Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:6]=[C:5]([NH:33][C:34]([NH:36][C@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[N:4]=1.[H-].[Na+].CC[O:49]C(C)=O.O.[CH2:54]1C[O:57][CH2:56][CH2:55]1>>[OH:49][CH:55]([CH3:54])[CH2:56][O:57][CH2:2][C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:6]=[C:5]([NH:33][C:34]([NH:36][C@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[N:4]=1
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@@H](C)c3ccccc3)nc(CCl)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@@H](C)c3ccccc3)nc(COCC(C)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To the solution of (S)-1-(4-(chloromethyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (50 mg, 0.083 mmol) in THF (1.0 ml) was added sodium hydride (4.98 mg, 0.125 mmol). The resulting reaction mixture was allowed to stir at rt for 10 min before (S)-1-(4-(chloromethyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (50 mg, 0.083 mmol) was added into the above solution. The reaction solution was stirred for 2 h at rt. EtOAc and water was added into the mixture and the organic layer was collected and washed by water and brine. After drying over Na2SO4, the solution was concentrated to give 1-(4-((2-hydroxypropoxy)methyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-((S)-1-phenylethyl)urea (53.3 mg, 0.083 mmol, 100% yield) without purification. MS: [M+H]+ m/z 642.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([N:9]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C@H:10]([C:23](OC)=[O:24])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)=[O:8])[N:4]=[CH:3]1.[BH4-].[Na+].Cl.O>C(O)C>[OH:24][CH2:23][CH:10]([N:9]([CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:7]([C:5]1[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=1)=[O:8])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=1
Reactant: COC(=O)[C@H](Cc1cccc(OC(F)(F)F)c1)N(C(=O)c1cn(C)cn1)C1CCOCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1cnc(C(=O)N(C2CCOCC2)C(CO)Cc2cccc(OC(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
To a solution of methyl N-[(1-methyl-1H-imidazol-4-yl)carbonyl]-N-(tetrahydro-2H-pyran-4-yl)-3-(trifluoromethoxy)phenylalaninate (55 mg) in ethanol (2.2 mL), sodium borohydride (23 mg) was added and the resulting mixture was heated under reflux for 3 hours. To the ice-cooled reaction mixture, 1 M HCl was added dropwise and the resulting mixture was stirred for 30 minutes at room temperature. After adding water, the mixture was subjected to extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure and the resulting residue was purified by TLC (silica gel plate; chloroform/methanol=10:1) and column chromatography (NH silica gel cartridge; chloroform) to give the titled compound (4.9 mg).
Reaction SMILES: [CH:1]1[C:6](O)=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9]([CH2:12][O:13][C:14]1[CH:24]=[CH:23][C:17]([CH:18](O)[C:19]([OH:21])=[O:20])=[CH:16][CH:15]=1)([OH:11])=[O:10]>O>[C:9]([CH2:12][O:13][C:14]1[CH:24]=[CH:23][C:17]([CH:18]2[C:1]3[CH:2]=[C:3]([CH3:8])[CH:4]=[CH:5][C:6]=3[O:21][C:19]2=[O:20])=[CH:16][CH:15]=1)([OH:11])=[O:10]
Reactant: O=C(O)COc1ccc(C(O)C(=O)O)cc1
Reactant: Cc1ccc(O)cc1
Solvent: O
Product: Cc1ccc2c(c1)C(c1ccc(OCC(=O)O)cc1)C(=O)O2
Yield: 81 %

Procedure:
A mixture of 41.6 g (0.39 mol) of p-cresol and 29.0 g (0.13 mol) of 4-carboxymethoxymandelic acid is maintained at 185° C. under a nitrogen atmosphere for 90 minutes, during which the water formed is distilled off. Excess p-cresol is then distilled off under reduced pressure. Crystallisation of the residue from 75 ml of xylene gives 31.4 g (81%) of 3-(4-carboxymethoxyphenyl)-5-methylbenzofuran-2-one, melting point 198°-203° C. (compound (101), Table 1).
Reaction SMILES: C1(C2ON=C(C3C(Cl)=CC=CC=3Cl)C=2COC2CCN(C3C=C(C4C=CC=CC=4)C(C(O)=O)=CC=3)CC2)CC1.C[O:41][C:42]([C:44]1[C:52]2[C:47](=[CH:48][C:49]([N:53]3[CH2:59][CH2:58][CH2:57][CH:56]([O:60][CH2:61][C:62]4[C:63]([C:70]5[C:75]([Cl:76])=[CH:74][CH:73]=[CH:72][C:71]=5[Cl:77])=[N:64][O:65][C:66]=4[CH:67]4[CH2:69][CH2:68]4)[CH2:55][CH2:54]3)=[CH:50][CH:51]=2)[N:46]([CH3:78])[CH:45]=1)=[O:43]>>[CH:67]1([C:66]2[O:65][N:64]=[C:63]([C:70]3[C:71]([Cl:77])=[CH:72][CH:73]=[CH:74][C:75]=3[Cl:76])[C:62]=2[CH2:61][O:60][CH:56]2[CH2:57][CH2:58][CH2:59][N:53]([C:49]3[CH:48]=[C:47]4[C:52]([C:44]([C:42]([OH:43])=[O:41])=[CH:45][N:46]4[CH3:78])=[CH:51][CH:50]=3)[CH2:54][CH2:55]2)[CH2:69][CH2:68]1
Reactant: COC(=O)c1cn(C)c2cc(N3CCCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)ccc12
Agent: O=C(O)c1ccc(N2CCC(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)CC2)cc1-c1ccccc1
Product: Cn1cc(C(=O)O)c2ccc(N3CCCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)cc21
Yield: 60.8 %

Procedure:
Following the procedure essentially as described in Example 1, Step 2 for 5-{4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-biphenyl-2-carboxylic acid, 6-{4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-azepan-1-yl}-1-methyl-1H-indole-3-carboxylic acid methyl ester (47 mg, 0.083 mmol) provided 28 mg (61%) of the title compound. LC-ES/MS m/z 554.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH:24]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:25]([O:27]C)=[O:26].[OH-].[Na+]>C1COCC1.CO.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH:24]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:25]([OH:27])=[O:26]
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(Cc1ccccc1)Oc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Yield: 92.4 %

Procedure:
A mixture of methyl 2-{[1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}-3-phenylpropanoate (197 mg, 0.363 mmol), prepared in the previous step, and 1 N NaOH (544 μL, 0.544 mmol) in 20 mL of THF plus 20 mL of methanol plus 10 mL of water was refluxed under nitrogen for 3 h. The reaction was filtered, acidified by the addition of 2 mL of 1 N HCl and then concentrated under reduced pressure. The solid was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (178 mg, 92%) as a white solid, mp 220-224° C. Elemental Analysis for C28H20BrNO3S+0.18H2O Calc'd: C, 63.02; H, 3.85; N, 2.62. Found: C, 63.13; H, 3.70; N, 2.54.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][S:14]2(=[O:20])=[O:19])[CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:54][O:55][C:56]1[CH:57]=[C:58]([CH:82]=[CH:83][CH:84]=1)[CH2:59][N:60]([CH2:68][C@@H:69]([OH:81])[C@@H:70]([NH2:80])[CH2:71][C:72]1[CH:77]=[C:76]([F:78])[CH:75]=[C:74]([F:79])[CH:73]=1)[C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64]>CN(C=O)C.C(OCC)(=O)C>[C:63]([O:62][C:61](=[O:67])[N:60]([CH2:68][C@@H:69]([OH:81])[C@@H:70]([NH:80][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][S:14]2(=[O:20])=[O:19])[CH:12]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)[CH2:71][C:72]1[CH:77]=[C:76]([F:78])[CH:75]=[C:74]([F:79])[CH:73]=1)[CH2:59][C:58]1[CH:82]=[CH:83][CH:84]=[C:56]([O:55][CH3:54])[CH:57]=1)([CH3:66])([CH3:64])[CH3:65]
Reactant: CC(=O)c1cc(C(=O)O)cc(N2CCCCS2(=O)=O)c1
Reactant: COc1cccc(CN(C[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)C(=O)OC(C)(C)C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cccc(CN(C[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(C)=O)cc(N3CCCCS3(=O)=O)c2)C(=O)OC(C)(C)C)c1
Reaction time: 0.17 h
Yield: 99.6 %

Procedure:
A mixture of 3-acetyl-5-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-benzoic acid (68.1 mg, 0.23 mmol), HATU (104.6 mg, 0.275 mmol) and Hunig's base (118.5 mg, 0.16 mL, 0.917 mmol) in DMF (1.1 mL) was stirred for 10 min and then tert-butyl 3-methoxybenzyl((2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl)carbamate (100 mg, 0.23 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with H2O 3 times and concentrated under vacuum to give the title compound (164 mg): 1H NMR (CD3OD, 500 MHz) δ ppm 1.48 (9H, s), 1.93-2.00 (2H, m), 2.32-2.38 (2H, m), 2.64 (3H, s), 2.88 (1H, dd, J=10, 15 Hz), 3.08-3.15 (1H, m), 3.20-3.23 (1H, m), 3.27-3.39 (2H, m), 3.38 (1H, m), 3.74-3.82 (6H, m), 3.96-4.00 (1H, m), 4.20-4.29 (2H, m), 6.76 (1H, m), 6.91-6.92 (3H, m), 7.05-7.08 (2H, m), 7.35 (1H, m), 8.04 (1H, m), 8.07 (1H, m), 8.11 (1H, m). HPLC retention time: 2.112 min (method A). MS (ESI) (M+Na)+ 738.28.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: CCCCCO
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Product: CCCCCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Yield: 76 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and 1-pentanol (8.8 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107. The title compound was obtained in 76% yield (18.8 mg). 1H NMR (500 MHz, CDCl3) δ ppm 0.89-0.95 (m, 3 H) 1.32-1.42 (m, 4 H) 1.67-1.75 (m, 2 H) 2.45 (s, 3 H) 4.26 (t, J=6.77 Hz, 2 H) 6.87 (s, 1 H) 7.36 (dd, J=8.10, 7.63 Hz, 1 H) 7.42 (ddd, J=8.10, 2.36, 1.25 Hz, 1 H) 7.44 (dd, J=8.70, 1.95 Hz, 1 H) 7.69-7.73 (m, 3 H) 7.84 (ddd, J=7.63, 1.50, 1.25 Hz, 1 H). MS (ESI+) m/z 452 [M+H]+.
Reaction SMILES: CS/[C:3](=[N:9]\[C:10](=O)[CH:11]=[C:12]([CH3:14])[CH3:13])/[N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:16][NH:17][NH2:18]>>[CH3:16][N:17]1[C:10]([CH:11]=[C:12]([CH3:14])[CH3:13])=[N:9][C:3]([N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)=[N:18]1
Reactant: CS/C(=N\C(=O)C=C(C)C)N1CCCC1
Reactant: CNN
Product: CC(C)=Cc1nc(N2CCCC2)nn1C
Yield: 106 %

Procedure:
Was prepared in the same manner as described in General procedure 1d, using 3-Methyl-but-2-enoic acid 1-methylsulfanyl-1-pyrrolidin-1-yl-meth-(Z)-ylideneamide and methylhydrazine as starting materials. Extraction and evaporation of the solvents afforded 1-Methyl-5-(2-methyl-propenyl)-3-pyrrolidin-1-yl-1H-[1,2,4]triazole (261 mg/106%) as yellow oil. MS: m/z=207.1 (M+H+)
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.[NH:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CCOC(C)=O>[N:13]1([C:2]2[C:6]3[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=3[O:4][N:3]=2)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCNC1
Reactant: COc1ccc2c(Cl)noc2c1
Solvent: CCOC(C)=O
Product: COc1ccc2c(N3CCCNCC3)noc2c1
Temperature: 140 °C
Reaction time: 0.75 h

Procedure:
3-Chloro-6-methoxy-1,2-benzisoxazole (5.0 g, 27.2 mmol) and homopiperazine (8.2 g, 81.6 mmol) were combined and mechanically stirred under N2 at 140° C. for 45 minutes. The reaction mixture was cooled to room temperature, dissolved with EtOAc (500 ml), and the solution was washed with water, brine, dried over MgSO4, and concentrated in vacuo. Flash column chromatography (silica gel, 20% MeOH/CH2Cl2) provided the product (2.0 g, m.p. 74-75° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([F:9])=[CH:11][CH:12]=2)=[O:15])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Cl)n1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1cccc(Cl)n1)c1ccc(F)cc1
Temperature: 45 °C
Yield: 65.8 %

Procedure:
To a cold (0° C.) solution of 6-chloro-2-picoline (21.4 mL, 196.0 mmol) and ethyl 4-fluorobenzoate (57.5 mL 391.2 mmol) in tetrahydrofuran (311 mL) was added lithium bis(trimethylsilyl)amide (391 mL, 1.0 M in tetrahydrofuran, 391.0 mmol) dropwise via a pressure equalizing funnel over 1 hour. Upon complete addition, the cold bath was removed and the resultant solution was heated to 45° C. for 15 hours. The mixture was cooled to room temperature and quenched by the addition of water. Ether was added and the organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration gave a solid residue which was purified by recrystallization from ethyl acetate-hexanes to provide 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (32.2 g, 66%) as a tinted off-white solid existing as a keto-enol tautomeric mixture. 1H NMR (CDCl3): for the keto tautomer δ 8.11 (m, 2H), 7.66 (t, 1H), 7.30–7.25 (m 2H), 7.17 (t. 2H), 4.48 (s 2H). 19F NMR (CDCl3) δ−104.72 (keto), −111.64 (enol); MS m/z 250 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].[CH2:18]([NH:20][CH2:21][CH2:22][OH:23])[CH3:19]>C(Cl)Cl>[Si:14]([O:23][CH2:22][CH2:21][NH:20][CH2:18][CH3:19])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCNCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.5 %

Procedure:
DIPEA (5.48 ml, 31.38 mmol) and tert-butylchlorodimethylsilane (6.76 g, 22.42 mmol) were added to a solution of 2-(ethylamino)ethanol (1.998 g, 22.42 mmol) in DCM (39.3 ml) at room temperature. The mixture was stirred at room temperature for 20 hours, partitioned between H2O/Et2O (50 ml/50 ml). The aqeuous phase was extracted with ether (3×30 ml). The combined organic layers were concentrated under reduced pressure to give a residue which was re-dissolved in DCM (50 ml), dried (Na2SO4), filtered and concentrated under vacuum to give the title compound (3.9 g, yield: 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10]O)[C:6]=2[CH:12]=1.S(Cl)([Cl:15])=O>C(Cl)Cl.CN(C)C=O>[Cl:15][CH2:10][C:7]1[C:6]2[CH:12]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1coc2ccc(F)cc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1ccc2occ(CCl)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-fluorobenzofuran-3-ylmethanol (14 g) in methylene chloride (250 mL) was treated successively with 5 drops of dimethylformamide and thionyl chloride (28 mL). After stirring for 16 h at room temperature the reaction was concentrated in vacuo giving 3-chloromethyl-5-fluorobenzofuran as an oil (19.4 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.Cl.[CH3:10][N:11]([CH3:15])[CH2:12][CH2:13][Cl:14]>CCO>[Cl-:14].[CH3:10][N:11]([CH3:15])[CH2:12][CH2:13][N+:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccncc1
Reactant: CN(C)CCCl
Agent: Cl
Solvent: CCO
Product: CSc1cc[n+](CCN(C)C)cc1
Product: [Cl-]

Procedure:
The starting material may be obtained as follows: Reaction of 4-methylthiopyridine with one equivalent of 2-dimethylaminoethyl chloride hydrochloride in EtOH at reflux for 18 hours gave 1-(2-dimethylaminoethyl)-4-methylthiopyridinium chloride. n.m.r. in solvent B: 2.7(s, 3H); 2.87(s, 6H); 3.75(t, 2H); 4.92(t, 2H); 7.98(d, 2H); 8.84(d, 2H). Oxidation of this compound with metachlorperbenzoic acid in CH2Cl2 /TFA at 0° to ambient temperature for 40 minutes gave 1-(2-dimethylaminoethyl)-4-methanesulphinylpyridinium chloride. n.m.r. in solvent B: 3.0(s, 6H); 3.34(s, 3H); 3.87(t, 2H); 5.16(t, 2H); 8.52(d, 2H); 9.36(d, 2H).
Reaction SMILES: C1C=CC=CC=1.[Br:7]Br.P(Br)(Br)Br.[C:13]1(=[O:20])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[Br:7][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:13]1=[O:20]
Reactant: O=C1CCCCCN1
Reactant: BrBr
Agent: BrP(Br)Br
Solvent: c1ccccc1
Product: O=C1NCCCCC1Br
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A benzene (50 g; manufactured by JUNSEI CHEMICAL Co., Ltd.) solution in which 240 g (1.5 mol) of bromine (manufactured by JUNSEI CHEMICAL Co., Ltd.) were dissolved was cooled with ice to 10° C. To the cooled solution, 450 g (1.6 mol) of 90% phosphorus tribromide (manufactured by Wako Pure Chemical Industries Ltd.) were added while the temperature of the reaction solution was maintained at 10° C. or less, and the resultant reaction solution was stirred for 60 minutes. Into the reaction solution, a benzene (220 g) solution in which 85 g (0.75 mol) of commercially available 6-hexanolactam (trade name: ε-caprolactam; manufactured by Tokyo Chemical Industry Co., Ltd.) were dissolved was added dropwise through a dropping funnel over 30 minutes while maintaining the temperature of the reaction solution at 10° C. or less.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=O)([O-:3])=[O:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][NH2:9])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCc1cccc([N+](=O)[O-])c1

Procedure:
Commercially available 3-nitrobenzamide is reduced with LAH under standard conditions to afford (3-nitrophenyl)methanamine, which is reacted with 4-methoxybenzylisocyanate to afford 1-(3-nitrobenzyl)-3-(4-methoxybenzyl)urea. This material is subsequently reacted with oxalyl chloride to afford 1-(3-nitrobenzyl)-3-(4-methoxybenzyl)imidazolidine-2,4,5-trione whose nitro group is reduced and oxidized to afford 1-(3-hydrazinylbenzyl)-3-(4-methoxybenzyl)imidazolidine-2,4,5-trione. This material is deprotected with TFA under standard conditions to afford the title compound I-(3-hydrazinylbenzyl)imidazolidine-2,4,5-trione.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14]O>C(Cl)Cl>[C:1]([O:4][C@@:12]([CH3:14])([CH2:11][CH2:10][CH3:9])[C:13]#[N:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CO
Reactant: c1ccncc1
Solvent: ClCCl
Product: CCC[C@@](C)(C#N)OC(C)=O
Temperature: 25 °C
Reaction time: 34 h
Yield: 95 %

Procedure:
The purified cyanohydrin was dissolved in 2 ml of absolute methylene chloride and the solution was treated at room temperature with 2 mol equivalents of acetic anhydride and with 2 mol equivalents of pyridine and stirred at room temperature for 34 hours with exclusion of moisture. 350 μl of absolute methanol were then added and the mixture was stirred at room temperature for 0.5 hour. It was then diluted with 10 ml of methylene chloride and extracted with 10 ml each of 5% H2SO4, distilled water and saturated NaHCO3 solution and dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. 112 mg (95%) of (S)-2-acetoxy-2-methylpentanenitrile were obtained. e.e.=75% (determined by gas chromatography)
Reaction SMILES: [Cl:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:9]=2)[N:7]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>C(#N)C>[ClH:1].[CH:20]1([CH2:19][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[C:8]([C:6]3[N:7]=[C:3]([CH2:2][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])[S:4][CH:5]=3)=[CH:9]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1cccc2c(-c3csc(CCl)n3)cn(CC3CCCCC3)c12
Reactant: CCNCC
Solvent: CC#N
Product: CCN(CC)Cc1nc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)cs1
Product: Cl

Procedure:
Methanesulfonyl chloride (174 μl, 2.25 mmol) was added to a solution of 1-(cyclohexyl)methyl-3-[2-(hydroxymethyl)thiazol-4-yl]7-methoxy-1H-indole (0.40 g, 1.12 mmol) and pyridine (182 μl, 2.25 mmol) in dichloromethane (8 ml). The resulting mixture was stirred at room temperature overnight. Further methanesulfonyl chloride (87 μl, 1.12 mmol) was added and stirring continued for 0.5 h. The mixture was concentrated in vacuo and the resulting orange residue was purified by flash column chromatography eluting with dichloromethane to afford 3-[2-(chloromethyl)thiazol-4-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole as a yellow oil (0.415 g). 3-[2-(Chloromethyl)thiazol-4-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole (0.08 g, 0.214 mmol) and diethylamine (221 μl, 2.14 mmol) were dissolved in acetonitrile (2 ml). The resulting mixture was exposed to microwave irradiation at 100° C. for 5 min. The mixture was concentrated in vacuo and the resulting residue was purified by column chromatography eluting with 33% (v/v) ethyl acetate in n-heptane. The resulting product was taken up in diethyl ether and hydrogen chloride (1M solution in diethyl ether; 1 ml) was added. The solution was concentrated in vacuo and the resulting solid triturated with ether, then dried to afford the title compound as a 1:1 hydrochloride salt (0.034 g). 1H NMR (400 MHz, CD3OD) δ 0.99-1.25 (5H, m), 1.43 (6H, t, J 7.5), 1.56-1.90 (6H, m), 3.35-3.42 (4H, m), 3.96 (3H, s), 4.27 (2H, d, J 7.5), 4.75-4.80 (2H, s, masked by H2O peak), 6.75 (1H, d, J 8.0), 7.08 (1H, dd, J 8.0, 8.0), 7.64-7.68 (3H, m). EsIMS: m/z 412.1 [M+H]+, 339.0.
Reaction SMILES: [P:1]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9]C(C)(C)[O:11]2)[C@H:7]([N:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH2:23])=[O:22])[C:16]2=[O:24])[O:6]1)=[O:2].Cl>O1CCCC1.O>[P:1]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([O:3][CH2:4][C@@H:5]1[C@@H:12]([OH:11])[C@@H:8]([OH:9])[C@H:7]([N:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH2:23])=[O:22])[C:16]2=[O:24])[O:6]1)=[O:2]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COP(=O)(OCc1ccccc1)OCc1ccccc1)O[C@H]2n1ccnc(C(N)=O)c1=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1nccn([C@@H]2O[C@H](COP(=O)(OCc3ccccc3)OCc3ccccc3)[C@@H](O)[C@H]2O)c1=O
Reaction time: 48 h
Yield: 43 %

Procedure:
In a mixture of 2 mL of tetrahydrofuran and 1 mL of water was dissolved 100 mg of {(3aR,4R,6R,6aR)-6-[3-(aminocarbonyl)-2-oxo-1(2H)-pyrazinyl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl dibenzyl phosphate. After adjusting the pH value to 0.5 with 6 mol/L hydrochloric acid, the mixture was left to stand at room temperature for 2 days. The deposited solid matter was collected by filtration and washed with ethanol to obtain 40 mg of {(2R,3S,4R,5R)-5-[3-(aminocarbonyl)-2-oxo-1(2H)-pyrazinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl dibenzyl phosphate as a solid product.