Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11])[CH2:4][F:5].CC([Si](C)(C)[O:28][CH2:29][CH2:30][N:31]([CH3:43])[C:32](=[O:42])[C:33]1[CH:38]=[CH:37][C:36](F)=[C:35]([F:40])[C:34]=1F)(C)C.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[F:5][CH2:4][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([O:22][C:36]2[CH:37]=[CH:38][C:33]3[C:32](=[O:42])[N:31]([CH3:43])[CH2:30][CH2:29][O:28][C:34]=3[C:35]=2[F:40])[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11])[CH2:2][F:1]
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OC(CF)CF)c2)n1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1CCOc2c(ccc(Oc3cc(OC(CF)CF)cc(C(=O)Nc4ccn(C)n4)c3)c2F)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
A solution of 3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (100 mg, 0.32 mmol), N-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2,3,4-trifluoro-N-methylbenzamide (112 mg, 0.32 mmol) and potassium carbonate (89 mg, 0.64 mmol) in DMA (2 mL) was heated in a microwave reactor for 2 hours. Water (20 mL) was added and the solution extracted with ethyl acetate. The ethyl acetate layer was washed with brine (20 mL), dried (MgSO4) and evaporated to a residue which was taken up in DCM (10 mL) and TFA (5 drops) added. The mixture was stirred at RT for 2 hours. The solvent was evaporated to a residue, which was chromatographed by preparative HPLC on C18 reversed phase, eluting with 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA), to give the required product (5 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[S:19].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O1CCOCC1.O>[CH3:16][N:17]([CH3:21])[C:18]([O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)=[S:19]
Reactant: CN(C)C(=S)Cl
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CN(C)C(=S)Oc1cc(CC(=O)O)cc(C(F)(F)F)c1

Procedure:
The product from example 25 step (iv) (0.5 g), dimethylthiocarbamoyl chloride (0.32 ml), DMAP (0.026 g) and triethylamine (0.60 ml) in dry dioxane (10 ml) were stirred at 100° C. for 15 h. The mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4) and evaporated under reduced pressure to an oil. The oil was purified by flash column chromatography (eluent ether) to give the subtitle compound (0.52 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](O)(=[O:16])[C:13](O)=[O:14]>C(O)(=O)C>[OH:14][C:13]1[C:12]([OH:16])=[N:1][C:2]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[N:8]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2nc(O)c(O)nc12
Temperature: 25 °C

Procedure:
4 g (26.12 mmol) of 2,3-diaminonitrobenzene and 6.59 g (52.24 mmol) of commercial oxalic acid were dissolved in 50% acetic acid, and reaction was allowed at boiling point under an argon stream for 3 hr. After the reaction was over, the reaction mixture was cooled to room temperature, and the crystal precipitated was filtered out.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[CH:17]1([CH2:20][CH2:21][CH2:22][CH2:23][C:24](OC)=[O:25])[CH2:19][CH2:18]1>O1CCCC1.CCCCCC.C(O)(=O)C>[O:25]=[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH:17]1[CH2:19][CH2:18]1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)CCCCC1CC1
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC(=O)CCCCC1CC1)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 49.6 g (0.40 mole) dimethyl methylphosphonate (Aldrich) in 500 ml dry tetrahydrofuran is cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution is added 188 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rises above -65°. After an additional 5 minutes stirring at -78°,25.6 g (0.20 mole) methyl 5-cyclopropylvalerate is added dropwise at a rate that keeps the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture is allowed to warm to ambient temperature, neutralized with 25 ml acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in 75 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the cmbined organic extracts are backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled to give dimethyl 2-oxo-6-cyclopropylhexylphosphonate.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Na+].Cl[C:27]([F:32])([F:31])C([O-])=O>CN(C=O)C.O>[F:31][CH:27]([F:32])[O:18][C:13]1[N:12]=[C:11]([S:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:16]=[C:15]([OH:17])[CH:14]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1cc(O)nc(SCc2cccc(F)c2F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc(OC(F)F)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
To a solution of 2-[[(2,3-difluorophenyl)methyl]thio]-4,6-pyrimidinediol (3 g) in DMF (30 mL), cesium carbonate (4.3 g) and chlorodifluoro-acetic acid sodium salt (1.9 g) was added. The resulting mixture was heated at 100° C. for 2 h. The reaction mixture was cooled then diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and dried (MgSO4), filtered and evaporated. Purification was by column chromatography on silica gel using EtOAc/isohexane (2:8) as eluent to give the subtitle compound as a white solid. Yield: 0.4 g
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:5]=[C:6]([CH3:11])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:28])([F:27])[F:26].Cl>CN(C)C=O.O>[Cl:10][C:9]1[CH:8]=[CH:7][C:6]([CH3:11])=[CH:5][C:4]=1[NH:3][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:26])([F:28])[F:27]
Reactant: Cc1ccc(Cl)c(N)c1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(Nc2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
Powdered potassium hydroxide (2.0 g.) was added in portions over 5 minutes to a stirred solution of 3-amino-4-chlorotoluene (2.8 g.) in dimethylformamide (15 ml.) at the ambient temperature and stirring was continued for a further 5 minutes. A solution of 2-chloro-3,5-dinitro-benzotrifluoride (5.4 g.) in dimethylformamide (15 ml.) was then added over 5 minutes, and following the addition, the mixture was stirred for 30 minutes. After acidification with concentrated hydrochloric acid the mixture was poured into water (15 ml.). The precipitated solid was separated from the supernatant liquid by decantation and recrystallised from methylated spirit to yield 2(2-chloro-5-methylanilino)-3,5-dinitrobenzotrifluoride, with a melting point of 127° C.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.C(N(CC)CC)C.[O:44]1[C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=[N:45]1>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([C:49]([C:48]4[O:44][N:45]=[CH:46][CH:47]=4)=[O:50])[CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: O=C(Cl)c1ccno1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)c1ccno1)C2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (38.1 mg, 0.074 mmol) in DCM (736 μL) at 0° C. was treated with triethylamine (30.8 μL, 0.221 mmol), followed by isoxazole-5-carbonyl chloride (14.2 μL, 0.147 mmol). The reaction mixture was allowed to warm to room temperature and stir for 45 min. The reaction mixture was concentrated under reduced pressure and purified directly by HPLC Method B, with the exception that a Phenomenex Gemini® C18, 5 μm, ID 30×75 mm column was used, using a 55% to 90% ACN gradient to give the title compound, as a TFA salt, as a tan oil (18.6 mg, 41.2%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.30 (m, 6H), 1.96 (m, 2H), 2.13 (m, 2H), 2.89 (m, 2H), 3.11 (m, 2H), 3.46 (m, 2H), 3.91-4.21 (m, 3H), 4.49 (m, 1H), 4.78 (br s, 2H), 6.87 (m, 1H), 6.92 (s, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H), 8.55 (s, 1H); ESI-MS m/z [M+H]+ 499.5.
Reaction SMILES: N12CCCN=C1CCCCC2.[SH:12][C:13]1[S:14][CH2:15][CH2:16][N:17]=1.Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([NH2:29])(=[O:28])=[O:27]>C(#N)C.O>[S:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][S:12][C:13]1[S:14][CH2:15][CH2:16][N:17]=1)(=[O:27])(=[O:28])[NH2:29]
Reactant: NS(=O)(=O)c1ccccc1CCl
Reactant: SC1=NCCS1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: NS(=O)(=O)c1ccccc1CSC1=NCCS1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
With cooling, 7.9 g of 97%, 1,8-diazabicyclo[5.4.0]undec-7-ene are added to a suspension of 6.2 g of 97% 4,5-dihydro-2-mercaptothiazole in 50 ml of acetonitrile. To the yellow solution so obtained are added 10.3 g of 2-chloromethylbenzenesulfonamide and the reaction mixture is stirred for 1 hour at 20°-25° C. The reaction solution is then diluted with about 1 liter of water. The precipitate is isolated by filtration and dried, affording 11.9 g (76% of theory) of 4,5-dihydro-2-(2-sulfamoylphenylmethylthio)thiazole of m.p. 123°-125° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].Cl.[CH2:15]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH2:16][CH2:17][CH2:18][CH3:19].[CH2:26]=O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH2:26][N:23]1[CH2:22][CH2:21][N:20]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:25][CH2:24]1)[C:12]#[N:13]
Reactant: C=O
Reactant: CCCCCN1CCNCC1
Reactant: N#CCc1ccc2ccccc2c1
Agent: Cl
Product: CCCCCN1CCN(CC(C#N)c2ccc3ccccc3c2)CC1

Procedure:
In a manner similar to Preparation 11 react 2-naphthaleneacetonitrile with 4-pentylpiperazine hydrochloride and paraformaldehyde to obtain the title compound.
Reaction SMILES: FC1C=C(C=CC=1OC)C(O[C:8]1[C:13]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=2)=[CH:12][C:11]([O:26][CH3:27])=[CH:10][C:9]=1[Br:28])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1C=CC(C)=CC=1>O>[Br:28][C:9]1[C:8]2[O:25][C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][C:13]=2[CH:12]=[C:11]([O:26][CH3:27])[CH:10]=1
Reactant: COc1cc(Br)c(OC(=O)c2ccc(OC)c(F)c2)c(NC(=O)c2ccc(OC)c(F)c2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccc(C)cc1
Solvent: O
Product: COc1cc(Br)c2oc(-c3ccc(OC)c(F)c3)nc2c1
Reaction time: 0.17 h

Procedure:
A suspension of 2-bromo-6-[(3-fluoro-4-methoxybenzoyl) amino]-4-methoxyphenyl 3-fluoro-4-methoxybenzoate. (46.0 g, 88.1 mmol), p-toluenesulfonic acid monohydrate (33.5 g, 177.2 mmol) and anhydrous p-xylene (1 l) was refluxed for 3 h with continuous water removal (Dean Stark Trap). The initial suspension turned into a brown solution at refluxing temperature. The solids were filtered off and washed with ethyl ether. The solids were suspended in ethyl ether (200 mL), stirred for 10 min, filtered off and dried to give a tan solid (25.1 g, m.p. 175–177° C.). The ethyl ether layer was concentrated to 20 mL and 2.5 g of additional product was obtained (90% overall yield). MS m/e 352 (M+H)+.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH:19]=O)=[CH:13][CH:12]=1>CCCCCC>[C:14]1(/[CH:17]=[CH:18]/[CH:19]=[N:10]/[NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C/C=C/c1ccccc1
Solvent: CCCCCC
Product: O=C(N/N=C/C=C/c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A mixture of 1a (3.00 g, 22.0 mmol) and trans cinnamic aldehyde (4.35 g, 32.9 mmol, origin: Aldrich) in hexane (100 ml) was stirred at room temperature for 2 h. The reaction mixture was filtered, the residue washed with hexane and dried under vacuum to give 4.95 g (90%) of a white solid.
Reaction SMILES: N[C:2]([CH3:6])([CH3:5])[CH2:3]O.[N+:7]([C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].C([N:22](CC)CC)C.O>O1CCOCC1>[N+:7]([C:10]1[CH:11]=[C:12]([S:16]([NH:22][CH2:3][CH:2]2[CH2:6][CH2:5]2)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(N)CO
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NCC2CC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
To a stirred solution of 2-amino-2-methyl-1-propanol (0.95 ml, 9.93 mmol) in dioxane (25 ml) was added at room temperature 3-nitrobenzenesulfonyl chloride (2.0 g, 9.02 mmol) and triethylamine (1.38 ml, 9.93 mmol). The light yellow suspension was stirred at room temperature for 6 h, poured into water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organic layers were washed with water (100 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (heptane/ethyl acetate 1:1) to yield 3-nitro-N-cyclopropylmethyl-benzenesulfonamide (1.04 g, 42%) as a light yellow solid. MS (ISP) 273.2 [(M−H)−].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH:16]=[C:15]([CH2:17][N:18]2[C:22](=[O:23])[N:21]([CH2:24][C@H:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[C:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[N:19]2)[N:14]=[N:13]1)[C:9](O)=[O:10].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH3:52]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH:16]=[C:15]([CH2:17][N:18]2[C:22](=[O:23])[N:21]([CH2:24][C@H:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[C:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[N:19]2)[N:14]=[N:13]1)[C:9]([NH2:52])=[O:10]
Reactant: N
Reactant: O=C(O)C(c1ccccc1Cl)n1cc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)nn1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)C(c1ccccc1Cl)n1cc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)nn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
25 mg (0.045 mmol) of the compound from Example 104 were initially charged in 1 ml of DMF, and 9 mg (0.058 mmol) of HOBt and 11 mg (0.058 mmol) of EDC were added. After 10 min of stirring at RT, 0.5 ml (0.90 mmol) of ammonia solution (35% strength in water) was added, and the reaction was stirred at RT for 16 h. The reaction mixture was then purified directly, without any further work-up, by chromatography [Method 19]. This gave 10 mg (40% of theory) of the target compound.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[H-].[Na+].Br[CH:28]([CH2:33][CH3:34])[C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:28]([CH2:33][CH3:34])[C:29]([O:31][CH3:32])=[O:30])[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Reactant: CCC(Br)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.3 g (3.61 mmol) of (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 42, Step A) in DMF (14.43 mL) at 0° C. was added a dispersion of 60% sodium hydride in mineral oil (0.361 g, 9.02 mmol). The grey slurry was stirred at 0° C. for 30 minutes. Then methyl 2-bromobutanoate (1.246 mL, 10.83 mmol) was added. The mixture was warmed to room temperature and stirred at room temperature for 1 h. The mixture was quenched with sat. NH4Cl. The mixture was extracted with ethyl acetate. The organic layer was washed with water, 1 M LiCl (2×), and sat. aq. NaCl solution. The organic layer was dried over Na2SO4 filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (80 g column; eluent: 10 to 35% EtOAc in hexanes) to give the title compound as the less polar, major diastereomer.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+]([O-])=O)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].[CH3:16][OH:17]>>[CH3:16][O:17][C:9]1[CH:10]=[CH:11][CH:12]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=1[C:7]#[N:8]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CO
Agent: [Na]
Product: COc1cccc([N+](=O)[O-])c1C#N
Yield: 94 %

Procedure:
A solution of sodium methoxide, obtained by adding sodium (1.68 g, 73.1 mmol) to anhydrous MeOH (73 mL), was added to 2,6-dinitrobenzonitrile (13.20 g, 68.4 mmol) in dry MeOH (284 mL) under nitrogen at room temperature over 10 min. The reaction was refluxed for 1 hour, and then MeOH was removed under vacuum. Dichloromethane (400 mL) was added, and the insoluble solids were filtered out. The organic layer was washed with brine (100 mL), dried with MgSO4, and removed under vacuum to give 11.45 g (94%) of 2-methoxy-6-nitrobenzonitrile, which was used without further purification. 1H-NMR (400 MHz, DMSO-d6) δ 7.87-7.94 (m, 2H), 7.68-7.75 (m, 1H), 4.01 (s, 3H).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:8]1[O:12][CH:11]([N:13]2[CH:18]=[CH:17][C:16]([N:19]=[CH:20][N:21]([CH3:23])[CH3:22])=[N:15][C:14]2=[O:24])[C:10]([OH:26])([CH3:25])[CH:9]1[OH:27])([CH3:4])([CH3:3])[CH3:2].[C:40]([NH:47][C@H:48]([C:52](O)=[O:53])[CH:49]([CH3:51])[CH3:50])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[C:1]([SiH2:5][O:6][C:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:8]1[CH:9]([O:27][C:52](=[O:53])[CH:48]([NH:47][C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH:49]([CH3:51])[CH3:50])[C:10]([OH:26])([CH3:25])[CH:11]([N:13]2[CH:18]=[CH:17][C:16]([N:19]=[CH:20][N:21]([CH3:22])[CH3:23])=[N:15][C:14]2=[O:24])[O:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=Nc1ccn(C2OC(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)C(O)C2(C)O)c(=O)n1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC1C(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(N=CN(C)C)nc2=O)C1(C)O

Procedure:
The prior art process shown in FIG. 5 comprised reacting benzoylcytosine, BSA and SnCl4/acetonitrile with 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose (4) to form 4-benzoylamino-1-(3,4-dibenzoyloxy-5-benzoyloxymethyl-3-methyl-tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (5a); reacting (5a) with NH3 in methanol and chromatographically separating the product, 4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (6), also known as β-D-2′-C-methyl-cytidine; reacting (6) with Me2NCH(OMe)2 in DMF at room temperature for 1.5 hours to form N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine (7); reacting (7) with TBDPSCl and pyridine at room temperature for 6 hours to provide N′-{1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine (8); reacting (8) with N-Boc-L-valine, DEC and DMAP in THF/DMF at room temperature for 2 days and subjecting the product formed from this reaction to HPLC in order to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylaminomethyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (9a); refluxing (9a) with NH4F in MeOH for about 3 hours to remove the silyl and amino-protecting groups, and subjecting the product to chromatographic purification to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester (10); and finally reacting (10) with HCl in EtOAc at room temperature to provide 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester, dihydrochloride salt (11) as a final product.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8](=[O:23])[C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:12]([F:21])=[CH:11][C:10]=2[OH:22])=[C:4]([F:26])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl>CC(C)=O>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][O:22][C:10]1[CH:11]=[C:12]([F:21])[C:13]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:14][C:9]=1[C:8](=[O:23])[NH:7][CH2:6][C:5]1[CH:24]=[CH:25][C:2]([Br:1])=[CH:3][C:4]=1[F:26])[CH3:39]
Reactant: O=C(NCc1ccc(Br)cc1F)c1cc(N2CCOCC2)c(F)cc1O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(F)c(N2CCOCC2)cc1C(=O)NCc1ccc(Br)cc1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
A solution of N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-hydroxy-5-morpholin-4-yl-benzamide (0.8 g, 2.13 mmol) in acetone (11 mL), was treated with aq 2 N K2CO3 (1.6 mL, 3.20 mmol) and ethyl bromoacetate (0.35 mL, 3.20 mmol), and heated to 50° C. After stirring for 30 min, the reaction was cooled to room temperature and acidified to pH 7 with aq 2 N HCl. The resulting solution was extracted with ethyl acetate and washed with saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated to give [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-morpholin-4-yl-phenoxy]-acetic acid ethyl ester (0.8 g, 81%): 1H NMR (DMSO-d6 300 MHz) δ 9.05 (t, J=6 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.09 (ddd, J1=8.4 Hz, J2=2.4 Hz, J3=0.9 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.54 (d, J=10.2 Hz, 1H), 7.15 (d, J=14.1 Hz, 1H), 4.94 (s, 2H), 4.63 (d, J=6 Hz, 2H), 4.14 (q, J=7.2 Hz, 2H), 3.71 (t, J=4.7 Hz, 4H), 2.92 (t, J=4.7 Hz, 4H), 1.16 (t, J=7.2 Hz, 3H).