Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[C:7]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][C:9]=2[O:18][CH3:19])=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1.C(N(CC)CC)C.Cl[C:29]([O:31][CH3:32])=[O:30].O>O1CCCC1>[CH3:32][O:31][C:29]([O:1][CH:2]1[C:7]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][C:9]=2[O:18][CH3:19])=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1)=[O:30]
Reactant: COC(=O)Cl
Reactant: COc1cc(OC)c(C2=CCN(C)CC2O)c(OC)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)OC1CN(C)CC=C1c1c(OC)cc(OC)cc1OC
Temperature: 5 °C
Reaction time: 3 h

Procedure:
8.37 g (30 mmol) of 3(R,S)-hydroxy-1-methyl-4(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (VII) were dissolved in 83.7 ml of tetrahydrofuran and treated with 12.4 ml (90 mmol) of triethylamine. The mixture was cooled to 5° C., 2.55 ml (33 mmol) of methyl chloroformate were added dropwise in the course of 15 min and the mixture was stirred at 5-10° C. for a further 3 h. Since TLC checking still showed starting material, a further 1.0 ml (12.9 mmol) of methyl chloroformate were added and the mixture was stirred again for 1 h. 50 ml of water were then added and the mixture was extracted twice with 50 ml of ethyl acetate each time. The combined organic phases were washed with 30 ml of saturated sodium chloride solution, then dried over sodium sulfate and evaporated in vacuo on a rotary evaporator.
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][CH2:8]O)=[O:6])=[N+:2]=[N-:3].C(Cl)(=O)C([Cl:13])=O>>[N:1]([CH2:4][C:5]([NH:7][CH2:8][Cl:13])=[O:6])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC(=O)NCO
Reactant: O=C(Cl)C(=O)Cl
Product: [N-]=[N+]=NCC(=O)NCCl
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To 2-azido-N-(hydroxymethyl)-acetamide (650 mg, 5 mmol) at −10° C. oxalyl chloride (635 mg, 5 mmol) was added. After 10 min gas evolution had ceased. The mixture was diluted in CDCl3. NMR-Spectrum in CDCl3: 4.1 (s, 2H), 5.2 (d, 2H, J=10 Hz), 7.3 (broad signal, 1H) ppm. The NMR was consitent with 2-azido-N-(chloromethyl)-acetamide (yield 75%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:16][CH:13]1[CH2:14][CH2:15][N:10]([C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:7]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: C1CCNCC1
Reactant: CC1CCN(C(=O)c2cccc(Br)n2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC1CCN(C(=O)c2cccc(N3CCCCC3)n2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
(6-bromopyridin-2-yl)(4-methylpiperidin-1-yl)methanone (40 mg, 0.142 mmol), piperidine (13 mg, 0.156 mmol), Pd2(dba)3 (2.6 mg, 0.00284 mmol), xantphos (5.0 mg, 0.00864 mmol), and sodium-tert-butoxide (20.0 mg, 0.208 mmol) were suspended in toluene (2 ml), and then stirred at 100° C. under nitrogen stream for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (30% EtOAc/Hexanes), to obtain 31 mg of pale yellow oil (80%). MS (ESI): 288 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([O:18]CC)=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([OH:18])=[O:17])=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cc2ccccc2n1Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2ccccc2n1Cc1ccc(F)cc1
Yield: 97.2 %

Procedure:
Ethyl 1-(4-fluorobenzyl)-1H-indole-2-carboxylate (409 mg, 1.376 mmol) was suspended in ethanol (5 mL) and 7M NaOH (5 mL) and stirred at 50° C. for 3 h. Ethanol content was reduced in vacuo. The solution was then acidified to pH 2 and the precipitate was collected over a filter, washed with a small amount of ice cold-water, air dried on the filter, and then finally vacuum dried to give 360 mg of the title compound as a fine, white powder.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=[C:13]3[C:12]([C:20]3[CH:21]=[N:22][N:23]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:24]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[H-].[Na+].[CH3:46][Si:47]([CH2:50][CH2:51][O:52][CH2:53]Cl)([CH3:49])[CH3:48].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[Br:19][C:17]1[CH:18]=[C:13]2[C:12]([C:20]3[CH:21]=[N:22][N:23]([C:25]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:24]=3)=[CH:11][N:10]([CH2:53][O:52][CH2:51][CH2:50][Si:47]([CH3:49])([CH3:48])[CH3:46])[C:14]2=[N:15][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c2cc(Br)cnc21
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c2cc(Br)cnc21
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a solution of azaindole 1 (0.5 g, 0.99 mmol) in DMF (2.5 mL) was added NaH (60% w/w in mineral oil, 59.4 mg, 1.48 mmol) portionwise. Then the reaction mixture was stirred for 0.5 h. SEM-Cl (263 μL, 1.48 mmol) was then added in one portion. The reaction mixture was stirred overnight and poured cautiously onto a stirred mixture of EtOAc (20 mL)/saturated aq. NH4Cl (20 mL). The layers were separated. The aqueous layer was extracted with EtOAc (2×30 mL), the combined organic extracts dried (MgSO4) and concentrated. The residue was purified by SGC using EtOAc:hexane (gradient elution up to 8:92, v/v) to give (III-d) as a white foam (345 mg, 55%); 1H NMR (400 MHz, CDCl3) δ 0.002 (9H, s), 0.97 (t, J=8.3 Hz, 2H), 3.58 (t, J=8.3 Hz, 2H), 5.69 (s, 2H), 7.30 (m, 6H), 7.40 (m, 9H), 7.46 (s, 1H), 7.65 (s, 1H), 7.98 (d, J=0.7 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.41 (d, J=2.2 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[CH:26]=[C:27]([CH3:29])[CH3:28])[CH2:14][C:13]2[C:8](=[C:9]([F:16])[CH:10]=[CH:11][C:12]=2[F:15])[CH2:7]1)=[O:5])C.[OH-].[K+]>CCO.O>[F:15][C:12]1[CH:11]=[CH:10][C:9]([F:16])=[C:8]2[C:13]=1[CH2:14][C:6]([NH:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[CH:26]=[C:27]([CH3:28])[CH3:29])([C:4]([OH:5])=[O:3])[CH2:7]2
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=C(C)C)Cc2c(F)ccc(F)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2c(F)ccc(F)c2C1
Temperature: 25 °C

Procedure:
4,7-Difluoro-2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (391) (133 mg, 0.32 mmol) is dissolved in EtOH (20 mL) and set to stir at RT. To this solution was added 5M KOH (2 ml). The reaction mixture was stirred at RT. After concentration in vacuo, the residue obtained is dissolved in water (20 mL) and washed with EtOAc (20 mL). The phases are separated and the aqueous phase is acidified with concentrated HCl to pH 2. The aqueous phase is washed with 100 mL EtOAc. The organic phases were collected, concentrated to dryness, and then the resulting residue is purified on an HPLC. The desired product (392) is obtained as white solid (38 mg, 28%).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][CH:3]=1.COC(=O)CC1C=CC([NH2:22])=CC=1>>[C:6]([NH2:22])(=[O:7])[C:5]1[CH:10]=[CH:11][CH:2]=[CH:3][CH:4]=1
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: COC(=O)c1ccc(N)cc1
Product: NC(=O)c1ccccc1

Procedure:
Reacting 3,4-dialkoxy benzoic acid with methyl 4-aminobenzoate or 4-aminophenyl acetic acid methylester to produce a benzamide compound;
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([OH:29])[C:26]3[C:21](=[CH:22][C:23]([CH3:30])=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:32]([O:39][C:40](=[O:44])[C@H:41]([CH3:43])O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][C@@H:41]([C:40]([O:39][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:44])[CH3:43])[C:26]3[C:21](=[CH:22][C:23]([CH3:30])=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O[C@H](C)C(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6 g 4-{2-[(4-Hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester and 2.5 g benzyl-L-lactate in 97 ml THF were added 5.5 g triphenylphosphine and 3.6 g diethylazodicarboxylate. After stirring for 16 h at RT LCMS indicated complete conversion and water was added to the reaction mixture which was then extracted with ethyl acetate. The residue obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 5.5 g
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18]CC)=[O:17])=[CH:5]2.CS(CCO)(=O)=[O:24].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([OH:24])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2c(ccc(Cl)c2F)OC1C(F)(F)F
Reactant: CS(=O)(=O)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C1=Cc2c(ccc(Cl)c2O)OC1C(F)(F)F

Procedure:
To the mixture of ethyl 6-chloro-5-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (2g, 6.2 mmol) and 2-methylsulfonylethanol (2.3 g, 18.5 mmol) in 40 mL of dry DMF at 0° C. was added sodium hydride (60% mineral oil suspesion, 1.48 g, 37.2 mmol) slowly with stirring. Bubbling was observed during the process. Then the resulting black solution was stirred at room temperature for three hrs. LC-MS indicated that no any more starting material was observed. The reaction was poured into ice/aqueous ammonium chloride mixture. The product was extracted with ethyl acetate, and the resulting organic solution was washed with brine, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified on silica gel column with 1:1 EtOAc/hexane+1% HOAc. The product was obtained as colorless oil, 0.8 g. Part of the product was further purified on reverse phase HPLC and gave an off-white solid. LC-MS (ES+) 295.2(M+1, 100). 1H NMR (CD3OD/300 MHz) 8.11(s, 1H), 7.30(d, J=8.7 Hz, 1H), 6.53(d, J=9.0 Hz, 1 H), 5.75(q, J=7.5 Hz, 1 H),. 19F NMR(CDCl3/300 MHz) −80.31 (d, J=7.1 Hz). High resolution MS (ES−): m/e calc. For C15H6ClF3O4: 292.9828(M−H), found: 292.9853.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][CH2:13][OH:14].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([O:14][CH2:13][CH3:12])=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
2,6-Difluorobenzoyl chloride was diluted with CH2Cl2 (5 ml) and cooled to 0° C. A mixture of EtOH (1.2 ml, 20 mmol) and pyridine (1.6 ml, 20 mmol) was added, dropwise, over 5 minutes to the reaction mixture. The ice bath was removed after 5 minutes and the reaction mixture stirred at 25° C. for 45 min. The solvent and volatiles were evaporated under reduced pressure and the residue was partitioned between 1N HCl and EtOAc (10 ml each). The aqueous phase was separated and extracted with 2×7 ml EtOAc. The combined organic extracts was washed with NaHCO3 (10 ml), brine (7 ml), dried over MgSO4 and concentrated to give 1.562 g ethyl 2,6-difluorobenzoate as an almost colorless oil. (84% yield from steps B and C).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:18])[O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])[N:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29](OC(C)=O)=[O:30]>CCOC(C)=O.[Pd]>[C:29]([NH:25][C:21]1[CH:20]=[C:19]([N:7]2[C:8]([NH:10][C:11](=[O:18])[O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]2)[CH:24]=[CH:23][CH:22]=1)(=[O:30])[CH3:28]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc([N+](=O)[O-])c2)n1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73 %

Procedure:
2,2,2-Trichloroethyl 3-t-butyl-1-(3-nitrophenyl)-1H-pyrazol-5-ylcarbamate (0.67 g, 1.538 mmol, 1.00 eq) in EtOAc (30 ml) was shaken under H2 (3.5 arm) at 22° C. over 10% Pd/C (0.327 g, 0.154 mmol, 0.10 eq, 50% H2O) overnight. The completed hydrogenation was treated with Ac2O (3 ml) and stirred at RT. After 45 min, the mixture was filtered through Celite, rinsing forward with EtOAc. The filtrate was treated with a roughly equal volume of satd. NaHCO3 and stirred briskly at RT for 3 h. The layers were separated and the organic layer washed with satd. NaHCO3 (2×). The combined aqueous layers were extracted with EtOAc (1×). The combined organics were washed with brine (1×), dried (MgSO4), filtered and evaporated to afford 2,2,2-trichloroethyl 1-(3-acetamidophenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate (0.50 g, 73% yield) as a white solid which was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6): δ 10.10 (s, 1H), 9.95 (brs, 1H), 7.74 (brs, 1H), 7.54-7.51 (m, 1H), 7.37-7.31 (m, 1H), 7.08 (d, J=7.6 Hz, 1H), 6.26 (s, 1H), 4.84 (s, 2H), 2.03 (s, 3H), 1.26 (s, 9H); MS (ESI) m/z: 447.0 (M+H), 449.0 ((M+2+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][P:18](=[O:29])([O:24][CH2:25][CH2:26][O:27][CH3:28])[O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=2)[N:3]=1.[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH2:46][CH2:45]2)=[C:37]2[C:41]=1[C:40](=[O:42])[N:39]([CH3:43])[CH2:38]2>>[OH:50][C@H:47]1[CH2:48][CH2:49][C@H:44]([C:36]2[CH:35]=[CH:34][C:33]([NH:32][C:2]3[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:31]=[CH:30][C:16]([CH2:17][P:18](=[O:29])([O:24][CH2:25][CH2:26][O:27][CH3:28])[O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=4)[N:3]=3)=[C:41]3[C:37]=2[CH2:38][N:39]([CH3:43])[C:40]3=[O:42])[CH2:45][CH2:46]1
Reactant: CN1Cc2c(C3CCC(O)CC3)ccc(N)c2C1=O
Reactant: COCCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCCOC
Product: COCCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCCOC

Procedure:
The title product was prepared according to the procedure for Example 102 using bis(2-methoxyethyl) (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Compound 189A, 39.5 mg, 0.0816 mmol) and 7-amino-4-(4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (24.7 mg, 0.0949 mmol). The reaction mixture concentrated and purified by MDP [under basic conditions; ammonium bicarbonate basic buffer (pH 9)]. The title compound was obtained as a white solid, 36.2 mg (61%). 1H NMR (400 MHz, DMSO-d6) δ 10.58 (br s, 1H), 9.89 (s, 1H), 8.46 (s, 1H), 8.65 (br s, 1H), 7.57 (br s, 2H), 7.38 (d, J=8.8 Hz, 1H), 7.26 (dd, J=8.6, 2.0 Hz, 2H), 4.56-4.65 (m, 1H), 4.52 (s, 2H), 3.94-4.09 (m, 4H), 3.49-3.55 (m, 1H), 3.44-3.49 (m, 4H), 3.27 (d, J=13.4 Hz, 2H), 3.24 (s, 6H), 3.08 (s, 3H), 1.93 (d, J=9.9 Hz, 2H), 1.70-1.80 (m, 2H), 1.47-1.66 (m, 2H), 1.22-1.38 (m, 2H). MS (ES+): m/z 708.26 (100) [MH+]. HPLC: tR=3.61 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[C:17]([O:19][CH3:20])=[O:18])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-][Si]([O-])=O.[Mg+2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[C:17]([O:19][CH3:20])=[O:18])[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CO)cc1SCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)cc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 92.3 %

Procedure:
A solution of 30 g 3-benzylmercapto-4-carbomethoxy benzyl alcohol in 900 ml of methylene chloride is stirred with 60 g of Florisil (activated magnesium silicate) in 900 ml of methylene chloride. To the thus-obtained slurry is added 39 g of solid pyridinium chlorochromate and the black reaction mixture obtained is stirred for 3-4 hours at room temperature, filtered over Celite (diatomaceous earth), and washed with 600 ml of methylene chloride. The methylene chloride filtrate is stirred overnight with a solution of 14 g of potassium hydroxide in 500 ml of water which removes all the dark color from the organic layer. The methylene chloride layer is separated, washed with 100 ml of 2N hydrochloric acid and then with 300 ml of water, dried over sodium sulfate and evaporated to dryness to yield 27.5 g of 3-benzylmercapto-4-carbomethoxy benzaldehyde having a melting point of 91°-93° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([F:14])[CH:7]=1>S(=O)(=O)(O)O>[Br:5][C:6]1[C:13]([N+:1]([O-:4])=[O:2])=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([F:14])[CH:7]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=Cc1cc([N+](=O)[O-])c(Br)cc1F
Reaction time: 2 h

Procedure:
Nitric acid (25 mL) is added dropwise to a solution of 4-bromo-2-fluorobenzaldehyde (5.12 g, 25.2 mmol) in sulfuric acid (25 mL). The mixture is stirred for 2 hours and then is poured over ice. Product is extracted into MTBE (100 mL). The organic layer is washed with saturated aqueous NaHCO3 (100 mL), dried (Na2SO4), and evaporated yielding 5.98 g of yellow solid. 1H NMR (DMSO-d6) δ 10.13, 8.49, 8.22.
Reaction SMILES: FC1C=CC(CN2CCC3C(=C(O)C(=O)N(C(C)C)C=3C(N(C)C)=[O:18])C2=O)=CC=1.N[C:31]1[C:32](=[O:60])[N:33]([CH2:56][CH:57]([CH3:59])[CH3:58])[C:34]([C:51]([N:53]([CH3:55])[CH3:54])=[O:52])=[C:35]2[C:40]=1[C:39](=[O:41])[N:38]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[C:45](Cl)[CH:44]=1)[CH2:37][CH2:36]2>>[F:49][C:46]1[CH:47]=[CH:48][C:43]([CH2:42][N:38]2[CH2:37][CH2:36][C:35]3[C:40](=[C:31]([OH:18])[C:32](=[O:60])[N:33]([CH2:56][CH:57]([CH3:59])[CH3:58])[C:34]=3[C:51]([N:53]([CH3:54])[CH3:55])=[O:52])[C:39]2=[O:41])=[CH:44][CH:45]=1
Reactant: CC(C)n1c(C(=O)N(C)C)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: CC(C)Cn1c(C(=O)N(C)C)c2c(c(N)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Product: CC(C)Cn1c(C(=O)N(C)C)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)cc1)CC2

Procedure:
The title compound was prepared in a manner similar to that described for 6-(4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isopropyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (Example 69), using 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isobutyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (Example 14). (ES MS M+1=416)
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[K+].[CH2:5]([O:7][C:8](=[O:13])[CH2:9][C:10]([O-:12])=O)[CH3:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:26][C:27]1[CH:28]=[C:29]([CH2:34]C(O)=O)[CH:30]=[CH:31][C:32]=1[F:33].Cl>C1COCC1>[Br:26][C:27]1[CH:28]=[C:29]([CH2:34][C:10](=[O:12])[CH2:9][C:8]([O:7][CH2:5][CH3:6])=[O:13])[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: O=C(O)Cc1ccc(F)c(Br)c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)Cc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 107.6 %

Procedure:
Magnesium chloride (3.7 g) was added to a suspension of 3-ethoxy-3-oxopropanoic acid potassium salt (5.5 g) in THF (100 ml), and the mixture was stirred at room temperature for 2.5 hours (Reaction Solution 1). In another vessel, carbonyldiimidazole (4.2 g) was added in small portions to a solution of 2-(3-bromo-4-fluorophenyl)acetic acid (5 g) in THF (50 ml) at room temperature, and the mixture was stirred for 30 minutes (Reaction Solution 2). Reaction Solution 2 was added to Reaction Solution 1 at room temperature, and the mixture was stirred at 60° C. for three hours. Hydrochloric acid (1 N aqueous solution, 200 ml) was added, followed by extraction with ethyl acetate. The resulting organic layer was sequentially washed with water, a saturated aqueous sodium bicarbonate solution and brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 7 g of the title compound as an oily substance.
Reaction SMILES: [C:1]([O-:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Li+].C(O)CCCCCCC.C([Li])CCC.[Br:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br>O1CCCC1.C(N(C)C)=O.CCCCCC>[CH2:1]([O:10][CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[Br:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: BrCc1ccccc1Br
Reactant: CCCCCCCC(=O)[O-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCCCCO
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCCCCCOCc1ccccc1Br

Procedure:
Lithium octanoate, prepared from octanol and n-butyllithium, in a mixture of tetrahydrofuran/hexane dimethyl formamide was condensed with 2-bromobenzyl bromide to yield 2(octyloxy)methylbromobenzene. This material was treated with n-butyllithium in ether/hexane mixture and subsequently treated with paraformaldehyde to yield 2-(octyloxy)methylbenzyl alcohol. This material was then treated with triphenyl phosphonine bromide to yield [[2-[(octyloxy)-methyl]phenyl]methyl]triphenyl phosphonium bromide. Condensation of this material with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester, as in Example 3, followed by hydrolysis, as in Example 5, gave the (All-E)-3,7-Dimethyl-9-[2-[(octyloxy)-methyl]phenyl]-2,4,6,8-nonatetraenoic acid, mp 120°-121° (from methane/hexane mixture).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3([C:14]4[CH:15]=[C:16]5[C:21](=[CH:22][CH:23]=4)[N:20]=[CH:19][CH:18]=[CH:17]5)[CH2:13][CH2:12]3)=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:20]1[C:21]2[C:16](=[CH:15][C:14]([C:11]3([C:8]4[N:6]5[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]5=[N:10][N:9]=4)[CH2:13][CH2:12]3)=[CH:23][CH:22]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6-[1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-cyclopropyl]-quinoline (30 mg, 0.093 mmol), PdCl2(PPh3)2 (6.5 mg, 0.0093 mmol) and tributyl(1-ethoxyvinyl)stannane (67 mg, 0.186 mmol) in 1,4-dioxane (3 mL) was heated at 90° C. for 3 h under N2. The reaction mixture was diluted with EtOAc, washed with aqueous KF. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in HOAc and 3 N HCl, and stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue was dissolved in DCM, washed with sat. aq. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silica gel eluting with a EtOAC/MeOH gradient to afford the title compound as yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.89 (dd, 1H); 8.13-8.04 (m, 3H), 7.93 (d, 1H), 7.87 (dd, 1H), 7.70 (d, 1H), 7.40 (dd, 1H), 2.51 (s, 3H), 1.92-1.89 (m, 2H), 1.73-1.69 (m, 2H). LCMS (method A): [MH]+=330, tR=4.18 min.