Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([NH:15][CH:16]([CH3:18])[CH3:17])[C:13]([CH2:19][CH2:20][CH3:21])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:34].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([NH:15][CH:16]([CH3:17])[CH3:18])[C:13]([CH2:19][CH2:20][CH3:21])=[N:12][C:7]=3[C:8]([NH2:34])=[N:9][C:10]=2[CH:11]=1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1NC(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1NC(C)C
Reaction time: 2 h

Procedure:
A solution of N-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (9.10 g, 26.2 mmol) in 200 mL of chloroform was placed under an atmosphere of nitrogen and cooled in an ice water bath. The solution was treated with MCPBA (8.28 g, 28.8 mmol, 77% max) and allowed to slowly come to ambient temperature. After 2 h, LC/MS and HPLC indicated complete conversion to the 5-N-oxide intermediate. The reaction mixture was again cooled in an ice water bath. The reaction mixture was treated with ammonium hydroxide solution (50 mL, 30%) and stirred vigorously. The mixture was treated with p-toluenesulfonyl chloride (5.24 g, 27.5 mmol) and allowed to come to ambient temperature. After 30 min, the reaction was diluted with 50 mL of water, and the phases were separated. The organic portion was washed with water (75 mL), brine (75 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light brown solid. The solid was purified by chromatography (SiO2, 95:5 CHCl3:MeOH) and then recrystallized from acetonitrile to give 4.52 g of 7-bromo-N1-isopropyl-2-propyl-1H-imidazo[4,5-c]quinoline-1,4-diamine as off white crystals. mp 226–228° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.44 (d, J=8.7 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.36 (dd, J=8.7, 2.1 Hz, 1H), 6.99 (d, J=1.7 Hz, 1H), 6.73 (s, 2H), 3.53–3.40 (m, 1H), 2.90 (s, 2H), 1.93–1.80 (m, 2H), 1.05–1.00 (m, 9H); 13C NMR (125 MHz, DMSO-d6) δ 154.9, 152.9, 146.3, 132.5, 127.8, 124.2, 123.5, 123.1, 119.7, 114.0, 79.5, 51.4, 28.2, 21.1, 20.6, 14.3; MS (APCI) m/z 362, 364 (M+H)+; Anal. Calcd for C16H20BrN5.0.25H2O: C, 52.40; H, 5.63; N, 19.09; Found: C, 52.03; H, 5.42; N, 19.14.
Reaction SMILES: C1(C)C=CC(S([CH2:10][C:11]2[N:16]=[C:15]([CH2:17][OH:18])[N:14]=[C:13]([CH2:19][OH:20])[N:12]=2)(=O)=O)=CC=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:10][C:11]1[N:12]=[C:13]([CH2:19][OH:20])[N:14]=[C:15]([CH2:17][OH:18])[N:16]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(CO)nc(CO)n2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nc(CO)nc(CO)n1
Temperature: 50 °C

Procedure:
4-(p-Toluenesulfonylmethyl)-2,6-dihydroxymethyl-s-triazine is dissolved in DMF and sodium azide (1.1 eq.) is added. The reaction mixture is heated to 50° C. for 4 hours. The DMF is removed under reduced pressure and the residue is partitioned between CH2Cl2 and water. The CH2Cl2 layer is separated and the water layer is extracted several times with CH2Cl2. The CH2Cl2 layers are combined, dried (MgSO4), and concentrated. The resultant residue is purified by silica gel flash column chromatography to give 4-(azidomethyl)-2,6-dihydroxymethyl-s-triazine.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:29].CCOCC>O1CCOCC1>[ClH:29].[Br:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(Br)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Brc1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 20 mL vial which contained a solution the product from step 4 (130 mg, 0.3 mmol) in dioxane was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stirred at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. the resulting solid was filtered out and dried in vacuo to yield the title product as a hydrogen chloride salt (80 mg, 80%); LCMS; 99%, ESI+, (Calcd: 346.3, Found m/z: 347.6, (M+1), 348.1, (M+2). 1H NMR (400 MHz, DMSO-d6); δ 1.68-1.76 (m, 1H), 1.86-2.02 (m, 2H), 2.07-2.14 (m, 1H), 3.15-3.24 (m, 2H), 3.86 (s, 2H), 3.83-3.92 (m, 1H), 4.02-4.07 (m, 1H), 4.21 (dd, J1=10.4 Hz, J2=3.6 Hz, 1H), 6.91 (d, J=8.8 Hz, 2H), 7.15-7.18 (m, 4H), 7.46 (d, J=8.4 Hz, 2H):
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:15][C:16]1[N:21]=[C:20](S(C)(=O)=O)[CH:19]=[CH:18][N:17]=1>O1CCCC1>[Cl:15][C:16]1[N:21]=[C:20]([O:3][CH2:2][CH2:1][OH:4])[CH:19]=[CH:18][N:17]=1
Reactant: CS(=O)(=O)c1ccnc(Cl)n1
Reactant: OCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOc1ccnc(Cl)n1
Reaction time: 0.25 h
Yield: 61.1 %

Procedure:
To a suspension of ethylene glycol (865 μL, 15.5 mmol) in tetrahydrofuran (19 mL) was added sodium bis(trimethylsilyl)amide (2.0 M in tetrahydrofuran, 4.66 mL, 4.7 mmol) at room temperature. The mixture was stirred for 15 minutes, then 2-chloro-4-(methylsulfonyl)pyrimidine (747 mg, 3.88 mmol) was added. The reaction mixture was stirred for 1 h at room temperature, concentrated, then purified by column chromatography on silica gel (Biotage 50 G, eluting with 0:100 to 100:0 ethyl acetate:hexanes) to give 2-[(2-chloropyrimidin-4-yl)oxy]ethanol (416 mg, 2.37 mmol, 61% yield) as a white solid. MS ESI: [M+H]+ m/z 175.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCc1ccc(F)c(F)c1
Temperature: 25 °C

Procedure:
To a solution of 2-(3,4-difluoro-phenyl)-ethanol (1.00 g, 6.33 mmol) in tetrahydrofuran (63.0 mL) at 0° C. was added triethylamine (1.95 mL, 13.9 mmol) followed by methanesulfonyl chloride (0.538 mL, 6.96 mmol). The solution was allowed to warm to room temperature overnight, quenched with water (20 mL), and diluted with ethyl acetate (100 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with saturated NaHCO3 (1×20 mL), brine (1×20 mL), dried over MgSO4, filtered, and concentrated to give the title compound. 1H NMR (CDCl3) δ 2.92 (s, 3H), 3.01 (t, J=6.59 Hz, 2H), 4.37–4.40 (m, 2H), 6.94–6.97 (m, 1H), 7.03–7.06 (m, 1H), 7.07–7.15 (m, 1H) ppm. 19F NMR (CDCl3) 8–140.48–, 137.71 ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[NH:47][CH2:48][CH2:49][CH3:50])[C:42]#[N:43]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:15])[NH:38][C:39]1[CH:40]=[C:41]([C:42]#[N:43])[CH:44]=[CH:45][C:46]=1[NH:47][CH2:48][CH2:49][CH3:50])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Reactant: CCCNc1ccc(C#N)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCNc1ccc(C#N)cc1NC(=O)CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In chloroform (5.0 ml), 5-t-butoxycarbonylaminovaleric acid (387 mg), WSCI hydrochloride (466 mg), and HOBt (328.3 mg) were dissolved. Then, the solution was stirred at room temperature for 1 hour. A solution (3.0 ml) of 3-amino-4-propylaminobenzonitrile (283 mg) in chloroform was dropped in this solution. Then, the solution was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and then washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and saturated saline solution, followed by drying with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound as a colorless viscous substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]1[C:16]([OH:17])=[CH:15][CH:14]=[C:13]([CH3:18])[CH:12]=1>>[CH3:18][C:13]1[CH:12]=[CH:11][C:16]([O:17][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[CH:15][CH:14]=1
Reactant: Cc1ccc(O)cc1
Reactant: Brc1ccc2[nH]ccc2c1
Product: Cc1ccc(Oc2ccc3[nH]ccc3c2)cc1

Procedure:
Prepared by Procedure J and Scheme U using 5-bromo-1H-indole and p-cresol: ESMS m/e: 224.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:14]([NH:17][S:18]([CH2:21][C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:19])([CH3:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)[N:5]([CH2:26][CH3:27])[N:4]=1.C([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])C>CN(C)C=O.O>[CH2:26]([N:5]1[C:6]([C:8]2[CH:9]=[C:10]([C:14]([NH:17][S:18]([CH2:21][C:22]([F:23])([F:24])[F:25])(=[O:20])=[O:19])([CH3:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)=[CH:7][C:3]([CH2:2][N:30]2[CH2:31][CH:32]=[C:21]([C:22]([F:25])([F:24])[F:23])[CH2:34][CH2:33]2)=[N:4]1)[CH3:27]
Reactant: CCN(CC)CC
Reactant: CCn1nc(CCl)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(CN2CC=C(C(F)(F)F)CC2)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1
Temperature: 80 °C

Procedure:
The chloride from Step 1 (45 mg, 0.106 mmol) was dissolved in dimethylformamide (3 ml) and treated with triethylamine (0.03 ml, 0.212 mmol) and the appropriate amine (20 mg, 0.108 mmol). The reaction was then heated to 80° C. for 16 hours. The reaction was then diluted with water (20 ml) and the products extracted into ethyl acetate (2×20 ml). The combined organic phase was washed with brine, dried over MgSO4 and evaporated to dryness. The product was isolated using silica gel chromatography eluting with hexane-ethyl acetate mixtures to give 0.06 g. 1H NMR (CDCl3, 360 MHz) δ 7.57-7.54 (2H, m), 7.48 (1h, t, J=7.6 Hz), 7.35 (1H, d, J=7.5 Hz), 6.26 (1H, s), 6.29 (1H, m), 5.01 (1H, brs), 4.15-4.11 (2H, q, J=7.1, 14 Hz), 3.70 (2H, s), 3.49-3.43 (2H, q, J=8.7, 17.6 Hz), 3.20 (2H, m), 2.74 (2H, t, J=5.6 Hz), 2.32 (2H, m), 1.82 (6H, s) and 1.39 (3H, t, J=7.2 Hz). MS (ES+) 539 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:5][NH:6][C:7]([C:9]1[C:18]([OH:19])=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][N:10]=1)=[O:8].[Br:24]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:24][C:11]1[N:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]2[CH:20]=[C:21]([Cl:23])[CH:22]=[C:2]([Cl:1])[CH:3]=2)=[O:8])[C:18]([OH:19])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2
Reactant: O=C(NCc1cc(Cl)cc(Cl)c1)c1ncc2cccnc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(Br)c2cccnc2c1O
Reaction time: 4 h

Procedure:
To a solution of N-(3,5-dichlorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide from Example 1, Step 3 (1.28 g, 3.69 mmol) in CH2Cl2 (100 ml) at room temperature was added N-bromosuccinimide (0.689 g, 3.87 mmol). The reaction was stirred for 4 hrs and then poured into water. The organic phase was washed with water (3×100 ml), and dried (Na2SO4). The solvent was evaporated in vacuo and the residue triturated with CH2Cl2 to afford the title compound as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11]I)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[C:13]([O-:16])(=[S:15])[CH3:14].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:11][S:15][C:13](=[O:16])[CH3:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CI)CCCCC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(CSC(C)=O)CCCCC1
Temperature: 10 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
To a cold solution of crude 1261-B (109 mmol) in DMF (90 ml) was added Potassium thioacetate (1.2 equiv, 131 mmol, 15 g) maintaining temperature below 30° C. The reaction was stirred for 18 h then cooled to 10° C. and water (160 mL) was added. Reaction was extracted with EtOAc and washed with NaHCO3 sat., then brine. The dark organic layer was dried over MgSO4, filtered and concentrated down to a dark oil. Purification—HPFC (High Pressure Flash Chromatography) 75+M prepacked silica cartridge (1 to 5% EtOAc), UV collection. After concentration, 20.43 g of product 1261-C was obtained.
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]=[CH2:4].N1C=CC=CC=1.P(Br)(Br)[Br:22]>CCCCCC>[Br:22][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: BrP(Br)Br
Reactant: C=CC(C)(O)CCC=C(C)CC(C)C
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(=CCBr)CCC=C(C)CC(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
19.8 g. of 3,7,9-trimethyl-1,6-decadien-3-ol, 100 ml. of hexane and 1 ml. of pyridine and cooled to -15° C. and treated dropwise over a period of 1.5 hours with a solution of 4 ml. of phosphorus tribromide in 50 ml. of hexane while maintaining the temperature between -15° and -10° C. The mixture is stirred for a further 90 minutes while slowly warming to room temperature. For the working-up, the mixture is poured on to 50 ml. of ice-water, the organic phase is separated and washed once with 20 ml. of 10% soda solution, once with 50 ml. of semi-saturated aqueous sodium chloride solution and once with 50 ml. saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. There is obtained 1-bromo-3,7,9-trimethyl-2,6-decadiene.
Reaction SMILES: [CH2:1]([N:8]([CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:18][CH2:17]2)[CH:13]=[CH:12][C:11]=1[O:37]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([N:8]([CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:18][CH2:17]2)[CH:13]=[CH:12][C:11]=1[OH:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc1C(=O)N(Cc1ccccc1)C1CCCCC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(c1cc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)ccc1O)N(Cc1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.9 %

Procedure:
The compound (46 mg) prepared in Example 70 was dissolved in dichloromethane (3.8 ml). A 1 M solution (0.23 ml) of boron tribromide in dichloromethane was added to the solution at 0° C. The mixture was stirred at 0° C. for 20 min, and was then stirred at room temperature for 30 min. Water and a saturated aqueous sodium hydrogencarbonate solution were added to the reaction solution, and the mixture was extracted with dichloromethane, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was developed by preparative TLC (chloroform:methanol=20:1) to give the title compound (35 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:25](OCC)(=[O:27])[CH3:26].O.N>C(OC(=O)C)(=O)C.[Cl-].[Zn+2].[Cl-]>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([N:16]([C:25](=[O:27])[CH3:26])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc(NC2=NN(c3ccc([N+](=O)[O-])cc3)C(=O)C2)cc1
Reactant: CCOC(C)=O
Agent: N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(N(C(C)=O)C2=NN(c3ccc([N+](=O)[O-])cc3)C(=O)C2)cc1
Temperature: 5 °C

Procedure:
32.6 g of 1-(4-nitrophenyl)-3-(4-methoxyanilino)-5-oxo-2-pyrazoline was dispersed in 110 g of acetic anhydride and 2.7 g of zinc chloride was added thereto and heated (70° to 80° C) on a steam bath with stirring. The mixture became a uniform solution as the reaction proceeded. After the completion of the reaction, 500 ml of ethyl acetate and 500 ml of water were added the reaction mixture and concentrated aqueous ammonia (28%) was added dropwise thereto under cooling to completely decompose the excess acetic anhydride. The crystals deposited in the ethyl acetate were collected by filtration. The filtrate was sufficiently washed with water and the ethyl acetate solution was concentrated to one-third of its original volume and cooled (5° C) to yield a second amount of crystals which was added to the first crystals obtained. Total yield of the product was 31 g. The melting point was 165° to 167° C.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][CH2:6][O:7][C:8]([CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])=[O:9]>O.C(O)(=O)C>[CH2:6]([O:7][C:8](=[O:9])[C:10](=[N:1][OH:3])[C:11](=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:5]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A solution of sodium nitrite (56.5 g, 0.815 mol) in water (400 mL) was added to a solution of ethyl benzoyl acetate (120 g, 0.625 mol) in glacial acetic acid (300 mL) at 0-10° C. over a period of 2 h. The product started precipitating during the course of addition and the reaction mixture was warmed to room temperature and stirred for 30 min. Water (2.5 L) was added and the mixture was stirred for a further 30 min and then filtered under suction. The solid was washed with water (20 mL), petroleum ether (200 mL) and then dissolved in chloroform (700 mL). The filtrate was extracted with chloroform (2×100 mL) and the combined organic phase was washed with water (2×200 mL), brine solution (2×250 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford ethyl-2-hydroxyimino-3-oxo-3-phenyl-propanoate (122.5 g, 88%).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:26](OCC)=[O:27]>C1COCC1.CCCCCC>[C:15]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:26]=[O:27])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cn1nnnc1C=C(c1ccccc1)c1ccccc1
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nnnc1C(C=O)=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
A solution of 2,2-diphenyl-1-(1-methyl-1H-tetrazol-5-yl)ethene (3.75 g; 14.29 mmole) in dry THF (40 mL) was cooled to -78° C. and treated with n-butyllithium (6.3 mL of a 2.5M soln. in hexane; 15.75 mmole) and the resulting mixture stirred at -78° C. for 30 minutes. Ethyl formate (1.5 mL; 18.58 mmole) was added and the mixture stirred at -78° C. for 2 hours. The reaction was quenched with 2N HCl and the solvent removed by evaporation. The residue was extracted with EtOAc (3×30 mL) and the combined organic layers were dried (MgSO4) and evaporated. The residue was purified by chromatography using 25-35% EtOAc-hexane as eluent to afford starting material (1.35 g; 36%) and the desired title compound (1.65 g; 39%); m.p.=185°-186° C. (crystallized EtOAc-hexane). MS (EI): m/e=290 for M+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:24])[C:9](=[O:23])[C:10]([C:13]2[CH:18]=[C:17]([O:19]C)[CH:16]=[C:15]([O:21]C)[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH:3]=1.C(Cl)Cl>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:24])[C:9](=[O:23])[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([OH:21])[CH:14]=2)([CH3:11])[CH3:12])=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH:3]=1
Reactant: COc1cc(OC)cc(C(C)(C)C(=O)N(C)c2cnc(Cl)cc2-c2ccccc2C)c1
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(O)cc(O)c1
Reaction time: 15 h
Yield: 95.1 %

Procedure:
To a solution of 2.8 g (6.4 mmol) N-(6-chloro-4-o-tolyl-pyridin-3-yl)-2-(3,5-dimethoxy-phenyl)-N-methyl-isobutyramide in 70 ml CH2Cl2 19 ml (19 mmol) BBr3 (1 M in CH2Cl2) were added at 0° C. The reaction mixture was allowed to reach ambient temperature and stirred for 15 h After addition of 50 ml water the mixture was extracted with three portions of dichloromethane. The combined organic extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by flash-chromatography (SiO2, CH2Cl2/methanol) to give 2.5 g (95%) of the title compound as a white foam.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)C#N)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS(C)=[O:26]>>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[O:26])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(C)=O
Reactant: N#CC(c1cccs1)C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Product: O=C(c1cccs1)C1CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 35 %

Procedure:
To a stirred mixture of 29.6 parts of 1-(phenylmethyl)-α-(2-thienyl)-4-piperidineacetonitrile in 100 parts of dimethyl sulfoxide are added portionwise 4 parts of a sodium hydride dispersion 60%. Upon completion, stirring is continued overnight. The reaction mixture is poured onto water. The precipitated product is filtered off and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 10 parts (35%) of [1-(phenylmethyl)-4-piperidinyl](2-thienyl)methanone; mp. 100.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:16]1[CH2:21][CH2:20][NH:19][C@@H:18]([CH2:22][CH:23]=[CH2:24])[C:17]1=[O:25])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[C:27]([O:31][C:32]([NH:34][C@H:35]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([N:16]1[CH2:21][CH2:20][N:19]([C:36](=[O:37])[C@H:35]([NH:34][C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:33])[CH2:39][C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[C@@H:18]([CH2:22][CH:23]=[CH2:24])[C:17]1=[O:25])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)O
Reactant: C=CC[C@@H]1NCCN([C@@H](Cc2ccc3ccccc3c2)C(=O)OC)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@H]1C(=O)N([C@@H](Cc2ccc3ccccc3c2)C(=O)OC)CCN1C(=O)[C@@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 85 %

Procedure:
To a solution of (S,S)-2-(3-allyl-2-oxo-piperazin-1-yl)-3-naphthalen-2-yl-propionic acid methyl ester, 5, (500 mg, 1.42 mmol) in CH2Cl2 (5.0 mL) are added 2-(R)-tert-butoxycarbonylamino-3-(4-fluorophenyl)propionic acid (473 mg, 1.67 mmol), benzotriazole-1-yl-oxy-tris-pyrrolidinol-phosphonium hexafluorophosphate (PyBOP) (960 mg, 1.85 mmol) and triethylamine (169 mg, 1.67 mmol). The reaction mixture is stirred for 20 h, quenched with 10% NaHCO3 aqueous solution and extracted with EtOAc. The extract is dried over Na2SO4, filtered and concentrated. The residue is purified over silica gel (hexanes/ethyl acetate, 4:1 to 3:2) to afford 0.745 g (85% yield) of the desired product.