Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S(CC=C(C2OCC(C)(C)CO2)C)(=O)=O)C=CC=CC=1.C[O-].[K+].CC1(C)C[O:30][CH:29]([C:32](=[CH:34][CH:35]=[CH:36][C:37]([CH3:47])=[CH:38][CH:39]2OCC(C)(C)CO2)[CH3:33])[O:28]C1>>[CH3:33][C:32]([CH:34]=[CH:35][CH:36]=[C:37]([CH3:47])[CH2:38][CH3:39])=[C:29]([OH:28])[OH:30]
Reactant: CC(C=CC=C(C)C1OCC(C)(C)CO1)=CC1OCC(C)(C)CO1
Agent: CC(=CCS(=O)(=O)c1ccccc1)C1OCC(C)(C)CO1
Agent: C[O-]
Agent: [K+]
Product: CCC(C)=CC=CC(C)=C(O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
20.5 g (0.1 mol) of 3-chloromethylcrotonaldehyde neopentyl glycol acetal were added to a solution of 31.0 g (0.1 mol) of 3-(5,5-dimethyl-1,3-dioxan-2-yl)-crotyl phenyl sulfone in 200 ml of DEK prepared as in Example 5A. The mixture was then cooled to 0° C. while stirring, and 17 g (0.24 mol) of solid potassium methylate were added over the course of 20 min. After 1 h the reaction mixture was allowed to warm to RT and was then stirred for 2 h. HPLC checks showed that 30.6 g (corresponding to 91% of theory) of 2,7-bis(5,5-dimethyl-1,3-dioxan-2-yl)-6-methyl-2,4,6-heptatriene had been produced. The reaction mixture was washed with a little water, and 60 ml of isopropanol and 60 ml of 2% strength H2SO4 and 17.4 g of propionaldehyde were added to the isolated DEK solution of the product for transacetalization. Hydrolysis was complete after stirring at 40° C. for 2 h. The aqueous phase was then separated off, and the organic phase was concentrated. After addition of 50 ml of isopropanol to the residue, 11.1 g (corresponding to 75% of theory) of 2,6-dimethyloctatrienedial crystallized, melting point 99°-100° C.
Reaction SMILES: [C:1]1(=O)O[CH2:4][CH2:3][CH2:2]1.[CH2:7]([CH2:10][NH3+:11])[CH2:8][NH3+:9]>>[CH2:3]1[CH2:4][N:11]2[C:1](=[N:9][CH2:8][CH2:7][CH2:10]2)[CH2:2]1
Reactant: O=C1CCCO1
Reactant: [NH3+]CCC[NH3+]
Product: C1CN=C2CCCN2C1
Yield: 47.2 %

Procedure:
Using a method similar to Example 1, 25.4 mol of butyrolactone were reacted with 35 mol of 1,3-DAP (molar ratio=1.38). After a reaction time of 32 hours, the temperature of the liquid in the flask was 220° C. and 73% of the theoretically possible amount of water had been distilled off. Distillation gave 12 mol of DBN having a purity of more than 99.1%. The total yield of DBN, including the amount still present in the distillation residues, was 83.3%.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si](C)(C)O[Si](C)(C)C.[Cl:24][C:25]1[CH:30]=[C:29]([NH:31][NH:32][C:33]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)=O)[N:28]=[C:27]([S:40][CH3:41])[N:26]=1.N>C1(C)C(C)=CC=CC=1>[Cl:24][C:25]1[N:26]=[C:27]([S:40][CH3:41])[N:28]2[C:33]([C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)=[N:32][N:31]=[C:29]2[CH:30]=1
Reactant: CSc1nc(Cl)cc(NNC(=O)c2ccco2)n1
Agent: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: CSc1nc(Cl)cc2nnc(-c3ccco3)n12
Temperature: 90 °C
Yield: 78.4 %

Procedure:
In an argon atmosphere, 225 g (1.58 mol) of diphosphorus pentaoxide was suspended in 320 mL of xylene, and 340 mL (256 g, 1.58 mol) of hexamethyldisiloxane was added thereto, followed by heating at 90° C. for about 1.5 hours. After the contents were almost dissolved, 90 g (316 mmol) of Compound A was added thereto, followed by heating at 160° C. for another 2 hours. After completion of the reaction, the reaction solution was cooled, and ice-water was added thereto. Then, the mixture was made alkaline by adding aqueous ammonia under cooling (inner temperature: 5° C. or lower), and was extracted with chloroform. After evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1:1) to obtain 66.1 g of Compound B as a white solid (yield: 78%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:56])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([N:51]=[N+:52]=[N-:53])[CH:47]([O:54][CH3:55])[CH2:46]2)[CH:7]([CH3:57])[CH:6]=[CH:5][C:4]1=[O:58])[CH3:2].C(O)(=O)C.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:56])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([N:51]=[N+:52]=[N-:53])[CH:47]([O:54][CH3:55])[CH2:46]2)[CH:7]([CH3:57])[CH2:6][CH2:5][C:4]1=[O:58])[CH3:2]
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 17-ethyl-20-fluoro-1-hydroxy-12-[2'-(4"-azido-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-14,18-diene-2, 3,10,16-tetraone (55 mg), tetrakistriphenylphosphine palladium (10 mg), and acetic acid (10 μl) in 3 ml of dry toluene is stirred for 5 min at room temperature under nitrogen atmosphere. To this yellow solution is added tributyltin hydride (30 μl) and stirred an additional 45 min at room temperature. The reaction mixture is subjected to column chromatography on silica gel (elute first with hexane and then with 50% ethyl acetate/hexane) to give the title compound.
Reaction SMILES: [CH:1]1([CH:4]([OH:16])[C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=2[OH:15])[C:8]([O:10][CH3:11])=[O:9])[CH2:3][CH2:2]1>[O-2].[Mn+4].[O-2].O1CCOCC1>[CH:1]1([C:4]([C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=2[OH:15])[C:8]([O:10][CH3:11])=[O:9])=[O:16])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(O)c(C(O)C2CC2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(O)c(C(=O)C2CC2)c1

Procedure:
To a flask with methyl 3-(cyclopropyl(hydroxy)methyl)-4-hydroxybenzoate (T29.2) (845 mg, 0.38 mmol) was added manganese (IV) oxide (1.65 g, 1.9 mmol). Then dioxane 3.5 mL was added and the reaction was heated at reflux for 4 hours. The reaction was filtered and concentrated and silica gel chromatography afforded 693 mg of T29.3 (83%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.[NH2:10][CH:11]([CH2:19][CH3:20])[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([NH:10][C:7](=[O:9])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:19][CH3:20])[CH:16]([CH3:17])[CH3:18]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1cccs1
Product: CCC(NC(=O)Cc1cccs1)C(=O)OCC(C)C

Procedure:
Following General Procedure I′ above and using 2-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]([CH3:50])[CH2:44][C@H:45]1[CH2:49][CH2:48][CH2:47][O:46]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]([CH3:50])[CH2:44][C@H:45]2[CH2:49][CH2:48][CH2:47][O:46]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C[C@H]1CCCO1)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)C[C@H]2CCCO2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 19.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-[(R)-tetrahydrofuran-2-ylmethyl]acetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.2 mg) was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)=[O:30])=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:43])[CH3:44])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Cl)cn4)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Cl)cn4)ccc3Oc3ccc(N)cc3)ncnc2n1
Yield: 76.3 %

Procedure:
The product of Example 199D (162.2 g, 0.2591 mmol) was treated with trifluoroacetic acid (2 mL) in methylene chloride (2 mL) at room temperature for 30 minutes. The solvents were removed by rotary evaporation and the residual oil taken up in ethyl acetate (75 mL) and washed with saturated aqueous sodium bicarbonate (30 mL), water (2×30 mL), and brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography eluting with 4% methanol/methylene chloride afforded the title compound (104 mg, 76%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.32 (d, J=6.99 Hz, 6 H) 3.09-3.30 (m, 1 H) 5.04 (s, 2 H) 6.57 (d, J=8.82 Hz, 2 H) 6.78 (d, J=8.83 Hz, 1 H) 6.79 (d, J=8.82 Hz, 2 H) 7.60 (d, J=8.46 Hz, 1 H) 7.94-7.98 (m, 2 H) 8.20-8.27 (m, 2 H) 8.43 (d, J=2.94 Hz, 1 H) 8.62 (s, 1 H) 8.85 (d, J=8.46 Hz, 1 H) 9.97 (s, 1 H) 10.91 (s, 1 H); MS (ESI+) m/z 526/528 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.[CH3:25][N:26]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=1)[C:27](Cl)=[O:28]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:25][N:26]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][C:38]([F:39])([F:40])[F:41])=[CH:35][CH:36]=1)[C:27](=[O:28])[O:13][CH2:12][C@@:11]([OH:15])([CH3:14])[CH2:10][N:3]1[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]1[Cl:1]
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: CN(Cc1ccc(OC(F)(F)F)cc1)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(OC(F)(F)F)cc1)C(=O)OC[C@](C)(O)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 76.7 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (2.16 g, 9.18 mmol), N,N-diisopropylethylamine (2.67 ml, 15.30 mmol) and 4-dimethylaminopyridine (0.19 g, 1.53 mmol) were added to a suspension of N-methyl-N-(4-trifluoromethoxybenzyl)carbamoylchloride (2.05 g, 7.65 mmol) in toluene (40 ml) followed by stirring at 100° C. for 3.5 hours. The reaction mixture was diluted with ethyl acetate, and the solution washed with 10% hydrochloric acid, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl N-methyl-N-(4-trifluoromethoxybenzyl)carbamate (2.74 g, yield 77%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:13]([CH3:12])[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[O:6]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 21 %

Procedure:
3,4-Dichlorobenzoyl chloride (60 mg, 0.29 mmol, CAS RN 2905-60-4) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (45 mg, 0.23 mmol, example 1, intermediate a) and DIPEA (79 μL, 0.45 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the product as a waxy solid (18 mg, 21%). MS (ESI): m/z=371.0 [M+H]+.
Reaction SMILES: C(=O)(O)O.[OH:5][CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[CH2:7][NH2:8].[CH2:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:27][CH2:28][C:29](=[O:33])[NH:30][C:31]=2[CH3:32])=[CH:22][CH:21]=1)[C:17]([CH3:19])=O.C([BH3-])#N.[Na+]>CO>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH:6]([OH:5])[CH2:7][NH:8][CH:17]([CH3:19])[CH2:16][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:27][CH2:28][C:29](=[O:33])[NH:30][C:31]=2[CH3:32])=[CH:24][CH:25]=1
Reactant: CC(=O)Cc1ccc(C2=C(C)NC(=O)CC2)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Agent: O=C(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC1=C(c2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2)CCC(=O)N1
Reaction time: 16 h

Procedure:
A mixture of 2-hydroxy-2-(3-chlorophenyl)ethanamine carbonate (0.34 g) and 3,4-dihydro-5-(4-acetonylphenyl)-6-methyl-2(1H)-pyridone (0.4 g) was dissolved in methanol (30 ml). Sodium cyanoborohydride (0.1 g) was added and the mixture was allowed to stand at room tempeature for 16 hr. The solvent was evaporated, the residue partitioned between ethylacetate and water, the organic layer separated, dried (MgSO4) and evaporated to give an oil which was chromatographed on Silica. Elution with methanol-chloroform (3:97) gave 5-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenyl]-3,4-dihydro-6-methyl-2(1H)-pyridinone as a 1:1 mixture of diastereoismers, m.pt. 103°-106° C. (ethyl acetate ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:20])[CH2:17]OC)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[O:29])[CH2:27][CH2:26]1)=[O:24].[CH:38]1(C(O)=O)[CH2:41]C[CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:17]1([C:16]([NH:15][C:11]2[CH:10]=[C:9]([O:8][C:6]3[C:5]([F:21])=[CH:4][C:3]([NH:22][C:23]([C:25]4([C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)=[O:29])[CH2:26][CH2:27]4)=[O:24])=[C:2]([F:1])[CH:7]=3)[CH:14]=[CH:13][N:12]=2)=[O:20])[CH2:41][CH2:38][CH2:39]1
Reactant: COCC(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: O=C(O)C1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)C1CCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a solution of N-(4-(2-chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 0.45 mmol) (as prepared in Example 9) and cyclobutanecarboxylic acid (90 mg, 0.9 mmol) in DMF (3 ml) was added HATU (513 mg, 1.35 mmol), followed by DIEA (516 mg, 4 mmol). The mixture was sparged with nitrogen and stirred overnight at 60° C. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give N-(4-(2-(cyclobutanecarboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (97 mg, yield 41.1%). 1H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 10.42 (s, 1H), 9.80 (s, 1H), 8.18 (d, J=6.0 Hz, 1H), 8.08 (dd, J=12.4, 6.8 Hz, 1H), 7.68 (s, 1H), 7.60-7.54 (m, 3H), 7.17 (t, J=8.8 Hz, 2H), 6.73 (dd, J=5.6, 2.4 Hz, 1H), 2.18-2.02 (m, 4H), 1.92-1.83 (m, 1H), 1.76-7.69 (m, 1H), 1.62-1.55 (m, 4H); MS (ESI): m/z 525.1 [M+H]
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([CH3:22])[C:18](OC)=[O:19])[N:11]=1)([CH3:3])[CH3:2].O.[NH2:24][NH2:25]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([CH3:22])[C:18]([NH:24][NH2:25])=[O:19])[N:11]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](C)Nc1nccc(N2C(=O)OC[C@@H]2C(C)C)n1
Reactant: NN
Solvent: O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C(=O)NN)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a solution of (S)-methyl 2-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)propanoate (120 mg, 0.39 mmol in 5 ml of MeOH) was added 99% hydrazine hydrate, the reaction solution was stirred at room temperature overnight (24 hours), the solvent was removed to yield the desired product (99 mg) in 78% yield, and was used for next step without purification. LCMS m/z 309.1 (M+H)+ RT=1.25 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN(C)C=O>[Cl:15][C:12]1[C:13](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:10][C:11]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(Cl)cc1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1c(Cl)c(N2CCNCC2)cnn1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
55.1 g (200 mmol) of 2-(4-chlorophenyl)-4,5-dichlorpyridazin-3-one are introduced with 41.6 ml (300 mmol) of triethylamine in 400 ml of dimethylformamide. 137.82 g (1600 mmol) of piperazine are added, and the mixture is stirred at 80° C. overnight. The reaction mixture is cooled and then concentrated under high vacuum. The residue is taken up in dichloromethane and washed twice with water, dried over magnesium sulfate and concentrated. The product is isolated by chromatography (gradient: dichloromethane/methanol from 95:5 to 9:1) on silica gel and subsequent crystallization with ether.
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[H][H]>[Pt].CO>[CH2:25]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C@@H:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)[OH:11])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: [H][H]
Reactant: O[C@H](c1ccccn1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Product: O[C@@H](C(Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)[C@@H]1CCCCN1
Yield: 94.3 %

Procedure:
Add 2-(S)-dibenzylamino-3-phenyl-1-pyridin-2-yl-propan-1-(S)-ol (1.05 g, 2.57 mmol), 5% platinum on carbon sulfided (215 mg), glacial acetic acid (2 mL) and methanol (40 mL) and stir 18 h under 1 atmosphere of hydrogen gas. Add filter agent, filter and concentrate. Add ethyl acetate and wash with saturated aqueous sodium bicarbonate, dry (magnesium sulfate) and concentrate to give the title compound as a white foam (1.005 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](Cl)=[O:11].[NH2:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][CH2:16]1>C(OCC)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([NH:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][CH2:16]1)=[O:11]
Reactant: CCc1cn([C@H]2CC[C@@H](CN)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCc1cn([C@H]2CC[C@@H](CNC(=O)Cc3c(Cl)cccc3Cl)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h

Procedure:
A solution of (2,6-dichlorophenyl)acetyl chloride (prepared from 146 mg of the acid) in 1 ml of diethyl ether was added to a solution of 170 mg of 5'-amino-2',3',5'-trideoxy-5-ethyluridine in 2.72 ml of 0.26M sodium hydroxide solution and the mixture was shaken for 10 minutes. The mixture was filtered and the solid was recrystallized from 20 ml of ethanol to give 150 mg of 2',3',5'-trideoxy-5'-[2-(2,6-dichlorophenyl)acetamido]-5-ethyluridine in the form of a white solid of melting point 237°-238° C.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]([NH:11][OH:12])(=[O:10])[CH3:9].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([O:12][NH:11][C:8](=[O:10])[CH3:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)NO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
60% sodium hydride (11.68 g, 0.292 mol) was added to a dimethylformamide solution (200 ml) of acetohydroxamic acid (21.9 g, 0.292 mol) with cooling in an ice bath. After stirring for 1 hour at room temperature, benzylbromide (50 g, 0.292 mol) was added thereto and allowed to react for 24 hours at room temperature. The reaction solution was poured into 500 ml of water, and extracted with ethyl acetate. The organic layer was rinsed with water and dried. After removing the solvent by evaporation, the residue was purified with silica gel chromatography to obtain 31.3 g of N-benzyloxyacetamide (yield: 65%). The proton NMR spectrum of the compound is 1.85 s (3H); 4.89 bs (2H); 7.37 s (5 H); 8.30 bs, 8.81 bs (1H) (solvent: CDCl3).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.CN(C)C=O.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2)(=[O:24])[CH3:23]
Reactant: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)OCCOCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 9-(2-hydroxyethoxymethyl)guanine (4.6 g), dry dimethylformamide (46 ml), acetic anhydride (16 ml) and dry pyridine (24 ml) was stirred at room temperature overnight. The resulting white solid was removed by filtration and dissolved in warm dimethylformamide (100 ml), pyridine (10 ml) and acetic anhydride (8 ml) added and the mixture stirred for 18 hr. The white solid formed was removed by filtration, washed with ethyl acetate and recrystallized from dimethylformamide to give 9-(2-acetyloxyethoxymethyl)guanine (3.3 g), m.p. 240°-241° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:14](OCC)=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH2:14][OH:15])=[C:11]([CH3:13])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1oc(-c2ccc(Cl)cc2)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(Cl)cc2)oc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
9.3 g (35.1 mmol) of ethyl 2-(4-chlorophenyl)-4-methyl-5-oxazolecarboxylate were dissolved in 40 ml of dry tetrahydrofuran and the solution was added dropwise during 10 minutes to a stirred suspension of 1.75 g (46.1 mmol) of lithium aluminium hydride in 60 ml of dry tetrahydrofuran at 0° C. The suspension was stirred at 0° C. for 1 hour and then at room temperature for 1.5 hours. Excess lithium aluminium hydride was destroyed by the dropwise addition of saturated aqueous sodium sulphate, followed by the addition of 100 ml of dilute aqueous sulphuric acid. The aqueous phase was extracted twice with dichloromethane. The combined extracts were washed once with water, dried over magnesium sulphate, filtered and evaporated. The residue was recrystallized from chloroform/hexane to give 6.44 g (82%) of 2-(4-chlorophenyl)-4-methyl-5-oxazolemethanol of melting point 135° C.