate (137.5 g) was added to a stirred solution of sodium methoxide [prepared by dissolving sodium (39.8 g) in anhydrous methanol (2350 ml)]. The stirred mixture was heated at reflux for 30 minutes and then for a further 150 minutes during the gradual addition of a solution of 3-[4-(4-chlorophenyl)-phenoxy]propyl bromide (188 g) in anhydrous tetrahydrofuran (940 ml) and then the mixture was stirred and heated at reflux for a further 18 hours. Part of the solvent (approximately 2400 ml) was removed by distillation at atmospheric pressure and the remaining mixture was diluted with water (3000 ml). The resulting suspension was cooled to 40° C., and the solid was filtered off, washed well with water and dried at 85° C. The solid was then dissolved in hot dimethylformamide (1000 ml) and the resulting solution was filtered through diatomaceous earth and treated, successively, with concentrated hydrochloric acid (50 ml) and acetone (2000 ml). The resulting suspension was cooled to 10° C. and filtered, and the solid was washed well with acetone to give 2,4-diamino-5-[3-{4-(4-chlorophenyl)phenoxy}propoxy]-6-methylpyrimidine monohydrochloride (178 g), m.p. 263°-265° C. (with slight decomposition).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[CH3:8])=[O:6]>CO.O>[F:17][C:16]([F:19])([F:18])[C:15]([C:12]1[CH:13]=[CH:14][C:9]([N:7]([C:5]2[O:6][CH2:2][CH2:3][N:4]=2)[CH3:8])=[CH:10][CH:11]=1)([OH:24])[C:20]([F:23])([F:22])[F:21]
Reactant: CN(C(=O)NCCCl)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: O
Solvent: CO
Product: CN(C1=NCCO1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Yield: 86.3 %

Procedure:
Dissolve 10.0 g (26 m. mole) of N-(2-chloroethyl)-N'-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl]-N'-methyl-urea in a mixture of 50 ml of methanol and 100 ml of water. Heat for 1 hour on a steam bath. Concentrate, and partition between 1N aqueous sodium bicarbonate solution and ether (diethyl) and then extract with 200 ml of 1N hydrochloric acid. Add sodium bicarbonate and then extract with 200 ml of ether. Dry the ether extract and concentrate to obtain 7.8 g of the title compound as a white solid, m.p. 188°-190° C. The salts may be prepared by standrad techniques such as by treatment of a solution of the free base in a suitable organic solvent, e.g. ether, with the desired acid, e.g. hydrochloric, and then filtering off the precipitated salt. The hydrochloride salt melts at 147°-149° C.
Reaction SMILES: [OH:1][CH:2]([N:15]1[C:21](=[O:22])[C@@H:20]2[C@H:16]1[S:17][C:18]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:19]2)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].C1(C)C=CC(S(O)(=O)=[O:37])=CC=1.Br[CH2:42][C:43]([C@@H:45]1[C@H:49]([O:50][CH3:51])[C@@H:48]([O:52][CH3:53])[CH2:47][O:46]1)=[O:44].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.ClCCl.O.CC(C)=O>[OH:1][CH:2]([N:15]1[C@H:16]([S:17][CH2:42][C:43]([C@@H:45]2[C@H:49]([O:50][CH3:51])[C@@H:48]([O:52][CH3:53])[CH2:47][O:46]2)=[O:44])[C@H:20]([NH:19][C:18](=[O:37])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]1=[O:22])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@H]3N=C(Cc4ccccc4)S[C@H]32)cc1
Reactant: CO[C@@H]1[C@@H](OC)CO[C@@H]1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SCC(=O)[C@H]2OC[C@H](OC)[C@H]2OC)cc1
Yield: 42.1 %

Procedure:
4-Methoxybenzyl (RS)-2-hydroxy-2-[(lR,5R)-3-benzyl-4-thia-2,6-diazabicyclo[3.2.0)hept-2-en-7-on-6-yl]acetate (6.0 g, 14.6 mmol) in 50% acetone/dichloromethane (60 ml) was cleaved with 4-toluenesulphonic acid (5.0 g, 26.3 mmol) in water (12 ml). The product was reacted with crude bromide from Example 34 (e) (3.40 g, 13.4 mmol) in acetone (70 ml) followed by potassium carbonate (1.0 g, 7.2 mmol) as described in Example 6 (b). After work-up, the residue was purified by chromatography on silica gel eluting with 50, 70 and 100% ethyl acetate in hexane to yield the title compound (3.40 g, 42%); νmax (CH2Cl2) 3400, 1781, 1735, 1682, 1613 and 1516 cm-1. (Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (625)].
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(O[C@@H:45]1[O:57][C@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[C@@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@H:46]1[O:47][C:48](=[O:50])[CH3:49])(=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClC(Cl)(Cl)C.C(OCC)(=O)C>[C:48]([O:47][C@@H:46]1[C@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@@H:56]([CH2:58][O:59][C:60](=[O:62])[CH3:61])[O:57][C@H:45]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[N:18][C:10]=2[NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:50])[CH3:49]
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A suspension of methyl 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 7) (1.5 g, 4.02 mmol) in 1,1,1-trichloroethane (40 ml) was treated with N,O-bis(trimethylsilyl)acetamide (4.8 ml, 19.6 mmol). The mixture was heated under reflux for two hours. The solution was allowed to cool to room temperature and the solvent removed under reduced pressure. The residue was taken up in anhydrous toluene (40 ml) and 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (1.65 g, 5.19 mmol) and trimethylsilyl trifluoromethanesulfonate (0.98 ml, 5.43 mmol) added. The resulting solution was heated under reflux under a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (200 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was separated, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel using gradient elution with ethyl acetate:pentane (70:30, by volume) then ethyl acetate:pentane (80:20, by volume) then ethyl acetate to afford the title compound as a foam (2.05 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[C:13]([C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)(=O)[CH3:14].N1CCCCC1>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[C:13]([C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])#[N:2]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)c1ccc[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(=C1C(=O)Nc2ccc(C#N)cc21)c1ccc[nH]1

Procedure:
To a suspension of 5-cyanoindolin-2-one (158 mg, 1 mmol) in ethanol (15 mL) was added 2-acetylpyrrole (95 mg, 1 mmol) and piperidine (0.1 mL). The reaction mixture was refluxed for 2 hours. A golden-colored product precipitated from the reaction mixture, which was filtered and washed with ethanol to afford 5-cyano-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one; (160 mg) 1H NMR (400 MHz, DMSO-d6) δ 2.80 (s, 3H), 6.40. (m, 1H), 7.04 (d, 1H), 7.20 (m, 1H), 7.42 (m, 1H), 7.60 (dd, 1H), 8.04 (s, 1H), 11.40 (s, 1H) ppm.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]([CH:29]([OH:35])[CH2:30][O:31][CH2:32][O:33][CH3:34])=[CH:21][C:22]3[NH:26][CH:25]=[N:24][C:23]=3[C:27]=2[F:28])=[C:14]([Cl:36])[CH:13]=1>C(Cl)Cl.O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]([C:29](=[O:35])[CH2:30][O:31][CH2:32][O:33][CH3:34])=[CH:21][C:22]3[NH:26][CH:25]=[N:24][C:23]=3[C:27]=2[F:28])=[C:14]([Cl:36])[CH:13]=1
Reactant: COCOCC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: COCOCC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a solution of oxalyl chloride (0.11 mL, 0.22 mmol) in CH2Cl2 (1 mL) at −78° C. is added DMSO (0.016 mL, 0.22 mmol). After stirring for 3 minutes, a solution of 1-[6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-2-methoxymethoxy-ethanol 10l (25 mg, 0.056 mmol) in methylene chloride (1 mL) is added. The resulting solution is stirred for 30 minutes at −78° C. TEA (0.1 mL, 0.71 mmol) is added. The reaction mixture is slowly warmed to room temperature, stirred for 5 minutes at room temperature, and diluted with water and CH2Cl2. The organic layer is separated, dried over MgSO4, filtered, and concentrated to give the crude product which is directly used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[NH:14][S:15]([C:18]1[S:19][CH:20]=[C:21]([CH3:23])[N:22]=1)(=[O:17])=[O:16].C(P(CCCC)CCCC)CCC.[F:37][C@@H:38]([CH3:41])[CH2:39]O.N(/C(N1CCCCC1)=O)=N\C(N1CCCCC1)=O>C1COCC1>[F:37][C@@H:38]([CH3:41])[CH2:39][N:14]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:5]=1[O:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][CH2:9]2)[S:15]([C:18]1[S:19][CH:20]=[C:21]([CH3:23])[N:22]=1)(=[O:17])=[O:16]
Reactant: C[C@H](F)CO
Reactant: COCOc1cc2c(cc1NS(=O)(=O)c1nc(C)cs1)CCC2
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COCOc1cc2c(cc1N(C[C@H](C)F)S(=O)(=O)c1nc(C)cs1)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
896 mg of N-[6-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl]-4-methyl-1,3-thiazole-2-sulfonamide, 665 mg of tributyl phosphine, and 257 mg of (2S)-2-fluoropropan-1-ol were dissolved in 8.96 mL of THF, and 829 mg of 1,1′-[(E)-diazen-1,2-diyldicarbonyl]dipiperidine was added thereto, followed by stirring overnight at room temperature. After the insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10 to 50:50) to obtain 632 mg of N-[(2S)-2-fluoropropyl]-N-[6-(methoxymethoxy)-2,3-dihydro-1H-inden-5-yl]-4-methyl-1,3-thiazole-2-sulfonamide.
Reaction SMILES: CCCCCC.C([Li])CCC.[F:12][C:13]1[CH:21]=[CH:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH:14]=1.[Br:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([CH:33]=[O:34])[CH:24]=1.[Cl-].[NH4+]>C1COCC1>[Br:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([CH:33]([C:18]2[S:17][C:16]3[CH:20]=[CH:21][C:13]([F:12])=[CH:14][C:15]=3[CH:19]=2)[OH:34])[CH:24]=1
Reactant: Fc1ccc2sccc2c1
Reactant: O=Cc1cc(Br)c2ccccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1cc(Br)c2ccccc2c1)c1cc2cc(F)ccc2s1
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 1.68 ml, 2.68 mmol) was added dropwise to a solution of 5-fluorobenzo[b]thiophene (410 mg, 2.68 mmol) in THF (10 ml) and the reaction solution was stirred at the same temperature for 10 minutes. To this solution, a solution of 4-bromonaphthalene-2-carbaldehyde (600 mg, 2.55 mmol) in THF (5 ml) was added dropwise at −78° C. The obtained mixture was stirred at the same temperature for two hours, and then a saturated ammonium chloride aqueous solution was added and the mixture was extracted with ether. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (680 mg, 69%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH3:21])=[N:19][N:20]=3)[N:17]=2)[CH:7]=1)=[O:4].[H-].[Na+].CI.[C:27](=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH3:22])[C:3]([N:5]([CH3:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH3:21])=[N:19][N:20]=3)[N:17]=2)[CH:7]=1)=[O:4]
Reactant: O=C([O-])O
Reactant: Cc1nnc2ccc(-c3cccc(NC(=O)N(C)C)c3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1nnc2ccc(-c3cccc(N(C)C(=O)N(C)C)c3)nn12
Reaction time: 0.5 h

Procedure:
A suspension of 1.0 g of N,N-dimethyl-N'-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]urea and 0.09 g of sodium hydride in 100 ml of dry dimethylformamide was stirred for 30 minutes, then 0.23 ml of methyl iodide was added. This solution was stirred overnight, then poured into saturated aqueous sodium bicarbonate and extracted with four 100 ml portions of dichloromethane. The extracts were combined and treated as described in Example 19, giving 0.8 g of the desired product as off-white crystals mp 159°-6° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[O:26]C2CCCCO2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:26][CH:22]1[CH2:23][CH2:24][CH2:25][CH:21]1[CH2:20][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)[C:12]([NH:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1)=[O:13]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2OC2CCCCO2)C(=O)Nc2nccs2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2O)C(=O)Nc2nccs2)cc1
Temperature: 60 °C
Yield: 26.7 %

Procedure:
A solution of 2-(4-methanesulfonyl-phenyl)-3-[2-(tetrahydropyran-2-yloxy)-cyclopentyl]-N-thiazol-2-yl-propionamide (350.8 mg, 0.73 mmol) in ethanol (7.3 mL) was treated with pyridinium p-toluenesulfonate (18.4 mg, 0.073 mmol). The resulting reaction mixture was heated at 60° C. for 4 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The resulting yellow residue was diluted with ethyl acetate (100 mL) and then washed with a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 1/3 hexanes/ethyl acetate) afforded the 3-(2-hydroxy-cyclopentyl)-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (77.0 mg, 27%) as a white solid: mp 205–206° C.; EI-HRMS m/e calcd for C18H22N2O4S2 (M+) 394.1021, foound 394.1018.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[N:5]=[C:6]=[O:7].[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17]>>[CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH:5][C:6]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:7]
Reactant: CC(C)(C)O
Reactant: COC(=O)[C@H](Cc1ccccc1)N=C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 99.5 %

Procedure:
To 60.9 g of the N-carbonyl-L-phenylalanine methyl ester, 66.0 g of t-butanol was added and the reaction was conducted under reflux for eight hours. Then, the unreacted t-butanol was distilled off at 65° C. under reduced pressure from the reaction solution to obtain 82.5 g of a crude oily N-t-butoxycarbonyl-L-phenylalanine methyl ester. The reaction yield was 99.5%. The optical purity of the N-t-butoxycarbonyl-L-phenylalanine methyl ester preparation was 97.5%ee.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>CS(C)=O.CCOC(C)=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][S:15][C:13](=[O:16])[CH3:14])=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: CC([O-])=S
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)SCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.6 %

Procedure:
A solution of 2.00 g (8.69 mmol) of 1-(2-bromo-ethyl)-4-nitro-benzene in DMSO (10 mL) was treated with 1.99 g (17.4 mmol) of potassium thioacetate and stirred at RT for 5 h. The mixture was diluted with EtOAc (100 mL) and washed with water (6×60 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 1.48 g (76%) of the title compound as a brown oil: 1H-NMR (CD3OD; 400 MHz): δ 8.23-8.15 (m, 2H), 7.60-7.53 (m, 2H), 3.27-3.10 (m, 4H), 3.03-2.94 (m, 3H).
Reaction SMILES: N[C@@H](C(C)C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.B.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:36]3[CH:37]=[C:38]4[O:43][CH2:42][O:41][C:39]4=[CH:40][C:35]=3[CH2:34][C:33]([CH3:44])=[N:32][N:31]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22]>C(Cl)Cl.C1COCC1.C(O)C>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:30]2[C:36]3[CH:37]=[C:38]4[O:43][CH2:42][O:41][C:39]4=[CH:40][C:35]=3[CH2:34][CH:33]([CH3:44])[NH:32][N:31]=2)=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Agent: B
Agent: CC(C)[C@H](N)C(O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCO
Solvent: C1CCOC1
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A solution of (S)-(-)-2-amino-3-methyl-1,1-diphenylbutan-1-ol (4.75 g) in dry methylene chloride was cooled to -70° C. and treated with a solution of borane in THF (1.8M, 9.5 ml) over a 20 minute period under an atmosphere of dry nitrogen. The resulting solution was gradually warmed to 0° C. and allowed to stand overnight at 4° C. This mixture was treated with a solution of 1-(4-nitrophenyl)-4-methyl-7.8-methylenedioxy-5H-2,3-benzodiazepine (5.0 g) in dry methylene chloride (100 ml) at room temperature over a period of about 1 hour. The resulting solution was allowed to stand at room temperature for seven days. The reaction was quenched by the addition of 10% sodium carbonate (15 ml). The resulting phases were separated, and the organic layer washed with water (2×50 ml), dried ever sodium sulfate, and concentrated in vacuo to give a yellow crystalline solid. This solid was suspended in ethanol (50 ml), filtered, and dried to give 4.47 g of the title compound. Proton NMR spectroscopy using a shift reagent (Eu(hfc)3) shows the product as 90:10 mixture of enantiomers. This material was dissolved in hot ethyl acetate (24 ml) and allowed to stand at room temperature overnight. The crystalline precipitate was separated by filtration, washed with ethyl acetate (3×5 ml), and dried to give 2.87 g of the title compound. Proton NMR spectroscopy using a shift reagent (Eu(hfc)3) shows this material to have an enantiomeric purity of more than 98%. Melting point 171°-172.5° C.