Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](B(O)O)=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[CH:16]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][C:38]([O:44][CH3:45])=[CH:39][CH:40]=2)[CH:35]=1)(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C(=CC(=CC=1)C)C)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.O.CC(O)C>[CH3:45][O:44][C:38]1[CH:37]=[C:36]2[C:41]([CH:42]=[CH:43][C:34]([C:18]3[C:17]4[C:12]([C:11]([C:1]5[C:10]6[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=6)[CH:4]=[CH:3][CH:2]=5)=[C:24]5[C:19]=3[CH:20]=[CH:21][CH:22]=[CH:23]5)=[CH:13][CH:14]=[CH:15][CH:16]=4)=[CH:35]2)=[CH:40][CH:39]=1
Reactant: OB(O)c1c2ccccc2c(-c2cccc3ccccc23)c2ccccc12
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(C)c(C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc2ccc(-c3c4ccccc4c(-c4cccc5ccccc45)c4ccccc34)cc2c1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
Under the nitrogen atmosphere, (10-(naphthalen-1-yl)anthracen-9-yl)boronic acid (25.1 g), 7-methoxynaphthalen-2-yl trifluoromethane sulfonate (24.3 g), Pd(PPh3)4 (0.9 g), potassium phosphate (30.6 g), and a mixture solvent (260 ml) of pseudo cumene, IPA, and water (pseudo cumene/IPA/water=8/4/1 (volume ratio)) were added to a flask and refluxed for 4.5 hours. Once the heating is completed, water was added. After cooling to room temperature, a solid was collected by suction filtration. The obtained solid was washed with water and subsequently with methanol, dissolved in toluene, and purified with a silica gel short column. Crystals obtained by slow distillation of the solvent under reduced pressure were collected by suction filtration to give 9-(7-methoxynaphthalen-2-yl)-10-(naphthalen-1-yl)anthracene (17.5 g) as a third intermediate compound. The scheme is shown in the following “Reaction 4”.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].C([O-])(O)=O.[Na+].[CH3:12][C:13]([CH3:19])([CH3:18])[CH2:14][C:15](Cl)=O.[OH-].[Na+].Cl>O>[CH2:14]([C:15]1[NH:6][C:4](=[O:5])[NH:3][N:2]=1)[C:13]([CH3:19])([CH3:18])[CH3:12]
Reactant: NNC(N)=O
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)Cc1n[nH]c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 30.8 %

Procedure:
Semicarbazide hydrochloride (1.50 g, 13.6 mmol) was dissolved in water (15 mL). NaHCO3 (2.40 g, 28.6 mmol) was slowly added to the solution over 30 min at RT followed by the addition of 3,3-dimethylbutyryl chloride (2 g, 14.86 mmol). The mixture was stirred at RT for 12 h followed by the addition of solid NaOH (1.08 g, 27 mmol). The reaction mixture was stirred at 100° C. for 3 h, allowed to cool to RT and stirred for an additional 12 h. The reaction mixture was neutralized by the drop-wise addition of concentrated HCl. The solids were collected by filtration, washed with water, and dried in vacuo to afford 3-neopentyl-1H-1,2,4-triazol-5(4H)-one (0.65 g, 31%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.12 (s, 1H), 11.10 (s, 1H), 2.20 (s, 2H), 0.90 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([OH:14])[CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[C:34]2[C:29](=[N:30][CH:31]=[N:32][C:33]=2[Cl:35])[N:28]([CH3:36])[N:27]=1>>[Cl:35][C:33]1[N:32]=[CH:31][N:30]=[C:29]2[N:28]([CH3:36])[N:27]=[C:26]([CH2:25][O:14][C:12]3[CH:13]=[C:8]([O:7][CH2:6][C:5]4[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:9]=[CH:10][C:11]=3[CH3:15])[C:34]=12
Reactant: Cn1nc(CBr)c2c(Cl)ncnc21
Reactant: Cc1ccc(OCc2ccc(Cl)cc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(OCc2ccc(Cl)cc2)cc1OCc1nn(C)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(4-chloro-benzyloxy)-2-methyl-phenol (95.6 mg, 0.384 mmol) and potassium carbonate (58.2 mg, 0.421 mmole) was stirred at room temperature for 30 minutes before 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (90.1 mg, 0.344 mmole, Example 5) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure to remove dimethylformamide. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product was purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 60/40) to give pure 4-chloro-3-[5-(4-chloro-benzyloxy)-2-methyl-phenoxymethyl]-1-methyl-1H-pyrazolo[3,4-d]pyrimidine as a white solid. (Yield 38.0 mg).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][C:28]=1[N+:29]([O-])=O)[C:10]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23](=[NH:25])[NH2:24])[CH:19]=2)[CH:14]=1)=[O:11].[CH3:32][S:33]([OH:36])(=[O:35])=[O:34].[H][H]>[Pd].CN(C=O)C>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:32][S:33]([OH:36])(=[O:35])=[O:34].[NH2:29][C:28]1[CH:27]=[CH:26][C:9]([C:10]([O:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:23](=[NH:24])[NH2:25])[CH:19]=3)[CH:14]=2)=[O:11])=[CH:8][C:7]=1[CH3:6]
Reactant: Cc1cc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)ccc1N

Procedure:
To 25 ml of DMF (anhydrous), were added 2.2 g of 6-amidino-2-naphthyl 3-methyl-4-nitrobenzoate methanesulfonate, 0.63 g of methanesulfonic acid, and 0.23 g of 10% Pd-C. Into the mixture, while being vigorously stirred, was introduced hydrogen. After removal of Pd-C by filtration, the reaction mixture was mixed with ethyl ether to separate an oily substance which was washed with ether and recrystallized from an ethanol-ethyl ether mixture to obtain 2.8 g of a white to pale brown powder of 6-amidino-2-naphthyl 4-amino-3-methylbenzoate dimethanesulfonate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[O:15][C:14]2[C:9](=[C:10]([OH:16])[CH:11]=[CH:12][CH:13]=2)[O:8]1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>CN(C=O)C.O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1)[N:21]=[CH:20][N:19]=[C:18]2[O:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[O:15][CH2:7][O:8][C:9]=12
Reactant: Oc1cccc2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Potassium carbonate (0.092 g) was added to a solution of 2,3-methylenedioxyphenol (0.067 g) in DMF (3 ml) and the mixture was stirred at ambient temperature for 10 minutes. 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (0.15 g) was added and the mixture was heated to 70° C. for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. There was thus obtained the title compound as a solid (0.16 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 2.3 (m, 2H), 3.15 (m, 2H), 3.35 (m, 2H), 3.55 (d, 1H), 3.7 (t, 2H), 4.0 (s, 3H), 4.05 (m, 2H), 4.35 (t, 2H), 6.05 (s, 2H), 6.95 (m, 3H), 7.5 (s, 1H), 7.6 (s, 1H), 8.7 (s, 1H); Mass Spectrum: M+H+ 440; Elemental Analysis: Found C, 62.66; H, 5.78; N, 9.48; C23H25N3O6 requires C, 62.86; H, 5.73; N, 9.56%.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]=[N+:22]=[N-:23])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:37]([OH:40])[C:38]#[CH:39].CCN(C(C)C)C(C)C>C1COCC1.CCOCC.[Cu]I>[CH2:1]([O:4][C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:39]=[C:38]([CH2:37][OH:40])[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:24])[C:12]=2[C@H:25]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C#CCO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN=[N+]=[N-])nn23)CC1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(Cn4cc(CO)nn4)nn23)CC1
Reaction time: 22 h

Procedure:
To a stirred colorless clear solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.049 g, 0.098 mmol), propargyl alcohol (0.029 ml, 0.490 mmol) and DIEA (0.086 ml, 0.490 mmol) in THF (2 mL) was added CuI (0.037 g, 0.196 mmol) at rt. The resulting turbid yellow reaction mixture stirred for 22 h and diluted with Et2O (50 mL), washed with 1% aq NH4OH (2×10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated to afford (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate as pale yellow paste which was used in the next step without purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1.[Si:27]([O:34][CH2:35][CH2:36][C:37]1[S:41][C:40]([CH:42]=O)=[CH:39][CH:38]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1>[Si:27]([O:34][CH2:35][CH2:36][C:37]1[S:41][C:40]([CH2:42][N:24]2[CH2:25][CH2:26][C:20]3([O:19][CH2:18][CH2:17][N:16]([C:14]([C:12]4[N:13]=[C:9]([CH3:8])[S:10][CH:11]=4)=[O:15])[CH2:21]3)[CH2:22][CH2:23]2)=[CH:39][CH:38]=1)([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:29])[CH3:28]
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4ccc(CCO[Si](C)(C)C(C)(C)C)s4)CC3)C2)cs1

Procedure:
A solution of (2-methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 4, step h) (0.25 g) and 5-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde (example 14, step a) (0.171 g) in NMP (5 mL) with acetic acid (0.036 mL) was treated with sodium triacetoxyborohydride (0.201 g) and the resultant mixture stirred at 20° C. for 18 hours. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution, the organic layer was washed with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.3 g.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH2:28]Br)=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[SH:36].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:4]1[C:5]([CH2:28][S:36][C:32]2[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=2)=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2c(C(C)=O)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: Cn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(C(C)=O)c(CSc3nccn3C)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
A mixture of 3-acetyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (1.5 g), 1-methyl-2-mercaptoimidazole (0.417 g), potassium carbonate (0.495 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried over magnesium sulfate. Evaporation of the solvent gave 3-acetyl-4-(3,4-dimethoxy-phenyl)-6,7-dimethoxy-2-[(1-methylimidazol-2-yl)thiomethyl]-quinoline (1.1 g, 71%). This compound was recrystallized from ethanol to give colorless prisms, mp. 175°-176° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[N:11]([CH3:19])[C:10]=1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)(O)=[O:2].S(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[Cl:28][C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[N:11]([CH3:19])[C:10]=1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[O:2]
Reactant: Cn1c(-c2cccnc2)c(CCCCCC(=O)O)c2cc(Cl)ccc21
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cn1c(-c2cccnc2)c(CCCCCC(=O)Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1.52 g of 3-(5-carboxypentyl)-5-chloro-1-methyl-2-(3-pyridyl)indole in 50 ml of toluene under nitrogen is added dropwise at room temperature 0.31 ml of thionyl chloride. The resulting mixture is heated under reflux for 1 hour. An additional 0.10 ml portion of thionyl chloride is added and the solution is stirred at room temperature overnight. The resulting suspension is evaporated to dryness to give 3-(5-chlorocarbonylpentyl)-5-chloro-1-methyl-2-(3-pyridyl)indole. A suspension of the acid chloride in 20 ml of concentrated ammonium hydroxide is stirred at room temperature overnight. The resulting solid is filtered off to yield 3-(5-carbamoylpentyl)-5-chloro-1-methyl-2-(3-pyridyl)indole.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:28]=[C:27]([F:29])[C:26]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[C:14]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1.[ClH:43]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:43][C:10]1[CH:28]=[C:27]([F:29])[C:26]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[C:14]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
88 mg of isoamyl nitrite was added to a mixture of 0.24 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine, 99 mg of copper(I) chloride, 0.20 g of copper(II) chloride and 2.5 ml of acetonitrile dropwise at room temperature, and the mixture was stirred for 1 hour. This reaction solution was poured into 2% hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.21 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [present compound 7-7].
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].CCN(CC)CC.C(Cl)Cl.[CH:20]1([C:23]#[CH:24])[CH2:22][CH2:21]1>C1COCC1.CCOCC.[Cu]I>[CH:20]1([C:23]#[C:24][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[F:9])[CH2:22][CH2:21]1
Reactant: C#CC1CC1
Reactant: Nc1ccc(I)c(F)c1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: Nc1ccc(C#CC2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.1 %

Procedure:
To a stirred solution of 4-iodo 3-fluoro aniline (2.25 g, 9.49 mmol) in THF (25 ml) at 0° C. to −5° C., CuI (90 mg, 0.47 mmol) and Et3N (3.5 ml, 25.62 mmol) were added. The reaction mixture was deoxygenated by purging with a stream of Argon for 30 minutes at −5° C. Addition of Pd(dppf)Cl2.CH2Cl2 (346 mg, 0.47 mmol) and purging was continued. After 10 minutes, cyclopropyl acetylene (0.72 ml, 8.54 mmol) was added at −5° C. and stirred at room temperature for 16 h. The reaction mixture was diluted with ether (200 mL), filtered through celite pad, washed with ether (2×25 mL). The filtrate was concentrated and the residue purified by column chromatography (100-200 mesh silica gel) using hexane as eluent to afford title compound as pale brown liquid (750 mg, 45%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14]([OH:16])=[O:15])[N:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=[CH:7]2)([O-])=O>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14]([OH:16])=[O:15])[N:10]=[C:9]([C:17]([F:20])([F:18])[F:19])[CH:8]=[CH:7]2
Reactant: O=C(O)c1cc2nc(C(F)(F)F)ccc2cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc2ccc(C(F)(F)F)nc2cc1C(=O)O

Procedure:
6-Nitro-2-trifluoromethyl-quinoline-7-carboxylic acid is hydrogenated in ethanol in the presence of Raney-Ni analogously to the procedure described for example H-18, step g). This gives the title product as yellow crystals. LC/MS: 257 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[C:8]([O:12][C:13](=[O:27])[C@@H:14]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][C:16](O)=[O:17])([CH3:11])([CH3:10])[CH3:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>CN(C=O)C>[C:23]([O:22][C:20]([NH:19][C@@H:14]([CH2:15][C:16]([NH:7][C:4]1[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:17])[C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:27])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: Cn1ccc(N)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(NC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of 1-methyl-1H-pyrazol-3-amine (0.336 g) and (3S)-4-tert-butoxy-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid (1.0 g) in DMF (17.28 mL) were added HATU (1.577 g) and diisopropylethylamine (0.905 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.17 g).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]1[C:14]([CH2:15][C:16]([OH:18])=O)=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:4])#[N:2].[OH2:22].N>>[O:18]=[C:16]1[CH2:15][C:14]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=2[O:8][C:7]2[CH:6]=[C:5]([CH:3]([CH3:4])[C:1]([NH2:2])=[O:22])[CH:21]=[CH:20][C:19]1=2
Reactant: CC(C#N)c1cccc(Oc2ncccc2CC(=O)O)c1
Reactant: O
Agent: N
Product: CC(C(N)=O)c1ccc2c(c1)Oc1ncccc1CC2=O
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The mixture of 1.3 g of 2-[3'-(α-cyanoethyl)-phenoxy]-3-pyridylacetic acid and 30 g of polyphosphoric acid was stirred at 150° C. for 2 hours. After cooling, to this was added ice-water and the mixture was alkalified with 10% ammonia water and extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the oil, which was chromatographed over silica gel, eluted with chloroform/ethanol (50/1), and there was obtained a solid substance. This was recrystallized from methanol to give 250 mg of 2-(5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]oxepin-9-yl)-propionamide as pale yellow powder having a melting point of 89°-90° C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][CH:12]=1)=O.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:4]([C:2]#[N:1])=[C:5]([CH:22]=1)[O:6][C:7]1[CH:8]=[C:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2C(N)=O)c1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2C#N)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
The above amide (490 mg) and triethylamine (0.37 ml) in dichloromethane (10 ml) was treated dropwise with trichloroacetyl chloride (0.16 ml) in dichloromethane (10 ml) with stirring at 0-5° C. After 0.5 h, more trichloroacetyl chloride (0.8 ml) was added and stirring continued for 0.25 h. The reaction mixture was washed with aqueous sodium bicarbonate solution, dilute hydrochloric acid, water, then brine, and dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography (silica gel, dichloromethane as eluent) to give 1,1-dimethylethyl {[3-(5-chloro-2-cyanophenoxy)phenyl]methyl}carbamate (240 mg) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)CBr
Reactant: O=C1c2c(cc(O)c(Cl)c2Cl)CC1c1ccccc1
Product: COC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2

Procedure:
Reaction of 6,7-dichloro-5-hydroxy-2-phenyl-1-indanone with methyl bromoacetate according to the procedure of Example 1, STEP (a), affords the title compound, m.p. 151.5°-153° (from benzenecyclohexane).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([O:13][Si](C(C)(C)C)(C)C)[C:5]=1[CH2:21]Br.[CH3:24][NH2:25].CO.Cl>C1COCC1>[OH:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]2[C:5]=1[CH2:21][N:25]([CH3:24])[C:3]2=[O:2]
Reactant: CN
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(O[Si](C)(C)C(C)(C)C)c1CBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CN1Cc2c(O)ccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
At room temperature, a solution of 2-bromomethyl-3-(tert-butyl-dimethyl-silanyloxy)-6-nitro-benzoic acid methyl ester (12.6 g, 25.1 mmol) in 60 mL of THF is added 2M solution of methylamine in THF (37.7 mL, 75.3 mmol) at 0° C. and then the reaction mixture is stirred for 6 hours at the room temperature. Methanol and 1M Hydrochloric acid solution are added to the reaction mixture. The mixture is evaporated in vacuo and the precipitate is collected to give 4-hydroxy-2-methyl-7-nitro-2,3-dihydro-isoindol-1-one (2.1 g) as yellow solid in 40% yields for 3 steps.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>C1COCC1.O>[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Clc1ccncc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cnccc1Cl
Temperature: 25 °C

Procedure:
To a solution of LDA (1.1 eq) in THF (0.05M) at −78° C. was added 4-chloropyridine (1 eq). After 1.5 h tributyltin chloride (1.5 eq) was added and the reaction mixture was warmed at rt over 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (hexane:EtOAc, 95:5) to afforded the title compound.