Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1.S(Cl)(Cl)(=O)=[O:21].C(O)C>ClCCl.ClC(Cl)C>[NH2:1]/[C:2](/[C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1=[O:21]
Reactant: O=S(=O)(Cl)Cl
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccc(F)cc1
Solvent: CC(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: N/C(=C1\C(=O)c2ccccc2S1=O)c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 15 h

Procedure:
2.61 gm (9.61 mmols) of (E)-2-[(amino)-4-fluorophenylmethylene]-benzo[b]thiophen-3(2H)-one were dissolved in 50 ml of dichloromethane, the solution was cooled to -70° C, and then a solution of 1.5 gm (11.1 mmols) of sulfuryl chloride in 5 ml of dichloroethane was added dropwise thereto. After 15 hours, 20 ml of 95% ethanol were added, and the reaction mixture was brought to room temperature by removal of the cooling bath. It was then neutralized with aqueous sodium carbonate, the dichloromethane phase was dried with sodium sulfate, the solvent was evaporated in vacuo, and the residue was recrystallized from glacial acetic acid/ethanol (1:4 v/v).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Br:10]Br>C(O)(=O)C>[Br:10][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1
Reactant: BrBr
Reactant: c1ccc2sccc2c1
Solvent: CC(=O)O
Product: Brc1csc2ccccc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
Benzothiophene (2.68 g, 20.0 mmol) was dissolved in glacial acetic acid (100 mL) and cooled to 0° C. The resulting solution was treated by dropwise addition of bromine (1.08 mL, 21.0 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The crude mixture was concentrated to an oil. The residue was purified by silica gel chromatography eluting with hexane to obtain 4.02 g (94%) 3-bromobenzothiophene.
Reaction SMILES: [NH2:1][C:2](=[N:29][N+:30]([O-:32])=[O:31])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1)=[O:17])[NH:8]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl.O>[NH2:1][C:2](=[N:29][N+:30]([O-:32])=[O:31])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](=[O:28])[CH3:27])=[CH:24][CH:25]=1)=[O:17])[NH2:8]
Reactant: CC(=O)c1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)c1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1

Procedure:
Prepared analogously to Example 5e) from (R)-N5 -[amino(nitroimino)methyl]-N2 -(tert.-butoxycarbonyl)-N-[[4-(1-oxoethyl)-phenyl]methyl]-ornithinamide by treating with trifluoroacetic acid in dichloromethane. The salt thus obtained was dissolved in water, this solution was made ammoniacal and the desired base was finally precipitated from the aqueous solution by saturating with common salt. The product obtained was dried in vacuo in diphosphorus pentoxide and used in the following stage without any further purification.
Reaction SMILES: [C:1]12([C:11]3[CH:31]=[CH:30][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=4[OH:29])[C:23](O)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:65][N:66]([CH3:70])[CH2:67][CH2:68][NH2:69].CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C.CO>[C:1]12([C:11]3[CH:31]=[CH:30][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=4[OH:29])[C:23]([NH:69][CH2:68][CH2:67][N:66]([CH3:70])[CH3:65])=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)O)ccc1O
Reactant: CN(C)CCN
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN(C)CCNC(=O)c1ccc(O)c(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Yield: 29.3 %

Procedure:
3-[2-(4-adamantan-1-yl-phenoxy)acetylamino]-4-hydroxy-benzoic acid (60.1 mg, 0.14 mmol) and PyBOP (148.3 mg, 0.29 mmol) in DMF 3.0 ml was added N,N-dimethylethylenediamine (25.1 mg, 0.29 mmol, 0.03 ml) and DIPEA (0.05 ml, 0.29 mmol) at room temperature. The reaction mixture was separated with ethyl acetate and sodium bicarbonate. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by preparative TLC(CH2C2:MeOH=7:1) to give 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-(2-dimethylamino-ethyl)-4-hydroxy-benzamide as a yellow solid (20.2 mg, 28.7% yield).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:12][CH2:13][CH2:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][CH2:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]1=2)=[O:5])C.[OH-].[Na+].[ClH:32]>C(O)C.O>[ClH:32].[CH:26]1[C:17]2[CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([CH2:14][CH2:13][CH2:12][N:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]3[C:4]([OH:5])=[O:3])[C:16]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCCCN1CCCN1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCCCN1CCCN1c2ccccc2CCc2ccccc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
The above ester (0.83 g, 0.002 mol) was dissolved in a mixture of ethanol (8 ml), water (2 ml) and sodium hydroxide (0.58 g, 0.015 mol). The reaction mixture was stirred at room temperature for 50 h and at 50° C. for 5 h. Water. (50 ml) and concentrated hydrochloric acid (3 ml) were added, and the resulting mixture was extracted with dichloromethane (3×10 ml). The combined organic extracts were washed with brine (2×20 ml), dried (MgSO4) and concentrated in vacuo. The residue was re-dissolved in methanol (2 ml) and ethyl acetate (5 ml) and concentrated in vacuo. The solid residue was washed with a small amount of ethyl acetate and dried, affording 0.6 g (73%) of the title compound as a powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(OCC)=O.[CH2:22]([NH2:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:22]([NH:30][C:13]([C@@H:11]1[CH2:12][C@H:10]1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:15])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCN
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a stirred slurry of 4.1 g. of trans-2-(4-nitrophenyl)cyclopropanecarboxylic acid in 50 ml. of chloroform was added 2.2 g. of triethylamine. The clear solution thus obtained was cooled to ca. 5° C., and a solution of 2.4 g. of ethyl chloroformate in 15 ml. of chloroform was added dropwise with stirring during 15 minutes. Stirring was continued for 20 minutes, and then a solution of 2.8 g. of octylamine in 15 ml. of chloroform was added dropwise with stirring, at 0°-5° C., during 10-15 minutes. The cooling bath was removed, and stirring was continued for 1 hour. At this point, the solvent was removed by evaporation in vacuo, and the residue was triturated under a mixture of 70 ml. of water and 15 ml. of ethanol. The solid which remained out of solution was recovered by filtration, washed with water, and dried, to give 6.2 g. of the title compound as a white solid, m.p. 126°- 129° C.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][CH:12]=1)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:13]([C:10]1[N:9]2[C:4](=[O:3])[NH:5][N:6]=[CH:7][C:8]2=[CH:12][N:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)NN=Cc1c[nH]c(Cc2ccccc2)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1[nH]ncc2cnc(Cc3ccccc3)n12

Procedure:
A 7.0 gm. portion of 3-[(2-benzyl-4-imidazolyl)methylene]carbazic acid ethyl ester in 50 ml. of diphenyl ether is reacted as described in Example 70 giving the desired product as white crystals. m.p. 215°-217° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29].Cl>>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2=[CH:11][C:10]3[C:14](=[O:16])[N:29]([CH2:28][C:27]4[CH:30]=[CH:31][CH:32]=[C:25]([O:24][CH3:23])[CH:26]=4)[C:17](=[O:18])[C:9]=3[CH:8]=[C:7]2[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: COc1cccc(CN)c1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1cccc(OC)c1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with m-methoxybenzylamine (0.17 mL, 1.3 mmol). Purification using silica gel, eluting with 3:1 hexane/acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 104 as a white solid (m.p. 247-248° C.).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[S:24][CH:23]=[CH:22][N:18]2[C:19](=[O:21])[CH:20]=1.[I:27]N1C(=O)CCC1=O.C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>C(#N)C>[CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[S:24][CH:23]=[CH:22][N:18]2[C:19](=[O:21])[C:20]=1[I:27]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC(C)(C)C
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC(C)(C)C

Procedure:
A solution of Step 1 intermediate (275 mg, 5.816 mmol) was treated with N-iodosuccinimide (143 g, 6.327 mmol) in acetonitrile (10 ml) according to the procedure described in Step 4 of Intermediate 2 to afford a crude product which was purified by column chromatography using 2% ethyl acetate in chloroform as eluent to afford 510 mg of the desired compound as a yellow solid; 1H NMR (300 MHz, DMSO-d6) 1.08 (s, 9H), 3.58 (m, 2H), 3.81 (m, 3H), 7.07-7.12 (m, 2H), 7.30-7.33 (m, 2H), 7.41-7.48 (m, 1H), 7.94-7.96 (m, 1H), 8.23-8.29 (m, 1H); ESI-MS (m/z) 497.21 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:55][C:56]1[CH:63]=[CH:62][C:59]([CH2:60][NH2:61])=[C:58]([C:64]([F:67])([F:66])[F:65])[CH:57]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:61][CH2:60][C:59]3[CH:62]=[CH:63][C:56]([F:55])=[CH:57][C:58]=3[C:64]([F:67])([F:65])[F:66])=[O:21])=[CH:22][CH:23]=2)[N:10]=1
Reactant: O=C(O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: NCc1ccc(F)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1C(F)(F)F)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 16.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoic acid (Intermediate-9, 0.100 g, 0.30 mmol), THF (5 mL), di-isopropyl ethyl amine (2.0 mL), TBTU (0.177 g, 0.540 mmol) and 4-fluoro-2-trifluoromethyl benzylamine (0.089 g, 0.600 mmol) to afford 0.025 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 4.63 (d, J=4.5 Hz, 2H), 7.48-7.50 (m, 6H), 8.05 (s, 4H), 9.16 (t, 1H), 12.67 (br, 1H); MS (m/z): 509.05 (M+H)+.
Reaction SMILES: COC(=O)[CH:4]([O:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)[C:5](=[O:40])[CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@H:12]1[C@@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:15][C@@H:14]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C@@H:13]1[CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].[Li+].[OH-]>C1COCC1>[Si:33]([O:32][CH2:31][C@H:13]1[C@H:14]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH2:15][C@H:16]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C@@H:12]1[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][C:5](=[O:40])[CH2:4][O:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)([C:36]([CH3:39])([CH3:37])[CH3:38])([CH3:34])[CH3:35]
Reactant: COC(=O)C(OC1CCCCO1)C(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@@H]1OC1CCCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@@H](C/C=C\CCCC(=O)COC2CCCCO2)[C@@H](OC2CCCCO2)C[C@H]1OC1CCCCO1
Yield: 85.5 %

Procedure:
Ketone of example 51 (60 mg, 0.086 mmol), THF (3 mL), and LiOH (0.3 ML, 1M in H2O, 0.34 mmol;) were combined and refluxed under N2 for 2 h. The THF was evaporated, the aqueous phase was extracted with CH2Cl2 (2×), and the combined organics were washed with brine and dried (Na2SO4) filtered and concentrated in vacuo. FCC (silica gel 1:4, EtOAc/hex) afforded the desired ketone (47 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:9]([O-])=O)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.O.O.[SH-].[Na+]>CO.CCO>[NH2:9][C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CCO
Solvent: CO
Product: Cc1ccc(O)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
7.00 g of 3-hydroxy-6-methyl-2-nitropyridine (Aldrich, 0.045 mol) was dissolved in 250 mL of MeOH and 20 mL of H2O along with 15 g of sodium hydrosulfide hydrate (6 eq, 0.27 mol). The reaction mixture was stirred under reflux for 5 hours. The reaction mixture was cooled to room temperature and diluted with 300 mL of absolute EtOH and concentrated to dryness. The resulting residue was dissolved in 300 mL of CH2Cl2 and 10 mL of MeOH. The mixture was sonicated for 10 min and allowed to stand at room temperature for 3 hours. The resulting salts that precipitated out at this point were removed by filtration. The filtrate was concentrated to afford the crude amine. This was purified by passing through a short plug of silica gel and eluting with 95% CH2Cl2, 4% MeOH and 1% Et3N. A total of 5.0 g of the desired amine was obtained (89% yield).
Reaction SMILES: [ClH:1].[CH:2]1([O:8][C:9]([C:11]2[N:12]=[C:13]([CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[S:14][CH:15]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C(OCC)C.O1CCOCC1>[Cl-:1].[CH:2]1([O:8][C:9]([C:11]2[N:12]=[C:13]([CH:16]3[CH2:17][CH2:18][NH2+:19][CH2:20][CH2:21]3)[S:14][CH:15]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)OC3CCCCC3)cs2)CC1
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(OC1CCCCC1)c1csc(C2CC[NH2+]CC2)n1
Product: [Cl-]
Temperature: 0 °C

Procedure:
Under argon and at 0° C., a 2-molar solution of hydrogen chloride in diethyl ether (50 ml) is added dropwise to a solution of tert-butyl 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (IX-1, 2.63 g) in dioxane (20 ml). The reaction mixture is stirred at 0° C. and then slowly warmed to room temperature. After stirring overnight, the solvent and excess hydrogen chloride are removed. This gives 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (2.19 g, 99%)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.CCO.[H][H]>CN(C=O)C.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl (1-(4-nitrophenyl)piperidin-4-yl)carbamate (I74) (1.038 g, 3.230 mmol) was dissolved in dry DMF (15 mL), EtOAc (15 mL) and absolute EtOH (15 mL) under an atmosphere of nitrogen. 10% Pd/C (0.200 g) in EtOAc (5 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with balloon and stirred at room temperature for 18 hours. The catalyst was removed by filtration through celite, which was washed with EtOAc (5×10 mL). The solvent was removed in vacuo to give a pink solid which was purified by silica gel chromatography using a gradient of 0-80% ethyl acetate in petroleum benzine 40-60° C. to give the title compound (I75) (0.730 g, 78%) as a purple-brown solid;
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].[Cl-].[Na+]>ClCCl>[CH3:23][S:24]([O:15][CH2:14][C:10]1([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:12][CH2:13]1)(=[O:26])=[O:25]
Reactant: OCC1(COCc2ccccc2)CCC1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(COCc2ccccc2)CCC1
Reaction time: 2 h

Procedure:
To a solution of 12.0 g (59.0 mmol) of {1-[(benzyloxy)methyl]cyclobutyl}methanol in 180 mL of dichloromethane was added 9.93 ml (70.8 mmol) of triethylamine at 0° C. followed by the addition of 5.02 mL (64.9 mmol) of methanesulfonyl chloride. After stirring for 2 h, saturated sodium chloride solution was added. The organic phase was isolated, dried using magnesium sulfate, and concentrated under vacuum to afford the crude product, which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 7.39-7.32 (m, 5H), 4.57 (s, 2H), 4.30 (s, 2H), 3.52 (s, 2H), 2.98 (s, 3H), 1.95 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH3:19][S:20]([C@@:8]1([OH:9])[C@:10]([S:20]([CH3:19])(=[O:22])=[O:21])([OH:11])[C@@H:12]([CH:13]([S:20]([CH3:19])(=[O:22])=[O:21])[OH:14])[O:15][C@H:7]1[N:6]1[CH:16]=[C:2]([CH3:1])[C:3](=[O:18])[NH:4][C:5]1=[O:17])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: Cc1cn([C@@H]2O[C@H](C(O)S(C)(=O)=O)[C@](O)(S(C)(=O)=O)[C@]2(O)S(C)(=O)=O)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a stirred mixture of 5-methyluridine (12.8 g, 50 mmol) in pyridine (75 mL) at 0° C. was added methanesulfonyl chloride (17.4 mL, 225 mmol). The reaction mixture was stirred at 0° C. for five hours then poured into ice-water (500 mL) with stirring. Trimethanesulfonyl-5-methyluridine (2) precipitated and the mixture was stirred for 5 min. The solid product was collected by filtration and washed with water (3×200 mL) and dried. Yield, 21.6 g, 89%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7](O)(=[C:12]1[C:20](=[O:21])[CH2:19][C:16]([CH3:18])([CH3:17])[CH2:15][C:13]1=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10]>CCO.C(O)(C(F)(F)F)=O>[NH:1]([C:7](=[C:12]1[C:13](=[O:14])[CH2:15][C:16]([CH3:17])([CH3:18])[CH2:19][C:20]1=[O:21])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)CC(O)=C1C(=O)CC(C)(C)CC1=O
Reactant: NCCC(=O)O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(NCCC(=O)O)=C1C(=O)CC(C)(C)CC1=O
Yield: 98 %

Procedure:
To a stirred suspension of H-β-Ala-OH (1.02 g, 11.4 mmol) and ivDde-OH (5 ml, 22.9 mmol) in EtOH was added TFA (88 μL, 1 mmol) at room temperature.1 The mixture was then refluxed for 24 hours. After the solvent was evaporated in vacuo, a crude product was purified by column chromatography with CH3OH/CH2Cl2 (0.1% TFA) gradient to afford ivDde-β-Ala-OH (3.3 g, 97.6%). 1H NMR (CDCl3) δ 1.02 (m, 12H), 1.90-2.03 (m, 1H), 2.39 (s, 4H), 2.75 (t, J=6.0 Hz, 2H), 3.06 (br d, J=6.0 Hz, 2H), 3.78 (q, J=6.0 Hz, 2H); 13C NMR (CDCl3) δ 22.8, 28.4, 29.4, 30.2, 34.1, 37.4, 39.6, 52.9, 107.4, 173.0, 177.2; MS (MALDI): m/z: calcd for C16H26NO4 296.2; found 296.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])O1.[C-:19]#[N:20].C([Al+]CC)C.[OH2:26].Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:26])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@@H:11]([CH3:12])[C:19]#[N:20]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O
Reactant: [C-]#N
Agent: CC[Al+]CC
Agent: Cl
Solvent: Cc1ccccc1
Product: C[C@@H](C#N)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution with 5 g (20.0 mmol) of optically active (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane dissolved in 40 ml of toluene, were added 80 ml of diethylaluminum cyanide (1.0M toluene solution) in a nitrogen atmosphere. The mixture was heated at 50° C. for 12 hours, and 10 ml of water and 120 ml of 1N HCl were successively added dropwise thereto. The resulting mixture was stirred for 2 hours at room temperature, filtered through a Florisil pad and then subjected to extraction with ethyl acetate. The resultant organic layer was washed 4 times with a liquid obtained by mixing water and saturated saline at a ratio of 1:1, and finally with saturated saline. After the solvent was distilled out under reduced pressure, the residue was washed with diisopropyl ether, thereby obtaining 3.15 g (56.6%) of optically active (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyronitrile. Physical properties of this product are described below.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:11][CH:12]=2)[N:7]([CH3:20])[CH:6]=1.[NH4+:22].[OH-]>>[CH3:20][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:9]=2)[C:5]([CH2:4][C:3]([NH2:22])=[O:2])=[CH:6]1
Reactant: COC(=O)Cc1cn(C)c2cc(N3CCOCC3)ccc12
Reactant: [NH4+]
Agent: [OH-]
Product: Cn1cc(CC(N)=O)c2ccc(N3CCOCC3)cc21
Reaction time: 24 h
Yield: 94 %

Procedure:
(1-Methyl-6-morpholin-4-yl-1H-indol-3-yl)-acetic acid methyl ester (2.67 g, 9.26 mmol) was suspended in concentrated NH4OH (20 mL) in a 100 mL flask, sealed and stirred for 24 h. The mixture was transferred into a 500 mL flask and more NH4OH (80 mL) was added. The flask was again sealed and stirring was continued for another 24 h. The volatiles were removed under reduced pressure. (1-methyl-6-morpholin-4-yl-1H-indol-3-yl)acetamide (2.39 g, 94%) was obtained after lyophilization.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH:15]O>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-:15])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(-c2ccccn2)c1
Reactant: OO
Solvent: CC(=O)O
Product: N#Cc1cccc(-c2cccc[n+]2[O-])c1

Procedure:
Starting from 2-(3-cyanophenyl)-pyridine, the title compound is prepared by oxidation with H2O2 in glacial acetic acid [J. Heterocycl. Chem. 11. 299 (974)].