Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16][C:17]1[C:26]([O:27][CH:28]([C:36]([O:38][CH3:39])=[O:37])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([CH2:40][NH3+:41])=[CH:22]2.[Cl-].C(N(CC)CC)C>C(Cl)Cl>[CH3:39][O:38][C:36](=[O:37])[CH:28]([O:27][C:26]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:40][NH:41][C:11](=[O:12])[C:10]3[CH:14]=[CH:15][C:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)[CH:22]=2)[C:17]=1[Br:16])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(C[NH3+])ccc2c1Br
Reactant: O=C(Cl)c1ccc(C2CCCCC2)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(CNC(=O)c3ccc(C4CCCCC4)cc3)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
4-Cyclohexyl-benzoyl chloride (0.67 mmol) was added under nitrogen to a suspension of 5-bromo-6-(1-methoxycarbonyl-2-phenyl-ethoxy)-naphthalen-2-ylmethyl-ammonium; chloride (0.30 g, 0.67 mmol), prepared in step 3 of Example 53, in 20 mL of methylene chloride at room temperature. Triethylamine (0.186 mL, 1.33 mmol) was then added to the mixture. After the addition the reaction was stirred at room temperature for 18 h (overnight). The reaction was diluted with methylene chloride, extracted one time with 1N HCl and two times with 5% NaHCO3. The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure to give 2-{1-bromo-6-[(4-cyclohexyl-benzoylamino)-methyl]-naphthalen-2-yloxyl}-3-phenyl-propionic acid methyl ester (0.3362 g, 84%) as an off-white solid, mp 160-161° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12]([C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:11][N:10]([CH3:31])[C:5]2=[C:6]([O:8][CH3:9])[N:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.O>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[O:22][C:14]1[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=1[C:12]1[C:4]2[C:5](=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:40]3[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=3)[CH:3]=2)[N:10]([CH3:31])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1nc(Br)cc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Yield: 73.8 %

Procedure:
A mixture of Example 182B (238 mg, 0.485 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (150 mg, 0.485 mmol), phenylallylchloro[1,3-bis(diisopropylphenyl)-2-imidazol-2-ylidene]palladium(II) (31.4 mg, 0.048 mmol) and potassium phosphate (309 mg, 1.454 mmol) in 9 mL tetrahydrofuran and 3 mL water was heated at 60° C. for 3 hours. Water was added, extracted with ethyl acetate (3×), washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel with a gradient of 0-50% ethyl acetate in heptanes to give the title compound (212 mg, 0.358 mmol, 73.8% yield) as a yellow solid.
Reaction SMILES: [I-:1].[Na+].Cl[C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[CH2:10][N:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][C:5]=12>C(#N)C>[I:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[CH2:10][N:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][C:5]=12
Reactant: [I-]
Reactant: CCOC(=O)N1Cc2nccc(Cl)c2C1
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)N1Cc2nccc(I)c2C1

Procedure:
Sodium iodide (3.93 g, 26.2 mmol) and Ex 11-Step 1 product, hydrochloride salt (step 1, 2.30 g, 8.74 mmol) in acetonitrile (20 mL) were refluxed for 3 days. The reaction mixture was cooled, concentrated and partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The phases were separated and the aqueous phase was re-extracted twice with CH2Cl2 (total volume 750 mL). The solution was passed through a plug of silica gel (0.5″) layered with celite (0.5″) using 1:1 EtOAc/CH2Cl2 for elution to yield 1.98 g (71%) of Ex 11-Step 2 product as a brown solid: 1H NMR shows a ˜1:1 mixture of rotamers (400 MHz, CDCl3) δ 8.08-8.11 (overlapping doublets, 1H total), 7.61 (br d, J=5.3, 1H), 4.89/4.84 (br singlets, 2H total), 4.68/4.64 (br singlets, 2H total), 4.23-4.29 (overlapping quartets, 2H total), 1.32-1.37 (overlapping triplets, 3H total).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][OH:11])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[NH4+].[OH-].[CH3:23][N:24](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:5]1[CH:6]=[CH:7][C:2]([C:23]#[N:24])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18]
Reactant: CN(C)C=O
Reactant: OCCN(CC(F)(F)F)c1ccc(Br)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [NH4+]
Product: N#Cc1ccc(N(CCO)CC(F)(F)F)c(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
A mixture of 2-[[4-bromo-2-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]ethanol (0.699 g, 1.92 mmol) and Zn(CN)2 (0.157 g, 1.34 mmol) in DMF (5 mL) was sparged with N2 for 15 min at rt and Pd(PPh3)4 (0.111 g, 0.096 mmol) was added in one portion, taking care not to allow air into the reaction flask. The mixture was heated to 80° C. under N2 for 40 min, cooled, poured into dilute NH4OH, and the whole was extracted with Et2O (×3). The combined organic portions were washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.571 g of the title compound as a colorless gum: 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J=1.6 Hz, 1H), 7.82 (dd, J=8.4, 1.8 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 3.86 (q, J=8.9 Hz, 2H), 3.69 (t, J=2H), 3.50 (t, J=5.2 Hz, 2H), 1.74 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH:19]([O:26]S(C)(=O)=O)[C:18]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[CH2:31]([O-])C.[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH:19]([O:26][CH3:31])[C:18]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: CC[O-]
Reactant: COc1cc(Nc2ncc3c(n2)C(OS(C)(=O)=O)CCC3)ccc1-n1cnc(C)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(Nc2ncc3c(n2)C(OC)CCC3)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 31.5 %

Procedure:
To a solution of methanesulfonic acid 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-5,6,7,8-tetrahydro-quinazolin-8-yl ester (86 mg, 0.2 mmol) in methanol (2 mL) was added sodium ethanolate (17 mg, 0.3 mmol). The reaction was stirred at room temperature over night under nitrogen, heated to reflux for 1 hour. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified by reversed phase preparative HPLC using a mixture of water containing formic acid and acetonitrile to yield the title compound (23 mg, 28%) as a yellow gum. MS ISP (m/e): 366.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.35 (s, 1H), 8.26 (s, 1H), 7.85 (d, 1H), 7.75 (s, 1H), 7.16 (d, 1H), 7.09 (d, 1H), 6.88 (s, 1H), 4.19 (t, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 2.55-2.80 (m, 2H), 2.33 (s, 3H), 2.15 (m, 1H), 1.72-2.05 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH2:29][O:30][CH3:31])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:36]=[N+:37]=[N-:38])(C)C.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.CO.C(Cl)Cl.O>[CH3:31][O:30][CH2:29][C:17]1[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:38][N:37]=[N:36][N:2]=3)=[CH:10][CH:11]=2)[C:20]2[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1
Reactant: COCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: COCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A mixture of methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methoxymethylbenzimidazole-7-carboxylate (0.4 g) and trimethyltin azide (1.0 g) in toluene (10 ml) was refluxed for 49 hours. The reaction solution was concentrated to dryness to give a residue and the residue was dissolved in methanol (6 ml) and 1N-HCl (6 ml). The solution was allowed to stir for 3 hours and concentrated to dryness to give a residue. The residue was dissolved in CH2Cl2 -H2O and the mixture was made neutral with 1N-NaOH. The organic layer was washed with H2O, dried and concentrated to dryness to give a residue, which was purified by column chromatography on silica gel to give a crystalline product. Recrystallization from ethyl acetate-isopropylether gave colorless needles (0.3 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[C:12]([Br:13])=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]>Cl.C(O)C.[Cl-].[Na+].O.[Fe]>[Cl:1][C:2]1[C:12]([Br:13])=[CH:11][C:10]([NH2:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cc(Br)c1Cl
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(N)cc(Br)c1Cl
Temperature: 80 °C
Yield: 88.5 %

Procedure:
2.25 kg (7.3 mol) of ethyl 2-chloro-3-bromo-5-nitrobenzoate was dissolved in a mixture comprising 4000 ml of concentrated hydrochloric acid and 4000 ml of ethanol. 1 kg of powdered iron was added to the obtained solution in portions so as to maintain the bulk temperature at 80° C. The reaction mixture was cooled, followed by the addition of a saturated brine. The resulting mixture was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to give 1.8 kg of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=O)[O:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[C:4]([F:19])[CH:3]=1.[CH3:20][NH2:21].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:10])[N:21]([CH3:20])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[C:4]([F:19])[CH:3]=1
Reactant: CN
Reactant: O=c1oc(C(F)(F)F)ccc1-c1ccc(Cl)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Product: Cn1c(C(F)(F)F)ccc(-c2ccc(Cl)cc2F)c1=O
Reaction time: 2 h

Procedure:
9.3 g (32 mmol) of 3-(4-chloro-2-fluorophenyl)-6-trifluoromethyl-2H-pyran-2-one was added to 160 ml of methanol, and 3.8 g (48 mmol) of a 40% methylamine/methanol solution was dropwise added under cooling with ice, followed by stirring for 2 hours under cooling with ice. This reaction solution was acidified by an addition of a 10% citric acid aqueous solution and then extracted with ethyl acetate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The obtained residue was dissolved in 160 ml of toluene, and 0.4 g (2.1 mmol) of p-toluenesulfonic acid was added thereto, followed by refluxing for 4 hours. After cooling, the reaction solution was washed with water. Then, the organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain 5.7 g (19 mmol) of the desired product. Melting point: 103-104° C.
Reaction SMILES: [CH3:1][C:2]1([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[C:10](=[O:11])[C:9]2[C:4](=[CH:5][C:6]([OH:14])=[C:7]([Cl:13])[C:8]=2[Cl:12])[C:3]1=[O:15].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31]CC)=[O:30].[OH-].[Na+].Cl>CN(C)C=O.O>[O:15]=[C:3]1[C:4]2[C:9](=[C:8]([Cl:12])[C:7]([Cl:13])=[C:6]([O:14][CH2:28][C:29]([OH:31])=[O:30])[CH:5]=2)[C:10](=[O:11])[C:2]1([CH3:1])[C:16]1[S:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CBr
Reactant: CC1(c2cccs2)C(=O)c2cc(O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2cccs2)C(=O)c2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 100 °C

Procedure:
A stirred mixture of 2-methyl-2-(2-thienyl)-4,5-dichloro-6-hydroxyindan-1,3-dione (3.26 g., 0.01 mole), potassium carbonate (2.77 g., 0.02 mole) and ethyl bromoacetate (3.34 g., 0.02 mole) in dimethylformamide (40 ml.) is warmed at 55°-60°C. for 2 hrs., then treated with water (40 ml.) and 10N sodium hydroxide solution (4 ml., 0.04 mole) and heated at 100°C. for 1 hr. The reaction mixture is added slowly to crushed ice-water (700 ml.)-12N hydrochloric acid (10 ml.) to precipitate [1,3-dioxo-2-methyl-2-(2-thienyl)-4,5-dichloro-6-indanyloxy]acetic acid.
Reaction SMILES: C(O[C:6]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])=O)(C)(C)C.[CH3:20][C@:21]12[C:27]([CH3:29])([CH3:28])[C@H:24]([CH2:25][CH2:26]1)[CH:23]([C:30](Cl)=[O:31])C2=O.N1C=CC=CC=1.Cl>ClCCCl.O1CCOCC1.C(O)(=O)C>[F:19][C:16]([F:17])([F:18])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:9]1[C:30](=[O:31])[C:23]2[C@@H:24]3[C:27]([CH3:29])([CH3:28])[C@@:21]([CH3:20])([CH2:26][CH2:25]3)[C:6]=2[NH:8]1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CC(C)(C)OC(=O)NNc1ccccc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3C(F)(F)F)c(=O)c12
Temperature: 50 °C
Yield: 46.6 %

Procedure:
N′-(2-Trifluoromethyl-phenyl)-hydrazinecarboxylic acid tert-butyl ester (1.85 g, 6.6 mmol) was added in one portion to a ice-bath-cooled solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 1.09 g, 5.1 mmol) in a mixture of 1,2-dichloroethane (12 mL) and pyridine (0.6 mL, 7.6 mmol). The mixture was diluted with 1,2-dichloroethane (6 mL) to facilitate stirring. The reaction mixture was heated at 50° C. for 1 h, then cooled to room temperature. A 4 M solution of HCl in dioxane (3.6 mL) was added via the condenser and the solution was stirred for several minutes. Glacial acetic acid (7 mL) was added and the reaction mixture was heated in an oil bath at ˜100° C. for 2 h. The reaction mixture was stirred overnight at room temperature and then evaporated. Dichloromethane was added and the solution was washed twice with brine. The aqueous washes were back-extracted with dichloromethane, and the combined organic layers were washed with brine, dried (magnesium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an Analytical Sales Aspire 120 g column, eluting with 0-40% ethyl acetate/hexanes to give (4S,7R)-2-(2-trifluoromethyl-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (0.80 g, 46%) as a light brown solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.O1CCCC1.C(OCC)(=O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=3)[N:7]=2)=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26]
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 3 h
Yield: 51.8 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (656 mg, 2.00 mmol), 4-amino-3-nitrophenol (616 mg, 4.00 mmol), potassium carbonate (411 mg, 3.00 mmol) and N,N-dimethylformamide (6.0 mL) was stirred at 150° C. for 3 hr. After allowing the reaction mixture to cool to room temperature, ethyl acetate (100 mL), tetrahydrofuran (40 mL) and water (40 mL) were added to the mixture, and the insoluble material was filtered through celite. The organic layer was collected from the filtrate, washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, and filtrated. Dichloromethane (20 mL) was added to the residue, and the precipitate was collected by filtration to give the title compound (367 mg, 52%). The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/19→ethyl acetate alone) to give the title compound (125 mg, 18%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1>CN(C)C=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:9]2[CH2:10][CH2:11][N:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[C:8]2=[O:12])=[CH:25][CH:26]=1
Reactant: Clc1ccc(OCCCCCCCBr)cc1
Reactant: O=C1NCCN1c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCCCCOc2ccc(Cl)cc2)CCN1c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-pyridyl)-2-imidazolidinone (0.10 g, 0.62 mmol) dissolved in 10 mL dimethylformamide cooled in an ice bath was added NaH (60% dispersion in mineral oil, 27.2 mg, 0.68 mmol). The mixture was stirred at room temperature for 30 minutes then cooled in ice bath again. 1-Bromo-7-(4-chlorophenoxy)heptane (0.19 g, 0.62 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with methanol, and the solvent was removed under reduced pressure. 5 mL of saturated aqueous NH4Cl solution and 10 mL dichloromethane were successively added to the residue. The dichloromethane layer was separated and dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 2) as a white solid (0.15 g, 62%).
Reaction SMILES: [Mg].[CH3:2]I.CN(OC)[C:6]([C:8]1[C:16]2[S:15][N:14]=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:7].Cl>C(OCC)C.BrBr.O1CCCC1>[C:6]([C:8]1[C:16]2[S:15][N:14]=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)(=[O:7])[CH3:2]
Reactant: CON(C)C(=O)c1cccc2nnsc12
Reactant: CI
Agent: BrBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cccc2nnsc12
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
0.59 g of magnesium turnings in 3 ml of diethyl ether are activated with 1 drop of bromine, and a solution of 1.5 ml of methyl iodide in 5.5 ml of diethyl ether is added dropwise with stirring. When the exothermic reaction has subsided, the mixture is heated and kept for a further 1.5 hours at bath temperature 55° C. The resulting solution is added dropwise under a nitrogen atmosphere and with stirring at -10° C. to the initially introduced solution of 4.9 g of N-methyl-N-methoxybenzo-1,2,3-thiadiazole-7-carboxamide in 150 ml of absolute tetrahydrofuran. After stirring has been continued for 1 hour at -10° C., the mixture is heated and refluxed at bath temperature 75° C. for 6 hours. The reaction mixture is then cooled, poured into ice-water, acidified with 2 N hydrochloric acid and extracted several times using ethyl acetate. The extracts are washed with water, dried over sodium sulfate and evaporated. The residue is purified on silica gel (CHCl3), giving the title compound of m.p. 126°-127° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][C:17]#[N:18])=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][C:17]#[N:18])=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CC#N)c2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(Cl)cc(CC#N)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a solution of 0.30 g (0.8 mmol) of 5-chloro-7-cyanomethyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in CH2Cl2 (8 ml) at RT was added 2 ml of TFA. The reaction mixture was stirred at RT for one hour and concentrated under vacuo The crude was taken up in EtOAc and neutralized with aqueous NaHCO3. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Preparative HPLC (30% CH3CN/H2O) afforded 81 mg (35%) of 5-chloro-7-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=[C:7]([CH3:9])[CH:8]=1)=O.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.ClC(Cl)C.C([O-])(O)=O.[Na+]>[C:18]([N:21]1[CH2:26][CH2:25][N:24]([CH2:1][C:3]2[CH:4]=[C:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=[C:7]([CH3:9])[CH:8]=2)[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1cc(C=O)cc(NC(=O)OC(C)(C)C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)N1CCN(Cc2cc(C)cc(NC(=O)OC(C)(C)C)c2)CC1

Procedure:
To a solution of tert-butyl 3-formyl-5-methylphenylcarbamate (200 mg, 0.85 mmol) and acetylpiperazine (131 mg, 1.02 mmol) in 0.1 mL HOAc and 4 mL dichloroethane was added NaBH(OAc)3 (216 mg, 1.02 mmol) at room temperature. After 2 hours additional acetylpiperazine (131 mg, 1.02 mmol) and NaBH(OAc)3 (216 mg, 1.02 mmol) were added. After 2 hours the mixture was diluted with saturated NaHCO3. The layers were separated and the aqueous extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (5% MeOH/CH2Cl2) gave tert-butyl 3-[(4-acetylpiperazin-1-yl)methyl]-5-methylphenylcarbamate as a white foam:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=2)[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:6]1=[O:27].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH3:36][NH:37][CH3:38]>C(#N)C.C1COCC1>[CH3:36][N:37]([CH3:38])[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=2)[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:6]1=[O:27]
Reactant: CNC
Reactant: COc1ccc(CN2C(=O)C(CCCCl)Cc3cc([N+](=O)[O-])ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(CCCN(C)C)Cc3cc([N+](=O)[O-])ccc32)cc1
Temperature: 80 °C

Procedure:
A suspension of 3-(3-chloropropyl)-1-(4-methoxybenzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (120 mg, 0.31 mmol), sodium iodide (47 mg, 0.31 mmol) and potassium carbonate in 3 mL acetonitrile was treated with dimethylamine in THF (0.3 mL of a 2M solution, 0.62 mmol). The mixture was heated at 80° C. in a sealed tube for 22 hours. The reaction was cooled to room temperature then filtered through a pad of celite. The filter pad was rinsed with methanol and the filtrate was concentrated to give a brown residue which was used without further purification. Yield: 115 mg (93.5%). 1H-NMR (CDCl3) δ: 8.07 (d, J=2.4 Hz, 1H), 8.00 (dd, J=2.7, 9 Hz, 1H), 7.11-7.08 (m, 2H), 6.98 (d, J=9.0 Hz, 1H), 6.87-6.84 (m, 2H), 5.15 (dd, J=4.2, 20.4 Hz, 2H), 3.76 (s, 3H), 3.15 (dd, J=5.4, 15.6 Hz, 1H), 2.95-2.87 (m, 4H), 2.48 (s, 6H), 1.92-1.61 (m, 4H).