Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.F[C:10]1[C:15]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([N:23](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:17]=2)=[CH:14][C:13]([CH2:42][N:43]2[CH2:48][CH2:47][N:46]([S:49]([CH3:52])(=[O:51])=[O:50])[CH2:45][C@@H:44]2[CH3:53])=[CH:12][N:11]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:23])[N:17]=3)=[CH:14][C:13]([CH2:42][N:43]3[CH2:48][CH2:47][N:46]([S:49]([CH3:52])(=[O:50])=[O:51])[CH2:45][C@@H:44]3[CH3:53])=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)n2)cc1
Product: Cc1nc(N)nc(-c2cc(CN3CCN(S(C)(=O)=O)C[C@@H]3C)cnc2Nc2ccc(Cl)nc2)n1

Procedure:
The title compound was prepared from 6-chloropyridin-3-amine (Sigma Aldrich, Inc.) and (S)-4-(2-fluoro-5-((2-methyl-4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (preparation similar as reported in Example 316, Steps 1 to 2; from (S)-tert-butyl 3-methylpiperazine-1-carboxylate (Sigma Aldrich, Inc.)) via similar steps as previously described in Example 316 and isolated as a yellow solid. m/z (ESI, +ve ion) 504 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.16 (s, 1H) 8.88 (d, J=2.74 Hz, 1H) 8.73 (d, J=2.35 Hz, 1H) 8.47 (dd, J=8.71, 2.84 Hz, 1H) 8.31 (d, J=2.35 Hz, 1H) 7.93 (br. s., 1H) 7.78 (br. s., 1H) 7.45 (d, J=8.61 Hz, 1H) 3.94 (d, J=13.11Hz, 1H) 3.07-3.29 (m, 3H) 2.86-2.97 (m, 1H) 2.85 (s, 3H) 2.64-2.79 (m, 2H) 2.54-2.64 (m, 1H) 2.45 (s, 3H) 2.14-2.29 (m, 1H) 1.16 (d, J=6.06 Hz, 3H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[CH:6]=[CH:7]/[CH2:8]P(OCC)(OCC)=O)=[O:5].C([Li])CCC.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1>[C:23]1(/[CH:22]=[CH:8]/[CH:7]=[CH:6]/[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C=C/c1ccccc1
Yield: 82.1 %

Procedure:
To a solution of 16 ml (72 mmol) of triethyl 4-phosphonocrotonate in anhydrous tetrahydrofuran (100 ml) was added 43 ml (69 mmol) of a 1.6 M n-butyllithium solution dropwise with stirring in an ice-salt bath under nitrogen, and the mixture was stirred for 30 minutes. Then, 5.0 ml (49 mmol) of benzaldehyde was added dropwise to this reaction mixture over about 5 minutes, and the resultant mixture was stirred for 10 minutes in the ice-salt bath and for an additional 3 hours at room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture to conduct extraction with ether. An organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resultant crude oil (15.9 g) was purified by chromatography on silica gel, thereby obtaining 8.14 g (yield: 82%) of ethyl 5-phenylpenta-(2E,4E)-dienoate.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([O:7][CH2:8][CH3:9])[NH:4][C:3]=1[CH:10]=[O:11].[C:12]([O:16][C:17]([C:19]1[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([F:33])[CH:26]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>>[C:12]([O:16][C:17]([C:19]1[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:4]3[C:3]([CH:10]=[O:11])=[C:2]([Br:1])[N:6]=[C:5]3[O:7][CH2:8][CH3:9])=[C:27]([F:33])[CH:26]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOc1nc(Br)c(C=O)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
5-Bromo-2-ethoxy-3H-imidazole-4-carbaldehyde (6.0 g, 27.4 mmol), 4′-bromomethyl-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester (10.0 g, 27.4 mmol), and potassium carbonate (3.8 g, 27.4 mmol) were dissolved in DMF (383 mL, 4950 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water, and the mixture was extracted with EtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The resulting material was purified by silica gel chromatography (0-30% EtOAc:hexanes) to yield intermediate (16a) (9.5 g). MS m/z: [M+H+] calcd for C24H24BrFN2O4, 503.3. found 503.2. 1H-NMR (CDCl3): 9.57 (1H, s), 7.80 (1H, d), 7.48 (2H, m), 7.27 (1H, s), 7.11 (1H, t), 7.01 (2H, d), 5.47 (2H, s), 4.33 (2H, q), 1.41 (3H, t), 1.24 (9H, s).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]2[S:23][CH3:24])[C@H:15]2[C@@:6]1([F:27])[C@:7]1([CH3:26])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:25])[CH:9]=[CH:8]1)(=O)C>CO.O1CCCC1>[F:27][C@:6]12[C@@H:5]([OH:4])[CH2:22][C@@:20]3([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]3[S:23][CH3:24])[C@@H:15]1[CH2:14][CH2:13][C:12]1[C@:7]2([CH3:26])[CH:8]=[CH:9][C:10](=[O:25])[CH:11]=1
Reactant: CS[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@]12C
Solvent: CO
Solvent: C1CCOC1
Product: CS[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of (11β,17β)-11-(acetyloxy)-9-fluoro-17-(methylthio)androsta-1,4-dien-3-one (2.0 g; 5.09 mmole) in a mixture of methanol (15 ml) and tetrahydrofuran (15 ml) was flushed well with nitrogen, 3M aqueous sodium hydroxide (2.0 ml) was added and the mixture was stirred at room temperature for 45 minutes. A moderate excess of acetic acid was added, the mixture was concentrated in vacuo and was diluted with water. The steroid that separated was isolated by filtration, washed with water, dried, crystallized from ethyl acetate-hexane and dried (100° C., 0.3 mm of Hg, 10 hours) to afford the homogeneous (tlc) analytical specimen of the title commpound (1.4 g), melting point 269°-270° C. with consistent spectral data.
Reaction SMILES: [ClH:1].C(OC([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=O)C1C=CC=CC=1.[CH:20]1[N:24]([CH2:25][O:26][CH:27]([CH2:30]O)[CH2:28][OH:29])[C:23]2[N:32]=[C:33]([NH2:37])[N:34]=[C:35]([OH:36])[C:22]=2[N:21]=1.C(O)(C)C>[Pd].C(O)C>[CH3:16][CH:14]([C@H:13]([NH2:12])[C:17]([O:19][CH2:30][CH:27]([O:26][CH2:25][N:24]1[C:23]2[NH:32][C:33]([NH2:37])=[N:34][C:35](=[O:36])[C:22]=2[N:21]=[CH:20]1)[CH2:28][OH:29])=[O:18])[CH3:15].[ClH:1]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nc(O)c2ncn(COC(CO)CO)c2n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: CC(C)[C@H](N)C(=O)OCC(CO)OCn1cnc2c(=O)nc(N)[nH]c21
Yield: 75.2 %

Procedure:
Hydrochloric acid (2.6 g) and 10% palladium on carbon (1.1 g, 50% wet) were added to a solution of mono-benzyloxycarbonyl-L-valine ganciclovir (10 g) in aqueous ethanol (Ethanol:Water::96 mL:26 mL) at ambient temperature. The reaction mass was flushed with nitrogen twice and hydrogenated at about 35° C. to 40° C. under a hydrogen pressure of about 0.5-1 kg/cm2 for about 1 hour. The reaction mass was filtered and washed with 10% aqueous ethanol (10 mL). Ethanol was distilled out completely under reduced pressure at about 30° C. to 35° C. The residue was dissolved in water (6.25 mL) and stirred to obtain clear solution. Iso-propanol (56 mL) was added slowly over a period of about 1 hour. The reaction mass was cooled to about 10° C. to 15° C., maintained for about 1 hour, filtered, washed with 10% aqueous iso-propanol (10 mL) followed by washing with iso-propanol (10 mL) and dried to obtain valganciclovir hydrochloride (5.8 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[I:10].[C-:11]#[N:12].[K+]>CCO.O>[Cl:9][C:5]1[C:4]([I:10])=[C:3]([CH2:2][C:11]#[N:12])[CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: Clc1cccc(CBr)c1I
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1cccc(Cl)c1I
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A mixture of 1-(bromomethyl)-3-chloro-2-iodobenzene (7 g, 21 mmol) in 100 mL EtOH was treated with a solution of potassium cyanide (2 mL, 42 mmol) in 20 mL water. The mixture was refluxed for 2.5 hours. The mixture was cooled to room temperature and concentrated. The residue was diluted with 200 mL EtOAc, washed with water (2×50 mL), saturated NaCl (50 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (20% EtOAc/hexane) to give 3.2 g pale yellow solid. MS m/e: (M+H)+ 278.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16]>ClCCl>[CH3:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1ccc(N)cc1C
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: ClCCl
Product: Cc1ccc(Nc2cc(O)ccc2[N+](=O)[O-])cc1C
Temperature: 150 °C
Reaction time: 2 h

Procedure:
3 g of 3-fluoro-4-nitrophenol and 6.9 g of 3,4-dimethylaniline were mixed and stirred for 2 hours at 150° C. After cooling, it was dissolved in dichloromethane and extracted six times with 1N aqueous hydrochloric acid. The organic phase was discarded, and the combined aqueous phases were extracted three times with chloroform. The combined extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[C:11]([CH3:12])[C:6]=2[O:5][C:4](=[O:19])[CH:3]=1.[C:20]1([C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N+]=[N-])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOCC>CN(C=O)C>[C:20]1([CH:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:1][C:2]2[C:7]3[CH:8]=[CH:9][C:10]([CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][O:14]4)=[C:11]([CH3:12])[C:6]=3[O:5][C:4](=[O:19])[CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1c(C2CCCCO2)ccc2c(O)cc(=O)oc12
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1c(C2CCCCO2)ccc2c(OC(c3ccccc3)c3ccccc3)cc(=O)oc12
Temperature: 40 °C
Reaction time: 3 h
Yield: 22.7 %

Procedure:
55 g of 4-hydroxy-8-methyl-7-(tetrahydro-2H-pyran-2-yl)-2H-1-benzopyran-2-one is introduced into 250 ml of anhydrous dimethylformamide heated to 40° C., and a solution of 58.3 g of diphenyldiazomethane in 250 ml of DMF is added dropwise. The addition is made over 3 hours while maintaining the temperature at 40° C. Several portions of 3 g of diphenyldiazomethane are added again and agitation is carried out for one hour at 40° C. The reaction medium is poured into 2 l of sulphuric ether. The organic solution is washed with an aqueous solution of sodium bicarbonate, with a solution of soda (0.1 M), with water and with salt water followed by evaporation to dryness. The residue is agitated in an isopropyl ether-hexane mixture (1-2) followed by separation. The insoluble part is dried. 20.5 g of sought product is obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:40]=[CH:39][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:46][C:47](=[O:51])[CH2:48][CH2:49][NH2:50])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:50][CH2:49][CH2:48][C:47]([OH:46])=[O:51])=[O:37])=[CH:39][CH:40]=2)=[CH:41][CH:42]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)O)cc2)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)NCCC(=O)O)cc2)cc1

Procedure:
The product from Example 234B and beta-alanine ethyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ11.84-12.51 (br.s, 1 H), 8.94 (s, 1 H), 7.85 (t, 1 H), 7.22 (m, 7 H), 7.03 (t, J=7.8 Hz, 1 H), 6.94 (m, 6 H), 6.82 (d, 2 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.92 (t, 2 H), 3.23 (dd, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.36 (t, 2 H), 2.11 (t, 2 H), 1.64 (m, 4 H); MS (ESI+) m/z 660 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]#[N:15].[NH4+].[Cl-]>O.CO.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][CH2:12][CH2:13][C:14]#[N:15])=[C:2]([F:1])[CH:7]=1
Reactant: N#CCCCc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: N#CCCCc1ccc(N)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A mixture of compound 67 (1.32 g, 6.3 mmol), NH4Cl (5.08 g, 95 mmol) and iron powder (3.52 g, 63 mmol) in water (30 mL) and CH3OH (50 mL) was stirred at 90° C. for 1 h. After cooling, the reaction mixture was filtered and the solid was washed by DCM. The filtrates were separated, the organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness to give compound 68 (1.07 g, 96%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ6.88-6.97 (m, 1H), 6.30-6.44 (m, 1H), 3.65 (br s, 2H), 2.67 (t, 2H, J=7.3 Hz), 2.31 (t, 2H, J=7.2 Hz), 1.86-1.96 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:14][CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C1COCC1.C(N(C(C)C)CC)(C)C>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:19]2[CH2:20][CH2:21][CH:16]([CH2:15][OH:14])[CH2:17][CH2:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OCC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCC(CO)CC2)cc1

Procedure:
Prepared in identical fashion to the 4-carboxamide analog by reacting 4-nitrobenzenesulfonyl chloride with 4-hydroxymethylpiperidine in THF containing 1 equivalent of diisopropyethylamine overnight at ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:14]=1)[CH:6]=[N:5]2
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(Nc2cnc3cc(Cl)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Nc2cnc3cc(Cl)ccc3n2)cc1

Procedure:
A mixture of 4-[N-(6-chloroquinoxalin-2-yl)amino]phenol (10 mmole), ethyl 2-bromopropionate (10 mmole), anhydrous potassium carbonate (2.0 g) and methyl ethyl ketone (100 ml) was heated under reflux for a period of 12 hours. The mixture was filtered and the solvent was removed by distillation under reduced pressure. The residue was chromatographed over alumina (eluent dichloromethane) to give ethyl 2-{4-[N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionate, mp 136° C.
Reaction SMILES: [H-].[Na+].C(=N[OH:11])C1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([N+]([O-])=O)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.O>CS(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([OH:11])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: ON=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
250 cc of DMSO and 4.8 g sodium hydride are placed in a 500 cc flask and heated at 70° C for 1 hour, by which time the solution has become clear. A solution of 24.2 g (0.2 mole) of benzaldoxime in 100 cc of DMSO is then added drop by drop. The solution is maintained at 70° C for 1 hour, then allowed to cool to 15° C. A solution of 26 g (0.1 mole) of 4'-chloro-4-nitrobenzophenone in 150 cc of DMSO is then added. The reaction mixture is stirred for 20 hours at ambient temperature and then poured into acidulated water. The mixture is extracted with ether and then with ether containing 2N caustic soda. On acidification the product is precipitated. Yield 15 g (65%). Melting point 178° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[N:4][C:5]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([NH2:21])[N:13]=2)=[N:6][CH:7]=1.[C:30](O)(=[O:36])[CH2:31][CH2:32][C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>>[NH2:21][C:14]1[N:13]=[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:5]2[N:4]=[C:3]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[C:2]([N:1]3[C:33](=[O:34])[CH2:32][CH2:31][C:30]3=[O:36])=[CH:7][N:6]=2)[CH:17]=[CH:16][C:15]=1[N+:18]([O-:20])=[O:19]
Reactant: Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl
Reactant: O=C(O)CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCNc2ncc(N3C(=O)CCC3=O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1 mmol of [5-amino-4-(2,4-dichlorophenyl)pyrimidin-2-yl]{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amine, and 2 mmol of succinic acid, 4 mmol of HBTU, and 5 mmol of N,N-diisopropylethylamine were added to solution and stirred for six hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography 5-10% methanol/methylene chloride to obtain 1-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]pyrrolidine-2,5-dione.
Reaction SMILES: CS[C:3]1[CH:13]=[CH:12][C:11](CCCC2C=CC=CC=2)=[CH:10][C:4]=1[CH:5]=[CH:6][C:7](O)=[O:8].CN(C=O)C.C(Cl)(=O)C([Cl:31])=O>C(Cl)Cl>[C:7]([Cl:31])(=[O:8])[CH:6]=[CH:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:3]=1
Reactant: CSc1ccc(CCCc2ccccc2)cc1C=CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To dry methylene chloride (32 ml) there is added 2-methylthio-5-(3-phenylpropyl)cinnamic acid (1.0 g, 3.2 mmol). To this mixture is added DMF (0.25 ml, 3.2 mmol) and the reaction mixture cooled in an ice bath. Oxalyl chloride (.61 ml, 7.04 mmol) is slowly added dropwise and the resulting mixture stirred at room temperature for 2 hours to afford 2-methylthio-5-3-phenylpropyl)cinnamic acid chloride in solution.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:15]>C1COCC1>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][C:14](=[O:15])[O:12][C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][N:4]=2)=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: O=C1NCc2ccccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OC1=NCc2ccccc21)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of NaH (18 mg, 60% dispension in mineral oil, 0.454 mmol) in THF (10 mL), 2,3-dihydro-isoindol-1-one (55 mg, 0.413 mmol) was added. The reaction mixture was stirred at room temperature for 1 hours. The p-nitrophenyl chloroformate (91.5 mg, 0.454 mmol) was added and the reaction mixture was stirred at room temperature for overnight. Solvent was concentrated and the residue was washed with methanol. White solid was collected as pure product carbonic acid 3H-isoindol-1-yl ester 4-nitro-phenyl ester (37 mg, 30% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[S:16][C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:20][C:18]1[N:19]=[C:15]([NH:14][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[S:16][C:17]=1[CH3:21]
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Cc1nc(N)sc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)sc1C

Procedure:
Prepared analogously to example 3c with 4-amino-3-nitro-benzoic acid and 2-amino-4,5-dimethyl-thiazole using TBTU and TEA in DMF.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10](=[O:29])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][C:21]=2[F:28])[CH2:4][O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][C:21]=1[F:28]
Reactant: CCc1ccc(Nc2c(C(=O)NOC[C@H]3COC(C)(C)O3)ccc(F)c2F)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CCc1ccc(Nc2c(C(=O)NOC[C@H](O)CO)ccc(F)c2F)c(F)c1
Reaction time: 17 h
Yield: 94.4 %

Procedure:
To a stirring solution of the product of Example 31, Step E, N-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-(4-ethyl-2-fluoro-phenylamino)-3,4-difluoro-benzamide (0.515 g, 1.213 mmol) in methanol (10 mL) and water (1 mL) was added p-toluenesulfonic acid (0.115 g, 0.607 mmol). After stirring for 17 hours the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed twice saturated sodium carbonate solution and twice with brine. The organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo to afford N-[(R)-2,3-dihydroxy-propoxy]-2-(4-ethyl-2-fluoro-phenylamino)-3,4-difluoro-benzamide (0.440 g, 94.4%) as a clear oil/foam. 1NMR (400 MHz; CD3OD) δ 7.35 (1 H, m), 6.84-6.95 (3 H, m), 6.76-6.79 (1 H, m), 3.91-3.94 (1 H, m), 3.81-3.85 (2 H, m), 3.53-3.55(2 H, m), 2.57(2 H, q, J=15.1, 7.6 Hz), 1.19(3 H, t, J=7.6 Hz); 19F-NMR (376 MHz; CD3OD) δ −132.3, −134.8, −147.3; MS(APCI+)=385; Anal. calcd/found for C18H19F3N2O4: C, 56.25/56.22; H, 4.98/4.93; N, 7.29/7.17; [α]25D −5.6° (c 10.8, EtOH).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)#[N:2].[H][H]>[Pd]>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])#[N:2]
Reactant: N#CCCC1CCCCC(=O)O1
Reactant: [H][H]
Agent: [Pd]
Product: N#CCCCCCCCC(=O)O

Procedure:
In a reactor with a catalyst composed of palladium on carbon at 5% deposited on the walls, 167 g of 7-cyanoethyl-2-oxepanone are heated to 500° C. in a hydrogen atmosphere, collecting 1 g/minute of liquid condensed product mainly formed by 8-cyanooctanoic acid with 95% lactone conversion and 80% selectivity.
Reaction SMILES: [N:1]1[N:2]2[CH:9]=[CH:8][N:7]=[C:3]2[N:4]=[CH:5][CH:6]=1.C([O-])(=O)C.[Na+].[Br:15]Br>C(O)(=O)C>[Br:15][C:9]1[N:2]2[N:1]=[CH:6][CH:5]=[N:4][C:3]2=[N:7][CH:8]=1
Reactant: c1cnn2ccnc2n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1cnc2nccnn12
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 92.2 %

Procedure:
To a solution of imidazo[1,2-b][1,2,4]triazine (0.206 g, 1.715 mmol), in acetic acid (5 ml) was added sodium acetate (0.211 g, 2.27 mmol), then, dropwise over 3 min, bromine (114.8 μl, 2.23 mmol). The solution was stirred at room temperature for 30 min, then partitioned between saturated aqueous NaHCO3 (200 ml) and ethyl acetate (200 ml). The organic extracts were dried (Na2SO4), silica gel added and evaporated in vacuo. The residue was purified by chromatography (silica gel, 50% EtOAc/isohexane) to afford 0.3147 g (74%) of the title compound: 1H NMR (360 MHz, CDCl3) δ 7.25 (1H, s), 8.05 (1H, s), 8.48-8.50 (1H, m); MS (ES+) m/z 199.