Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([C:37](O)=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:52][S:53]([NH2:56])(=[O:55])=[O:54].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([CH3:36])([CH3:35])[C:37]([NH:56][S:53]([CH3:52])(=[O:55])=[O:54])=[O:38])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Br)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Br)ccc2OC(C)(C)C(=O)NS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.1 %

Procedure:
A solution of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (20 mg, 0.032 mmol) and CDI (11 mg, 0.064 mmol) in DMF (0.2 mL) was heated at 60° C. for 30 min, then cooled to room temperature. To this solution was added a mixture of methanesulfonamide (19 mg, 0.2 mmol) and NaH (8 mg, 60%, 0.2 mmol) in DMF (0.2 mL). The resulting mixture was stirred at room temperature for 10 min, purified by prep-HPLC to give the title compound as a white solid (10 mg).
Reaction SMILES: [F:1][C:2]1[C:15]([N:16]2[C:20](=[O:21])[C:19](=[C:22]([CH3:24])[CH3:23])[NH:18][C:17]2=[O:25])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[CH3:26][N:18]1[C:19](=[C:22]([CH3:23])[CH3:24])[C:20](=[O:21])[N:16]([C:15]2[C:2]([F:1])=[CH:3][C:4]3[O:9][CH2:8][C:7](=[O:10])[N:6]([CH2:11][C:12]#[CH:13])[C:5]=3[CH:14]=2)[C:17]1=[O:25]
Reactant: O=C([O-])[O-]
Reactant: C#CCN1C(=O)COc2cc(F)c(N3C(=O)NC(=C(C)C)C3=O)cc21
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: C#CCN1C(=O)COc2cc(F)c(N3C(=O)C(=C(C)C)N(C)C3=O)cc21
Temperature: 70 °C

Procedure:
3-[7-fluoro-4-propargyl-2H-1,4-bezoxazin-3(4H)-on-6-yl]-5-isopropylidenehydantoin (1.2 g), potassium carbonate (3.0 g) and iodomethane (3.0 g) were dissolved in N,N-dimethylformamide (30 ml), followed by heating at 70° C. for 6 hours. The reaction mixture was allowed to cool, combined with water and extracted with ethyl acetate. The organic layer was purified by silica gel column chromatography using a mixture of toluene and ethyl acetate as the eluent to give Compound No. 32 (1.1 g).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:12]([NH:14][CH:15]2[C:25](=[O:26])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=O.C([O-])(=O)C.[Na+].O>O1CCCC1>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[C:12]([NH:14][CH:15]2[C:25](=[O:26])[N:17]3[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: O=C(O)C1=CCS[C@@H]2C(NC(=O)C(=NOCc3ccc(F)cc3)c3csc(NC(=O)C(F)(F)F)n3)C(=O)N12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCc2ccc(F)cc2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 111 %

Procedure:
A mixture of 7-[2-[2-(2,2,2-trifluoroacetamido)-thiazol-4-yl]-2-(4-fluorobenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.9 g.), sodium acetate (4.1 g.), water (60 ml.) and tetrahydrofuran (30 ml.) was treated in a similar manner to that of Example 16-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(4-fluorobenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.68 g.), m.p. 203° to 207° C. (dec.).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH:51][C:52]([C:54]1[S:55][C:56]2[CH2:57][NH:58][CH2:59][CH2:60][C:61]=2[N:62]=1)=[O:53]>CN(C=O)C>[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH:51][C:52]([C:54]1[S:55][C:56]2[CH2:57][N:58]([C:7]([C:4]3[CH:3]=[CH:2][C:1]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:6][CH:5]=3)=[O:9])[CH2:59][CH2:60][C:61]=2[N:62]=1)=[O:53]
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1nc2c(s1)CN(C(=O)c1ccc(-c3ccccc3)cc1)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of biphenyl-4-carboxylic acid (1.0 mmol) in dry 10 mL DMF, were added 1-hydroxybenzotriazole (1.2 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2 mmol) and N-methylmorpholine (2.0 mmol). Solution was cooled to 0° C.N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained from step VIII of example 1 (1.1 mmole.) was then added and mixture was stirred at room temperature overnight. Reaction mixture was concentrated, diluted with water, extracted with dichloromethane, washed with brine solution, and dried over anhydrous Na2SO4. Concentrated and purified by column chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[N+:4]([O-])[C:3]=1[C:12]([O:14][CH3:15])=[O:13].P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:1][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[N:4][C:5]([CH2:8][O:9][CH3:10])=[CH:6][C:7]=1[Cl:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1ccc(Cl)c(C(=O)OC)[n+]1[O-]
Solvent: CC#N
Product: COCc1cc(Cl)c(Cl)c(C(=O)OC)n1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
To a solution of methyl 3-chloro-6-(methoxymethyl)pyridine-2-carboxylate 1-oxide (1.64 g, 7.08 mmol) in acetonitrile (28 mL) was added phosphorus oxychloride (1.32 mL, 14.16 mmol) and the mixture stirred at reflux for 4 hours. After cooling to room temperature the mixture was concentrated to dryness in vacuo. The residue was diluted with ethyl ether and carefully washed with saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with ethyl ether. After the organic layers were combined, the solution was dried (MgSO4), filtered and concentrated to dryness to give crude methyl 3,4-dichloro-6-(methoxymethyl)pyridine-2-carboxylate (1.74 g) as a yellow oil; 1H NMR (CDCl3): δ 7.70 (s, 1H), 4.60 (s, 2H), 4.00 (s, 3H), 3.40 (s, 3H).
Reaction SMILES: CN1CC[O:5]CC1.[C:8]([C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][CH:16]([NH:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH2:21])[CH3:17])=[CH:12][CH:11]=1)#[N:9].[CH:28]1[CH:33]=[CH:32][C:31]([O:34][C:35](Cl)=S)=[CH:30][CH:29]=1.O>C(Cl)Cl>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH:16]([NH:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:23])[CH3:24])[NH:21][C:35]([O:34][C:31]2[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=2)=[O:5])[CH3:17])=[CH:26][CH:27]=1)#[N:9]
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Reactant: CN1CCOCC1
Reactant: S=C(Cl)Oc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C
Temperature: 25 °C
Yield: 76.7 %

Procedure:
0.4 g of N-methylmorpholine was added to a suspension containing 1.1 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 40 ml of methylene chloride, at -15° C. After 0.7 g of phenyl chlorothionoformate was added to the mixture at -15° C., the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and then the whole mixture was stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus yielding 1.2 g of the desired product in the form of a yellow glutinous substance (yield: 75%).
Reaction SMILES: [CH2:1]([N:6]([C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1)[C:7](Cl)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1>N1C=CC=CC=1.O>[CH2:1]([N:6]([C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1)[C:7](=[O:8])[NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][CH:35]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCCCCN(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: c1ccncc1
Solvent: O
Product: CCCCCN(C(=O)Nc1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 15 h
Yield: 21.5 %

Procedure:
A solution of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-carbamoyl chloride (35) (900 mg, 2.6 mmole) in 20 mL pyridine was treated with 481 mg of ethyl p-aminobenzoate (3 eq.) and stirred at 40° C. for 15 hours. The reaction mixture was diluted with 100 mL of cold water and extracted with two 100 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give an orange oil, which was purified by flash chromatography (SiO2, 5% ethyl acetate/hexanes) to provide 260 mg of ethyl 4-[3-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (37) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C1C=CC2N(O)N=NC=2C=1.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][C:34]=1/[C:35](/[NH:38]O)=[N:36]/[H])[NH:31][CH:30]=[C:29]2[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(OCC)(=O)C.C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:14][N:36]=[C:35]([C:34]3[CH:33]=[C:32]4[C:28]([C:29]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:30][NH:31]4)=[CH:27][C:26]=3[F:25])[N:38]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reactant: [H]/N=C(\NO)c1cc2[nH]cc(CCC(=O)OCC)c2cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)c(F)cc12
Temperature: 120 °C
Yield: 60.8 %

Procedure:
To a solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (210 mg) in tetrahydrofuran (THF) (10 mL) was added EDC (373 mg) and HOBt (298 mg). The mixture was stirred for half an hour. Ethyl 3-{5-fluoro-6-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D155) (286 mg) was then added and the resulting mixture was stirred further for 1 hour. Finally, TBAF (1019 mg) was added to the solution and the reaction vessel was sealed and heated in microwave at 120° C. for two hours. After cooling the reaction, the solution was diluted with ethyl acetate (80 mL) and washed with water (2×60 mL). The organic layer was then concentrated under vacuo and the residue was chromatographed on silica gel to give the designed product ethyl 3-[6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D158) (280 mg). MS (ES): C23H22ClFN4O4 requires 472.1; found 473.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:24][CH:25]=O)[CH2:9][N:10]([CH3:23])[C:11]([C:13]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[O:27]=[C:28]1[NH:33][CH2:32][CH2:31][CH2:30][N:29]1[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[O:27]=[C:28]1[NH:33][CH2:32][CH2:31][CH2:30][N:29]1[CH:34]1[CH2:39][CH2:38][N:37]([CH2:25][CH2:24][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][N:10]([CH3:23])[C:11]([C:13]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:36][CH2:35]1
Reactant: CN(CC(CC=O)c1ccc(Cl)cc1)C(=O)c1cccc2c1CCCC2
Reactant: O=C1NCCCN1C1CCNCC1
Product: CN(CC(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)cc1)C(=O)c1cccc2c1CCCC2

Procedure:
Using standard reductive amination conditions N-[2-(4-chlorophenyl)-4-oxobutyl]-N-methyl-5,6,7,8-tetrahydro-1-naphthamide was reacted with with 4-(tetrahydro-2-oxo-1(2H)-pyrimidinyl)piperidine and converted to the citrate salt. MS: m/z 537 (M+H). Analysis for C3H41CIN4O2.C6H8O7. H2O: calculated: C, 59.36; H, 6.87; N, 7.46; found: C, 59.42; H, 6.71; N, 7.12.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=[O:36].C(OCC)(OCC)OCC.NC1CCOCC1>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([CH:1]4[CH2:6][CH2:5][O:36][CH2:3][CH2:2]4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: NC1CCOCC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1C1CCOCC1
Yield: 57.1 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), 4-aminotetrahydropyrane (0.102 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 76.7 mg (0.25 mmol, 57.1% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:24][N:25]=[C:26]=[O:27]>ClCCl.C(#N)C.CCN(C(C)C)C(C)C>[CH3:24][NH:25][C:26]([N:21]1[CH2:20][CH2:19][CH:18]([CH2:17][N:13]([CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)[CH2:14][CH2:15][CH3:16])[CH2:23][CH2:22]1)=[O:27]
Reactant: CCCN(CC1CCNCC1)C1CCc2ccc(OC)cc2C1
Reactant: CN=C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CCN(C(=O)NC)CC1)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-ylmethyl-propyl-amine (200 μL of a 0.25 M solution in dichloromethane, 50 μmole) was added 220 μL of a 0.25 M solution of methyl isocyanate in acetonitrile and 30 μL of DIEA. The solution was allowed to stir for 24 h at 25° C. under N2 and then concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1 % TFA)) to afford 4-{[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidine-1-carboxylic acid methylamide (17.1 mg) 25 [M+H]+=374.
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].C[O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[N:22][O:23][C:24]=2[CH3:25])=[N:14][CH:13]=1>C1(C)C=CC=CC=1.O1CCOCC1>[CH:5]([O:23][CH:24]([CH3:25])[CH3:20])([CH3:7])[CH3:6].[CH:5]([NH:8][C:11](=[O:10])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([CH2:26][CH2:27][C:28]([F:31])([F:29])[F:30])=[N:22][O:23][C:24]=2[CH3:25])=[N:14][CH:13]=1)([CH3:7])[CH3:6]
Reactant: COC(=O)c1ccc(OCc2c(CCC(F)(F)F)noc2C)nc1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)OC(C)C
Product: Cc1onc(CCC(F)(F)F)c1COc1ccc(C(=O)NC(C)C)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 128 %

Procedure:
Trimethylaluminium (1.22 mL of a 2 M solution in toluene, 2.44 mmol) was added dropwise to a stirred solution of isopropylamine (144 mg, 2.46 mmol) in dioxane (4 mL) at room temperature and under argon. After 1 h, a solution of 6-[5-methyl-3-(3,3,3-trifluoro-propyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (210 mg, 0.61 mmol) in dioxane (4 mL) was added and the reaction mixture warmed to 90° C. After 10 h the reaction mixture was cooled and poured onto ice/water. The resultant mixture was extracted with ethylacetate then the combined extracts were washed with Seignette salt solution. The organic phase was dried, filtered and evaporated then purified by chromatography (silica, 0 to 60% ethyl acetate in heptane) then trituration with diisopropyl ether to give the title compound (145 mg, 64%) as a white solid. MS: m/e=372.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:3]=1.Cl.[CH3:18][NH:19][CH3:20].C(N(CC)CC)C>CN(C=O)C>[CH3:18][N:19]([CH3:20])[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: Cc1ccc(Nc2cc(Cl)nc(N)n2)cc1
Reactant: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(Nc2cc(N(C)C)nc(N)n2)cc1
Temperature: 170 °C
Yield: 38.5 %

Procedure:
A mixture of 6-chloro-N4-(4-methylphenyl)-2,4-pyrimidinediamine (1.5 g, 6.4 mmol), and N,N-dimethylamine hydrochloride (0.56 g, 7 mmol) and triethylamine (1.4 g, 14 mmol) in DMF (2 mL), was heated at 170° C. for 16 h. The product was filtered out and the organic layer was treated with saturated NaHCO3 (50 mL) and extracted with EtOAC (3×50 mL). The organic layer washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (0.6 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:25])[CH:3]=1.Cl.[NH2:27][OH:28].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:27][OH:28])=[C:4]([CH3:25])[CH:3]=1
Reactant: Cc1cc(C(=O)C[C@@H](c2ccccc2)c2ccc(Cl)cc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(C[C@@H](c2ccccc2)c2ccc(Cl)cc2C)=NO)ccn1

Procedure:
In analogy to example 132, step 6, from (S)-3-(4-chloro-2-methylphenyl)-1-(2-methyl-pyridin-4-yl)-3-phenylpropan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white solid, MS (ESI+): m/z=365.1 ([M+H]+).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13]1([C:29]3[CH:28]=[CH:27][C:26]4[CH:30]=[C:31](O)[CH:32]=[CH:33][C:25]=4[C:24]=3[O:23][C:22]3[CH:21]=[C:20]([N:35]([CH3:37])[CH3:36])[CH:19]=[CH:18][C:17]1=3)[O:12][C:11]2=[O:38])([OH:7])=[O:6].C(OC(=O)C)(=O)C>O>[C:1]([O:4][C:31]1[CH:32]=[CH:33][C:25]2[C:24]3[O:23][C:22]4[CH:21]=[C:20]([N:35]([CH3:36])[CH3:37])[CH:19]=[CH:18][C:17]=4[C:13]4([C:14]5[C:10](=[CH:9][C:8]([C:5]([OH:7])=[O:6])=[CH:16][CH:15]=5)[C:11](=[O:38])[O:12]4)[C:29]=3[CH:28]=[CH:27][C:26]=2[CH:30]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CN(C)c1ccc2c(c1)Oc1c(ccc3cc(O)ccc13)C21OC(=O)c2cc(C(=O)O)ccc21
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc2c3c(ccc2c1)C1(OC(=O)c2cc(C(=O)O)ccc21)c1ccc(N(C)C)cc1O3
Reaction time: 8 h

Procedure:
To prepare the acetate from 8, 300 mg 5'-carboxy-10-dimethylamino-3-hydroxy-spiro[7H-benzo[c]xanthene-7,1'(3'H)-isobenzofuran]-3'-one was added 5 ml acetic anhydride and the solution refluxed for 2 hours. The solution was poured into water and stirred overnight to hydrolyze excess actic anhydride. The resulting solid was collected and purified by silica gel chromatography with 10% methanol with chloroform to give 0.16 g dark violet solid, Rf =0.37 with methanol:chloroform (1:9). Absorbance maxima in potassium phosphate buffer at pH 7.0 at 511 and 540 nm; extinction coefficients of 24,100 and 21,700 cm-1M-1 respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][C@@:12]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][CH:22]=3)[CH3:20])[CH2:14][CH2:13]2)=[CH:5][CH:4]=1.C1C[O:40]CC1>>[OH:40][CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([C@@H:19]([N:15]2[CH2:14][CH2:13][C@:12]([CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:36][CH:35]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:17][C:16]2=[O:18])[CH3:20])=[CH:26][CH:25]=1
Reactant: C=Cc1ccc([C@H](C)N2CC[C@](CCCOCc3ccc(OC)cc3)(c3ccccc3)OC2=O)cc1
Reactant: C1CCOC1
Product: COc1ccc(COCCC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(CCO)cc3)C(=O)O2)cc1
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of (R)-6-(3-(4-methoxybenzyloxy)propyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (260 mg, 0.536 mmol) in THF (3 mL) was added BH3 THF (1.6 mL, 1 mol/L) at 0° C. under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched with water. Then aqueous NaOH solution (1 mol/L, 2 mL) and H2O2 (1 mL) were added to the above mixture. The resulting mixture was stirred for 1.5 h. The mixture was extracted with EtOAc and the combined organic phase was concentrated to give crude (R)-3-((S)-1-(4-(2-hydroxyethyl)phenyl)ethyl)-6-(3-(4-methoxybenzyloxy)propyl)-6-phenyl-1,3-oxazinan-2-one (260 mg, 96%), which was used for the next step without purification. 1H NMR (CDCl3): δ=1.32 (m, 2H), 1.41 (d, 3H), 1.89 (m, 2H), 2.12 (m, 1H), 2.22 (m, 2H), 2.68 (m, 1H), 2.81 (m, 1H), 3.27 (m, 2H), 3.72 (s, 3H), 4.26 (s, 2H), 5.53 (q, 1H), 6.71-6.88 (m, 5H), 7.13 (m, 2H), 7.26 (m, 4H).
Reaction SMILES: C(O[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:37])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([CH2:27][CH2:28][CH2:29][NH:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(C)(C)C.[ClH:38]>O1CCOCC1.C(OCC)C>[ClH:38].[ClH:38].[ClH:38].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:37])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([CH2:27][CH2:28][CH2:29][NH:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)ONc1ccccc1NC(=O)c1ccc(-c2ccnc(CCCNN3CCOCC3)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Nc1ccccc1NC(=O)c1ccc(-c2ccnc(CCCNN3CCOCC3)n2)cc1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
N-(2-t-Butoxyaminophenyl)-4-[2-(3-morpholinoaminopropyl)-pyrimidin-6-yl]benzamide (Method 20, 64 mg, 0.120 mmol) was suspended in 1,4 dioxane (1.5 ml) and a 4M solution of hydrogen chloride in 1,4-dioxane (1 ml) added. The reaction mixture was stirred at ambient temperature for 64 hours. The reaction mixture was diluted with diethyl ether, and the resultant precipitate was collected by filtration, washed with diethyl ether and air dried, to yield the title compound (as its hydrochloride salt) as an off white solid (62 mg, 95%); Mass Spectrum: M+H+ 433.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[Br:12]C[C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([N+:22]([O-:24])=[O:23])=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:18]=2[CH:31]=1.CC(C)=O>C(OCC)C>[BrH:12].[N+:22]([C:20]1[O:21][C:17]2[CH:16]=[CH:15][C:14]([N:1]3[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]3)=[CH:31][C:18]=2[C:19]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCOCC
Solvent: CC(C)=O
Product: Br
Product: CCOC(=O)C1CCN(c2ccc3oc([N+](=O)[O-])c(-c4ccccc4)c3c2)CC1

Procedure:
A mixture of 1.04 g. (0.0066 mole) of ethyl isonipecotate and 2 g. (0.006 mole) of 5-bromomethyl-2-nitro-3-phenylbenzofuran in 100 ml. of acetone is heated at reflux for 40 hours. The mixture is cooled and then evaporated to provide a residue which is diluted with diethyl ether. A yellow precipitate is separated by filtration to provide ethyl N-(2-nitro-3-phenylbenzofuran-5-yl)isonipecotate hydrobromide, m.p. 220°-221° C., having the structure ##STR19##