Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([OH:13])=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:10][C:9]=2[N:20]=1)([CH3:4])[CH3:3].[C:21]([O-])(=[O:23])[CH3:22].[Na+]>C(OC(=O)C)(=O)C>[C:21]([O:13][C:12]1[C:8]2[CH:7]=[CH:6][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[N:20][C:9]=2[S:10][C:11]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)c1ccc2c(O)c(-c3ccccc3)sc2n1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1c(-c2ccccc2)sc2nc(C(C)(C)C)ccc12
Yield: 91.6 %

Procedure:
A solution of 1.42 g (5 mmol) of 6(1,1-dimethylethyl)-3-hydroxy-2-phenyl-7-azabenzo[b]thiophene and 1.42 g sodium acetate in 20 mL of acetic anhydride was heated at reflux for 1 hour. The solution was concentrated and the residue was partitioned between ether and water. The ether layer was washed with sodium bicarbonate solution and brine, dried and concentrated. The residue was crystallized from ether-hexane to afford 1.49 g (91%) of fine white needles, m.p. 128°-9° C.
Reaction SMILES: N#N.C[O:4][C:5]([C:7]1[O:8][C:9]([CH2:12][N:13]2[N:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[N:14]2)=[CH:10][CH:11]=1)=O.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.C1(C)C=CC=CC=1>[N+:18]([C:16]1[CH:15]=[N:14][N:13]([CH2:12][C:9]2[O:8][C:7]([CH2:5][OH:4])=[CH:11][CH:10]=2)[N:17]=1)([O-:20])=[O:19]
Reactant: COC(=O)c1ccc(Cn2ncc([N+](=O)[O-])n2)o1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cnn(Cc2ccc(CO)o2)n1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(4-nitro-[1,2,3]triazol-2-ylmethyl)-furan-2-carboxylic acid methyl ester (325 mg, 1.28 mmol) in THF (13.0 mL) was treated dropwise, at −10° C. with DiBAL (4.36 mL of a 1M solution in toluene, 4.36 mmol). The reaction mixture was stirred at −10° C. for 1 h followed by 1 h at rt. Sat. aq. Rochelle's salt (40 mL) was added and the reaction mixture was stirred for 1 h at rt. The aq. layer was extracted with EA (2×30 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound: TLC:rf (50:50 hept-EA)=0.28. LC-MS-conditions 02: tR=0.77 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[I:14]I.O>CN(C)C=O.C(OCC)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[I:14]
Reactant: II
Reactant: COC(=O)c1ccc(N)nc1OC
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)c(N)nc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
A mixture of methyl 6-amino-2-(methyloxy)-3-pyridinecarboxylate (2.1 g, 11.8 mmol) and iodine (15 g, 59 mmol) in N,N-dimethylformamide (50 ml) was stirred overnight at room temperature. The mixture was poured into water (200 ml) and extracted with ethyl acetate (50 ml×2). The combined organic layer was washed with saturated sodium bicarbonate, 20% aqueous thiosulphate and brine, dried over magnesium sulfate, and concentrated in vacuo gave a brown solid. The residue was suspended in diethyl ether and collected by filtration to afford 2.9 g (79%) of the title compound as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[CH3:15]C(C(OC)=O)C(OC)=O>>[Cl:8][C:6]1[C:7]([CH3:15])=[C:2]([Cl:1])[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:5]=1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: COC(=O)C(C)C(=O)OC
Product: Cc1c(Cl)nc(N2CCOCC2)nc1Cl

Procedure:
4,6-Dichloro-5-methyl-2-morpholinopyrimidine was prepared by similar procedure as 4,6-dichloro-2-morpholinopyrimidine (in Method 22) using dimethyl 2-methylmalonate in place of diethyl malonate. LC/MS (m/z): 248.1 (MH+).
Reaction SMILES: [Cl-:1].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C@:10]([OH:52])([C@H:33]([N:35]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH:50]=[N:49][N:48]=[N:47]3)=[CH:42][CH:41]=2)[C:36]1=[O:51])[CH3:34])[CH2:11][NH+:12]1[CH2:16][N:15]([CH2:17][O:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][O:25]CC2C=CC=CC=2)=[O:20])[CH:14]=[N:13]1.Cl>CO.[C].[Pd]>[Cl-:1].[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[C@:10]([OH:52])([C@H:33]([N:35]1[CH2:39][CH2:38][N:37]([C:40]2[CH:41]=[CH:42][C:43]([N:46]3[CH:50]=[N:49][N:48]=[N:47]3)=[CH:44][CH:45]=2)[C:36]1=[O:51])[CH3:34])[CH2:11][NH+:12]1[CH2:16][N:15]([CH2:17][O:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:20])[CH:14]=[N:13]1
Reactant: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(C[NH+]1CN(COC(=O)OCCCOCc2ccccc2)C=N1)c1ccc(F)cc1F
Agent: [Pd]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(C[NH+]1CN(COC(=O)OCCCO)C=N1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.8 %

Procedure:
1-[(2R,3R)-2-(2,4-Difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[(3-benzyloxypropoxy)carbonyloxymethyl]-1H-1,2,4-triazolium chloride(Compound 25, 0.66 g) was dissolved in methanol (25 ml), and to the solution were added 1N-hydrochloric acid (0.89 ml) and 10% palladium-carbon (50% wet, 0.33 g). The mixture was stirred for 1.5 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent: methanol/water=3/2) and recrystallized from ethanol to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[(3-hydroxypropoxy)carbonyloxymethyl]-1H-1,2,4-triazolium chloride(Compound 26, 0.19 g) as colorless powdery crystals.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([O:18][CH3:19])=[O:17])=[CH:5][CH:4]=1.[Br:20][Si](C)(C)C>C(Cl)Cl>[Br:20][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([O:18][CH3:19])=[O:17])=[CH:5][CH:4]=1
Reactant: COC(=O)Nc1ccccc1-c1ccc(CO)cc1
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: COC(=O)Nc1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.8 %

Procedure:
A solution of 4-hydroxymethyl-2'-(methoxycarbonyl)amino-1,1'-biphenyl (239 mg, 0.93 mmol) in methylene chloride (4 mL) was treated with bromotrimethylsilane (3.0 mL, 22.7 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with additional methylene chloride and washed with saturated aqueous sodium chloride. After drying over magnesium sulfate, the filtered organic layer was evaporated under vacuum The residue was purified by preparative thin layer chromatography on silica gel, eluting with methylene chloride/methanol (100:3) to give 190 mg of the product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:5]=[C:4]([C:20]#[N:21])[CH:3]=1.C1COCC1.[NH4+:27].[OH-]>C(OCC)(=O)C>[NH2:27][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:5]=[C:4]([C:20]#[N:21])[CH:3]=1
Reactant: [NH4+]
Reactant: N#Cc1cc(Cl)nc(SCc2ccc3ccccc3c2)n1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cc(N)nc(SCc2ccc3ccccc3c2)n1

Procedure:
6-chloro-2-(2-naphthylmethyl)thio-4-pyrimidine carbonitrile (Cpd 276; 60 mg, 3.07 mmol) was stirred in THF/NH4OH (1:1, 15 ml) at 22° C. for 6 hrs. The reaction was diluted with ethyl acetate, washed with brine, dried with MgSO4, then concentrated in vacuo: 871 mg (2.97 mmol, 97%), mp 154-155° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH:5]2[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C2[O:36]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.[NH4+].[Cl-]>O1CCCC1>[OH:36][CH:3]1[C:2](=[O:1])[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH:5]2[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)CCC2C1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)C(O)CC2C1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 41.7 %

Procedure:
To a solution of the product from Example 207A (0.20 g, 0.832 mmol) in anhydrous tetrahydrofuran (6 mL) at −78° C. under N2 was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.25 mL, 1.25 mmol). The resulting mixture was stirred at −78° C. for 20 minutes, and then a solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (0.326 g, 1.248 mmol) in anhydrous tetrahydrofuran (3 mL) was added dropwise. The mixture was stirred at −78° C. for 20 minutes and then warmed to −40° C. and stirred for 2 hours. A solution of NH4Cl (10% in water, 2 mL) was added, and the mixture was allowed to warm to room temperature and partitioned between water and ethyl acetate (5×). The combined organic layers were dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-10% CH3OH in CH2Cl2 to give the title compound (89 mg, 42%).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7][CH:6]=1)=[O:4].O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:13][CH2:12][N:11]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]3)[CH2:10][CH2:9]2)[CH2:7][CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)C1=CCC2(CCNCC2)c2ccccc21
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCCl
Solvent: CO
Product: CCOC(=O)N1CCC(N2CCC3(CC=C(C(=O)N(C)C)c4ccccc43)CC2)CC1
Reaction time: 18 h

Procedure:
A solution of N,N-dimethyl-2H-spiro[naphthalene-1,4′-piperidine]-4-carboxamide (B3) (33 mg, 0.13 mmol) and ethyl 4-oxopiperidine-1-carboxylate (60 mg, 0.35 mmol) in 1,2-dichloroethane (2 ml) was stirred at 40° C. for 5 h, followed by addition of titanium (IV) isopropoxide (0.05 ml, 0.17 mmol). The reaction mixture was stirred for 18 h and treated with sodium triacetoxyborohydride (50 mg, 0.23 mmol) for 24 h. Methanol (1 ml) was added and the reaction mixture was stirred for 1 h, evaporated and the residue was dissolved in methanol (1 ml) and purified by C-18 HPLC to give ethyl 4-(4-(dimethylcarbamoyl)-2H-spiro[naphthalene-1,4′-piperidine]-1′-yl)piperidine-1-carboxylate (Compound No. 4). LC-MS: m/e=426.3 (M+H). Rt=1.55 min. 1H-NMR (500 MHz, DMSO-d6): 9.32 (br. s, 1H), 7.39 (d, 1H), 7.34 (t, 1H), 7.26 (t, 1H), 6.95 (d, 1H), 5.97 (t, 1H), 4.12 (d, 2H), 4.05 (q, 2H), 4.04 (m, 2H), 3.43 (br. d, 2H), 3.22 (q, 2H), 2.98 (s, 3H), 2.81 (s, 3H), 2.80 (m, 1H), 2.56 (d, 2H), 2.14-2.07 (m, 4H), 1.92 (d, 2H), 1.56 (qd, 2H), 1.19 (t, 3H).
Reaction SMILES: [Sn](O)(C)(C)C.C[O:7][C:8]([C:10]1[N:11]=[C:12]([CH:15]([OH:40])[CH2:16][CH:17]([N:21]([C:30](=[O:39])[CH:31]([N:36]=[N+:37]=[N-:38])[CH:32]([CH3:35])[CH2:33][CH3:34])[CH2:22][O:23][C:24](=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27])[CH:18]([CH3:20])[CH3:19])[S:13][CH:14]=1)=[O:9]>ClC(Cl)C>[N:36]([CH:31]([CH:32]([CH3:35])[CH2:33][CH3:34])[C:30]([N:21]([CH2:22][O:23][C:24](=[O:29])[CH2:25][CH:26]([CH3:27])[CH3:28])[CH:17]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH:15]([C:12]1[S:13][CH:14]=[C:10]([C:8]([OH:9])=[O:7])[N:11]=1)[OH:40])=[O:39])=[N+:37]=[N-:38]
Reactant: CCC(C)C(N=[N+]=[N-])C(=O)N(COC(=O)CC(C)C)C(CC(O)c1nc(C(=O)OC)cs1)C(C)C
Agent: C[Sn](C)(C)O
Solvent: CC(Cl)Cl
Product: CCC(C)C(N=[N+]=[N-])C(=O)N(COC(=O)CC(C)C)C(CC(O)c1nc(C(=O)O)cs1)C(C)C
Temperature: 55 °C
Yield: 35.5 %

Procedure:
Me3SnOH (736 mg, 4.07 mmol) was added to a 0.020 M solution of methyl ester 15 (260 mg, 0.509 mmol) in dichloroethane (25.0 mL). The reaction mixture was heated to 55° C. for 22 h and then concentrated. Normal-phase HPFC (100:0 to 90:10:1 CH2Cl2:MeOH:AcOH) followed by reverse-phase HPFC (20:80 to 100:0 MeCN:H2O) and lyophilization afforded 90.0 mg (36%) of 16 as an amorphous solid. [α]D23=+51.5 (c=1.0, MeOH). IR: 1088, 1217, 1651, 1735, 2100, 2964 cm−1. 1H NMR (500 MHz, MeOD): δ 0.88-0.94 (m, 9H), 0.97 (app t, 6H, J=6.8), 1.03 (d, 3H, J=6.5), 1.31 (sept, 1H, J=7.4), 1.72-1.81 (m, 1H), 1.82-1.90 (br s, 1H), 100-2.09 (m, 2H), 2.10-2.17 (m, 1H), 2.18-2.28 (m, 1H), 2.31 (app t, 2H, J=7.5), 3.75 (d, 1H, J=9.5), 4.44-4.68 (br s, 1H), 4.77 (d, 1H, J=9.5), 5.48 (d, 1H, J=12.5), 5.58 (d, 1H, J=12.5), 8.24 (s, 1H). 13C NMR (125 MHz, MeOD): δ 10.8, 16.0, 20.3, 20.6, 22.71, 22.73, 26.0, 26.5, 32.0, 36.7, 39.1, 44.1, 64.6, 69.5, 128.5, 149.2, 164.7, 173.58, 173.61, 179.5. HRMS (FAB) calcd for C22H35N5O6SNa (M+Na): 520.2206. Found: 520.2200.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1>[Fe].C(O)C.O>[NH2:23][C:20]1[CH:21]=[CH:22][C:3]([Cl:2])=[C:4]([CH:19]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc([N+](=O)[O-])ccc2Cl)CC1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(N)ccc2Cl)CC1
Yield: 86.2 %

Procedure:
Iron (1.7 g, 26.7 mmol) and concentrated hydrochloric acid (0.2 mL) were added to ethanol/water (45 mL/45 mL), and refluxed for 1 hour. The mixed reaction solution was added with tert-butyl 4-(2-chloro-5-nitrobenzyl)piperazine-1-carboxylate (1.9 g, 5.34 mmol) obtained in <Step 1> above, and further refluxed for 1 hour. The reaction mixture was filtered through a Celite pad under reduced pressure, and washed with ethanol and chloroform/2-propanol=3/1 (v/v). The resulting filtrate was distilled under reduced pressure and dissolved in ethanol and chloroform/2-propanol=3/1 (v/v). The organic layer was washed with an aqueous solution of sodium bicarbonate and brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (chloroform:methanol=30:1 (v/v)) to obtain the title compound (1.5 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.[CH:24]([C:27]1[S:28][CH:29]=[C:30]([CH2:32][CH2:33][NH2:34])[N:31]=1)([CH3:26])[CH3:25].CCN(CC)CC.Cl.CN(C)CCCN=C=NCC>C1COCC1.O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:34][CH2:33][CH2:32][C:30]1[N:31]=[C:27]([CH:24]([CH3:26])[CH3:25])[S:28][CH:29]=1)=[O:9]
Reactant: CC(C)c1nc(CCN)cs1
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc(CCNC(=O)c2cc(Cl)ccc2O)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-chlorosalicylic acid (863 mg, 5.0 mmol, 1.0 eq.) in THF (3 mL) and water (4 mL), 1-hydroxybenzotriazole hydrate (1.01 g, 7.5 mmol, 1.5 eq.) was added. The resulting solution was stirred at r.t. for 30 minutes. Then 2-(2-isopropyl-1,3-thiazol-4-yl)ethanamine hydrochloride (1.03 g, 5.0 mmol, 1.0 eq.) in THF (3 mL) and NEt3 (1.39 mL, 10.0 mmol, 2.0 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.44 g, 7.5 mmol, 1.5 eq) in water (4 mL) were added in sequence. The resulting mixture was stirred at r.t. for 18 hours. The reaction mixture was poured in sat. aq. NaHCO3 (75 mL). The mixture was extracted with AcOEt (2×50 mL). The comb. org. phases were washed with 1M aq. HCl soln. (50 mL) and sat. aq. NaCl soln. (1×20 mL), dried over MgSO4, and concentrated in vacuo to give the desired amide as a brown oil. The product was used without further purification.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[OH:11][C@H:12]([CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:13][N:14]1[CH2:19][CH2:18][C:17]2[NH:20][CH:21]=[C:22]([CH3:23])[C:16]=2[C:15]1=[O:24]>ClCCl>[OH:11][C@H:12]([CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:13][N:14]1[CH2:19][CH2:18][C:17]2[NH:20][C:21]([CH:8]=[O:9])=[C:22]([CH3:23])[C:16]=2[C:15]1=[O:24]
Reactant: Cc1c[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 74.9 %

Procedure:
Phosphorus oxychloride (674 μL, 4.04 mmol) and N,N-dimethylformamide (963 μL, 12.32 mmol) were dissolved in 21.18 mL of dichloromethane under stirring at room temperature, and the reaction solution was stirred for 15 minutes while maintaining the temperature at −10° C. in an ice-water bath. (R)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 1e (790 mg, 2.7 mmol) was dissolved in 10 mL of dichloromethane under stirring, and the solution was then added dropwise to the above reaction system. Upon completion of the addition, the ice-water bath was removed, and the reaction system was allowed to warm up to room temperature and stirred for another 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the reaction system was quenched with iced water and stirred for 15 minutes. The mixture was adjusted to pH about 12 with 10N sodium hydroxide solution and extracted with the solvent mixture of dichloromethane and methanol (V:V=20:1, 100 mL ×8). The combined organic extracts were washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to give the crude product (800 mg). The crude product was purified by silica gel column chromatography to give the title compound (R)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 1f (650 mg, yield 75%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[O:12].N1C2C(=CC=CC=2)C=[C:14]1C(OCC)=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:14])[CH:6]=[C:5]2[CH:11]=[O:12]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Product: Cn1cc(C=O)c2cc(F)ccc21
Yield: 50 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting 5-fluoro-1H-indole-3-carboxaldehyde (0.3 g, 1.8 mmole) for the ethyl indole-2-carboxylate, the title compound (0.16 g, 50%) was prepared as a viscous oil: MS (ES) m/e 178 (M+H)+.
Reaction SMILES: C1(C([O:14][C:15](=[O:53])[C@H:16]2[CH2:20][C@@H:19]([N:21]3[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[N:24]([C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:22]3=[O:23])[CH2:18][N:17]2CCNS(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)C2C=CC=CC=2)C=CC=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:30]([N:24]1[C:25](=[O:26])[C:27]([CH3:28])=[CH:29][N:21]([C@H:19]2[CH2:18][NH:17][C@@H:16]([C:15]([OH:53])=[O:14])[CH2:20]2)[C:22]1=[O:23])(=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1cn([C@@H]2C[C@H](C(=O)OC(c3ccccc3)c3ccccc3)N(CCNS(=O)(=O)c3ccccc3[N+](=O)[O-])C2)c(=O)n(C(=O)c2ccccc2)c1=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cn([C@H]2CN[C@@H](C(=O)O)C2)c(=O)n(C(=O)c2ccccc2)c1=O

Procedure:
A solution of N-(2-Nitrobenzenesulfonamidoethyl)-cis-4-(benzoylthymin-1-yl)-D-proline diphenylmethyl ester (5) (1.20 g, 0.46 mmol) was dissolved in dichloromethane (5 mL). Boc2O (110 mg, 0.50 mmol) and triethylamine (5 mL) was added with stirring followed by 4-dimethylaminopyridine (10 mg, cat.). The yellow solution was stirred at room temperature for 6.5 h then evaporated to dryness to give N-2-(N′-4-Nitrobenzenesulfonyl-N′-tert-butoxycarbonyl)aminoethyl)-cis-4-(benzoylthymin-1-yl)-D-proline as yellow foam. Treatment of this material (max 0.46 mmol) with anhydrous K2CO3 (85 mg, 0.60 mmol) and thiophenol (66 mg, 0.60 mmol) in DMF (2 mL) at room temperature afforded an orange-yellow solution. The reaction mixture was then diluted with dichloromethane, washed with water and evaporated to dryness. The resulting yellow oil was purified by column chromatography (SiO2; EtOAc:Light Petroleum 1:1→2:1) to give the product as white foam 186.3 mg (62%, 2 steps); δH (200 MHz; CDCl3) 1.46 [9H, s, tBu CH3], 1.90 [3H, s, thymine CH3], 1.95 and 2.60 [2H, 2×m, CH2(3′)], 2.70-3.30 [6H, m, CH2(5′) and 2×aminoethyl CH2], 3.42 [1H, dd, CH(2′)], 5.12 [1H, m, CH(4′)], 5.28 [1H, br m, NH], 6.98 [1H, s, CHPh2], 7.36 [10H, m, Dpm aromatic CH], 7.50 [2H, t, Bz m-CH], 7.63 [1H, t, Bz p-CH], 7.90 [2H, d, Bz o-CH] and 7.98 [1H, s, thymine C(6)H]; m/z (APCI+) 676 (M+Na+, 18.5%), 653 (M+H+, 59), 597 (M−C4H8+, 25), 554 (M−Boc+, 9), 475 (26.5), 167 (Ph2CH+, 100); [α]D22+6.5 (c=1.06, CHCl3)
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[N:17]=[C:16]([N:18]4[CH:22]=[C:21]([CH:23]=O)[C:20]([CH3:25])=[N:19]4)[CH:15]=[CH:14][N:13]=3)[CH:9]=2)[N:4]([CH3:26])[C:3]=1[CH3:27].Cl.[O:29]1[CH2:33][C@@H:32]([OH:34])[CH2:31][NH:30]1.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[N:17]=[C:16]([N:18]4[CH:22]=[C:21]([CH2:23][N:30]5[CH2:31][C@H:32]([OH:34])[CH2:33][O:29]5)[C:20]([CH3:25])=[N:19]4)[CH:15]=[CH:14][N:13]=3)[CH:9]=2)[N:4]([CH3:26])[C:3]=1[CH3:27]
Reactant: O[C@H]1CNOC1
Reactant: Cc1nn(-c2ccnc(Nc3ccc4c(c3)c(Cl)c(C)n4C)n2)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(-c2ccnc(Nc3ccc4c(c3)c(Cl)c(C)n4C)n2)cc1CN1C[C@H](O)CO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of Intermediate 3 (190 mg, 0.5 mmol), (S)-isoxazolidin-4-ol hydrochloride (95 mg, 0.75 mmol) and triethylamine (0.4 mL) in 10 mL of dichloromethane, was added NaBH(OAc)3 (0.32 g, 1.5 mmol) at room temperature. The reaction was stirred for 12 hour at room temperature and then quenched with 1N—NaOH. It was extracted with ethyl acetate and washed twice with brine. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography (DCM/MeOH) to afford desired Compound No. 31 as a pale yellow solid (159 mg, 70%); MS (ESI) m/z 454 [M+H]+. 1H NMR (300 MHz, CDCl3) δ 8.43 (s, 1H), 8.34 (d, J=5.4 Hz, 1H), 7.89 (s, 1H), 7.68 (s, 1H), 7.14-7.16 (m, 3H), 4.73 (brs, 1H), 4.23 (brs, 1H), 3.92-3.96 (m, 2H), 3.84 (brs, 1H), 3.63 (s, 3H), 3.25 (brs, 1H), 2.73 (brs, 1H), 2.40 (s, 3H), 2.36 (s, 3H
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[C:15]([N+]([O-])=O)[CH3:16])=[CH:10][N:9]=1)[CH3:3].C[OH:21]>[Fe]>[CH2:2]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:21])[CH3:16])=[CH:10][N:9]=1)[CH3:3]
Reactant: CO
Reactant: CCOCCOc1ccc(C=C(C)[N+](=O)[O-])cn1
Agent: [Fe]
Agent: Cl
Product: CCOCCOc1ccc(CC(C)=O)cn1

Procedure:
6.5 ml of concentrated hydrochloric acid are added dropwise to a boiling suspension of 800 mg (3.2 mmol) of 1-[2-(2-ethoxyethoxy)-5-pyridyl]-2-nitro-1-propene and 710 mg of iron filings in 10 ml of methanol. After 30 minutes the mixture is filtered and diluted with water. It is washed with ether, adjusted to pH 7 and extracted with ether. The organic phase is washed with 1% strength aqueous sodium hydroxide solution and then with water, dried over sodium sulphate and evaporated.