Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.[NH:12]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>CC#N>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][N:12]([CH2:10][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:18]
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CCOC(=O)CNCC(=O)OCC
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(CC(=O)OCC)Cc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.6 %

Procedure:
A suspension of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (12.0 g, 34.6 mmol) and diethyl iminodiacetate (7.0 mL, 39.1 mmol) in CH3CN (350 mL) was treated with triethylamine (10.7 mL, 76.1 mmol). After stirring at room temperature under N2 for 4 h, the solvent was removed in vacuo. The resulting yellow slurry was partitioned between H2O (400 mL) and EtOAc (400 mL), and the aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 99:1) gave the title compound (6.55 g, 51%) as a light tan oil: MS (ESI) m/e 374 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18].[OH-].[Na+].Cl>CC(C)=O>[Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[N:4]([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])[N:3]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Brc1n[nH]c(Br)c1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C(=O)O)n1nc(Br)c(Br)c1Br
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A quantity (3.04 gm., 0.01 mole) of 3,4,5-tribromopyrazole was dissolved in 70 ml. acetone and 2.76 gm. (0.02 mole) solid anhydrous potassium carbonate was added. The mixture was heated at the reflux temperature with stirring for 10 minutes and, after cooling, 2.0 gm. (0.011 mole) ethyl 2-bromopropionate was added. This reaction mixture was heated at the reflux temperature for 11/2 hrs. After cooling, an aqueous solution of sodium hydroxide (0.5 gm. in 90 ml. water) was added. The acetone was distilled off and the remaining aqueous solution was heated at the reflux temperature for 2 hrs. The clear solution thus obtained was cooled and acidified to about pH 2 with 2 N hydrochloric acid. A white precipitate that formed was collected on a filter, washed with water, and dried. There was thus obtained 3.55 gm. (95% yield) of 3,4,5-tribromo-α-methylpyrazole-1-acetic acid having a melting point at 162° to 164° C., identical with the product of Example 5.
Reaction SMILES: [O:1]=[C:2]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21](=[O:27])[NH:22][CH:23]2[CH2:26][CH2:25][CH2:24]2)=[O:15])[N:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]=1)=[O:6].C(N(CC)CC)C.[CH3:47][O:48][CH2:49][CH2:50][O:51][C:52](Cl)=[O:53]>ClCCl>[CH3:47][O:48][CH2:49][CH2:50][O:51][C:52]([N:37]1[CH2:38][CH2:39][N:34]([C:2](=[O:1])[CH2:3][NH:4][C:5]([C:7]2[CH:11]=[C:10]([O:12][CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21](=[O:27])[NH:22][CH:23]3[CH2:24][CH2:25][CH2:26]3)=[O:15])[N:9]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:8]=2)=[O:6])[CH2:35][CH2:36]1)=[O:53]
Reactant: O=C(NCC(=O)N1CCNCC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: COCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 100 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide in 5 ml dichloromethane were added at 0° C. 56 l triethylamine and 24 l chloroformic acid 2-methoxyethyl ester. After stirring for 12 h it was concentrated and the residue obtained was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])=[N:5][C:6]([CH3:15])=[CH:7][C:8]=1[NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12].Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:13]([CH:10]([N:9]1[C:8]2[CH:7]=[C:6]([CH3:15])[N:5]=[C:4]([O:16][C:17]3[C:18]([CH3:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=3[CH3:23])[C:3]=2[CH2:2][NH:1][C:27]1=[O:29])[CH2:11][CH3:12])[CH3:14]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1CN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCC(CC)N1C(=O)NCc2c1cc(C)nc2Oc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 310.3 %

Procedure:
To a mixture of [3-Aminomethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine (100 mg, 0.292 mmol) in dry THF was added triphosgene (34 mg, 0.114 mmol) at 0° C. The reaction mixture was allowed to gradually warm to rt and stir for 2 h. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness to give 130 mg of a clear oil. The solid was purified through silica gel column chromatography using 10% EtOAc in hexane as eluent to give 89 mg (82.4%)of the title compound as a white crystalline solid, mp 197-199° C. 1H NMR (CDCl3) d 6.86(s,2H), 6.44(s,1H), 5.14(brs,1H), 4.49(s,2H), 4.20(m,1H), 2.28(s,3H), 2.22(s,3H), 2.04(s,6H), 1.67(m,4H), 0.94(t,6H)ppm.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[CH:71][C:70]([CH3:73])=[C:69]([CH3:74])[CH:68]=2)[C:56]=1[CH3:75].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:74][C:69]1[CH:68]=[C:67]([C:57]2[C:56]([CH3:75])=[C:55]([NH:47][C:46]3[C:41]([N:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)=[N:42][CH:43]=[C:44]([N:48]4[CH2:49][CH2:50][O:51][CH2:52][CH2:53]4)[CH:45]=3)[C:64]3[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=3[F:65])[N:58]=2)[CH:72]=[CH:71][C:70]=1[CH3:73]
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)cc1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)cc1C

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.022 g, 0.045 mmol), 2,5-dimorpholinopyridin-3-amine (0.090 g, 0.34 mmol), 4-chloro-2-(3,4-dimethylphenyl)-5,7-difluoro-3-methylquinoline (0.090 g, 0.283 mmol), Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.068 g, 0.71 mmol) in toluene (2.8 mL) at 120° C. for 1 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product 2-(3,4-dimethylphenyl)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methylquinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 7.71-7.68 (1H, br d, J=10.0 Hz), 7.63 (2H, m), 7.37 (1H, br s), 7.28 (2H, m), 6.98 (1H, ddd, J=13.3, 8.6, 2.5 Hz), 6.36 (1H, d, J=2.2 Hz), 3.92 (4H, m), 3.83 (4H, app t, J=4.3 Hz), 3.25 (4H, br. s), 3.06 (4H, app t, J=4.3 Hz), 2.36 (6H, s), 2.15 (3H, s). Mass Spectrum (ESI) m/e=546.3 (M+1)
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH3:15])[CH:8]=[CH:7][CH:6]=1)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].O.Cl.[C:22](OCC)(=[O:24])[CH3:23]>>[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH3:15])[CH:8]=[CH:7][C:6]=1[C:22](=[O:24])[CH3:23]
Reactant: CCOC(C)=O
Reactant: CC(=O)Oc1cccc2cccc(C)c12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(=O)c1ccc2cccc(C)c2c1O

Procedure:
13 g of 8-methyl-1-naphthyl acetate and 13.8 g of aluminum chloride were reacted at 140° C. for 4 hours. Water, concentrated hydrochloric acid and ethyl acetate were added to the reaction mixture to dissolve all solid matters, followed by extraction with ethyl acetate. The organic phase was washed with a saturated saline solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (7% ethyl acetate/hexane) to obtain 5.5 g of the captioned compound as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:20]([CH3:22])[CH3:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH:23](=[O:26])[C:24]#[CH:25]>C1COCC1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([CH:20]([CH3:22])[CH3:21])[N:9]([CH:25]=[CH:24][CH:23]=[O:26])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1
Reactant: C#CC=O
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1C=CC=O

Procedure:
To a solution of 4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazole (492 mg) in dry THF under nitrogen was added propiolaldehyde (0.97 ml) and the reaction mixture heated to reflux. Further quantities of propiolaldehyde were added in portions (3×1.1 g) during successive 2 h periods. The reaction mixture was concentrated and the deep red residue was purified by FCC eluting with system A (1:4) to give the title product (398 mg) as an off-white solid and as a 1:1 mixture of geometric isomers. δ(CDCl3) 9.48 (d, 1H, J 7.5 Hz, cis CHO), 9.40 (d, 1H, J 7.5 Hz, trans CHO), 7.5 (d, 1H, J 15 Hz, trans CH=CHCHO), 7.45-6.85 (m, 17H, aromatic protons and cis CH=CHCHO), 5.98 (t,1H,J 7.5 Hz, cis CH=CHCHO), 5.63 (dd, 1H, J 15 and 7.5 Hz, trans CH=CH CHO), 3.25 (septet, 1H, J 7 Hz, CH(CH3)2 of trans isomer), 3.05 (septet, 1H, J 7 Hz, CH(CH3)2 of cis isomer).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][C:19](O)=[O:20])[CH:15]=3)[N:10]([C:22](=[O:30])[NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].Cl.[NH:32]1[CH2:35][CH2:34][CH2:33]1>>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][C:19]([N:32]4[CH2:35][CH2:34][CH2:33]4)=[O:20])[CH:15]=3)[N:10]([C:22]([NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)=[O:30])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1CNC1
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(CCC(=O)O)cc12
Agent: Cl
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(CCC(=O)N3CCC3)cc12

Procedure:
(3-(1′-Acetyl-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-5-yl)propanoic acid and azetidine hydrochloride
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].[Na].Cl.[CH3:7][O:8][N:9]=[C:10]1[CH2:14][CH2:13][NH:12][CH2:11]1>CO>[ClH:1].[CH3:7][O:8][N:9]=[C:10]1[CH2:14][CH2:13][N:12]([C:3](=[NH:4])[CH2:2][Cl:1])[CH2:11]1
Reactant: N#CCCl
Reactant: CON=C1CCNC1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CON=C1CCN(C(=N)CCl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.63 ml of chloroacetonitrile was added to a solution of 23 mg of metallic sodium in 4 ml of absolute methanol, the mixture was stirred at room temperature for about 30 minutes, then 1.5 g of 3-methoxyiminopyrrolidine hydrochloride were added and the resulting mixture stirred for a further 2 hours. After completion of the reaction, the solvent was distilled off and the concentrate mixed with anhydrous ether. The crystals which separated out were collected by filtration and washed with ether, giving 2.2 g of 2-(3-methoxyiminopyrrolidin-1-yl)-2-iminoethylchloride hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])=[N:6][CH:7]=1.[C:14]([O:19][CH2:20][CH3:21])(=[O:18])[C:15]([CH3:17])=O.B(F)(F)F.CCOCC>C(#N)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][CH:9]2[CH2:10][O:11][C:15]([CH3:17])([C:14]([O:19][CH2:20][CH3:21])=[O:18])[O:13][CH2:12]2)=[N:4][CH:3]=1
Reactant: CCOC(=O)C(C)=O
Reactant: OCC(CO)Nc1ncc(Br)cn1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)C1(C)OCC(Nc2ncc(Br)cn2)CO1
Reaction time: 24 h
Yield: 75.8 %

Procedure:
2-[(5-bromopyrimidin-2-yl)amino]propane-1,3-diol (100 mg, 0.40 mmol), ethyl pyruvate (80 μL, 0.72 mmol) and acetonitrile (2 mL) were combined at rt. An aliquot of borontrifluoride etherate (100 μL, 0.80 mmol) was added to the reaction mixture and stirring was continued at rt for 24 hrs. A further portion of borontrifluoride etherate (100 μL, 0.80 mmol) was added to the reaction mixture, which was stirred at rt for a further 24 hrs. The reaction mixture was loaded directly onto a column for flash chromatography (12 g silica column), eluting with 0-100% EtOAc gradient in n-heptane, to give desired product (105 mg, light brown oil). m/z 345.9/347.9 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.CCN(CC)CC.[Br:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>C1COCC1.CCOC(C)=O>[Br:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([N:6]2[CH2:7][CH2:8][CH2:9][C@H:5]2[C:4]([O:3][CH3:2])=[O:10])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=S(=O)(Cl)c1cccc(CBr)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
To a mixture of (S)-proline methyl ester hydrochloride salt (1.6 g, 9.65 mmol) in THF (20 mL) was added Et3N (1.34 mL, 9.65 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 min and cooled back down to 0° C. 3-Bromomethyl-benzenesulfonyl chloride (2.6 g, 9.65 mmol) and Et3N (1.34 mL, 9.65 mmol) were then added to the slurry. The resulting mixture was stirred at room temperature for 3 h and then diluted with EtOAc (100 mL). The organic phase was washed with water (2×50 mL), brine (20 mL) and dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by chromatography via silica gel chromatography, eluting with 0-20% EtOAc in isohexane, to give 550 mg of (S)-methyl 1-((3-(bromomethyl)-phenyl)sulfonyl)pyrrolidine-2-carboxylate that was used in the next step without further purification. This residue was taken up in acetone (20 mL) and transferred to a microwave vial. (S)-tert-butyl ((3-hydroxyphenyl)(phenyl)methyl)carbamate (I8, 251 mg, 1.82 mmol) and K2CO3 (546 mg, 1.82 mmol) were added, and the mixture was heated to 130° C. under microwaves irradiation for 1 h. The mixture was stirred at room temperature for 18 h and partitioned between EtOAc (50 mL) and water (20 mL). The layers were separated and the aqueous phase extracted with EtOAc (3×30 mL). The combined organic phases were washed with brine (30 mL) and dried over MgSO4. The mixture was filtered and the solvent was removed in vacuo. The residue was purified via silica gel chromatography, eluting with 0-20% EtOAc in isohexane, to give the title compound (636 mg, 60%).
Reaction SMILES: [C:1](Cl)(=[O:4])[O:2][CH3:3].[CH3:6][C:7]1([CH3:30])[CH2:12][CH:11]([NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[CH2:10][C:9]([CH3:29])([CH3:28])[NH:8]1>O>[CH3:3][O:2][C:1]([N:13]([CH:11]1[CH2:12][C:7]([CH3:30])([CH3:6])[NH:8][C:9]([CH3:29])([CH3:28])[CH2:10]1)[CH2:14][CH2:15][CH2:16][N:17]([C:1]([O:2][CH3:3])=[O:4])[CH:18]1[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21][C:22]([CH3:25])([CH3:24])[CH2:23]1)=[O:4]
Reactant: COC(=O)Cl
Reactant: CC1(C)CC(NCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Solvent: O
Product: COC(=O)N(CCCN(C(=O)OC)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1

Procedure:
83.2 g (0.88 mol) of methyl chlorocarbonate are reacted as described in Example 1 with 141 g (0.4 mol) of N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)-1,3-propanediamine dissolved in 420 ml of water.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]=[N+]=[N-])=[CH:12][CH:11]=1>C(O)C.[C].[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][NH2:18])=[CH:14][CH:15]=1
Reactant: [N-]=[N+]=NCCc1ccc(CCOC2CCCCO2)cc1
Agent: [Pd]
Solvent: CCO
Product: NCCc1ccc(CCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
To a solution of 4-(2-(tetrahydropyran-2-yloxy)ethyl)-1-(2-azidoethyl)benzene (4.30 g, 15.61 mmol) in ethanol was added 10% palladium-carbon (0.10 g). The mixture was stirred under an atmosphere of hydrogen gas at room temperature for 16 hours. Then 10% palladium-carbon was filtered off, and the solvent was evaporated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/methanol (=8/2) to give the desired 4-(2-(tetrahydropyran-2-yloxy)ethyl)phenethylamine (2.80 g, 72%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH:22][OH:23])[CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:22]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[O-:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: ONC1CCCC1
Solvent: ClC(Cl)Cl
Product: [O-][N+](=Cc1ccc(OCc2ccccc2)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.1 %

Procedure:
A mixture of 4-benzyloxybenzaldehyde (20 g, 94.23 mmol), N-cyclopentylhydroxylamine (14.3 g, 141.34 mmol), molecular sieves (60 g, 4A) and silica gel (15 g) in chloroform (300 mL) was stirred at room temperature under argon atmosphere for 48 hrs and then was refluxed for an additional 3 hrs. The mixture was filtered and rotary evaporated to give crystals which were recrystallized from hexanes and EtOAc to provide the title compound as white crystals, 23.7 g, 85.1% yield), m.p. 115.1° C. (Rf=0.35 on a silica gel plate using hexanes:EtOAc, 1:1, v:v, as an eluant).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][NH:20][C:21]([NH2:23])=[S:22].O>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[N:19][NH:20][C:21]([NH2:23])=[S:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=NNC(N)=S)c1ccccc1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
2-(tert-Butoxycarbonylamino)acetophenone (3.00 g) was dissolved in methanol (21.0 mL). To the solution was added an aqueous solution (water: 9.0 mL) of thiosemicarbazide hydrochloride (3.11 g, 24.4 mmol) at room temperature. After the mixture was stirred at the same temperature for 30 minutes, water (12.0 mL) was added, and the mixture was stirred at room temperature for 20 minutes and then at 0° C. for 1 hour. The deposited solid was collected by filtration and washed with cooled 50% aqueous methanol (20 mL). The resulting solid was dried at 40° C. under reduced pressure to give seed crystals of 2-(tert-butoxycarbonylamino)acetophenone thiosemicarbazone (3.56 g, yield: 95.1%) as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]([N+:31]([O-:33])=[O:32])=[C:20]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=1.[H-].[Na+]>CN(C)C=O>[CH3:30][N:22]([C:20]1[CH:21]=[C:16]([O:14][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:19]=1[N+:31]([O-:33])=[O:32])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Oc3ccccc3)cc2)ccc1[N+](=O)[O-]
Yield: 97.4 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-phenoxyphenol (4.0 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (5.8 g), sodium hydride (55 wt. %, 1.1 g) and anhydrous N,N-dimethylformamide (35 ml) and the reaction mixture was purified to give the title compound (8.6 g).
Reaction SMILES: O[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[CH:3]=1.P(Cl)(Cl)([Cl:19])=O>O>[Cl:19][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)cc(O)n(-c2ccccc2)c1=O
Solvent: O
Product: Cn1c(=O)cc(Cl)n(-c2ccccc2)c1=O
Temperature: 110 °C
Yield: 72 %

Procedure:
To the obtained 6-hydroxy-3-methyl-1-phenyluracil (12.2 g, 56 mM) was added phosphorus oxychloride (phosphoryl chloride, 167 ml, 2M) under cooling with ice and 3.4 ml of water was then added dropwise. The solution was heated gradually and maintained at 110° C. for 2 hours. The solvent was distilled off under reduced pressure. A product was obtained by crystallization with water and recovered by filtration to yield 6-chloro-3-methyl-1-phenyluracil (yield: 9.55 g, or 72% based on 6-hydroxy-3-methyl-1-phenyluracil).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6](=[O:12])[N:5]3[CH2:13][C@@H:14]([CH2:15][N:16]4[CH2:20][CH2:19][C@@H:18]([CH2:21][NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH2:17]4)[N:3]1[C:4]=23.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[O:12]=[C:6]1[CH:7]=[CH:8][C:9]2[CH:10]=[CH:11][C:2](=[O:1])[N:3]3[C@H:14]([CH2:15][N:16]4[CH2:20][CH2:19][C@@H:18]([CH2:21][NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH2:17]4)[CH2:13][N:5]1[C:4]=23
Reactant: O=C1CCc2ccc(=O)n3c2N1C[C@H]3CN1CC[C@@H](CNC(=O)C(F)(F)F)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(NC[C@@H]1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)C1)C(F)(F)F
Temperature: 80 °C
Reaction time: 10 h
Yield: 35.5 %

Procedure:
To a 25 mL round-bottomed flask was added N-[((3S)-1-{[(2R)-4,9-dioxo-1,2,8,9-tetrahydro-4H,7H-imidazo[1,2,3-ij]-1,8-naphthyridin-2-yl]methyl}-3-pyrrolidinyl)methyl]-2,2,2-trifluoroacetamide (240 mg, 0.602 mmol) in 1,4-dioxane (5 ml) at rt under nitrogen to give a orange solution. DDQ (205 mg, 0.904 mmol) was added and the reaction became very dark. The reaction was heated to 80° C. on an oil bath and stirred for 10 h. The reaction was cooled to rt. 5% Aqueous K2CO3 (20 mL) was added and the reaction was extracted with DCM (3×100 mL). The combined organic layers were washed with a saturated aqueous NaCl solution and the organic phase was dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was added to a silica gel column and was eluted with 0-20% MeOH/CHCl3 to give product (85 mg, 0.214 mmol, 35.6% yield) as an orange solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][OH:18])[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C@:13]2([CH2:16][CH2:17][OH:18])[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:20][CH:21]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1ccccn1
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and pyridine-2-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.462 min, m/z=420.18; 1H NMR (CDCl3) 1.48 (d, 3H), 2.03-2.30 (m, 5H), 2.85 (m, 1H), 3.50 (m, 1H), 3.72 (m, 1H), 5.65 (m, 1H), 6.98 (m, 4H), 7.24 (m, 2H), 7.60 (m, 1H), 7.74 (m, 3H), 8.62 (m, 1H).