Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[CH:25]=[C:26]4[C:32](=[O:33])[N:31]([CH2:34][CH2:35][CH2:36][C:37]#[N:38])[C:30](=[S:39])[N:27]4[C:28]=3[CH:29]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]>COCCOC>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[O:23][C:24]3[CH:25]=[C:26]4[C:32](=[O:33])[N:31]([CH2:34][CH2:35][CH2:36][C:37]5[N:1]=[N:2][NH:3][N:38]=5)[C:30](=[S:39])[N:27]4[C:28]=3[CH:29]=2)=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: N#CCCCN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: O=C1c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C(=S)N1CCCc1nn[nH]n1
Temperature: 25 °C

Procedure:
Sodium azide (76 mg, 1.17 mmol) and triethylamine hydrochloride (161 mg, 1.17 mmol) are added to a solution of Compound 35 (462.5 mg, 1.25 mmol) dissolved in DME (15 ml) and the suspension is refluxed for 48 hours. The mixture is then cooled to room temperature and the solvent is removed under reduced pressure. Water (30 ml) and ethyl acetate (30 ml) are added thereto and the aqueous phase is extracted three more times with ethyl acetate. The combined organic extracts are dried over Na2SO4 and the solvent is evaporated under reduced pressure. The crude product is recrystallized from ethanol to give Compound 36.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]2[O:13][C:14]([CH2:17][N:18]([CH3:20])[CH3:19])=[CH:15][CH:16]=2)=[N:5]S(=O)[N:3]=1.[ClH:22]>CO>[OH2:13].[ClH:22].[ClH:22].[ClH:22].[CH3:20][N:18]([CH2:17][C:14]1[O:13][C:12]([CH2:11][S:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])=[CH:16][CH:15]=1)[CH3:19]
Reactant: CN(C)Cc1ccc(CSCCNC2=NS(=O)N=C2N)o1
Agent: Cl
Solvent: CO
Product: CN(C)Cc1ccc(CSCCNC(=N)C(=N)N)o1
Product: O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52 %

Procedure:
A suspension of 3-amino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide (6.56 g; 20.0 mmoles) [prepared according to published U.K. patent application No. 2,067,987] in 200 mL of methanol was warmed slightly to achieve complete solution, then treated with 13.3 mL of concentrated HCl. After stirring at ambient temperature for 2.5 hours, the solution was concentrated and the residue was triturated with 70 mL of absolute ethanol. The crystals were collected by filtration and dried under vacuum to give 4.3 g (52%) of the title compound, m.p. 166°-169° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[N:13]=[C:12]2[CH3:19])[CH:5]=1.[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:24][C:23]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:22]=3[F:21])[N:13]=[C:12]2[CH3:19])[CH:5]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(O)cc2=O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)cc2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a solution of Intermediate 2 (500 mg, 1.82 mmol) in N,N-dimethylformamide (2 mL) was added 2,4-difluorobenzyl bromide (0.23 mL, 1.82 mmol), potassium carbonate (376 mg, 2.73 mmol) and 18-crown-6 (40 mg). The slurry was stirred at ambient temperature for one hour. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the alkylated product as a white semi-solid (260 mg, 36% yield). MS (M+H): 401
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11]OS(C)(=O)=O)[C:4]=2[CH2:3][CH2:2]1.[C-:17]#[N:18].[Na+]>CS(C)=O.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][C:17]#[N:18])[C:4]=2[CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCCc1cccc2c1CCO2
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCc1cccc2c1CCO2
Yield: 99.8 %

Procedure:
A solution of methanesulfonic acid 2-(2,3-dihydrobenzofuran-4-yl)-ethyl ester (1.71 g) in dimethylsulfoxide (14 ml) was treated with sodium cyanide (381 mg) and heated at 80° for 1 h. The suspension was cooled to 20°, diluted with water (14 ml) and extracted with ethyl acetate (2×17 ml). The combined extracts were washed with 5% aqueous sodium chloride (17 ml), dried (Na2SO4) and the solvent evaporated to give the title compound (1.22 g) as a brown oil which crystallised on standing.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.C(Cl)Cl.C(OCC)(=O)C>[C:15]([NH:14][CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NC1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NC1CCCNC1
Yield: 91198.7 %

Procedure:
A solution 464 mg of 1-(t-butoxycarbonyl)-3-(oleoylamino)piperidine in 6 ml of 50% trifluoroacetic acid-methylene chloride was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off. The residue obtained was dissolved in 20 ml of ethyl acetate. After adding saturated aqueous sodium carbonate solution to the solution to neutralize it, the organic layer was separated. The organic layer was washed with saturated saline, and dried over anhydrous sodium sulfate, followed by removal of the solvent therefrom by evaporation. The residue obtained was purified by silica gel column chromatography to obtain 332 g of the objective compound (yield: 91%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[N:3]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH2:25][CH3:26].O>ClCCl>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH:12]2[CH2:16][CH2:15][N:14]([C:24](=[O:27])[CH2:25][CH3:26])[CH2:13]2)[N:3]=1
Reactant: Cc1nc(OC2CCNC2)ccc1[N+](=O)[O-]
Reactant: CCC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(C)n2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-Methyl-3-nitro-6-(pyrrolidin-3-yloxy)pyridine (1.3 g) was dissolved in dichloromethane (20 ml) and triethylamine (1.57 ml) was added. The solution was cooled to 0° C. and a solution of propionyl chloride (574 mg) in dichloromethane (5 ml) was added dropwise over 5 min. The reaction mixture was allowed to come to room temperature and was stirred for another 5 min. Water (10 ml) was added. After stirring for 3 min, the phases were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane/methanol=98/2). Yield: 950 mg (64.9%, pale yellow oil).
Reaction SMILES: O.[CH3:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH3:11]>C1COCC1.[Pd]>[CH3:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC#CCCCC
Agent: [Pd]
Agent: *O[SiH2]*
Solvent: O
Solvent: C1CCOC1
Product: CCCC/C=C\CCCC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 94 %

Procedure:
To a solution of polysiloxane containing a homogeneous dispersion of palladium particles (0.13 g) prepared as described above in THF and water (0.05 mmol Pd), 5-decyne (0.138 g, 0.18 mL, 1.0 mmol) in a solution of THF (5mL) and water (1 mL) was added. Hydrogen was bubbled through the solution for 30 seconds and the reaction was then placed under a hydrogen atmosphere (balloon). The reaction was stirred at room temperature for 4.5 h. Capillary gas chromatograph analysis showed complete consumption of the alkyne and a 94% yield of Z-5-decene using dodecane as an internal standard. The product was too volatile for an accurate isolated yield. However, a portion was isolated and analyzed spectroscopically. IR (neat) 2925.5, 2850.0 1460.1 cm -1. 1H NMR (300MHz, CDCl3)δ5.33 (br t, J=4.5 Hz, 2H), 2.01 (br q, J=5.6 Hz, 4H), 1.3-1.2 (m, 8H), 0.86 (t, J= 6.8 Hz, 6H) [>12:1 Z/E stereochemistry]. 13C NMR (20 MHz, CDCl3)δ129.87, 30.25, 26.93, 22.25, 13.98.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.Cl.[CH3:30][O:31][NH:32][CH3:33]>CN(C=O)C.C(Cl)Cl>[CH3:30][O:31][N:32]([CH3:33])[C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13]
Reactant: CNOC
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A 250 mL RB flask was charged with quinoline-6-carboxylic acid (5.00 g, 28.9 mmol), DCM (100 ml, 1554 mmol), oxalyl chloride (3.79 ml, 43.3 mmol), and a few drops of DMF and stirred at RT for 2 hours, then concentrated. The residue was taken up in DCM (100 ml, 1554 mmol), cooled to 0° C., then Hunig's Base (17.7 ml, 101 mmol) and N-methoxymethanamine hydrochloride (2.96 g, 30.3 mmol) were added slowly. The mixture was stirred at room temperature for 16 hours (91463-3-1). The mixture was diluted with DCM (200 mL), then washed with water (250 mL), sat. NaHCO3 (250 mL), and brine (250 mL). The organic layer was dried with MgSO4, filtered, and concentrated to give a brown oil, which was purified by MPLC eluting with 2-6% MeOH/DCM to give N-methoxy-N-methylquinoline-6-carboxamide (5.943 g, 95.2% yield) as a brown oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:14]=[C:13]([CH2:15][Br:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(C)cc1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OC(C)=O
Temperature: 25 °C

Procedure:
A solution of methyl 2-acetoxy-4-methylbenzoate (24.5 g, 0.118 mole) in carbon tetrachloride (700 ml) was treated with N-bromosuccinimide (20.96 g, 0.118 mole), benzoyl peroxide (0.5 g, catalytic) and AIBN (0.03 g). The reaction mixture was heated to reflux, held at reflux for 1 hour and then allowed to cool to ambient temperature, filtered and evaporated to give methyl 2-acetoxy-4-bromomethylbenzoate which was used without further purification (34 g, 63% of mixture is desired product).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([N:8]=[C:9]=[O:10])[CH:7]=1.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][NH:18]2>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([NH:8][C:9]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)=[O:10])[CH:7]=1
Reactant: COc1ccc(Cl)cc1N=C=O
Reactant: Nc1cccc2[nH]ccc12
Solvent: ClCCl
Product: COc1ccc(Cl)cc1NC(=O)Nc1cccc2[nH]ccc12
Reaction time: 8 h
Yield: 70 %

Procedure:
A solution of 5-chloro-2-methoxyphenyl isocyanate (Int-4, 5.5 g, 30 mmol) in DCM (20 mL) was added dropwise to the 4-amino-1H-indole in DCM (30 mL) from Step A, and the resulting mixture was stirred overnight, then filtered to give the crude product 1-(5-chloro-2-methoxyphenyl)-3-(1H-indol-4-yl)urea (6.6 g, 70%), which was used directly in the next step without purification.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:12]1=[O:27])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:29])([CH3:28])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:12]1=[O:27])[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2cccc(C(F)(F)F)c2)C1=O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2cccc(C(F)(F)F)c2)C1=O
Yield: 77 %

Procedure:
A solution of Example 140B (0.261 g, 0.623 mmol) in dichloromethane (3 mL) was treated with trifluoroacetic acid (3 mL) at 25° C. for 16 h. The solvents were evaporated, and the crude residue was purified using reverse phase chromatography eluting with 95% water (0.1% trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give the title compound (0.172 g 77%).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([I:20])[CH:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:2].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([I:20])[CH:16]=2)[N:11]=[CH:10][C:9]=1[C:7]([NH:6][CH2:5][CH2:4][N:3]([CH2:21][CH3:22])[CH2:1][CH3:2])=[O:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN(CC)CCNC(=O)c1c[nH]c2ccc(I)cc2c1=O
Product: CCN(CC)CCNC(=O)c1cnc2ccc(I)cc2c1Cl
Temperature: 25 °C
Yield: 76 %

Procedure:
A stirred solution of compound 94 (9.00 g, 21.8 mmol) in phosphorus oxychloride (50 mL) was heated at 100° C. for 20 min. After cooling to room temperature, the solvent was evaporated under vacuum. The residue was poured into crushed ice (100 g). A 10% aqueous sodium hydrogenocarbonate solution (100 mL) and dichloromethane (100 mL) were added successively at 0° C. The mixture was stirred until the brown oil was totally dissolved. The solution was decanted and the aqueous layer was then extracted with dichloromethane (3×200 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under reduced pressure. The residue was chromatographed (Al2O3, AcOEt/cyclohexane, 9/1, v/v) to give compound 95 (7.12 g, 16.5 mmol) as a yellow solid. Yield 76%; Rf (Al2O3, AcOEt/cyclohexane, 9/1, v/v) 0.34; mp 76-78° C.: IR (KBr) ν 1329, 1477, 1558, 1636, 2798, 2966, 3300 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.01 (t, 6H, J=7.1 Hz), 2.58 (q, 4H, J=7.1 Hz), 2.70 (t, 2H, J=5.8 Hz), 3.55 (q, 2H, J=5.8 Hz), 7.39 (se, 1H), 7.73 (d, 1H, J=8.8 Hz), 7.96 (dd, 1H, J=1.8, 8.8 Hz), 8.55 (d, 1H, J=1.8 Hz), 8.93 (s, 1H); MS m/z 433 (M+2, 2), 431 (M+, 6), 417 (3), 415 (8), 317 (6), 315 (20), 289 (2), 287 (6), 189 (6), 161 (9), 128 (5), 99 (6), 86 (100), 72 (6), 56 (13).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[Br:18][CH2:19][C:20](Br)=[O:21].C(N(C(C)C)CC)(C)C>C1COCC1.C(OCC)(=O)C>[Br:18][CH2:19][C:20]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:12]=1)=[O:21]
Reactant: O=C(Br)CBr
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CBr)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.6 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (2 g, 9.04 mmol) in THF (50 mL), bromoacetyl bromide (0.83 mL, 9.5 mmol) was added, followed by diisopropylethylamine (DIEA, 1.8 mL, 10.85 mmol), at room temperature. The reaction mixture was stirred at room temperature for 24 hrs, the slurry was diluted with ethyl acetate and the organic phase was washed with water (50 mL). The insoluble solid was filtered and analysed to afford 2-bromo-N-(3-(quinoxalin-2-yl)phenyl)acetamide (700 mg, 22% yield). The mother liquer was evaporated in vacuo to afford a second batch of 2-bromo-N-(3-(quinoxalin-2-yl)phenyl)acetamide (1.8 g, 58% yield). LCMS calculated for C18H15N3O (M+H): 290.33. found 290.24. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.62 (1H, br.), 9.52 (1H, s), 8.55 (1H, m), 8.12-8.18 (2H, m), 8.05-8.08 (1H, m), 7.80-7.95 (3H, m), 7.55-7.60 (1H, m), 4.12 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[C:21]([C:26]1[CH:36]=[C:35]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])[CH:34]=[CH:33][C:27]=1[O:28][CH2:29][C:30](Cl)=[O:31])([CH2:24][CH3:25])([CH3:23])[CH3:22].O>C(O)(=O)C>[C:21]([C:26]1[CH:36]=[C:35]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])[CH:34]=[CH:33][C:27]=1[O:28][CH2:29][C:30]([NH:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1)=[O:31])([CH2:24][CH3:25])([CH3:23])[CH3:22]
Reactant: Nc1ccc(Nc2cccc(O)c2)cc1
Reactant: CCC(C)(C)c1ccc(OCC(=O)Cl)c(C(C)(C)CC)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC(C)(C)c1ccc(OCC(=O)Nc2ccc(Nc3cccc(O)c3)cc2)c(C(C)(C)CC)c1

Procedure:
To a solution of 11 g (0.055 mol) of 3-(4-aminoanilino)phenol in glacial acetic acid was added 4.6 g of anhydrous sodium acetate. During agitation at room temperature, the mixture was charged with 17.1 g (0.055 mol) of 2,4-di-tert-amylphenoxyacetyl chloride at a temperature below 30° C. After continuing the agitation for an additional 30 minutes at that temperature, the mixture was poured into iced water, and the deposited crystals were filtered, followed by recrystallization with methanol. The yield was 20 g and the melting point was 150°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][N:35]=1>ClCCl.C1(C)C=CC=CC=1>[Cl:33][C:34]1[N:35]=[CH:36][C:37]([NH:40][C:41]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:42])=[CH:38][CH:39]=1
Reactant: O=C=Nc1ccc(Cl)nc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)nc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (74.3 ul, 0.53 mmol) (Aldrich), followed by the addition of solution of 2-chloro-5-isocyanato-pyridine (1.28 mL, 0.26 mmol) in toluene (from Example 66a supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (6-chloro-pyridin-3-yl)-amide as a white solid. (Yield 32 mg, 28.3%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[CH3:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[C:31]([O:38][CH3:39])[CH:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:33]1[CH:34]=[C:29]([CH3:28])[CH:30]=[C:31]([O:38][CH3:39])[CH:32]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: COc1cc(C)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cc(C)cc(OC)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 4-methyl-2-methoxylphenylboronic acid (92 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate and concentrated to yield a yellow oil which was purified by flash column eluted with 30% ethyl acetate in hexane, then recrystallization from ethyl ether to yield 4-(3-methoxy-5-methyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a white powder.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]=[N:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:16]=1[OH:26])([O-])=O.ClC1C(=O)C2C(C(=[O:39])C=1Cl)=CC=CC=2.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>CO>[OH:26][C:16]1[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=1[N:14]1[N+:13]([O-:39])=[C:7]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]2=[N:3]1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: Cc1cc(N=Nc2ccc(Cl)cc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(-n2nc3cc(Cl)ccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
97% sodium hydroxide 9.6 g was added to methanol 100 ml, and was stirred at 65° C. for 30 minutes. After cooling to 50° C., 2-nitro-4-chloro-2'-hydroxy-3'-t-butyl-5'-methylazobenzene 11.6 g was added to the resultant mixture over 30 minutes, and thereafter 2,3-dichloro-1,4-naphthoquinone 0.7 g was added. Glucose 8 g was added to the resultant mixture at 40° to 45° C. over one hour, and the mixture was stirred for one hour at 40° to 45° C. As this result, almost all of the azobenzenes disappeared to produce 2-(2'-hydroxy-3'-t-butyl-5'-methylphenyl)-5-chlorobenzotriazole-N-oxide, thus the reaction of Process (b) being completed.
Reaction SMILES: [CH2:1]1[CH:3]2[CH2:4][C:5]3[C:6]([O:11][C:12]4[N:13]=[N:14][C:15]([Cl:19])=[CH:16][C:17]=4Cl)=[CH:7][CH:8]=[CH:9][C:10]=3[CH:2]12.[OH-:20].[Na+]>CS(C)=O>[CH2:1]1[CH:3]2[CH2:4][C:5]3[C:6]([O:11][C:12]4[N:13]=[N:14][C:15]([Cl:19])=[CH:16][C:17]=4[OH:20])=[CH:7][CH:8]=[CH:9][C:10]=3[CH:2]12
Reactant: Clc1cc(Cl)c(Oc2cccc3c2CC2CC32)nn1
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Oc1cc(Cl)nnc1Oc1cccc2c1CC1CC21
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
In dimethylsulfoxide (3 mL) was dissolved 32.6 mg (0.111 mmol) of 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yloxy)-4,6-dichloropyridazine obtained in Example 14(8), and 0.1 mL (0.2 mmol) of 2 mol/L aqueous sodium hydroxide solution was added to the solution and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice-cold 1 mol/L aqueous sodium hydroxide solution, and washed with ethyl acetate. The aqueous layer was separated, conc. hydrochloric acid was added thereto to adjust pH to 4 in an ice bath, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, dried over sodium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, 1 plate was used, developed by chloroform:methanol=10:1) to obtain 13.4 mg (0.0487 mmol, Yield: 43.9%) of 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yloxy)-6-chloro-4-pyridazinol (Compound No. 516).