Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([NH2:14])=[O:13])=[C:10]2[C:5]([CH:6]=[C:7]([CH3:15])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>CN(C)C=O>[CH3:18][N:19]([CH3:21])[CH:20]=[N:14][C:12]([C:11]1[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][C:7]([CH3:15])=[CH:6]2)=[O:13]
Reactant: COC(OC)N(C)C
Reactant: Cc1cnc2c(C(N)=O)c(Cl)ccc2c1
Solvent: CN(C)C=O
Product: Cc1cnc2c(C(=O)N=CN(C)C)c(Cl)ccc2c1

Procedure:
55.1 g (0.25 mole) of 7-chloro-3-methylquinoline-8-carboxamide were dissolved in 50 ml of N,N-dimethylformamide, 39.3 g (0.32 mole) of N,N-dimethylformamide dimethyl acetal were added, and the mixture was refluxed for 4 hours. After precipitation on ether, 44.0 g (64%) of colorless crystals of melting point 183°-185° C. (decomposition) were isolated (compound No. 22).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:26][CH:27]=O)[CH:21]=4)[CH2:16]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].CC[OH:34]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH2:26][CH:27]=[N:30][OH:31])[CH:21]=4)[C:16]3=[O:34])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=CCOc1ccc2c(c1)CCN(Cc1ccc(-c3ccc(F)cc3)cc1)C2
Reactant: NO
Reactant: CCO
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2ccc(OCC=NO)cc2CCN1Cc1ccc(-c2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of the above aldehyde (~23 mmol) in pyridine (20 ml) and EtOH (20 ml) is added hydroxylamine hydrochloride (3.2 g, 46 mmol). The reaction mixture is stirred overnight. The solvent is removed in vacuo and the residue dissolved in EtOAc (300 ml) and 2N HCl (300 ml). The EtOAc portion is washed with saturated NaHCO3 solution (300 ml), saturated NaCl solution (300 ml), dried over MgSO4, and concentrated in vacuo. The resulting material is purified by chromatography (silica gel 1:9 EtOAc/hexanes, 1:4 EtOAc/hexanes and 2:3 EtOAc/hexanes) yielding α-[2-(4'-fluoro-4-biphenylylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy]-acetaldehyde oxime.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:3]=1.[NH2:20][CH2:21][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:23][O:24][CH3:25].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:29]([O:28][C:27]([NH:26][C@@H:22]([CH2:23][O:24][CH3:25])[CH2:21][NH:20][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:3]=1)=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1-c1cnn(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC[C@@H](CNc1cc(C#N)c(C(=O)OC)c(-c2cnn(C)c2)n1)NC(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 12 h

Procedure:
To a screw-top vial was added methyl 6-chloro-4-cyano-2-(1-methyl-1H-pyrazol-4-yl)nicotinate (115 mg, 0.416 mmol), (R)-tert-butyl 1-amino-3-methoxypropan-2-ylcarbamate (93 mg, 0.457 mmol), and DIPEA (87 μL, 0.499 mmol) in DMF (308 μL). The resulting yellow solution was stirred for 12 h at 45° C. and then at 50° C. for 6 h. The reaction mixture was diluted with EtOAc (20 mL) and was washed with water (10 mL) and brine (20 mL). The organic layer was collected and dried over Na2SO4 and was concentrated to a yellow oil. The concentrate was purified via standard phase column chromatography eluting with EtOAc and hexanes (50-100% EtOAc gradient) to give the title compound as a light yellow residue (36.5 mg, 20%). [M+H] calc'd for C21H28N6O5, 445; found, 445.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.O.[NH2:17][NH2:18]>CCO>[NH:1]1[C:5]([C:6]2[CH:15]=[CH:14][C:9]([C:10]([NH:17][NH2:18])=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: NN
Reactant: COC(=O)c1ccc(-c2nnn[nH]2)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
To a suspension of methyl 4-(1H-tetrazol-5-yl)benzoate (1.00 g, 4.16 mmol) in EtOH (15 mL) was added hydrazine hydrate (3.0 mL). After stirring for 15 hrs at reflux, the reaction mixture was allowed to warm up to rt. A white solid precipitated out. Filtration, washing with EtOH (2×3 mL), EtOH/water (2×3 mL) and water (2×3 mL) and drying under vacuo at 70° C. for 5 hrs gave 677 mg of the title compound as a white solid in a 80% yield.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)[C:6]([NH:8][CH:9]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)[C:10]([N:12]1[CH2:17][CH:16]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[NH:15][C:14](=[O:29])[CH:13]1[CH2:30][C:31]1[N:32]=[CH:33][N:34](CC2C=CC=CC=2)[CH:35]=1)=[O:11])=[O:7])(=[O:3])[CH3:2].C1CCCCC=1>C(O)C.C(O)(=O)C.[Pd]>[C:1]([NH:4][CH:5]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)[C:6]([NH:8][CH:9]([CH2:43][C:44]1[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=1)[C:10]([N:12]1[CH2:17][CH:16]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[NH:15][C:14](=[O:29])[CH:13]1[CH2:30][C:31]1[N:32]=[CH:33][NH:34][CH:35]=1)=[O:11])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(Cc1ccc(O)cc1)C(=O)NC(Cc1ccc(F)cc1)C(=O)N1CC(Cc2ccc3ccccc3c2)NC(=O)C1Cc1cn(Cc2ccccc2)cn1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)NC(Cc1ccc(O)cc1)C(=O)NC(Cc1ccc(F)cc1)C(=O)N1CC(Cc2ccc3ccccc3c2)NC(=O)C1Cc1c[nH]cn1
Reaction time: 48 h

Procedure:
2-acetylamino-N-[2-[2-(1-benzyl -1H-imidazol-4-ylmethyl)-5-naphthalen-2-ylmehtyl-3-oxo-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-3-(4-hydroxyphenyl)-propionamide, 73, (0.22 g, 0.28 mmol) is dissolved in ethanol/acetic acid (4:1) (3 mL). Cyclohexene (3 mL) and Pd-black are added and the solution is refluxed with periodic replenishment of cyclohexene. The reaction is monitored by TLC and after 2 days is cooled and filtered through Celite to remove the catalyst. The filtrate is concentrated in vacuo to afford an oil which is purified by reverse phase C18 prep HPLC to afford the desired product.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=1.Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][C:16]=2[C:27]([F:30])([F:28])[F:29])=[N:22]1)=[O:12])[CH3:9]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2ccc(Cl)cc2C(F)(F)F)n[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ccc(Cl)cc2C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.2 %

Procedure:
Triethylamine (0.17 g, 1.65 mmol) and ethyl isocyanate (0.31 g, 2.2 mmol) were added to a solution of 3-(4-chloro-2-trifluoromethylphenyloxy)-5-methylpyrazole (0.55 g, 2.0 mmol) in ethyl acetate (5 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a colorless viscous substance of N-ethyl-3-(4-chloro-2-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.53 g, yield: 75.9%). 1H-NMR (CDCl3, TMS, ppm): δ 1.22 (t, J=7.3 Hz, 3H), 2.59 (d, J=0.7 Hz, 3H), 3.37 (q, J=7.3 Hz, 2H), 5.73 (q, J=0.7 Hz, 1H), 6.91 (br s, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.49 (dd, J=2.5 and 8.8 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]([C:36](Cl)=[O:37])[CH:27]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:36]([C:28]4[CH:27]=[N:26][C:35]5[C:30]([CH:29]=4)=[CH:31][CH:32]=[CH:33][CH:34]=5)=[O:37])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C(Cl)c1cnc2ccccc2c1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cnc5ccccc5c4)cc3)cc2C1=O
Yield: 20 %

Procedure:
The compound of example 650 was prepared analogous to the compound of example 640 by reaction of compound of example 6 with commercially available quinoline-3-carbonyl chloride.
Reaction SMILES: [Na].[CH2:2]([OH:4])[CH3:3].Cl[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[CH:22]=[O:23]>O>[CH2:2]([O:4][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[CH:22]=[O:23])[CH3:3]
Reactant: CCO
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Agent: [Na]
Solvent: O
Product: CCOC1=C(C=O)C(c2ccccc2)Oc2ccccc21
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
1.7 g sodium is allowed to react with 150 ml absolute ethanol. After complete disappearance of sodium, one adds 13.5 g 4-chloro-3-formyl-flav-3-ene. After stirring 30 minutes at 40° C., 300 ml of water is added and a precipitate is formed, filtered, washed with water and dried. The solid is crystallized in hexane. Pure 4-ethoxy-3-formyl-flav-3-ene is obtained as yellow crystals; m.p. 80°-82° C.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12.[F:19][C:20]1[CH:21]=[C:22]([CH2:29][CH:30]=O)[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27]>>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:30][CH2:29][C:22]4[CH:23]=[CH:24][C:25]([N+:26]([O-:28])=[O:27])=[C:20]([F:19])[CH:21]=4)[CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12
Reactant: O=CCc1ccc([N+](=O)[O-])c(F)c1
Reactant: O=C1CNCCN1CCc1ccc2nonc2c1
Product: O=C1CN(CCc2ccc([N+](=O)[O-])c(F)c2)CCN1CCc1ccc2nonc2c1

Procedure:
The title compound was prepared from 1-[2-(2,1,3-Benzoxadiazol-5-yl)ethyl]piperazin-2-one and (3-Fluoro-4-nitrophenyl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 414 [M+1]+.
Reaction SMILES: FC1C=CC=C(OC2C=CC(CCC)=CC=2OC)N=1.C(C1C=CC(OC2C=CC(N)=C(F)C=2)=C(OC)C=1)C.[CH2:39]([C:41]1[CH:55]=[CH:54][C:44]([O:45][C:46]2[CH:52]=[C:51]([F:53])[CH:50]=[CH:49][C:47]=2[NH2:48])=[C:43]([O:56]C)[CH:42]=1)[CH3:40]>>[NH2:48][C:47]1[CH:49]=[CH:50][C:51]([F:53])=[CH:52][C:46]=1[O:45][C:44]1[CH:54]=[CH:55][C:41]([CH2:39][CH3:40])=[CH:42][C:43]=1[OH:56]
Reactant: CCc1ccc(Oc2cc(F)ccc2N)c(OC)c1
Agent: CCCc1ccc(Oc2cccc(F)n2)c(OC)c1
Agent: CCc1ccc(Oc2ccc(N)c(F)c2)c(OC)c1
Product: CCc1ccc(Oc2cc(F)ccc2N)c(O)c1
Yield: 18.9 %

Procedure:
According to the procedure of example 5(b), except substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for a mixture of 4-(4-ethyl-2-methoxyphenoxy)-2-fluoroaniline and 2-(4-ethyl-2-methoxyphenoxy)-4-fluoroaniline (50.9 mg, 0.19 mmol), the title compound (8.9 mg; 19%) was obtained after purification by preparative TLC (dichloromethane/ethyl acetate: 9/1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[CH:5]=1.[Cl:12]Cl>C(Cl)(Cl)Cl>[Cl-:12].[Cl-:12].[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[CH:5]=1
Reactant: ClCl
Agent: COC(=O)c1cccc(I)c1
Solvent: ClC(Cl)Cl
Product: [Cl-]

Procedure:
A solution of 5.0 g methyl-m-iodobenzoate in 70 ml chloroform was cooled to 0°-10° and treated with gaseous chlorine for 1 hour. The resulting yellow solution was evaporated to afford 6.2 g methyl-m-iodobenzoate dichloride as yellow needles, mp=108°-110°. IR: 5.83, 7.80, 8.00, 8.90, 9.18, 10.52, 11.12, 12.39, and 13.48.
Reaction SMILES: [CH3:1]N(C=O)C.[Br:6][C:7]1[C:12]([OH:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=1.[H-].[Na+].CI>O>[Br:6][C:7]1[C:12]([O:13][CH3:1])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=1
Reactant: Oc1cc(Cl)cnc1Br
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cc(Cl)cnc1Br

Procedure:
To a DMF (60 mL) solution containing 2-bromo-5-chloro-3-hydroxypyridine (19.95 g, 95.7 mmol) at 0° C. was added NaH (2.53 g, 105.3 mmol) portion wise. After the cessation of H2 evolution, CH3I (14.26 g, 100.5 mmol) was added dropwise and the reaction stirred ~16 h. Water (1.9 mL) was added and the solvent removed under reduced pressure. The concentrate was triturated with 5 portions of CH2Cl2. The combined organic phases were washed with sat. NaCl solution, dried with K2CO3, filtered, and concentrated in vacuo. Silica gel chromatography (95:5 Hexane:EtOAc) of the concentrate afforded the title compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].C([Sn]([N:29]=[N+:30]=[N-:31])(CCCC)CCCC)CCC.Cl>CO>[C:10]1([CH:5]([CH2:4][CH2:3][C:1]2[NH:31][N:30]=[N:29][N:2]=2)[C:6]([O:8][CH3:9])=[O:7])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C(CCC#N)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: CO
Product: COC(=O)C(CCc1nnn[nH]1)c1ccccc1
Temperature: 160 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
Methyl (RS)-4-cyano-2-phenylbutanoate (see Preparation 21) (1.8 g) and tri-n-butyltin azide (3.23 g were mixed and heated at 160° C. for 3 hours, dissolved in methanol (100 ml), treated by the addition of hydrogen chloride gas for 10 minutes and left for 18 hours. Evaporation gave a residue which was triturated three times with diisopropyl ether then partitioned between 10% aqueous sodium carbonate and ethyl acetate. The aqueous later was acidifed with 2 M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and evaporated to give the title compound (1.34 g, 61%) as a brown oil.
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[O:14]>ClCCl>[CH2:1]([N:8]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[O:14])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1ccccc1
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Solvent: ClCCl
Product: CN(CC(=O)c1ccncc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of N-benzyl-N-methylamine (3.7 cm3) in dry dichloromethane (40 cm3), cooled to 0° C. was added with stirring, 4-bromoacetylpyridine hydrobromide (4.0 g). The reaction was allowed to warm to room temperature, then stirred for a further 18 hr. The solvent was stripped at reduced pressure, and the residue partitioned between ethyl acetate and dilute aqueous Na2CO3. The organic phase was separated, dried (Na2SO4), evaporated, and the residue subjected to chromatography on silica gel, eluent 5% methanol in dichloromethane, to afford 4-(N-benzyl-N-methylaminoacetyl)pyridine, 1.49 g, 43%, as a yellow gum.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[CH:25]([CH2:30][CH3:31])[C:26](=O)[CH2:27][CH3:28])C>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[C:25]([CH2:30][CH3:31])=[C:26]([CH2:27][CH3:28])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(CC)C(=O)CC
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Solvent: ClC(Cl)Cl
Product: CCc1c(CC)n2c(nc1=O)OC(COc1ccc(C3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 2-ethyl-3-oxo-pentanoic acid ethyl ester in accordance with the procedures of O.-S. Adetchessi, et. al., Tetrahedron, 61, (2005), 4453-4460. [α]D25 −11.20 (c 0.5, CHCl3).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5](#[N:9])[CH2:6][C:7]#[N:8].Cl.[NH2:11][C:12]([NH2:14])=[NH:13].Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C)C=O>[N:1]([C:6]1[C:5]([NH2:9])=[N:13][C:12]([NH2:14])=[N:11][C:7]=1[NH2:8])=[O:3]
Reactant: N#CCC#N
Reactant: N=C(N)N
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(N)c(N=O)c(N)n1
Temperature: 140 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
A solution of 70 g of sodium nitrite in 120 g of water was added dropwise at room temperature to a suspension of 66 g of malononitrile and 96 g of guanidine hydrochloride in 200 g of water, and the pH was kept at 4 by the addition of hydrochloric acid. After the reaction had continued for 4 hours at room temperature, 21 g of sodium carbonate and 400 g of dimethylformamide were added. The water was distilled off under reduced pressure. Thereafter, the reaction mixture was heated at 140° C. for 1 hour, isomerization to 5-nitroso-2,4,6-triamino-pyrimidine taking place. After the reaction was complete, 400 ml of water were added, and the product was filtered off and washed with water. After the product had been dried, 140 g of a pure raspberry-red 5-nitroso-2,4,6-triaminopyrimidine were obtained. The melting point of the product was above 340° C. and the yield was 91 percent.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([OH:9])[C:7]#[CH:8].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>ClCCl>[CH2:6]([O:9][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1)[C:7]#[CH:8]
Reactant: C#CCO
Reactant: C1=COCCC1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: C#CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of phosphoryl chloride (0.5 ml in 10 ml of dichloromethane [DCM])) was added with care to a solution of prop-2-yn-1-ol (7.00 g, 125 mmol) and dihydropyran (10.50 g, 125 mmol) in DCM (80 ml). The reaction mixture was stirred at room temperature for 16 h, washed with sodium hydrogen carbonate solution (3 times), dried (MgSO4) and the solvent removed in vacuo to yield a colorless oil. The crude product was purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1), Rf: 0.43] to yield a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:5](=O)[C:4](=[O:7])[C:3]=1[O:8]C.[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>N1C=CC=CC=1>[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:5]3[C:4](=[O:7])[C:3](=[O:8])[C:2]=3[NH2:1])[CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1c(N)c(=O)c1=O
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Solvent: c1ccncc1
Product: Nc1c(NCCCOc2cc(CN3CCCCC3)ccn2)c(=O)c1=O

Procedure:
1-Amino-2-methoxy-cyclobut-1-ene-3,4-dione is mixed with 3-[4-(piperidinomethyl)pyrid-2-yloxy]prop-1-ylamine in anhydrous pyridine and is heated at reflux temperature to give the title product.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[CH3:5][CH:6]([CH2:8][CH2:9][CH2:10][C@H:11]([CH2:13][CH2:14][CH2:15][C@H:16]([CH2:18][CH2:19][CH2:20]/[C:21](=[CH:23]/[CH2:24][OH:25])/[CH3:22])[CH3:17])[CH3:12])[CH3:7]>C(O)(=O)C.C(OCC)(=O)C>[C:2](=[O:1])([O:25][CH2:24]/[CH:23]=[C:21](/[CH2:20][CH2:19][CH2:18][C@@H:16]([CH2:15][CH2:14][CH2:13][C@@H:11]([CH2:10][CH2:9][CH2:8][CH:6]([CH3:5])[CH3:7])[CH3:12])[CH3:17])\[CH3:22])[NH2:3]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C/C(=C\COC(N)=O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
6.6 g of sodium cyanate was added to a solution of 10.0 g of phytol dissolved in 50 ml of acetic acid, in small portions. The resulting mixture was stirred for 6 hours at room temperature. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in 50 ml of ethyl acetate. The solution was washed with 3% aqueous sodium hydrogen-carbonate solution and water in this order and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure. The residue obtained was purified by a column chromatography (eluant: benzene) to obtain 10.0 g (yield: 87%) of oily phytyl carbamate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)=[O:17])[CH:12]=[C:11]([C:28]([O:30][CH3:31])=[O:29])[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:32]1([CH2:38][C:39](=O)[C:40](O)=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO>[CH2:38]([C:39]1[C:40](=[O:41])[N:8]([C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)=[O:17])[CH:12]=[C:11]([C:28]([O:30][CH3:31])=[O:29])[CH:10]=2)[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)c1cc(NC(=O)c2ccc3ccccc3c2)cc(Nc2ncccc2N)c1
Reactant: O=C(O)C(=O)Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(NC(=O)c2ccc3ccccc3c2)cc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Yield: 71.6 %

Procedure:
A mixture of 3-amino-2-[3-methoxycarbonyl-5-(2-naphthoylamino)phenylamino]pyridine (180 mg) and 3-phenylpyruvic acid (86 mg) in methanol (4 ml) was stirred under reflux for 4 hours. The precipitate was collected and washed with methanol to give 2-benzyl-4-[3-methoxycarbonyl-5-(2-naphthoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (169 mg).
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([O:17]/[CH:18]=[CH:19]/[C:20](=[O:22])[CH3:21])[C@H:15]([CH3:23])[O:14][C:13](=[O:24])[C@@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[C@H:15]([CH3:23])[O:14][C:13](=[O:24])[C@@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][CH2:19][CH:20]([OH:22])[CH3:21])[C@H:15]([CH3:23])[O:14][C:13](=[O:24])[C@@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)/C=C/O[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)CCO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Product: CC(O)CCO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Reaction time: 8 h
Yield: 69 %
Yield: 14 %

Procedure:
To a solution of tert-butyl ((3S,7S,8R,9S)-7-benzyl-9-methyl-2-oxo-8-(((E)-3-oxobut-1-en-1-yl)oxy)-1,5-dioxonan-3-yl)carbamate (601 mg, 1.34 mmol, 1.00 equiv) in EtOAc (13 mL) was added 10% Pd/C (72 mg, 0.067 mmol, 0.050 equiv). The resulting suspension was stirred under an atmosphere of hydrogen (1 atm, balloon) overnight. The catalyst was then filtered through a pad of Celite® that was flushed with EtOAc. The filtrate was concentrated to provide an oil. Purification by automated silica gel column chromatography (10-50% EtOAc in hexanes) provided tert-butyl ((3S,7S,8R,9S)-7-benzyl-9-methyl-2-oxo-8-(3-oxobutoxy)-1,5-dioxonan-3-yl)carbamate (417 mg, 69%) as well as tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-(3-hydroxybutoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (86 mg, 14%).