Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH3:39])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][N:14]=2)=[O:11])[C:6](=[O:32])[N:5]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:40]([N:50]([CH2:52][C:53](O)=[O:54])[CH3:51])([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:43]([O:42][C:40]([N:50]([CH3:51])[CH2:52][C:53]([O:1][C@H:2]([CH3:39])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10](=[O:11])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][N:14]=2)[C:6](=[O:32])[N:5]1[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:54])=[O:41])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)O)n(-c5ccccc5)c4=O)nc3)ccnc2c1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CN(C)C(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)nc3)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
To a mixture of (R)-1-(2-hydroxypropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (2.0 g, 3.81 mmol), N-Cbz-sarcosine (1.7 g, 7.62 mmol) and DMAP (0.93 g, 7.62 mmol, Aladdin) in 15 mL of CH2Cl2 at 0° C. was added EDC solid (2.19 g, 11.43 mmol, Aladdin) in portions. After stirring at 0° C. for 2 hrs, the mixture was allowed to heat to 40° C. and stirred overnight. The reaction was diluted with 100 mL of CH2Cl2. The resulted solution was washed with 0.1 N HCl (10 mL×2), saturated NaHCO3 (20 mL×2) and followed by water (20 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/MeOH=4/1) to give the title compound as a yellow solid (2.15 g, 77.3%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:2].[NH2:21][CH2:22][C@@H:23]([C:25]1[CH:26]=[CH:27][C:28]([OH:36])=[C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=1)[OH:24]>>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:21][CH2:22][C@H:23]([OH:24])[C:25]3[CH:26]=[CH:27][C:28]([OH:36])=[C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:30]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCOC(=O)/C=C/c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from (E)-3-[4-(4-oxo-piperidin-1-yl)-phenyl]-acrylic acid ethyl ester (which was obtained in Example 169) (0.27 g, 1.0 mmol) and N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) (0.27 g, 1.1 mmol) according to the procedure shown for Example 180 to give 0.40 g of yellow solid; m.p. 103–106° C.; 1H NMR (DMSO-d6) δ 1.24 (t, 3 H), 1.20–1.45 (m, 2 H), 1.75–1.95 (m, 2 H), 2.55–2.95 (m, 5 H), 2.92 (t, 3 H), 3.67–3.85 (m, 2 H), 4.14 (q, 2 H), 4.46–4.50 (m, 1 H), 6.34 (d, 1 H), 6.96 (d, 1 H), 6.79–7.05 (m, 3 H), 7.05 (d, 1 H), 7.17 (d, 1 H), 7.56 (d, 2 H); MS (ES) m/z: 504.0 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH3:15][N:16]1[CH:20]=[C:19](I)[CH:18]=[N:17]1.C(O)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.[Cu](I)I>[CH3:15][N:16]1[CH:20]=[C:19]([N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])[CH:18]=[N:17]1
Reactant: Cn1cc(I)cn1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Cn1cc(N2CCN(C(=O)OC(C)(C)C)CC2=O)cn1
Temperature: 100 °C

Procedure:
To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (0.164 g, 0.819 mmol) in 3 mL of isopropanol under an atmosphere of nitrogen was added 1-methyl-4-iodo-1H-pyrazole (0.204 g, 0.983 mmol), ethylene glycol (0.051 g, 0.82 mmol), copper iodide (0.031 g, 0.16 mmol), and potassium phosphate (0.695 g, 3.28 mmol). The reaction was heated to 100° C. for 8 h, cooled to rt, and concentrated in vacuo. The residue was dissolved in dichloromethane, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 10-100% ethyl acetate in hexanes to provide tert-butyl 4-(1-methyl-1H-pyrazol-4-yl)-3-oxopiperazine-1-carboxylate that gave a mass ion (ES+) of 281.1 for [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:43]1[CH2:49][CH2:48][CH2:47][C@H:44]1[CH2:45][OH:46]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([N:43]1[CH2:49][CH2:48][CH2:47][C@H:44]1[CH:45]=[O:46])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: OC[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C=O
Temperature: 4 °C
Reaction time: 21 h

Procedure:
In 200 ml of THF was dissolved 29.9 g of t-butyloxycarbonyl-phenylalanine. To this solution were added under cooling with edible salt and ice 11.5 g of HOSu and 20.6 g of DCC, and the mixture was stirred for 21 hours at 4° C. The reaction liquid was filtered and the filtrate was evaporated whereby a semi-solid substance was obtained. This substance was recrystallized from chloroform to obtain a white solid substance which was then dissolved in 400 ml of THF. To this solution was added 7.4 g of L-prolinol, and the mixture was stirred for 72 hours at room temperature. After removal of THF by distillation, the residue was dissolved in 300 ml of ethyl acetate and the solution was washed with 100 ml of 1-M Na2CO3, dehydrated with anhydrous Na2SO4 and evaporated until dryness. To the resultant oily substance were added 29.2 g of WSCD.HCl and 120ml of redistilled DMSO, and the mixture was stirred for 10 minutes. Subsequently 5.8 ml of a DMSO solution of 2-M anhydrous H3PO4 was added and the mixture was stirred for further 2 hours. The reaction was stopped with 300 ml of a buffer solution of 1-M potassium phosphate of pH 7.5. The reaction mixture was extracted with 250 ml of ethyl acetate, and the extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off and the residue was dissolved in 250 ml of ethanol. To this solution was added 200 g of NaHSO3 in 350 ml of water, and the mixture was stirred vigorously for 10 minutes. After concentration of the ethanol up to about 350 ml, unreacted materials were eliminated twice with 100 ml of ether, and solid Na2CO3 was added until the pH value of the liquid became 9. After 5 minutes, the reaction liquid was extracted twice with 100 ml of ether, and the ether was then distilled off to leave an oily substance. Yield 3.3 g (8.4%).
Reaction SMILES: C.C1C(Br)=C(Br)[NH:4]C=1C(O)=O.N([O-])=O.[Na+].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N+:23]([O-:26])([OH:25])=[O:24]>C(O)(C)C.O>[N+:23]([O-:26])([O-:25])=[O:24].[C:17]1([N+:16]#[N:4])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc(Br)c(Br)[nH]1
Agent: C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: N#[N+]c1ccccc1
Product: O=[N+]([O-])[O-]

Procedure:
A carbon black with a CTAB surface area of 350 m2 /g and a DBPA of 120 ml/100 g was used. A suspension of 50 g of this carbon black was prepared by stirring it into 450 g of water that contained a few drops of isopropanol. A solution of 5.12 g of NaNO2 in 10 g of cold water was slowly added to a solution of 5.62 g of aniline and 11.88 g of concentrated nitric acid in 10 g of water that was cooled in an ice bath. Benzenediazonium nitrate was formed. After 15 minutes of stirring, the mixture was added to the stirring carbon black suspension. Bubbles were released. When the bubbling had stopped, the product was collected by filtration, washed twice with water and dried in an oven at 125° C. The carbon black product had attached phenyl groups.
Reaction SMILES: Cl[C:2]([C:28]1[CH:32]=[CH:31][O:30][CH:29]=1)([C:22]1[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1.CC(O)C.[NH3:37]>C1COCC1>[NH2:37][C:2]([C:28]1[CH:32]=[CH:31][O:30][CH:29]=1)([C:22]1[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1
Reactant: N
Reactant: Cn1cncc1C(Cl)(c1ccoc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cn1cncc1C(N)(c1ccoc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 5 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
A mixture of 6-[chloro-3-furanyl(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (obtained in stage b) (0.0045 mol) in THF (30 ml) was cooled to 5° C. 2-Propanol-NH3 saturated (30 ml) was added dropwise quickly. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated till dryness. The residue was taken up in DCM and water and the mixture was decanted. The organic layer was dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (2.2 g) was purified by column chromatography over silica gel (eluent: toluene/2-propanol/NH4OH 85/13/1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN and DIPE. The precipitate was filtered off and dried, yielding 0.55 g (27.5%) of (±)-6-[amino-3-furanyl(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, melting point 197° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].C1(C)C=CC=CC=1.C([O:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])C.[OH-].[Na+]>C(OCC)(=O)C.O>[CH3:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:4]1[CH2:3][CH2:2][NH:1][C:20](=[O:19])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CN1CCCC1CCN
Reactant: CCCCCCCCCCCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCC(=O)NCCC1CCCN1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.7 %

Procedure:
Toluene (1.00 ml), dried using MS 4A, was mixed with 1.00 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 0.17 ml (0.78 mmol) of 2-(2-aminoethyl)-1-methylpyrrolidine was added dropwise over about 2 minutes. After stirring for 20 minutes, the temperature was raised to room temperature, and 0.5 ml of a toluene solution of 0.2 g (0.78 mmol) of myristic acid ethyl ester was added dropwise over 1 minute. After stirring for 2 hours at 70° C., the mixture was cooled with ice, and 1N NaOH solution was added dropwise. The mixture was stirred for 10 minutes, and water and ethyl acetate were added. Then, the mixture was separated into respective layers, and the organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride. After this layer was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure on a 30° C. water bath to obtain the captioned compound (yield 0.25 g). This compound was subjected to silica gel column chromatography (mobile phase: CHCl3:MeOH (19:1→9:1)) for purification. NMR and mass spectrum confirmed the purified compound to have the following structure:
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:9]([CH2:13][CH2:14][CH3:15])[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.[CH3:53][NH:54][O:55][CH3:56]>ClCCl.O>[CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:9]([CH2:13][CH2:14][CH3:15])[C:10]([N:54]([O:55][CH3:56])[CH3:53])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: CCC[C@@H](C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CCC[C@@H](C(=O)N(C)OC)N(Cc1ccccc1)Cc1ccccc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
(S)-2-(dibenzylamino)pentanoic acid (1.57 Kg; 5.286 mol) was dissolved in dry dichloromethane (9.42 L) under a nitrogen atmosphere and cooled to 0-5° C. The resulting solution was treated with N-hydroxybenzotriazole (HOBt; 928 g; 6.875 mol) followed by 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 1.51 Kg; 7.931 mol;) at 0-5° C. The reaction mixture was stirred for 3 hours at ambient temperature, then treated with N-methylmorpholine (NMM; 1.62 Kg; 16.07 mol) followed by N,O-dimethylhydroxylamine hydrochloride (1.29 Kg; 13.22 mol) at 0° C. The reaction mixture was stirred at ambient temperature for 15 hours, then water (2.5 L) added, and the mixture stirred for 10 minutes. The organic layer was separated, washed with 1% aqueous hydrochloric acid, followed by saturated aqueous sodium bicarbonate, then brine solution. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to provide (S)-2-(dibenzylamino)-N-methoxy-N-methylpentanamide, a compound of formula (6), as a syrupy oil.
Reaction SMILES: CC1C(O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@H]3O[C@H](C)[C@@H](O)[C@H](O)C3)C2)=C[C:5]2[C:10](C=1O)=[C:9](O)[C:8]1C([C@@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@H](O[C@H]4O[C@H](C)[C@H](O[C@H]5O[C@H](C)[C@@H](O)[C@](O)(C)C5)[C@H](O)C4)C3)[C@H:17]([C@H:19](OC)[C:20]([C@@H:22](O)[C@H:23](O)C)=O)[CH2:18][C:7]=1[CH:6]=2)=O.[OH-].[Na+].C[N:80](C)C=O>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].O>[CH:9]1[C:8]2[NH:80][C:17]3[C:18](=[CH:23][CH:22]=[CH:20][CH:19]=3)[C:7]=2[CH:6]=[CH:5][CH:10]=1
Reactant: CN(C)C=O
Reactant: CO[C@H](C(=O)[C@@H](O)[C@@H](C)O)[C@@H]1Cc2cc3cc(O[C@H]4C[C@@H](O[C@@H]5C[C@@H](O)[C@H](O)[C@@H](C)O5)[C@H](O)[C@@H](C)O4)c(C)c(O)c3c(O)c2C(=O)[C@H]1O[C@H]1C[C@@H](O[C@@H]2C[C@@H](O)[C@@H](O[C@@H]3C[C@](C)(O)[C@H](O)[C@@H](C)O3)[C@@H](C)O2)[C@H](O)[C@@H](C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2c(c1)[nH]c1ccccc12
Reaction time: 48 h

Procedure:
Heparin adipic hydrazide (70 mg) was dissolved in 6 ml of 0.1M sodium phosphate buffer, pH 5.8. Mithramycin (10 mg) was dissolved in 1 ml dimethylformamide and this solution was mixed with the heparin adipic hydrazide solution and left for 21/2 days at room temperature. The reaction mixture was then applied to a column of Sephadex G25 equilibrated in H2O whose pH had been raised to approximately 10 by the addition of dilute NaOH. The conjugate, which elated in the void volume, was collected and freeze dried. Quantitation of the drug by u.v spectrophotometric analysis and of the heparin by carbazole assay gave the composition of the conjugate as 0.54 mol mithromycin:mol heparin. The conjugate (Table III) has the structure shown in FIG. 2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[I:11]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[I:11][C:10]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7][NH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1csc(-c2cc[nH]n2)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1c[nH]nc1-c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
3-(2-thienyl)-1H-pyrazole (2.9 mmol) was dissolved in 8 mL N,N-dimethylformamide under argon atmosphere. N-Iodosuccinimide (3.1 mmol) was added in small portions. The reaction mixture was stirred at room temperature overnight. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h. The white precipitate was filtered, washed with little cold MTBE and dried in vacuum to afford 540 mg of 4-iodo-3-(2-thienyl)-1H-pyrazole (66% yield). The filtrate was extracted with ethyl acetate. The combined organic layers were successively washed with water and brine, dried over MgSO4, filtered and concentrated to afford 303 mg of 4-iodo-3-(2-thienyl)-1H-pyrazole (34% yield) that was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH2:9])=[O:8].[CH3:10][C:11]([CH:14]=O)([CH3:13])[CH3:12].[NH:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:16]1([CH:14]([NH:9][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:8])[C:11]([CH3:12])([CH3:13])[CH3:10])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: CC(C)(C)C=O
Reactant: NC(=O)c1ccccn1
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)c1ccccn1)n1nnc2ccccc21

Procedure:
A suspension of 2-pyridinecarboxamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the desired product.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CS(C)=O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCNCC3)nc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (632 mg, 2.00 mmol) in DMSO (10 ml) was added DIEA (516 mg, 3.99 mmol) and piperazine (688 mg, 7.99 mmol). The resulting solution was stirred for 3 hours at 80° C. and then quenched by the addition of water (100 ml). The solids were collected by filtration to afford methyl 2-(4-fluorophenyl)-3-(piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid (540 mg, 74%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[CH3:12]N(C)C=O.N1CCCC1.C(O)(=O)C>CCOCC.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[CH:12][NH:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: [Zn]
Solvent: C1CCNC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: Brc1ccc2cc[nH]c2c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Combine 4-bromo-2-nitrotoluene (5.0 g, 23.1 mmol), dimethylformamide (50 ml), DMF-dimethylacetal (9.0 ml, 69.4 mmol), and pyrrolidine (2.0 ml, 23.1 mmol). Heat to 110° C. After 3 hours, cool to room temperature, dilute with ether, and wash with water. Combine the organic layers, and concentrate to give a residue. Combine the residue and 80% aq. acetic acid (120 ml) and heat at 75° C. Add zinc dust (13.1 g, 200.5 mmol) portionwise. Heat to 85° C. After 2 hours, cool and filter. Dilute the filtrate with ether, wash with water dry (Na2SO4), and concentrate to give a residue. Chromatograph the residue eluting with 9:1 hexane:EtOAc to give the title compound.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:14][C:13]3[CH:15]=[C:16](/[CH:19]=[CH:20]/[C:21]([N:23]([CH3:35])[CH2:24][C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:22])[CH:17]=[N:18][C:12]=3[NH:11][C:10](=[O:36])[CH2:9]2)=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C.CO.C(Cl)Cl>[CH3:35][N:23]([CH2:24][C:25]1[N:26]([CH3:34])[C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]1[CH:17]=[N:18][C:12]2[NH:11][C:10](=[O:36])[CH2:9][NH:8][CH2:14][C:13]=2[CH:15]=1
Reactant: COc1ccc(CN2CC(=O)Nc3ncc(/C=C/C(=O)N(C)Cc4cc5ccccc5n4C)cc3C2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CO
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)CNCC(=O)N2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
A solution of (E)-3-[4-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl]-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (2.00 g, 3.92 mmol), from Example 65, in dichloroethane (80 mL) was cooled in an ice bath and treated with 1-chloroethyl chloroformate (0.47 mL, 4.31 mmol). After stirring at 0° C. under N2 for 30 min and then at room temperature for 30 min, the mixture was heated to reflux for 1.5 h. The mixture was allowed to cool and then concentrated to dryness. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3) gave a tan solid. The solid was suspended in methanol and heated to reflux for 2 h. The mixture was allowed to cool and the solid was isolated by filtration, dissolved in CH2Cl2, washed with 1 N NaOH, dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3 to 95:5) gave the title compound (0.70 g, 49%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.38-8.33 (m, 2H), 7.72-7.67 (m, 1H), 7.60-7.57 (m, 2H), 7.32-7.20 (m, 3H), 7.14-7.09 (m, 1H), 6.90-6.80 (m, 1H), 6.49-6.38 (m, 1H), 4.93-4.78 (m, 2H), 4.08 (s, 2H), 3.95 (s, 2H), 3.71 (s, 3H), 3.13-3.07 (m, 3H); MS (ESI) m/e 390 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[S:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:38]=[C:37](C(Cl)(Cl)Cl)[O:36][N:35]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-:44].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:3]1[S:19][C:6]2[N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][C:37](=[O:44])[O:36][N:35]=4)=[CH:24][CH:23]=3)[C:8](=[O:18])[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: O=C([O-])[O-]
Reactant: CCc1cc2c(=O)n(-c3ccccc3)c(=O)[nH]c2s1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(-c3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.8 %

Procedure:
A mixture of 6-ethyl-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.25 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.48 g), potassium carbonate (0.15 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and methanol (5 mL). 1N Aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.1 g, 21%).