Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34](=[O:36])[CH3:35])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:42]>Cl.O1CCOCC1>[ClH:42].[ClH:42].[CH2:37]([C:18]1[N:17]=[N:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][C:19]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:23]([C:34](=[O:36])[CH3:35])[CH:22]=1)[CH2:38][CH2:39][CH3:40]
Reactant: ClCCl
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(C)=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(C(C)=O)c1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 4-[5-(3-acetyl-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.17 mmol) in DCM (2.0 mL), 4.0 M HCl in dioxane (2.0 mL) was added and stirring continued for 30 min. Solvent evaporated, resulting solid was washed with ether, dried to provide 1-{5-[3-butyl-6-(piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenyl}ethanone dihydrochloride salt (60 mg).
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:7][O:6][CH2:5][C:4](=[O:8])[NH:3]1.[NH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1O>>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]2[O:14][C:12]([C:11]3[CH:10]=[C:9]([C:2]4([CH3:1])[NH:3][C:4](=[O:8])[CH2:5][O:6][CH2:7]4)[CH:17]=[CH:16][CH:15]=3)=[N:18][C:19]=2[CH:24]=1
Reactant: CC1(c2cccc(C(=O)O)c2)COCC(=O)N1
Reactant: Nc1cc(Cl)ccc1O
Product: CC1(c2cccc(-c3nc4cc(Cl)ccc4o3)c2)COCC(=O)N1

Procedure:
The condensation of 3-((RS)-3-methyl-5-oxo-morpholin-3-yl)-benzoic acid (intermediate XXVI-1) and 2-amino-4-chloro-phenol with polyphosphoric acid at 130° C. during 3 hours yielded the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[N:40]([CH:41]([O:43][CH2:44][CH3:45])[CH3:42])[N:39]=[N:38][N:37]=3)=[CH:26][CH:25]=2)[C:8]2=[N:9][C:10]([C:19]([OH:21])=[O:20])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(NCC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:5]([N-:6][CH2:7][CH3:12])[CH3:1].[CH2:1]([C:5]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[N:40]([CH:41]([O:43][CH2:44][CH3:45])[CH3:42])[N:39]=[N:38][N:37]=3)=[CH:26][CH:25]=2)[C:8]2=[N:9][C:10]([C:19]([O-:21])=[O:20])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:12]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(-c3ccccn3)c(C(=O)O)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Agent: CN(C)c1ccncc1
Solvent: CCNCC
Solvent: ClCCl
Product: CCCCc1nc2cc(-c3ccccn3)c(C(=O)[O-])nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Product: CC[N-]CC
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.6 %

Procedure:
80 mg (0.13 mmole) of the compound obtained in step 1 was dissolved in 2 ml of CH2Cl2 and to the resulting solution were added 12 mg (0.16 mmole) of diethylamine, 33 mg (0.16 mmole) of DDC(Dithiocarb Sodium) and 2 mg (0.016 mmole) of DMAP. The resultant was stirred for 16 hours at room temperature and evaporated under reduced pressure to remove the residual solvent. The residue was purified with column chromatography (ethyl acetate) to obtain 34 mg of the title compound (yield 40%).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:32]1[C:33]2[C:34]3[CH:47]=[CH:46][S:45][C:35]=3[C:36](=[O:44])[NH:37][C:38]=2[CH:39]=[CH:40][C:41]=1[O:42][CH3:43]>>[CH:8]([NH:7][CH2:6][C:5]1[CH:11]=[CH:12][C:2]([C:32]2[C:33]3[C:34]4[CH:47]=[CH:46][S:45][C:35]=4[C:36](=[O:44])[NH:37][C:38]=3[CH:39]=[CH:40][C:41]=2[O:42][CH3:43])=[CH:3][CH:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)NCc1ccc(Br)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(C)C)cc1
Yield: 57 %

Procedure:
Following General Procedure E, N-(4-bromobenzyl)propan-2-amine (200 mg, 0.88 mmol) was reacted with bis(pinacolato)diboron (240 mg, 0.96 mmol) to afford the crude boronic ester which was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (270 mg, 0.88 mmol) to afford the desired product (190 mg, 57%) as a light brown solid: 1H NMR (500 MHz, CD3CD2OD) δ 7.68-7.63 (m, 2H), 7.56-7.49 (m, 2H), 7.41-7.34 (m, 3H), 6.04 (dd, J=5.4, 2.4 Hz, 1H), 4.33 (s, 2H), 3.72-3.67 (m, 3H), 3.56-3.50 (m, 1H), 1.45 (dd, J=6.6, 2.2 Hz, 6H).
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([CH:25]=O)=[CH:18][N:19]2[CH3:24].CN1C2C(=CC=CC=2)C(C)=C1C=O>>[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([CH2:25][NH:6][CH3:5])=[CH:18][N:19]2[CH3:24]
Reactant: Cn1cc(C=O)c2c(F)cccc21
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2cccc(F)c12
Yield: 77 %

Procedure:
According to the procedure of Preparation 11 (c), except substituting 4-fluoro-1-methyl-1H-indole-3-carboxaldehyde (0.3 g, 1.69 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.2 g, 77%) was prepared as a viscous oil: MS (ES) m/e 193 (M+H)+.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][CH2:19][C:20]2[C:25]([N+:26]([O-])=O)=[CH:24][N:23]=[C:22]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:21]=2)[CH2:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:26][C:25]1[C:20]([CH2:19][NH:18][CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:10])=[CH:21][C:22]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:23][CH:24]=1
Reactant: CC(C)(C)CCNC(=O)CC(NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)CCNC(=O)CC(NCc1cc(Oc2ccccc2)ncc1N)C1CCCCC1
Temperature: -78 °C
Reaction time: 3.5 h

Procedure:
In a Parr bottle 10% Pd/C (0.42 g) was added and cooled to −78° C., then a solution of 3-cyclohexyl-N-(3,3-dimethyl-butyl)-3-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-propionamide (0.42 g, 0.87 mmol) in ethyl acetate (5 mL) and ethanol (20 mL) was added. The resulting mixture was subjected to hydrogen atmosphere and shaken for 3.5 h. The hydrogen was purged with nitrogen, then the reaction mixture was filtered (glass fiber filter paper) and the solvent was evaporated under reduced pressure to yield the title compound as a residue.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[Cl:47][C:48]1[CH:65]=[CH:64][C:51]2[NH:52][C:53]([C@@H:55]([NH2:63])[CH2:56][C:57]3[CH:62]=[CH:61][N:60]=[CH:59][CH:58]=3)=[N:54][C:50]=2[CH:49]=1>CN(C)C=O>[Cl:47][C:48]1[CH:65]=[CH:64][C:51]2[NH:52][C:53]([C@@H:55]([NH:63][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:56][C:57]3[CH:58]=[CH:59][N:60]=[CH:61][CH:62]=3)=[N:54][C:50]=2[CH:49]=1
Reactant: N[C@@H](Cc1ccncc1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N[C@@H](Cc2ccncc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 0.150 g (0.579 mmol) of 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, 0.186 g (0.579 mmol) of TBTU, and 0.20 mL (1.78 mmol) of N-methylmorpholine in 2 mL of N,N-dimethylformamide is stirred for 10 minutes at ambient temperature and then combined with a solution of 0.158 g (0.579 mmol) of (S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-pyridin-4-ylethylamine. The reaction mixture is stirred for one day at ambient temperature, then poured onto ice water and extracted three times with ethyl acetate. The combined organic phases are dried with sodium sulfate and concentrated. The residue is chromatographed on silica gel, eluting with dichloromethane/methanol (95:10). Yield: 61.5 mg (22% of theory); Rf value: 0.44 (silica gel; dichloromethane/methanol=9:1); C27H26ClN5O2 (487.99); mass spectrum: (M−H)−=486/488 (chlorine isotope).
Reaction SMILES: [F:1][CH:2]([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].O.[NH2:10][NH2:11]>CCO>[F:1][CH:2]([F:8])[C:3]1[NH:11][N:10]=[C:5]([NH2:6])[CH:4]=1
Reactant: N#CCC(=O)C(F)F
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)F)[nH]n1
Temperature: 25 °C
Yield: 27 %

Procedure:
To a solution of 4,4-difluoro-3-oxobutanenitrile in EtOH (200 mL) was added hydrazine hydrate (30 mL). The reaction was heated at reflux for 12 h before cooling to RT. After evaporation in vacuo, the residue was extracted into DCM. The organic layers were washed with water, brine, dried (MgSO4). After filtration, the solvent was evaporated in vacuo. The crude product was purified by SiO2 chromatography to afford 5-(difluoromethyl)-1H-pyrazol-3-amine (8.0 g, 27% for two steps) as an oil: MS (ESI) m/z: 134.0 [M+1]+.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=1)[C:5](=O)[CH:6]([CH3:8])[CH3:7].[NH2:18]N>CO.CCOC(C)=O>[F:16][C:12]1[CH:11]=[C:10]([C:4]2[CH:3]=[N:2][NH:18][C:5]=2[CH:6]([CH3:8])[CH3:7])[CH:15]=[CH:14][N:13]=1
Reactant: CC(C)C(=O)C(=CN(C)C)c1ccnc(F)c1
Reactant: NN
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)c1[nH]ncc1-c1ccnc(F)c1
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To a solution of 1-dimethylamino-2-(2-fluoro-pyridin-4-yl)-4-methyl-pent-1-en-3-one (crude, 26.5 mmol) in methanol (50 mL) is added hydrazine (0.84 mL, 26.5 mmol) at 0° C. The reaction mixture is stirred for 4 h, diluted with EtOAc, and washed with water. The organic layer is washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography (SiO2, EtOAc/heptan 5:1) afforded 3.8 g of 2-fluoro-4-(5-isopropyl-1H-pyrazol-4-yl)-pyridine as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([OH:23])C.C(O)(=O)C.O>CC(O)(C)C.[Zn]>[CH3:20][N:18]([CH3:19])[CH2:17][CH2:16][C:12]1[CH:11]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C:2](=[O:23])[NH:1]3)[CH:15]=[CH:14][CH:13]=1
Reactant: CCO
Reactant: CN(C)CCc1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Zn]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CCc1cccc(-c2cccc3c2CC(=O)N3)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the suspension of {2-[3-(1H-indol-4-yl)-phenyl]-ethyl}-dimethyl-amine (600 mg, 2.2 mmol) in t-BuOH: ethanol: acetic acid (14.5 mL: 8.8 mL: 10.5 mL) was added pyridiniumn tribromide (2.3 g, 6.6 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (9.24 mL). Water (0.32 mL) and zinc dust (2.2 g, 61.2 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was dissolved in methanol (10 mL) and hydrogenated using 10% Pd-C for overnight. The reaction was filtered through celite and the filtrate was concentrated. The residue was purified on a silica gel column to give 4-[3-(2-dimethylamino-ethyl)-phenyl]-1,3-dihydro-indol-2-one
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH:5]1([NH:9][N:10]=[CH:11][C:12](=[O:14])[CH3:13])[CH2:8][CH2:7][CH2:6]1>O>[OH:14][C:12]1[C:11]([C:1](=[O:2])[CH3:3])=[N:10][N:9]([CH:5]2[CH2:8][CH2:7][CH2:6]2)[CH:13]=1
Reactant: O=CC=O
Reactant: CC(=O)C=NNC1CCC1
Solvent: O
Product: CC(=O)c1nn(C2CCC2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A 40% aqueous solution of glyoxal (1.13 mL, 9.84 mmol) was added to 2-oxopropanal cyclobutylhydrazone (1.38 g, 9.84 mmol) in H2O (70 mL). The mixture was then heated at reflux. After 1 hour, the mixture was cooled to room temperature and extracted with CH2Cl2 (4×). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford 1.53 g (86%) of 1-(4-hydroxy-1-cyclobutyl-1H-pyrazol-3-yl)ethanone as a yellow oil. The crude product was then used in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]1[CH2:14][NH:13][CH2:12][CH2:11][N:10]1[C:15]1[C:24]2[C:19](=[CH:20][C:21]([S:25]([NH:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][N:30]=3)(=[O:27])=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1.CC(C)([O-])C.[Na+].[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44](I)[CH:43]=1>O1CCOCC1>[F:41][C:42]1[CH:43]=[C:44]([N:13]2[CH2:12][CH2:11][N:10]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([S:25]([NH:28][C:29]5[CH:34]=[CH:33][N:32]=[CH:31][N:30]=5)(=[O:27])=[O:26])=[CH:22][CH:23]=4)[CH:18]=[CH:17][N:16]=3)[CH:9]([CH3:8])[CH2:14]2)[CH:45]=[CH:46][CH:47]=1
Reactant: CC1CNCCN1c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reactant: Fc1cccc(I)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CC1CN(c2cccc(F)c2)CCN1c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A vial was charged with 1-(2-methylpiperazin-1-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide 2,2,2-trifluoroacetate (0.037 g, 0.074 mmol), ruphos palladium(ii) phenethylamine chloride (6.06 mg, 7.42 μmol), and sodium tert-butoxide (0.029 g, 0.297 mmol). Dioxane (0.742 ml) and 1-fluoro-3-iodobenzene (0.013 ml, 0.111 mmol) were added and the reaction was flushed with argon and stirred at 100° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g, gradient elution 0-10% MeOH:DCM) to afford 1-(4-(3-fluorophenyl)-2-methylpiperazin-1-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=8.64-8.49 (m, 2H), 8.38-8.21 (m, 3H), 7.97 (d, J=10.1 Hz, 1H), 7.68 (d, J=5.8 Hz, 1H), 7.24 (q, J=8.2 Hz, 1H), 7.05 (br. s., 1H), 6.87-6.76 (m, 2H), 6.56 (dt, J=1.9, 8.2 Hz, 1H), 4.02 (d, J=3.1 Hz, 1H), 3.61-3.44 (m, 3H), 3.29-3.22 (m, 1H), 1.08 (d, J=6.3 Hz, 5H). m/z (ESI) 479.2 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH:7]1[CH2:12][C:13]([OH:15])=[O:14].O>C(O)C>[OH:11][CH:10]1[CH2:9][CH2:8][C@H:7]([CH2:12][C:13]([OH:15])=[O:14])[C@H:6]1[CH2:5]/[CH:4]=[CH:3]\[CH2:2][CH3:1]
Reactant: CC/C=C\CC1C(=O)CCC1CC(=O)O
Solvent: CCO
Solvent: O
Product: CC/C=C\C[C@H]1C(O)CC[C@@H]1CC(=O)O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
In a 50 ml three-necked flask equipped with a refrigerant, a thermometer and a magnetic stirring device, 1 g (4.8 mmol) of (+/−)-jasmonic acid (b) was dissolved in 15 ml of absolute ethanol. 430 mg (11.4 mmol) of sodium borohydride NaBH4 was added. The mixture was stirred for 4 hours at 50° C. Once the reaction had ended, 5 ml of water was slowly added. The precipitate formed was filtered off. The filtrate was acidified to a pH=5 with hydrochloric acid and was then extracted with ethyl acetate (3×30 ml). The organic phase was dried over sodium sulphate, filtered through filter paper, and then concentrated. The colorless oil obtained was purified by silica gel chromatography (eluent: dichloromethane/methanol). The colorless oil obtained was dried under vacuum.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:11]([NH:14][C@H:15]([CH2:20][OH:21])[C@@H:16]([CH3:19])[CH2:17][CH3:18])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10])([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]([S:11]([NH:14][C@H:15]([CH2:20][OH:21])[C@@H:16]([CH3:19])[CH2:17][CH3:18])(=[O:12])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: [H][H]
Reactant: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)c(N)c1
Reaction time: 0.83 h

Procedure:
A standard hydrogenation bottle was charged with 3-nitro-4-chloro-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]benzenesulfonamide (0.50 g, 1.48 mmol), 10% palladium on carbon (0.05 g), methanol (25 mL) and hydrogen gas. It was shaken on a Parr hydrogenation apparatus for 50 minutes. The reaction mixture was filtered and the solvent evaporated to produce a crude oil that was flash chromatographed (eluant: ethyl acetate-hexane, 3-2) to afford the product as a solid, mp 89-92° C. (0.12 g, 26%). MS (+APCI) 307.03 ([M+H]+). Anal. Calc'd for C12H19ClN2O3S: C, 46.98; H, 6.24; N, 9.13. Found: C, 47.44; H, 6.32; N, 8.88.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.[NH2:15][NH2:16]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:13])[NH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(Br)cc1
Solvent: CCO
Product: O=C1CCC(c2ccc(Br)cc2)=NN1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A solution of 4-(4-bromo-phenyl)-4-oxo-butyric acid (Aldrich, 25.0 g, 97.3 mmol) in EtOH (100 mL) was treated with aqueous hydrazine (Aldrich, 55%, 9.1 mL, 100 mmol) at 80° C. for 2 h. The mixture was cooled to room temperature and the precipitate was collected by filtration and dried under vacuum to provide the title compound (24 g, 97% yield). 1H NMR (300 MHz, CDCl3) δ 2.35-2.76 (m, 2 H), 2.80-3.11 (m, 2 H), 7.45-7.77 (m, 4 H), 8.55 (s, 1 H); MS (DCl/NH3) m/z 253 (M+H)+, 255 (M+H)+.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[OH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]2[CH2:21][C@@H:20](OS(C)(=O)=O)[CH2:19][N:18]2[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[O:28])=[O:16])[CH2:11][CH2:10]1>C(#N)C>[C:1]([S:3][C@@H:20]1[CH2:19][N:18]([C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)=[O:28])[C@H:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][OH:6])[CH2:10][CH2:11]2)=[O:16])[CH2:21]1)(=[O:4])[CH3:2]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC#N
Product: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 70.3 %

Procedure:
685 mg of potassium thioacetate were added to a solution of 2.0 g of (2S,4R)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step 54(a)(ii), 54(a)(ii') and 54(a)(ii") above] in 20 ml of dry acetonitrile, and the resulting mixture was stirred at 80° C. for 5 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, the residue was diluted with 200 ml of ethyl acetate, and the dilute solution was washed with an aqueous solution of sodium chloride; it was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a gradient elution method with mixtures of ethyl acetate and methanol ranging from 9:1 to 4:1 by volume as the eluent, to give 1.35 g of the title compound, as a powder.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27]C)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([O:22]C)[CH:15]=2)[CH2:9][CH2:8]1.Br.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O>[OH:22][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[OH:20])[CH2:13][N:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:26]([OH:27])=[C:3]([OH:2])[CH:4]=2)[CH2:12][CH2:11]1
Reactant: COc1ccc(CN2CCN(Cc3ccc(OC)c(OC)c3)CC2)cc1OC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(CN2CCN(Cc3ccc(O)c(O)c3)CC2)cc1O
Temperature: 145 °C

Procedure:
1,4-Bis(3,4-dimethoxybenzyl)piperazine (5 g, 12.95 mmol) was combined with hydrobromic acid (50 ml of 48% w/w solution in water) and the solution heated slowly over 1 hour to 145° C. Reaction was maintained at 145° C. for 12 h at which time TLC revealed disappearance of starting material. The cooled solution was diluted with water (200 ml), carefully neutralized with saturated aqueous sodium hydrogen carbonate, and ethyl acetate (100 ml) added. The crude aqueous solvent mixture was filtered through Celite and the ethyl acetate layer separated. The aqueous layer was extracted with ethyl acetate (2×50 ml), and the combined extracts washed with water (50 ml), and dried (Na2SO4). The solvent was removed under reduced pressure and the residue recrystallized from toluene and methyl ethyl ketone to afford the product, DC-0009, 100 mg (98%, pure by HPLC analysis).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Si:11]([O:18][C@@H:19]1[C@H:23]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C@@H:22]([CH3:32])[O:21][C@H:20]1[N:33]1[CH:40]=[C:39]([F:41])[C:37]([NH2:38])=[N:36][C:34]1=[O:35])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>N1C=CC=CC=1>[Si:11]([O:18][C@@H:19]1[C@H:23]([O:24][Si:25]([C:28]([CH3:30])([CH3:31])[CH3:29])([CH3:27])[CH3:26])[C@@H:22]([CH3:32])[O:21][C@H:20]1[N:33]1[CH:40]=[C:39]([F:41])[C:37]([NH:38][CH:8]=[O:10])=[N:36][C:34]1=[O:35])([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: O=CO
Reactant: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: C[C@H]1O[C@@H](n2cc(F)c(NC=O)nc2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 0.83 h

Procedure:
To ice cooled acetic anhydride (0.57 ml) was added dropwise 99% formic acid (286 μl). The solution was stirred for 15 minutes at 0° C. and for 50 minutes at 50° C., and then cooled to 0° C. To the solution was added 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluorocytidine (473 mg) obtained in Reference example (a) in dry pyridine (5 ml) at 0° C. The reaction mixture was stirred for 10 minutes at 0° C. and for 26 hours at room temperature. After removal of the solvent under reduced pressure the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane - ethyl acetate) followed by recrystallization from n-hexane - ethyl acetate to give 144 mg of 2',3'-bis-O-(tert-butyldimethylsilyl)-5 '-deoxy-5-fluoro-N4 -formylcytidine, mp 188° C. (dec.); MS 502 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC(=O)C[C@H]1C(O)=O)=O)(C)(C)C.NOC[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COc1ccc(CON)cc1
Agent: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Product: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Yield: 85 %

Procedure:
The same method as employed in the preparation of Intermediate 7, but starting from (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (Intermediate 1) and 1-[(aminooxy)methyl]4-methoxy-benzene (Intermediate 10) gave the title compound as a gum in a 85% yield.