Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.B(F)(F)F.CCOCC.[C:20]([O:23][C:24](C)([CH3:28])[C:25](=[O:27])[CH3:26])(=[O:22])[CH3:21].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:20]([O:23][CH:24]([CH3:28])[C:25](=[O:27])[CH2:26][CH:1]([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)(C)C(C)=O
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CC(=O)C(C)OC(C)=O)OCC
Temperature: -65 °C
Reaction time: 0.25 h

Procedure:
A 3 l round-bottomed flask fitted with a mechanical stirrer under an atmosphere of N2 was charged with triethyl orthoformate (304 ml, 1.83 mol) and CH2Cl2 (1.30 l). The solution was cooled to −65° C. and BF3.Et2O (255 ml, 2.01 mol) was added over 30 min to provide a yellow solution. After an additional 15 min, the cold bath was removed and the flask contents were allowed to warm to 0° C. After ageing at 0° C. for 45 min, the mixture was cooled to −60° C. to provide a thin white slurry. A solution of 3-acetoxy-3-methyl-2-butanone (131.55 g, 0.912 mol) and CH2Cl2 (100 ml) was added over 17 min. After a 40 min age at −65° C., diisopropylethylamine (404 ml, 2.32 mol) was added over 30 min maintaining an internal temperature below −63° C. After an additional 45 min at −65° C., the mixture was warmed to room temperature over 45 min and aged at that temperature for 5 h. The reaction mixture was poured onto saturated aqueous NaHCO3 (800 ml) and stirred for 15 min. The layers were partitioned and the organic phase was washed with 1M H2SO4 at 5° C. (2×800 ml), water at 5° C. (2×800 ml) and then dried over Na2SO4. The solvent was removed under diminished pressure to provide 4-acetoxy-1,1-diethoxy-4-methyl-3-butanone as an oil (270 g, 57 wt % pure) which was used without further purification in the subsequent steps. An analytical sample was prepared by HPLC on a Zorbax C-8 preparative column with gradient elution from 30% acetonitrile, 70% 0.1% H3PO4/H2O to 70% acetonitrile, 30% 0.1% H3PO4/H2O over 20 min: 1H NMR (CDCl3, 400 MHz) δ 4.95 (1H, t, J 5.6), 3.69 (2H, m), 3.53 (2H, m), 2.79 (2H, d, J 5.6), 2.07 (3H, s), 1.47 (6H, s), 1.18 (6H, t, J 6.8); 13C NMR (CDCl3, 100.61 MHz) δ 205.7, 170.4, 100.8, 83.7, 63.2, 41.4, 22.9, 21.1, 15.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=[C:2]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: c1c[nH]cn1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2ccnc2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.1) (0.15 g, 0.5 mmol) and commercially available imidazole (0.034 g, 0.5 mmol) according to the general procedure IVa. Obtained as an off-white solid (0.063 g, 39%). MS (EI) 324.1 [(M)+]; mp 175° C.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.ClCCl.[OH-].[Na+]>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[C:3]([NH2:4])=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Nc1ccccc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2N)cc1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
A stirred solution of 2-iodoaniline (5.0 g, 22.8 mmol), and 4-methylphenylboronic acid (3.1 g, 22.8 mmol) in tetrahydrofuran was treated under argon with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.37 g, 0.46 mmol), and a 5.0 N sodium hydroxide solution (9.1 mL, 45.7 mmol). The reaction mixture was heated under reflux for 24 hours, cooled to room temperature, and washed with a saturated, aqueous, sodium chloride solution. The aqueous phase was further extracted with ethyl acetate (3×). The combined organic phase was dried over anhydrous magnesium sulfate, and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:12) to yield the title compound (3.26 g, 17.8 mmol, 78%) as an orange oil;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](O)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=1>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: Cc1cccc(N)c1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O
Product: Cc1cccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.8 %

Procedure:
To solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (146 mg, 0.428 mmol), EDC (115, 0.599 mmol), and HOBT (81 mg, 0.599 mmol) in DMF (8 mL) into a 100 mL round-bottomed flask, was added m-toluidine (45.8 mg, 0.428 mmol), and the reaction mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured into water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (90 mg) as a yellow solid. LC-MS (ES) m/z=431 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C@H:23]4[CH2:25][C@@H:24]4[C:26]([O:28]C)=[O:27])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].C(O)(=O)C>C(O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C@@H:23]4[CH2:25][C@H:24]4[C:26]([OH:28])=[O:27])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: COC(=O)[C@H]1C[C@@H]1c1ccc(-c2nc(-c3ccc(OC(C)C)c(Cl)c3)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc([C@@H]4C[C@H]4C(=O)O)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a suspension of (1S, 2S)-methyl 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)cyclopropanecarboxylate (111 mg, 0.269 mmol) in ethanol (5 ml) was added 2 N NaOH (5 ml, 10.00 mmol). The mixture was stirred under nitrogen at room temperature overnight. Reaction mixture was neutralized by addition of acetic acid, and then acidified with a few drops of 1 N aqueous HCl (pH about 2). White solid precipitated and was collected by filtration, washed with 0.1N HCl (3×5 mL), and dried under vacuum to give Trans-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)cyclopropanecarboxylic acid (64 mg, 59%). LCMS (Table 1, Method f) Rt=2.99 min, m/z 399.16 (M+H)+. 1H NMR (400 MHz, DMSO) δ ppm 8.07 (d, 2H), 8.05 (d, 1H), 7.99 (dd, 1H), 7.45 (d, 2H), 7.38 (d, 1H), 4.82 (sept., 1H), 2.54 (m, 1H), 1.97 (m, 1H), 1.53 (td, 1H), 1.46 (ddd, 1H), 1.35 (d, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)OC(C)(C)C)=[CH:11][C:10]=2[C:23]([F:26])([F:25])[F:24])[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:23]([F:24])([F:25])[F:26])[CH2:4][CH2:3]1
Reactant: CN1CCC(Oc2ccc(NC(=O)OC(C)(C)C)cc2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(Oc2ccc(N)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
t-Butyl 4-(1-methylpiperidine-4-yloxy)-3-(trifluoromethyl)phenylcarbamate (82 mg, 0.299 mmol) was dissolved in methylene chloride (1 mL), and TFA (1 mL) was added thereto. The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The reaction mixture was diluted with ethylene chloride and washed with sat. NaHCO3 solution. The organic layer was dried with Na2SO4, filtered and concentrated to obtain the title compound (63 mg, 77%) without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:36])[CH2:33][O:34][CH3:35])[NH:27][C:26](=[O:37])[CH2:25]2>>[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:36])[CH2:33][O:34][CH3:35])[NH:27][C:26](=[O:37])[C:25]2=[CH:19][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: COCC(=O)Nc1cc2c(cc1F)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCCC1)CC3)C(=O)N2
Yield: 81.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide as starting materials to give N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide (51 mg, 81.7%) as a brown solid.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([CH2:22][C:21](=[O:23])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Reactant: CC(=O)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC[C@@H]1C(=O)N(C)c2cnc(CC(=O)c3ccccc3)nc2N1C1CCCC1
Temperature: 120 °C

Procedure:
5.0 g of Intermediate B, 2.5 eq of acetophenone, 0.05 eq of Pd2(dba)3, 0.1 eq of BINAP and 2.0 eq of Cs2CO3 were suspended in a mixture of 50 mL toluene and 10 mL of water, then heated to 120° C. under N2 for 60 hours. After cooling to rt, added 100 mL of water and washed the organic phase, dried with anhydrous Na2SO4, concentrated and purified by silica gel column (PE:EA=3:1) to give the pure Intermediate B-1 (1.2 g, 19%) as yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Reactant: C1COCCN1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (5.7 g, 14.7 mmol), morpholine (12.8 mL, 147 mmol), copper(I) iodide (1.68 g, 8.8 mmol), N,N-dimethylglycine hydrochloride (1.58 g, 11.8 mmol), and potassium carbonate (6.1 g, 44.1 mmol) in dimethyl sulfoxide (30 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (5.6 g, 96%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C24H30N2O3 (M+H)+: 395.52, observed: 395.2.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:16]([O:18][CH3:19])=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:30](Br)[CH:31]=[CH2:32]>O1CCCC1>[CH2:32]([C@H:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:16]([O:18][CH3:19])=[O:17])[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)C(=O)OC
Temperature: -70 °C
Reaction time: 2 h

Procedure:
11.01 g (40 mmol) of dimethyl Boc-glutamate (Advanced Chemtech) were dissolved in 160 ml of tetrahydrofuran and cooled to −70° C. 88 ml (88 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise at this temperature over a period of one hour, and the mixture was stirred at −70° C. for another 2 hours. 14.52 g (120 mmol) of allylbromide were then added dropwise, and after 2 h at this temperature, the cooling bath was removed and 200 ml of 2N aqueous hydrochloric acid and 400 ml of ethyl acetate were added. The organic phase was separated off, washed with water until neutral, dried over sodium sulphate and filtered, and the filtrate was concentrated. The crude product obtained in this manner was chromatographed in silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[CH2:10][C@H:8]1[OH:9].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].CO>N1C=CC=CC=1.C(OCC)(=O)C>[Si:18]([O:13][CH2:12][C@H:11]1[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([CH3:1])[C:3](=[O:17])[NH:4][C:5]2=[O:16])[C@H:8]([OH:9])[CH2:10]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: Cc1cn([C@@H]2O[C@H](CO)C[C@H]2O)c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1cn([C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)C[C@H]2O)c(=O)[nH]c1=O
Reaction time: 4.5 h
Yield: 84.4 %

Procedure:
5-Methyl-3'-deoxyuridine, from Step 1, was dissolved in 150 mL of dry pyridine and 3.6 g (24 mmol) of t-butyldimethylsilyl chloride was added in 4 portions at 4 times (t): t=0 h, t=2 h, t=3 h and at t=3.75 h. After 4.5 h, 8 mL of methanol was added to the reaction mixture and the reaction mixture was stirred for 0.5 h, then concentrated under reduced pressure to approximately 25% of volume. The concentrated reaction mixture was diluted with ethyl acetate, washed with dilute aqueous sodium bicarbonate solution and then concentrated under reduced pressure. The residue was purified by column chromatography on a 5 cm×37 cm silica gel column eluted with 90% ethyl acetate in hexane. The fractions containing the desired product were combined and concentrated in vacuo to give 7.27 g (84.4% yield based on 24.19 mmol of 2',5'-bis(O-(4"-chloro)benzoyl)-5-methyl-3 '-deoxyuridine) of 5'-O-(t-butyldimethylsilyl)-5-methyl-3'-deoxyuridine, [α]D23 =-19.6° (c, 1.42, MeOH). Analysis calculated for C16H28N2O5Si: C, 53.98; H, 7.91; N, 7.87. Found: C, 54.01; H, 7.85; N, 7.79.
Reaction SMILES: [CH:1]([N-:4]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[C:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:18]=[C:17]2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])=[CH:12][CH:11]=1.C1(C)C=CC(S(C#N)(=O)=O)=CC=1.C(OCC)C>C1COCC1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:20]([C:1]#[N:4])=[C:19]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[N:18]=[C:17]2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])=[CH:12][CH:11]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1C#N
Reaction time: 1 h

Procedure:
Lithium diisopropyl amide (LDA) (5.25 mL of a 2 M solution in THF, 0.0105 mol) is added dropwise to a cooled solution (−70° C.) of tert-butyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (4.24 gram, 0.010 mol) in anhydrous THF (80 mL) in a nitrogen atmosphere and the resulting mixture is stirred for one hour. A solution of p-toluenesulfonyl cyanide (1.88 gram, 0.011 mol) in anhydrous THF (20 mL) is added dropwise and the resulting red solution is stirred for one hour at −70° C. and then allowed to attain room temperature. Diethyl ether is added and the resulting solution is quenched with water and filtered over hyflo. The organic layer is collected and washed with water, dried over MgSO4, filtered and concentrated in vacuo to give an oil. This oil is purified by column chromatography (dichloromethane, silicagel) to give 3.4 gram of tert-butyl 1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate. Recrystallisation from diisopropyl ether gave crystalline tert-butyl 1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (2.57 gram, 57% yield). Melting point: 210-212° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C([O:15][CH2:16][CH:17]1[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]1)(=O)C1C=CC=CC=1>O>[CH3:22][C:19]1([CH3:23])[O:18][CH:17]([CH2:16][OH:15])[CH2:21][O:20]1
Reactant: CC1(C)OCC(COC(=O)c2ccccc2)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)OCC(CO)O1
Temperature: 100 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Then sodium carbonate (32.22 g, 0.304 mol) was added to a mixture of the crude 4-benzoyloxymethyl-2,2-dimethyl-1,3-dioxolane (48.06 g, 0.203 mol) and water (100 ml) resulting mixture was stirred for 8 hours at 100° C. After cooling the reaction mixture was extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and condensed in vacuo. The crude product was distilled to give 22.03 g of 2,2-dimethyl-1,3-dioxolane-4-methanol (yield 82%, b.p. 72° C. at 8 mmHg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]([C:14]([O:16]CC)=[O:15])[C:7]2=[O:19])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]([C:14]([OH:16])=[O:15])[C:7]2=[O:19])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2ccc(OCC)nc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc2[nH]cc(C(=O)O)c(=O)c2n1
Yield: 90.9 %

Procedure:
A mixture of ethyl 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (2.98 g), 1N NaOH (50 mL) and ethanol (10 mL) was heated at reflux for 2 h. The reaction mixture was cooled in an ice bath, acidified, and the resulting precipitate collected, rinsed with water and dried to give 2.42 g of 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid as a beige solid.
Reaction SMILES: [CH2:1]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[NH2:23][C:24]1([C:27]#[N:28])[CH2:26][CH2:25]1>>[C:27]([C:24]1([NH:23][C:17](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:21][CH:20]=2)[CH2:26][CH2:25]1)#[N:28]
Reactant: N#CC1(N)CC1
Reactant: CCCCCCCCCCCCc1ccc(C(=O)O)cc1
Agent: Cl
Product: CCCCCCCCCCCCc1ccc(C(=O)NC2(C#N)CC2)cc1
Yield: 37.5 %

Procedure:
General procedure G was used to convert 4-dodecylbenzoic acid (0.52 mmols) to the corresponding acyl chloride. After standard work up procedures, the intermediate was immediately subjected to conditions described in general procedure F in the presence of 1-amino-1-cyclopropanecarbonitrile hydrochloride (0.4 mmols). After flash chromatography, 0.15 mmols of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 7.68 (d, J=7.1, 2H), 7.23 (d, J=7.5, 2H), 6.82 (s, 1H), 2.63 (t, J=7.7, 2H), 1.65-1.57 (m, 4H), 1.35 (t, J=7.0, 2H), 1.29-1.25 (m, 17H), 0.88 (t, J=6.5, 3H). 13C NMR (126 MHz, CDCl3) δ 167.81, 148.06, 130.01, 128.75, 127.19, 120.07, 35.85, 31.89, 31.11, 29.61, 29.53, 29.42, 29.32, 29.20, 22.66, 20.88, 16.97, 14.08.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]>C(O)C.O1CCOCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Sc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(Sc2ccncc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 21.5 %

Procedure:
1.11 g of 4-mercaptopyridine was dissolved in 5 ml of ethanol, and 52.8 mg of sodium hydride was added little by little. The mixture was stirred for 5 minutes, and then a solution of 1.87 g of 4-chloro-3-nitroanisole in 5 ml of dioxane was added. The mixture was heated under reflux at 100° C. for 15 hours. The solvent was evaporated, and 2N hydrochloric acid was added to the residue. The residue was washed with ether, made alkaline by adding an aqueous solution of sodium hydroxide, and extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride. The solvent was evaporated. The resulting residue was subjected to silica gel column chromatography. The column was eluted with a 5:3 mixture of hexane and acetone, and the eluate was recrystallized from acetone-hexane to give 562 mg (yield 21.4%) of 4-(4-methoxy-2-nitrophenyl)thiopyridine as orange needles having a melting point of 57° to 59° C.
Reaction SMILES: [CH3:1][C:2]([N+:10]([O-])=O)([CH3:9])[CH2:3][CH2:4][S:5]([CH3:8])(=[O:7])=[O:6].C(=O)([O-])[O-].[H][H]>CCO.C(Cl)Cl.[Pd]>[CH3:1][C:2]([NH2:10])([CH2:3][CH2:4][S:5]([CH3:8])(=[O:7])=[O:6])[CH3:9]
Reactant: [H][H]
Reactant: CC(C)(CCS(C)(=O)=O)[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(N)CCS(C)(=O)=O
Yield: 92 %

Procedure:
At RT, Pd/C (1.262 g of 10% wt., 10.65 mmol) was added to a solution of 3-methyl-1-(methylsulfonyl)-3-nitrobutane (338a, 2.08 g, 10.65 mmol) in EtOH (53.3 mL) and DCM (53.3 mL). The reaction mixture was placed under hydrogen (46 psi) in a carbonate jacketed reaction vessel at RT for 16 h when the pressure had reduced to ambient pressure. The reaction vessel was pressurized again to 50 psi hydrogen for 3 d when the pressure had reduced to 40 psi. The mixture was filtered through a pad of Celite, covered with sand, and washed with DCM then MeOH. The filtrate was distilled to first remove the DCM and MeOH before a white solid was observed; this was filtered, washed with DCM, and dried in vacuo to give 2-methyl-4-(methylsulfonyl)butan-2-amine (338b, 1.62 g, 9.80 mmol, 92% yield) as a crystalline white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 2.00 (d, J=17.21 Hz, 1H) 2.00 (t, J=4.11 Hz, 1H) 3.02 (s, 3H) 3.29 (d, J=17.21 Hz, 1H) 3.29 (t, J=4.50 Hz, 1H) 8.20 (br. s., 2H). MS (ESI, pos. ion) m/z: 166.2 (M+1).