Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:6][C:7]1[O:8][C:9]([SH:12])=[N:10][N:11]=1)([O:3]CC)=[O:2].[OH-].[Na+]>O.C(O)C>[C:1]([CH2:6][C:7]1[O:8][C:9]([SH:12])=[N:10][N:11]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)Cc1nnc(S)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1nnc(S)o1

Procedure:
A solution of 3.15 g (0.017 mol) of 2-carbethoxymethyl-1,3,4-oxadiazole-5-thiol in 25 ml of water and 25 ml of ethanol was stirred for 5 hours while maintaining the pH at 10-11 by addition of 10% aqueous sodium hydroxide solution. The mixture was neutralized to pH 7.0 then evaporated to dryness. The residue was dissolved in 15 ml of water, 50 ml of ethyl acetate was added and the solution was acidified to pH 1.5 with 3N hydrochloric acid. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined extracts were dried (Na2SO4) and the solvent was evaporated to give a residue which was recrystallized from ether-cyclohexane to give 2-carboxymethyl-1,3,4-oxadiazole-5-thiol, m.p. 167°-169° (dec.)
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([CH2:7][NH:8][C:9]([CH:11]([O:28][CH2:29][CH3:30])[C:12]2[C:13]([F:27])=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=[CH:16][C:17]=2[F:18])=[O:10])=[CH:5][CH:4]=1)#[N:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].Br[C:57]1[CH:58]=[CH:59][CH:60]=[N:61][CH:62]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[C:1]([C:3]1[CH:32]=[CH:31][C:6]([CH2:7][NH:8][C:9](=[O:10])[CH:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]([C:60]3[CH:59]=[CH:58][CH:57]=[CH:62][N:61]=3)[C:13]=2[F:27])[O:28][CH2:29][CH3:30])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(OS(=O)(=O)C(F)(F)F)c1F
Reactant: Brc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: C1COCCO1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(-c2ccccn2)c1F
Temperature: 100 °C
Reaction time: 24 h
Yield: 64.9 %

Procedure:
To a solution of (RS)-trifluoro-methanesulfonic acid 3-[(4-cyano-benzylcarbamoyl)-ethoxy-methyl]-2,4-difluoro-phenyl ester (570 mg) in dioxane (20 ml) was added bis(pinacolato)diboron (454 mg), dry KOAc (351 mg) and [PdCl2(PPh3)2] (25 mg). The reaction mixture was stirred 24 h at 100° C. After cooling to rt 5-bromopyridine (377 mg), 2 N aq. Na2CO3 sol. (6 ml) and [PdCl2(PPh3)2] (25 mg) were added. The resulting mixture was stirred 1 h at 90° C. The solids were filtered away and washed with H2O (100 ml) and AcOEt (80 ml). The aqueous layer was isolated and extracted with more AcOEt (100 ml). The organic layers were washed with brine (2×80 ml), combined and dried over Na2SO4. The solvent was evaporated and the crude product was purified by CC (AcOEt/Hept 3:7 to 3:1) to obtain 315 mg (65%) of (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-pyridin-2-yl-phenyl)-2-ethoxy-acetamide. Colorless oil. MS 408.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.Cl.[CH2:9]([C:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:10].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[N:6]=[C:5]([N:14]2[CH2:15][CH2:16][C:11]([CH2:9][CH3:10])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:13]2)[S:4][N:3]=1
Reactant: Clc1nsc(Cl)n1
Reactant: CCOC(=O)C1(CC)CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CC)CCN(c2nc(Cl)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
3,5-dichloro-1,2,4-thiadiazole (135 mg, 0.87 mmol) was added to a solution of ethyl 4-ethylpiperidine-4-carboxylate hydrochloride (190 mg, 0.87 mmol) and Triethylamine (264 mg, 2.61 mmol) in THF (9 mL) and stirred at rt for 1 h, giving a suspension, which was filtered, and the filtrate concentrated in vacuo to give ethyl 1-(3-chloro-1,2,4-thiadiazol-5-yl)-4-ethylpiperidine-4-carboxylate as a yellow oil (260 mg, 98%). ESI-MI m/z 304.2 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)N)=[CH:6][CH:5]=1.C(O[CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])(=O)CCC(C)=O>C(O)(=O)C>[C:30]([O:32][CH:33]([O:32][C:30](=[O:31])[CH2:29][C:33]1[C:8]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[CH:9]=2)[N:10]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:34]=1[CH3:35])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)(=[O:31])[CH3:29]
Reactant: COc1ccc(N(N)C(=O)c2ccc(Cl)cc2)cc1
Reactant: CC(=O)CCC(=O)OCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c(CC(=O)OC(OC(C)=O)c1ccccc1)c(C)n2C(=O)c1ccc(Cl)cc1

Procedure:
5 g (0.016 mol) of N(1) -(p-methoxyphenyl)-p-chlorobenzhydrazide hydrochloride and 4.75 g (0.018 mol) of benzyl levulinoyloxyacetate were heated in 25ml of glacial acetic acid for 3 hours at 80°C. The solvent was then evaporated off under vacuum, the residue was taken up in chloroform and the solution was washed neutral by shaking with sodium bicarbonate solution and thereafter with water. After drying the chloroform solution, this was subjected to chromatography on aluminium oxide, the eluate was concentrated by evaporation and the viscous oil remaining as residue was crystallised by adding ether. The compound melted at 94°-95°C. The yield was 4.1 g which corresponds to 50.7% of the theoretical yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:41]O)[C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][N:28]([CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]2)=[CH:24][CH:23]=1>CCOC(C)=O>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:20]=[C:21]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][N:28]([CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]4)=[CH:24][CH:23]=3)[N:41]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: CC(C)(C)OC(=O)CCN1CCc2ccc(C(N)=NO)cc2C1
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Solvent: CCOC(C)=O
Product: COCc1cc(-c2nc(-c3ccc4c(c3)CN(CCC(=O)OC(C)(C)C)CC4)no2)ccc1-c1ccccc1C

Procedure:
Title compound was prepared following general procedure 2 starting from Intermediate 14 (154 mg; 0.6 mmol) and Intermediate 25 (182 mg; 0.6 mmol). The reaction mixture was diluted with EtOAc, washed with water and brine and evaporated under vacuum. Purification by silica column chromatography (c-Hex/(DCM/EtOAc 1:1), 90/10 to 50/50) afforded the title compound as a yellow oil. 1H NMR (DMSO-d6) δ 8.32 (d, J=1.6 Hz, 1H), 8.16 (dd, J=8.0, 2.0 Hz, 1H), 7.87 (dd, J=8.0, 1.6 Hz, 1H), 7.82 (d, J=1.4 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.38-7.26 (m, 4H), 7.15 (d, J=7.2 Hz, 1H), 4.25-4.14 (m, 2H), 3.71 (s, 2H), 3.25 (s, 3H), 2.91-2.86 (m, 2H), 2.78-2.70 (m, 4H), 2.53-2.46 (m, 2H), 2.04 (s, 3H), 1.40 (s, 9H). LC/MS (method B): 540.1 (M+H)+. HPLC (Method A) Rt 4.81 min (Purity: 97.4%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1([CH2:20][C:21]2([CH2:34][CH2:35][C:36](OCC)=[O:37])[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[OH:3][CH2:4][CH2:5][CH2:6][C:7]1([CH2:20][C:21]2([CH2:34][CH2:35][CH2:36][OH:37])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28]3[C:33]2=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: CCOC(=O)CCC1(CC2(CCC(=O)OCC)c3ccccc3-c3ccccc32)c2ccccc2-c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCC1(CC2(CCCO)c3ccccc3-c3ccccc32)c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 71.3 %

Procedure:
3-{9-[9-(2-Ethoxycarbonylethyl)-9H-fluoren-9-ylmethyl]-9H-fluoren-9-yl}-propionic acid ethyl ester (9.7 g) was dissolved in 200 mL of THF and treated with lithium aluminum hydride (1.97 g) at 0° C. under an atmosphere of nitrogen. After stirring overnight, the reaction mixture was treated with 2.0 mL of water followed by 2.0 mL of 15% NaOH solution and then 6.0 mL of water. The reaction mixture was filtered through a pad of CELITE, rinsing with ethyl acetate. The filtrate was washed with 1N HCl solution, water (2×) and brine. The organic portion was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a white solid. The white solid was crystallized from toluene to give 5.85 g of the title compound as white crystals. 1H NMR (CDCl3, 500 MHz) δ 7.04 (m, 4H), 6.98 (m, 4H), 6.83-6.77 (m, 4H), 3.19 (t, J=6.4 Hz, 4H), 3.09 (s, 2H), 1.94 (m, 4H), 1.00 (br s, 2H), 0.47 (m, 4H).
Reaction SMILES: Cl.Cl.[CH:3]1([C:9]2[N:10]=[N:11][C:12]([O:28][CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:3]1([C:9]2[N:10]=[N:11][C:12]([O:28][CH:29]3[CH2:30][CH2:31][N:32]([CH3:37])[CH2:33][CH2:34]3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1cc(-c2cc(OC3CCNCC3)nnc2C2CCCCC2)ccc1OC1CCCCC1
Agent: C=O
Agent: Cl
Solvent: ClCCl
Product: CN1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCCCC3)nn2)CC1
Reaction time: 2 h

Procedure:
To a solution of 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.079 mmol, 0.04 g) and aqueous formaldehyde (37%, 0.39 mmol, 0.035 mL) in dry DCM (1 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.47 mmol, 0.20 g). The mixture was shaken for 2 hours. The reaction was placed directly onto a 4 g SiO2 cartridge and the column was eluted with 4-6% (2N NH3 in MeOH) in DCM to give 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (0.5 mL) and DCM (0.5 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.04 g). LCMS: m/z 451 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.63-7.79 (1H, m), 7.38-7.43 (2H, m), 7.10-7.14 (2H, m), 5.33-5.57 (1H, m), 4.40-4.51 (1H, m), 3.66-3.69 (1H, m), 3.11-3.54 (3H, m), 2.94 (3H, s), 2.37-2.62 (2H, m), 2.20-2.30 (1H, m), 1.20-2.17 (22H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[C:27]([Cl:29])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21][CH2:20]3)[C:15]2=[O:26])=[C:11]([Cl:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].N1C=CN=C1>CN(C)C=O.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Cl:30])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:20][CH2:21][C@@H:22]([O:25][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:23][CH2:24]3)[C:15]2=[O:26])=[C:27]([Cl:29])[CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CC[C@@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1

Procedure:
Combine 10.8 g (R)-3-(4-benzyloxy-2,6-dichloro-benzyl)-cis-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one, 5.4 g tert-butyldimethylsilylchloride, and 2.7 g imidazole in 50 mL dry dimethylformamide and stir at ambient temperature over night. Pour into 300 mL brine and extract twice with 200 mL diethyl ether. Wash the combined extracts with brine, dry over magnesium sulfate and concentrate to dryness under vacuum. Purify by silica gel chromatography using 10-15% ethyl acetate in hexanes to recover 11.5 g of the product as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[CH3:21][O:22][C:23](=[O:27])[CH:24](Br)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH:24]([CH3:25])[C:23]([O:22][CH3:21])=[O:27])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)[CH3:2]
Reactant: COC(=O)C(C)Br
Reactant: CCOc1ccc(S(=O)(=O)Nc2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(S(=O)(=O)N(c2ccc(C)cc2)C(C)C(=O)OC)cc1
Temperature: 60 °C

Procedure:
The crude N-aryl-benzenesulfonamide building block XIII, e.g. 4-ethoxy-N-(4-methylphenyl)benzenesulfonamide (204 mg, 0.70 mmol, preparation described in example 1, step a)), was dissolved in DMF (5 mL). Methyl-2-bromopropionate (0.117 mL, 1.05 mmol) and potassium carbonate (193 mg, 1.40 mmol) were added. The mixture was heated overnight at 60° C. Solvents were evaporated. The crude residue was suspended in ethyl acetate (10 mL) and was washed with 1N HCl solution (7 mL) and with brine (7 mL). Organic phase was dried over MgSO4, fltrated and evaporated. The desired product, e.g. methyl 2-{[(4-ethoxyphenyl)sulfonyl]-4-methylanilino}propanoate (276 mg, quantitative crude yield) was isolated as a light yellow oil, in 94.3% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH:19]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].O1CCCC1.[Br:41]N1C(=O)CCC1=O>CO>[C:1]([NH:4][C:5]1[S:6][C:7]([Br:41])=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][CH:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1nc(CCc2ccc(NC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)c(Br)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
Di-tert-butyl {[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate (310 mg) prepared in a similar manner according to Step 5 of the following Production Example 18 was dissolved in methanol (6 ml) and tetrahydrofuran (3 ml) under nitrogen atmosphere. Then N-bromosuccinimide (164 mg) was added to the solution at 0° C. The reaction mixture was stirred at room temperature for 4 hours, and concentrated in vacuo. Chloroform and saturated sodium hydrogen carbonate solution were added to the residue. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with n-hexane/ethyl acetate (2:1) as an eluent to give di-tert-butyl {[(4-{2-[2-(acetylamino)-5-bromo-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate (271.4 mg) as a colorless amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([N+]([O-])=O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].NC1C=CC=CC=1.NC1C=CC(C(OC)=[O:28])=C(Br)C=1.S(=O)(=O)(O)O.N([O-])=O.[Na+]>O>[Br:1][C:2]1[CH:11]=[C:10]([OH:28])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(N)cc1Br
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: Nc1ccccc1
Product: COC(=O)c1ccc(O)cc1Br
Temperature: 90 °C
Reaction time: 5 h

Procedure:
2-Bromo-4-nitrobenzoic acid (6.2 g, 25.3 mmol) was dissolved in MeOH (120 mL), and SOCl2 (5.5 mL, 75.9 mmol) was added dropwise at 0° C. The reaction mixture was refluxed for 6 h. The reaction solvent was concentrated to dryness. Residual SOCl2 was removed by co-evaporation with CH2Cl2 (×3). The solid was dried under vacuum to afford methyl 2-bromo-4-nitrobenzoate in 99.5% (6.52 g) yield as a light yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.50 (1H, s, Ar), 8.21 (1H, d, J=8.4 Hz, Ar), 7.91 (1H, d, J=8.4 Hz, Ar), 3.97 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 165.2, 149.2, 137.9, 131.7, 129.1, 122.1, 122.0, 53.1; MS (ESI) m/z Calcd for C8H6BrNO4 (M+): 259.0, Found: 260.1 (M+H+). Next, the nitro group of methyl 2-bromo-4-nitrobenzoate (6.38 g, 24.6 mmol) was chemoselectively reduced with 5 nCl2.2H2O (27.8 g, 123.2 mmol) in a manner similar to that described for compound 6 to deliver methyl 4-amino-2-bromobenzoate in 96.0% (5.41 g) yield as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 7.74 (1H, d, J=8.8 Hz, Ar), 6.90 (1H, d, J=1.6 Hz, Ar), 6.55 (1H, dd, J=8.8 Hz, 1.6 Hz, Ar), 4.06 (2H, s, NH2), 3.83 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 165.9, 150.4, 133.6, 124.1, 119.7, 119.6, 112.7, 51.8; MS (ESI) m/z Calcd for C8H8BrNO2 (M+): 229.0, Found: 230.1 (M+H+). Finally, a solution of sulfuric acid (98%, 6 mL) in H2O (75 mL) was added to methyl 4-amino-2-bromobenzoate (1.23 g, 5.38 mmol) and the resulting suspension was heated to 90° C., then stirred for 5 h at this temperature. The reaction mixture was cooled to 0° C. and a solution of NaNO2 (384 mg, 5.57 mmol) in H2O (5 mL) was added dropwise, then the reaction was allowed to warm to ambient temperature. The reaction mixture was then added to a solution of sulfuric acid (98%, 6 mL) in H2O (75 mL) that had been preheated to 90° C. The reaction mixture was stirred at 90° C. for 1 h, and then allowed to cool. The reaction mixture was partitioned between EtOAc (200 mL) and aqueous solution. The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (35% EtOAc in hexanes) to afford compound 10 in 41.1% (508 mg) yield as a light brown solid. 1H-NMR (CDCl3, 400 MHz) δ 7.76 (1H, d, J=8.8 Hz, Ar), 7.09 (1H, s, Ar), 6.75 (1H, d, J=8.8 Hz, Ar), 3.84 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 166.2, 160.3, 133.5, 123.4, 122.1, 121.4, 114.3, 52.1; MS (ESI) m/z Calcd for C8H7BrO3 (M+): 230.0, Found: 231.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:26]3[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][CH2:30][CH2:31][C:25]=3[N:24]([CH3:39])[C:23]=2[N:40]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+].[ClH:58]>CS(C)=O.CCOCC.C(Cl)Cl.[Cu]I>[ClH:58].[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]([C:19]2[CH:20]=[CH:21][C:22]3[C:26]4[CH2:27][NH:28][CH2:29][CH2:30][CH2:31][C:25]=4[N:24]([CH3:39])[C:23]=3[N:40]=2)[C:8](=[O:12])[CH:7]=1
Reactant: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CCC2
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cc5F)cc4=O)nc31)CNCCC2
Temperature: 135 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
A suspension of 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (68 mg, 0.29 mmol), tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (120 mg, 0.316 mmol), CuI (65 mg, 0.34 mmol), 8-hydroxyquinoline (8 mg, 0.06 mmol) and Cs2CO3 (103 mg, 0.316 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2 and stirred at 135° C. for 24 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH) afforded a tan residue. 2 N HCl in Et2O (100 mL) was added to a solution of the tan residue in CH2Cl2 (5 mL) under N2, and the resulting suspension was stirred at 25° C. for 2 d. The suspension was filtered, and the solid was washed with Et2O and put in a vacuum oven at 40° C. for 1 h to afford 47 mg (35%) of the title compound as a white powder: 1H NMR (500 MHz, DMSO-d6) δ 8.86 (br s, 2H), 8.16 (d, J=8.5 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.67 (dd, J=15.5, 8.5 Hz, 1H), 7.40-7.34 (m, 2H), 7.18 (ddd, J=8.5, 8.5, 2.5 Hz, 1H), 7.15 (dd, J=8.0, 3.0 Hz, 1H), 6.06 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 4.51-4.45 (m, 2H), 3.77 (s, 3H), 3.60-3.42 (m, 2H), 3.17-3.13 (m, 2H), 2.12-2.05 (m, 2H); ESI MS m/z 437 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH3:31])[C:15]1=[O:32]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][CH:14]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]([CH3:31])[C:15]2=[O:32])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CN1C(=O)C(NC(=O)Cc2cc(F)cc(F)c2)N=C(c2ccccc2)c2ccccc21

Procedure:
Following General Procedure A above using 3,5-difluorophenylacetic acid (Oakwood) and 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-X), the title compound was prepared as a solid having a melting point of 236–239° C. The reaction was monitored by tlc on silica gel (Rf=0.7 in 10% methanol/dichloromethane) and purification was by silica gel chromatography using 10% methanol/dichloromethane as the eluant.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].[OH-].[Na+]>O1CCCC1.O>[CH2:25]([O:24][C:22]([NH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C(N)c1cccc(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)OCc1ccccc1)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a solution of methyl 2-amino-2-(3-(benzyloxy)phenyl)acetate (1.09 g, 4 mmol) in a mixture of tetrahydrofuran and water (1:1, 90 mL) at 0° C. was added benzyl chloroformate (0.57 mL, 4 mmol) and aqueous sodium hydroxide (4 N, 1 mL, 4 mmol) simultaneously. The mixture was stirred at 0° C. for one hour. The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and ethyl acetate (100 mL) and water (30 mL) were added. The layers were separated and the aqueous phase re-extracted with ethyl acetate (2×50 mL). The combined organic fractions were dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate in iso-hexane to afford the title compound (900 mg, 56%) as a brown oil.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[N:9]1[CH:10]=[CH:11][N:12]2[C:17]=1[CH:16]=[C:15]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22])[CH:14]=[N:13]2>CN(C=O)C>[I:1][C:11]1[N:12]2[N:13]=[CH:14][C:15]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:17]2=[N:9][CH:10]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cccc(-c2cnn3ccnc3c2)c1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2cnn3c(I)cnc3c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 50.1 %

Procedure:
N-Iodosuccinimide (280 mg, 1.3 mmol) was added to a mixture of methyl 3-imidazo[1,2-b]pyridazin-7-ylbenzoate (160.0 mg, 0.6318 mmol) in DMF (2 mL) and then the reaction was stirred at r.t. for 6 h. The precipitate formed was filtered and washed with ether to provide the desired product (0.12 g). LCMS (M+H)+: m/z=380.0