Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([NH2:13])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([NH:13][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[O:15][CH3:14])[CH:3]=1
Reactant: Nc1cc(Br)c2cc(Cl)ccc2n1
Reactant: COc1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccccc1CNc1cc(Br)c2cc(Cl)ccc2n1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
4-Bromo-6-chloro-quinolin-2-ylamine (3.12 g, 12 mmol) was dissolved in 100 mL 1,2-dichloroethane. 2-Methoxybenzaldehyde (1.98 g, 15 mmol) and acetic acid (2.91 g, 48 mmol) were added. The reaction mixture was stirred at 40° C. for 3 h. Sodium triacetoxy borohydride (5.99 g, 25 mmol) was added and stirring was continued at room temperature overnight. The reaction mixture was quenched by addition of 200 mL sat. sodiumbicarbonate solution. The mixture was extracted three times with dichloromethane (200 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->80:20 gradient). (4-Bromo-6-chloro-quinolin-2-yl)-(2-methoxy-benzyl)-amine was obtained as an off-white solid (2.2 g, 48%), MS: m/e=379.1 (M+H+).
Reaction SMILES: [NH2:1][OH:2].[NH2:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[C:11]=2[F:19])[N:7]=[C:6]([C:20](OC)=[O:21])[C:5]=1[Cl:24]>COCCOC>[NH2:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[C:11]=2[F:19])[N:7]=[C:6]([C:20]([NH:1][OH:2])=[O:21])[C:5]=1[Cl:24]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl
Reactant: NO
Solvent: COCCOC
Product: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)NO)n2)c1F
Temperature: 23 °C
Reaction time: 96 h
Yield: 103.2 %

Procedure:
A 50% aq solution of hydroxylamine (4.4 mL, 72 mmol, 50 equiv) was added to a stirred suspension of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (500 mg, 1.4 mmol, 1.0 equiv) in 1,2-dimethoxyethane (1.0 mL) at 23° C. The resulting white suspension was stirred at 23° C. for 4 days (d). The reaction mixture was concentrated by rotary evaporation to afford a white powder (500 mg, 99%): mp 166-169° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.19 (br s, 1H), 7.68 (t, J=8 Hz, 1H), 7.42 (m, 1H), 7.20 (m, 1H), 6.73 (br s, 2H), 6.53 (br s, 1H), 3.93 (s, 3H); IR (neat film) 3322 (m), 2941 (w), 2878 (w), 1653 (s), 1632 (s) cm−1; ESIMS m/z 346.2 ([M+H]+).
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])O1.[NH2:12][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:14][OH:15]>>[OH:15][CH2:14][CH:13]([N:12]1[C:3](=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:11])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(N)CO
Reactant: O=C1OC(=O)c2ccccc21
Product: CCCC(CO)N1C(=O)c2ccccc2C1=O
Yield: 62 %

Procedure:
2-(1-hydroxypentan-2-yl)isoindoline-1,3-dione was prepared in a similar manner to example 9c using isobenzofuran-1,3-dione and 2-aminopentan-1-ol. Yield 62%. 1H NMR (500 MHz, CDCl3): δ 0.92 (t, 3H); 1.33 (m, 2H); 1.76 (m, 1H); 1.95 (m, 1H); 3.88 (m, 1H); 4.06 (m, 1H); 4.39 (m, 1H); 7.72 (m, 2H); 7.83 (m, 2H).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[O:3][C:2]1=[O:11].[H-].[Na+].I[CH3:15].O>CN(C)C=O>[CH3:15][N:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[O:3][C:2]1=[O:11]
Reactant: CI
Reactant: O=c1[nH]c2ccsc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)oc(=O)c2sccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.60 (21.3 mmol) 1H-Thieno(3,2-d)(1,3)oxazine-2,4-dione were dissolved in dried dimethylformamide and cooled to 0° C. 664 mg (27.7 mmol) sodium hydride was slowly added (Argon) and the mixture was stirred for 30 min at 0° C. and 30 min at room temperature. After cooling again to 0° C. 3.93 g (1.73 ml, 27.7 mmol) iodomethane were added. After stirring for 1 h at room temperature 200 ml water were added. The residue was filtrated and washed with water and ethyl ether.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[NH:9]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.[Cu]I>[F:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10]2)[CH:6]=[CH:5][CH:4]=1
Reactant: Fc1ccccc1
Reactant: CCOC(=O)c1cc[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccn(-c2cccc(F)c2)n1
Temperature: 140 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A 50 mL of flask was charged with 2.62 g of 3-fluorobenzenebromide (15 mmol), 1.40 g of ethyl 1-H-pyrazole-3-carboxylate (10 mmol), 400 mg of CuI (2.0 mmol), 4.5 g of K2CO3 (3.3 mmol) and 0.9 mL of trans-N,N′-dimethylcyclohexayldiamine (2.0 mmol). The resulting mixture was stirred at 140° C. for 3 h. After the mixture was cooled down to room temperature, it was diluted with 200 mL EtOAc and then was washed with water (2×50 mL), and brine (2×50 mL). The organics were dried over MgSO4 and concentrated under reduced pressure. The residue was purified via flash column chromatography on silica gel (0-25% EtOAc in hexanes) to give the desired product (1.17 g, 50%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[CH:6][N:5]=[CH:4][N:3]=1>P(Cl)(Cl)(Cl)=O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:9]2[NH:8][C:7]3[C:2](=[N:3][CH:4]=[N:5][CH:6]=3)[N:1]=2)[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc(C(=O)Nc2cncnc2N)cc1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc3ncncc3[nH]2)cc1OC

Procedure:
An amount of 7.5 g of 4-amino-5-(3,4-dimethoxy-benzoylamino)-pyrimidine was refluxed in 100 ml of phosphorus oxychloride for six hours. After evaporation and pouring on water, the solution was neutralized by means of potassium carbonate. The solution was evaporated to dryness, and the residue was extracted with boiling ethanol. The alcoholic solution was evaporated, and the remaining product was purified over silicagel (eluate: methylene chloride/ethanol in a volume ratio of 19:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1>C1(C)C=CC=CC=1>[C:14]([O:16][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:13]=1[NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])([CH3:18])([CH3:15])[CH3:13]
Reactant: COc1ccc(S(=O)(=O)Nc2c(C)cccc2C(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)Nc2c(C)cccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
To a solution of 15.0 g (0.047 mol) of the product of Example 6 in 45 mL of toluene was added 50 mL of N,N-imethylformamide di-t-butyl acetal and the mixture was then heated to reflux for 18 h. The reaction was then cooled to room temperature and croatographed on silica gel eluting with EtOAc/Hexanes (1:3) to give 8.94 g (51%) of the product as a white solid. Electrospray Mass Spec: 378.1 (M+H)+.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:12][O:13][C:14]([C:17](=[O:30])[NH:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:28])[CH:22]=2)([CH3:16])[CH3:15])[C:9]([OH:11])=O)[N:7]=1.[NH2:31][CH:32]1[C:69](=[O:70])[N:34]2[C:35]([C:53]([O:55]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:54])=[C:36]([CH2:39][S:40][C:41]3[N:46]4[N:47]=[C:48]([CH2:50][OH:51])[N:49]=[C:45]4[N:44]=[C:43]([CH3:52])[CH:42]=3)[CH2:37][S:38][C@H:33]12.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>CN(C=O)C.CCOCC>[ClH:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:12][O:13][C:14]([C:17](=[O:30])[NH:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:28])[CH:22]=2)([CH3:16])[CH3:15])[C:9]([NH:31][CH:32]2[C:69](=[O:70])[N:34]3[C:35]([C:53]([OH:55])=[O:54])=[C:36]([CH2:39][S:40][C:41]4[N:46]5[N:47]=[C:48]([CH2:50][OH:51])[N:49]=[C:45]5[N:44]=[C:43]([CH3:52])[CH:42]=4)[CH2:37][S:38][C@H:33]23)=[O:11])[N:7]=1
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)n2nc(CO)nc2n1
Reactant: CC(C)(ON=C(C(=O)O)c1csc(N)n1)C(=O)NNC(=O)c1ccc(O)c(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NOC(C)(C)C(=O)NNC(=O)c4ccc(O)c(O)c4)c4csc(N)n4)[C@H]3SC2)n2nc(CO)nc2n1
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
In 40 ml of DMF were dissolved 6.44 g of 2-(2-amino-1,3-thiazol-4-yl)-2-{1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxyimino} acetic acid.hydrochloride, 12.2 g of diphenylmethyl 7-amino-3-[(2-hydroxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3-cephem-4-carboxylate obtained in Example 6 and 2.6 g of 1-hydroxybenzotriazole, and the solution was ice-cooled. To the solution was added of 3.5 g of DCC, and the mixture was stirred for 15 minutes under ice-cooling and further stirred at room temperature for one hour. After the reaction mixture was filtered, 30 ml of chloroform was added to the filtrate and the mixture was added dropwise into 40 liters of ether. After precipitates were collected by filtration and washed with ether, a powder obtained by drying was purified through silica gel column to obtain powder. A mixed solution of 60 ml of trifluoroacetic acid and 15 ml of anisole was ice-cooled, and the powder obtained previously was added thereto, followed by stirring for 30 minutes. The resulting mixture was added dropwise into 500 ml of ether, and precipitates formed was collected by filtration, washed with ether and dried to obtain 7.82 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:38])=[C:4]([CH3:37])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([NH:20][CH2:21][CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=O)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:35]=1[CH3:36].[ClH:39].C(=O)([O-])O.[Na+]>O1CCCC1.O.C(OC(C)C)(C)C>[ClH:39].[ClH:39].[ClH:39].[NH2:1][C:2]1[C:3]([CH3:38])=[C:4]([CH3:37])[C:5]2[O:9][C:8]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][NH:20][CH2:21][CH:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:14][CH2:13]3)([CH3:10])[CH2:7][C:6]=2[C:35]=1[CH3:36]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(C(=O)NCC(c3ccccc3)c3ccccc3)CC1)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(CNCC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 61 %

Procedure:
To a solution of 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(2,2-diphenylethyl)-4-piperidinecarboxamide (1.0 g) in tetrahydrofuran (20 mL) was added 12 mL of 1 M borane tetrahydrofuran complex solution in tetrahydrofuran dropwise with ice-cooling and the mixture was refluxed under nitrogen gas for 6 hours. After this reaction mixture was cooled with ice, 8 mL of 5N-hydrochloric acid was added dropwise, followed by stirring. The mixture was added dropwise to a suspension of sodium hydrogen carbonate (4 g) in water/diisopropyl ether for neutralization and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. After the residue was dissolved in methanol, 10 mL of 5N-hydrochloric acid was added and the mixture was refluxed for 1 hour. After ice-cooling, the mixture was diluted with 20 mL of 5N-aqueous sodium hydroxide and extracted with 3 portions of diethyl ether. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate/triethylamine=30:10:1 to 20:10:1) to recover 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(2,2-diphenylethyl)-4-piperidinemethylamine. After this product was dissolved in methanol, a stoichiometric excess of 10% HCl solution in methanol was added dropwise and the resulting mixture was concentrated under reduced pressure to provide 0.74 g of the title compound.
Reaction SMILES: Cl.C(CN(S(C1C=C2C(C(Cl)=CN=C2NC(N)=N)=CC=1)(=O)=O)CC(O)=O)(O)=O.C([O-])([O-])=O.[K+].[K+].Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].[C:44]([O:48][C:49](=[O:70])[CH2:50][NH:51][S:52]([C:55]1[CH:64]=[C:63]2[C:58]([C:59]([Cl:69])=[CH:60][N:61]=[C:62]2[NH:65][C:66]([NH2:68])=[NH:67])=[CH:57][CH:56]=1)(=[O:54])=[O:53])([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.CCOC(C)=O>[C:40]([O:39][C:37](=[O:38])[CH2:36][N:51]([CH2:50][C:49]([O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:70])[S:52]([C:55]1[CH:64]=[C:63]2[C:58]([C:59]([Cl:69])=[CH:60][N:61]=[C:62]2[NH:65][C:66]([NH2:68])=[NH:67])=[CH:57][CH:56]=1)(=[O:53])=[O:54])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)CC(=O)O)cc12
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 57.6 %

Procedure:
N-(Carboxymethyl)-N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]glycine hydrochloride ##STR31## Anhydrous K2CO3 (88 mg, 0.64 mmol) and then t-butyl bromoacetate (56 μL, 0.38 mmol) were added to a stirred solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]glycine t-butyl ester (132 mg, 0.33 mmol) in DMF (2.0 mL) and the mixture was stirred at 23° C. for 18 h. The mixture was diluted with EtOAc (300 mL), washed with brine (150 mL), water (200 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using pentane-EtOAc (80:20 to 50:50) as eluant to give N-(t-butoxycarbonylmethyl)-N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]glycine t-butyl ester (101 mg, 0.19 mmol) as a pale yellow foam.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH2:27]([NH:34][C:24]([CH:21]1[CH2:20][CH2:19][N:18]([C:11]2[CH:12]=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:9]([NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[CH2:23][CH2:22]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)C1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
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
Solvent: O
Product: O=C(NCc1ccccc1)C1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a solution of 1-(3-(benzylamino)-4-nitrophenyl)piperidine-4-carboxylic acid (0.2 g, 0.56 mmol) and benzylamine (0.06 mL, 0.56 mmol) in DMF (5 mL) was added diisopropylethylamine (0.198 mL, 1.12 mmol) under argon. The mixture cooled to 0° C., HATU (0.212 g, 0.56 mmol) was added at that temperature and then stirred at room temperature for 4 h. After completion of reaction (by TLC), H2O (5 mL) was added drop by drop. The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish N-benzyl-1-(3-(benzylamino)-4-nitrophenyl)piperidine-4-carboxamide (0.21 g), 84% yield. 1H NMR (500 MHz, DMSO): δ 1.51 (m, 2H), 1.74 (m, 2H), 2.48 (m, 1H), 2.96 (m, 2H), 3.93 (m, 2H), 4.26 (d, J=5.9 Hz, 2H), 4.59 (d, J=5.8 Hz, 2H), 5.95 (d, J=2.45 Hz, 1H), 6.42 (dd, J=2.5 Hz, 1H), 7.24 (m, 4H) 7.37 (m, 4H), 7.42 (m, 2H), 7.91 (d, J=9.7 Hz, 1H), 8.35 (m, 1H), 8.84 (m, 1H). HRMS (ESI) calculated for C26H28N4NaO3: 467.2054, Found: 467.2054.
Reaction SMILES: [CH3:1][O-].[Na+].[N:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[N:6][CH:5]=1>CN(C=O)C.CO>[CH3:1][N:14]1[CH:15]=[C:10]([C:7]2[CH:8]=[CH:9][N:4]=[CH:5][N:6]=2)[CH:11]=[CH:12][C:13]1=[O:16]
Reactant: O=c1ccc(-c2ccncn2)c[nH]1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1cc(-c2ccncn2)ccc1=O
Temperature: 60 °C

Procedure:
A solution of 4.8 g of sodium methoxide in 300 ml of dry DMF and 15 ml of methanol is added to a suspension of 5-(4-pyrimidinyl)-2(1H)-pyridone (2 g) in 200 ml DMF. The reaction mixture is filtered and 5.5 ml of methyl iodide added to the filtrate. The reaction mixture is heated to 60° C. for 2 hours, cooled to RT, and the solvent evaporated in vacuo leaving a liquid residue that crystallizes upon the addition of distilled H2O. The crystalline solid is stirred with 400 ml of distilled H2O, filtered, washed with H2O, isopropyl alcohol, and ether and then air dried to yield the desired 1-methyl-5-(4-pyrimidyl)-2-pyridone, M.P. 147°-149° C.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[C:16]([C:17]#[N:18])=[CH:15][C:14]([C:19](=[O:21])[CH3:20])=[C:13]([CH3:22])[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)(Cl)Cl>C(O)C.C(O)(=O)C>[CH2:3]([O:10][C:11]1[C:16]([C:17]#[N:18])=[CH:15][C:14]([CH:19]([OH:21])[CH3:20])=[C:13]([CH3:22])[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1cc(C#N)c(OCc2ccccc2)nc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1nc(OCc2ccccc2)c(C#N)cc1C(C)O

Procedure:
Sodium borohydride (0.35 g, 0.0092 mol) was added at room temperature to 2-benzyloxy-5-acetyl-6-methylpyridin-3-carbonitrile (2.44 g, 0.0092 mol) in ethanol (60 mL). After 2 hours chloroform was added plus a few drops of acetic acid. After washing with water and brine, the chloroform solution was evaporated to give product which was not purified further.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([N:15]=[N+]=[N-])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:6]>CCOC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([NH2:15])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:6]
Reactant: COC(=O)[C@@H](N=[N+]=[N-])[C@H](C)c1ccc(Cl)c(Cl)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](N)[C@H](C)c1ccc(Cl)c(Cl)c1
Reaction time: 16 h
Yield: 73.2 %

Procedure:
To a solution of (2S,3R)-2-azido-3-(3,4-dichloro-phenyl)-butyric acid methyl ester (0.42 g, 1.46 mmol) in EtOAc (30 mL) was added Lindlar's catalyst. The mixture was hydrogenated at 50 psi. After 16 h, the reaction mixture was filtered through SiO2 and concentrated to afford 0.28 g (74%) of the desired product. 1H NMR (500 MHz, CDCl3): 7.39 (d, J=8.3, 1H), 7.35 (d, J=2.1, 1H), 7.10 (dd, J=8.3, 2.1, 1H), 3.96 (d, J=6.4, 1H), 3.71 (s, 3H), 3.31-3.27 (m, 1H), 1.33 (d, J=7.0, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5](O)[CH:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[C:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11])C.O.[NH2:30][NH2:31]>C(O)(=O)C>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[C:7]([CH2:8][CH2:9][CH2:10][CH3:11])=[N:31][NH:30][C:4](=[O:3])[CH:5]=2)=[CH:14][CH:15]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NN
Reactant: CCCCC(=O)C(c1ccc(OCc2ccccc2)cc1)C(O)C(=O)OCC
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1n[nH]c(=O)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(4-benzyloxy-phenyl)-2-hydroxy-4-oxo-octanoic acid ethyl ester (28.08 mmol, 10.8 g) and hydrazine hydrate (15 mL) in acetic acid (45 mL) was stirred at 120° C. for 4 h. The reaction mixture was concentrated under reduced pressure and to the residue was added water (200 mL). This was extracted with DCM (3×200 mL), and the combined organic layer was dried and concentrated under reduced pressure. The resultant residue was purified by flash silica gel column chromatography eluting with 50% ethyl acetate in hexanes to afford 5-(4-benzyloxy-phenyl)-6-butyl-2H-pyridazin-3-one.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[NH2:25].[Li+].[Cl-].[CH3:28][C:29]1([CH3:44])[CH2:34][CH2:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH2:30]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([Si:18]([CH3:20])([CH3:19])[O:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:6]2[CH:5]=[CH:4][C:3]([NH2:25])=[C:2]([C:32]3[CH2:33][CH2:34][C:29]([CH3:44])([CH3:28])[CH2:30][CH:31]=3)[CH:7]=2)[CH2:10][CH2:11]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCN(Cc2ccc(N)c(Br)c2)CC1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: CC1(C)CC=C(c2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc2N)CC1
Temperature: 80 °C
Yield: 72 %

Procedure:
A solution of 2-bromo-4-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperazin-1-ylmethyl}-phenylamine (as prepared in the previous step, 305 mg, 0.712 mmol) in DME (15 mL) was treated with LiCl (36.2 mg, 0.854 mmol), 4,4-dimethyl-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (202 mg, 8.54 mmol), and aqueous Na2CO3 (2.85 mL, 5.69 mmol, 2.0 M). The mixture was degassed via sonication, placed under Ar, treated with Pd(PPh3)4 (82.2 mg, 0.0712 mmol), and heated to 80° C. for 21 h. The mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (60 mL) and water (60 mL). The layers were separated, and the organic layer was washed with brine (1×20 mL). The combined aqueous layers were extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue on a 20-g Isolute SPE column on a FlashMaster system with 50% EtOAc-hexane afforded the title compound (233 mg, 72%) as a light tan glassy solid. Mass spectrum (ESI, m/z): Calcd. for C27H47N3OSi, 458.4 (M+H). found 458.1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].O=[C:25]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(O)(=O)C>C(O)C>[C:19]([O:18][C:16]([CH2:15][N:4]1[CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7][CH2:8][CH:2]([NH:1][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:3]1=[O:23])=[O:17])([CH3:20])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CCCC1c1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)NC1CCCC(c2ccccc2)N(CC(=O)OC(C)(C)C)C1=O

Procedure:
A solution of 3.8 g of this amine, 3.7 g ethyl 2-oxo-4-phenylbutyrate and 0.68 ml acetic acid in 50 ml ethanol is hydrogenated and the isomers separated as described in Example 27 to afford 1-t-butoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropyl)amino-7-phenylperhydroazepin-2-one: