Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([NH:31][CH:32]=[O:33])[CH:28]=[CH:29][CH:30]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(OCC)(=O)C.O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([C:25]2[CH:26]=[C:27]([NH:31][CH:32]=[O:33])[CH:28]=[CH:29][CH:30]=2)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: CC1(C)OB(c2cccc(NC=O)c2)OC1(C)C
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2nc(Cl)nc(-c3cccc(NC=O)c3)c2cc1OC
Temperature: 60 °C
Reaction time: 6 h
Yield: 25.1 %

Procedure:
To a mixture of 2.00 g (7.72 mmol) of 2,4-dichloro-6,7-dimethoxyquinazoline, 2.38 g (9.26 mmol) of N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]formamide, tetrahydrofuran (50 mL), and 2 M aqueous sodium carbonate solution (10 mL) were added palladium acetate (17.7 mg) and 1,1′-bis(diphenylphosphino)ferrocene (42.8 mg) in this order, and the mixture was stirred at 60° C. for 6 hours. The mixture was allowed to cool, then 5% w/w sodium chloride solution (50 mL) and ethyl acetate (50 mL) were added followed by stirring for 5 minutes, and the insoluble matter was collected by filtration. The filtrate was transferred to a separatory funnel to extract the organic layer. The organic layer was washed twice with 5% w/w sodium chloride solution (50 mL) and then concentrated under reduced pressure. To the concentration residue were added 2-propanol (15 mL) and ethyl acetate (10 mL), and the mixture was suspended by stirring at 50° C. for 2 hours. The suspension was allowed to cool, and then the precipitated crystals were collected by filtration and dried to give 667 mg of a target product. Meanwhile, the insoluble matter collected by filtration was dissolved in a mixed solution of dichloromethane/methanol (300 mL/100 mL), the mixture was filtered to remove the insoluble matter, and the filtrate was concentrated under reduced pressure. To the concentration residue were added 2-propanol (15 mL) and ethyl acetate (10 mL), and the mixture was suspended by stirring at 50° C. for 2 hours. The mixture was allowed to cool, and then the precipitated crystals were collected by filtration and dried to give 1.78 g of a target product. A total of 2.45 g was yielded, and the yield was 91.3%.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[N+:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=O)([O-:8])=[O:7].C(O)C>O>[N+:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=[N:2][OH:3])([O-:8])=[O:7]
Reactant: NO
Reactant: O=C1CCOc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C(=NO)CCO2
Reaction time: 0.42 h

Procedure:
A solution of 79 g (1.14 mole) of hydroxylamine hydrochloride in 770 ml of H2O, contained in a 2 l. Erlenmeyer flask, was treated with 619 ml of 10% NaOH, 150 g (0.78 mole) of 6-nitro-4-chromanone and enough ethanol (750 ml) to produce a solution at the boiling point. The reaction mixture was boiled for 25 min., cooled to 50° over 2 hrs., and filtered. The filtrate was refrigerated overnight and filtered. The tan crystalline solid was washed with 200 ml of ethanol and dried, m.p. 173°-178°. Yield: 60 g (37%).
Reaction SMILES: Cl.[N:2]1([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH2:27][C:28](O)=[O:29])=[C:21]([N+:31]([O-:33])=[O:32])[CH:20]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl>[S:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([N:2]2[CH2:7][CH2:6][N:5]([C:28](=[O:29])[CH2:27][C:22]3[CH:23]=[C:24]([O:25][CH3:26])[C:19]([O:18][CH3:17])=[CH:20][C:21]=3[N+:31]([O-:33])=[O:32])[CH2:4][CH2:3]2)=[N:9]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: COc1cc(CC(=O)O)c([N+](=O)[O-])cc1OC
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)N2CCN(c3nsc4ccccc34)CC2)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
3-piperazin-1-yl-benzoisothiazole hydrochloride (5.29 g, 20.7 mmol) and 4,5-dimethoxy-2-nitrophenylacetic acid (5 g, 20.7 mmol) were combined in 200 mL methylene chloride with triethylamine (5.77 mL, 41.4 mmol). This solution stirred for 15 min before bis-(2-oxo-3-oxazolidinyl) phosphinic chloride (5.26 g, 20.7 mmol) was added. After stirring overnight at rt, the reaction was quenched with water and extracted into methylene chloride. The organic layer was washed with 0.5 N HCl, water, sodium bicarbonate then water before it was dried over Na2SO4 and concentrated. The residue was taken up in methylene chloride and washed with water. The organic layer was dried over sodium sulfate, and concentrated then purified by MPLC using a Biotage prepacked silica gel cartridge eluting with 3% methanol in methylene chloride to afford 6.5 g of a tan solid. Yield 71%; 100% purity at 214 nm; LCMS (APCI): 443 [M+H]+; mp 170° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14]C)=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(F)c(F)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: COC(C)(C)C
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(F)c(F)c1
Yield: 98.6 %

Procedure:
Dimethyl 2-(3,4-difluorobenzyl)piperidine-1,4-dicarboxylate (7.010 g, 21.42 mmol) was dissolved in acetonitrile (75 mL) and water (1.5 mL). Lithium bromide (14.88 g, 171.33 mmol) and triethylamine (11.87 mL, 85.66 mmol) were added and the resulting yellow suspension was heated at reflux for 3 h. Water (100 mL) and MTBE (300 mL) were added. The organic phase was extracted with water (×2). The pooled aqueous layer was acidified to pH 1 with 3.8 M HCl and then extracted with MTBE (×2). The combined organic layer was washed with water, dried over Na2SO4, filtered and evaporated to yield 2-(3,4-difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (6.62 g, 99%) as a yellow solid. MS m/z 314 (M+H)+
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]3[CH:17]=[N:18][C:19]([C:20](OCC)=[O:21])=[C:9]3[N:8]=2)[CH2:3][CH2:2]1.[CH:25]1([C:28](=[N:30]O)[NH2:29])[CH2:27][CH2:26]1.[H-].[Na+].C(O)(=O)C>CN(C=O)C.ClCCl>[CH:25]1([C:28]2[N:30]=[C:20]([C:19]3[N:18]=[CH:17][N:10]4[C:11]5[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[N:8][C:9]=34)[O:21][N:29]=2)[CH2:27][CH2:26]1
Reactant: NC(=NO)C1CC1
Reactant: CCOC(=O)c1ncn2c1nc(N1CCOCC1)c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc2c(c1)c(N1CCOCC1)nc1c(-c3nc(C4CC4)no3)ncn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A mixture of ethyl 5-morpholino-imidazo[1,5-a]quinazoline-3-carboxylate (2.5 g, 7.7 mmol), cyclopropanecarboxamide oxime (3.8 g), crushed 4 Å molecular sieves (7.5 g), and sodium hydride (0.3 g, 60% in mineral oil, 7.7 mmol) in 50 ml of dry DMF was stirred at room temperature for 1 h. Glacial acetic acid (2 ml) and dichloromethane (75 ml) was added, and the mixture was filtered through celite. The filtrate was evaporated and the residue was triturated with water (100 ml). Pale yellow crystals precipitated and was collected by filtration and dried to give 2.3 g of the title compound, m.p. 189°-191° C. A pure product was obtained by recrystallization from CH2Cl2 /ethyl acetate; yield 1.9 g (69%), m.p. 197°-198° C. (Compound 19).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:21](Cl)[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=O)=[CH:15][CH:14]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)C(Cl)c2ccc(OC)cc2)cc1
Reactant: NC(=S)c1ccc(Br)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(-c3ccc(Br)cc3)sc2-c2ccc(OC)cc2)cc1
Temperature: 100 °C
Yield: 57 %

Procedure:
Fifty ml. of dioxane was used to dissolve 7.43 g. (0.034 mole) of 4-bromothiobenzamide with heating to about 60° C. Then 10.0 g. (0.034 mole) of 4,4'-dimethoxydesyl chloride in 50 ml. of dioxane was added and the mixture was heated to 100° C. for two hours. The mixture was cooled and acidified with 1 N hydrochloric acid. Most of the dioxane was removed in vacuo and the solid formed was filtered. The solid was purified by silica gel chromatography (400 g.), using benzene as the eluting agent. The product had a melting point of about 155°-157° C. and weighed 8.83 g. (57% yield). The mass spectrum showed the expected molecular ions at m/e=451 and 453.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(N(CC)CC)C.ClC(OCC)=O.[CH2:22]([NH:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>CC(C)=O>[CH2:22]([N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[C:1](=[O:8])[CH2:2][CH2:3][C:4](=[O:5])[CH3:6])[CH2:23][CH2:24][CH3:25]
Reactant: CC(=O)CCC(=O)O
Reactant: CCCCNCCCC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCN(CCCC)C(=O)CCC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
A! A solution of 100 g (0.86 mole) of levulinic acid in 1 l of acetone was added with 118 ml (0.86 mole) of triethylamine, and stirred for 15 minutes at room temperature. The mixture was cooled to 5° C. and added with a solution of ethyl chloroformate (83.3 ml, 0.86 mole) in 500 ml of acetone, then stirred for 15 minutes. The solid was filtered off and the mother liquor was added to a solution of dibutylamine (180 ml, 1 mole) in 1 l of acetone, then stirred overnight at room temperature, evaporated to dryness under vacuum, and the residue was dissolved in 1 l of ethyl ether, washed with 400 ml of 0.5N HCl, then with 400 ml of 0.5N sodium hydroxide. The ether phase was anhydrified over sodium sulfate and evaporated to dryness thus providing 175.5 g of a crude which by distillation under vacuum gave 112.5 g (yield: 57%) of N,N-dibutyl-4-oxo-pentanamide (b.p. 135°-138° C./1 mmHg).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:22])([CH3:21])[CH2:7][N:8]2[Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[F:23].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](F)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:23][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[S:32]([C:29]1[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=1)(=[O:34])=[O:33])[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH2:7][C:6]2([CH3:22])[CH3:21]
Reactant: COc1ccc(S(=O)(=O)F)cc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)N1CC(C)(C)c2cc(F)c(Br)cc21
Product: COc1ccc(S(=O)(=O)c2cc3c(cc2F)C(C)(C)CN3[Si](C(C)C)(C(C)C)C(C)C)cc1
Yield: 54.9 %

Procedure:
The title compound was prepared starting from 6-bromo-5-fluoro-3,3-dimethyl-1-triisopropylsilanyl-2,3-dihydro-1H-indole (400 mg, 1.0 mmol) and 4-methoxy-benzenesulfonyl fluoride (190 mg, 1.0 mmol) following similar methods to those Preparation 77 to give the title compound (270 mg) as a yellow oil. 1H NMR (CDCl3): 7.92 (2H, dd), 7.20 (1H, d), 7.01-6.94 (2H, m), 6.67 (1H, d), 3.87 (3H, s), 3.49 (2H, s), 1.56-1.43 (3H, m), 1.25-1.21 (6H, m), 1.17 (18H, d).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[C:7]1([NH:13][C:14]2[C:23]3[C:18](=[CH:19][N:20]=[CH:21][CH:22]=3)[C:17]3[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:16]=3[N:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C)C=O.O>[C:7]1([NH:13][C:14]2[C:23]3[C:18](=[CH:19][N:20]=[CH:21][CH:22]=3)[C:17]3[CH:24]=[CH:25][C:26]([C:28]4[NH:29][N:3]=[N:2][N:1]=4)=[CH:27][C:16]=3[N:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#Cc1ccc2c(c1)nc(Nc1ccccc1)c1ccncc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(Nc2nc3cc(-c4nnn[nH]4)ccc3c3cnccc23)cc1
Temperature: 120 °C
Yield: 49.1 %

Procedure:
Sodium azide (65 mg, 1 mmol) and ammonium chloride (53 mg, 1 mmol) were added to a crude mixture of the 5-(phenylamino)benzo[c][2,6]naphthyridine-8-carbonitrile (25 mg, 0.084 mmol) in dimethylformamide (0.2 mL). The mixture was heated for 18 h at 120° C. at which time LCMS analysis indicated the absence of any starting material. The mixture was diluted with water and purified by preparative HPLC to give N-phenyl-8-(1H-tetrazol-5-yl)benzo[c][2,6]naphthyridin-5-amine (14 mg). LCMS (ESI) 340.3 (M+1)+. 1HNMR (400 MHz, CD3OD) 10.11 (1H, s), 8.96 (1H, d, 5.9 Hz), 8.85 (1H, d, 8.2 Hz), 8.53 (1H, d, 5.5 Hz), 8.47 (1H,$), 8.16 (1H, d, 8.6 Hz), 7.88 (1H, s), 7.86 (1H, d, 0.8 Hz), 7.57-7.51 (3H, m), 7.36-7.31 (2H, m).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][C:18]=3[F:28])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)[CH3:2]>O1CCCC1.[Pd]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][C:18]=3[F:28])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCCCCc1ccc(-c2ccc(C=Cc3ccc(CC)cc3)cc2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(CCc3ccc(CC)cc3)cc2)c(F)c1

Procedure:
A solution of 1.2 g of 1-(p-ethylphenyl)-2-[4'-pentyl-2'-fluorobiphenyl-4-yl]ethene [obtained by Heck coupling of p-ethyl styrene with 4'-n-pentyl-2'-fluoro-4-bromobiphenyl] in 50 ml of tetrahydrofuran is hydrogenated in the presence of Pd/C. Customary work-up gives 1-(p-ethylphenyl)-2-(4'-n-pentyl-2'-fluorobiphenyl-4-yl)ethane.
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=O)[CH2:16][CH2:15][CH2:14]2.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)=[CH:16][CH2:15][CH2:14]2
Reactant: O=C1CCCc2cc(Cl)ccc21
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: O
Product: Clc1ccc2c(c1)CCC=C2n1ccnc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.218 ml of thionyl chloride is added within a period of 15 minutes to a solution of 815 mg of imidazole in 3.2 ml of methylene chloride. At the end of the exothermic reaction, 451 mg of 6-chloro-1-tetralone are added to the resulting suspension. After stirring for 20 hours at room temperature, 497 mg of potassium carbonate in 2 ml of water are added, and the mixture is extracted twice with chloroform. After drying the organic extracts over sodium sulfate, concentration is carried out under reduced pressure. The resulting crude product is purified by column chromatography (SiO2, 0.04-0.063 mesh, 0.15 bar, ethyl acetate); m.p. (after dry crystallisation from ether) 68°-72°.
Reaction SMILES: O[C:2]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:16]([OH:18])=[O:17])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>>[CH:2]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3([C:16]([OH:18])=[O:17])[CH2:14][CH2:15]3)=[CH:11][CH:12]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1(c2ccc(C3(O)CCCC3)cc2)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1(c2ccc(C3CCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 1-[4-(1-hydroxycyclopentyl)phenyl]cyclopropanecarboxylic acid (120 mg, 0.00049 mol), triethylsilane (389 μL, 0.00244 mol) and TFA 0.3 mL was stirred at r.t. overnight. The mixture was concentrated to afford desired product. MS (ESI): 231.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13](Br)=[N:12][C:11]([Br:15])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:18][NH2:19]>O1CCOCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([NH:18][NH2:19])=[N:12][C:11]([Br:15])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)nc1Br
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(Br)nc1NN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3,5-Dibromo-pyrazin-2-yl)-carbamic acid tert-butyl ester (600 mg, 1.7 mmol) was dissolved in dioxane (10 mL) and cooled on an ice bath. Hydrazine monohydrate (3 mL, 61.7 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the remaining residue was re-dissolved in a mixture of ethylacetate, water and brine. The phases were separated and the aqeuous phase was extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with brine, dried over sodium sulphate, filtrated and concentrated in vacuo to give (5-bromo-3-hydrazino-pyrazin-2-yl)-carbamic acid tert-butyl ester as the crude product.
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=3[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:39](Br)[C:40]#[CH:41]>CC(C)=O>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[CH:8]2[CH2:12][CH2:13][CH:1]3[CH2:11][N:10]([CH2:41][C:40]#[CH:39])[CH2:9]2)=[N:16][CH:17]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
2-[2-(10-Aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide (30 mg, 0.0667 mmol) was placed in acetone (3 mL) and cesium carbonate (65 mg, 0.200 mmol, 3.0 eq) was added followed by propargyl bromide (80% in toluene) (7.9 μL, 0.0734 mmol, 1.1 eq). The reaction was stirred at room temperature for 24 hours and was then concentrated under reduced pressure. The residue was taken up in CH2Cl2 (10 mL) and washed with water (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent to obtain 2-[5-chloro-2-(10-prop-2-ynyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as an orange foam (30 mg, 92%). LCMS (m/e) 487 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.03 (s, 1H), 8.66 (d, 1H, J=8.5 Hz), 8.08 (s, 1H), 7.51-7.40 (m, 2H), 7.37 (d, 1H, J=2.2 Hz), 7.30-7.20 (m, 1H), 7.10-7.0 (m, 2H), 6.92 (s, 1H), 6.18 (bs, 1H), 3.37 (d, 2H, J=2.3 Hz), 3.03 (d, 3H, 4.9 Hz), 3.03-2.98 (m, 1H), 2.97-2.87 (m, 3H), 2.52-2.45 (m, 2H), 2.23-2.15 (m, 2H), 2.14 (t, 1H, J=2.3 Hz), 1.70-1.62 (m, 2H).
Reaction SMILES: [C:1]([O:22]C)(=[O:21])[CH2:2][CH2:3][CH:4]=[C:5]=[CH:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[K+:25]>C(O)C>[C:1]([O-:22])(=[O:21])[CH2:2][CH2:3][CH:4]=[C:5]=[CH:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[K+:25]
Reactant: CCCCCCCCCCC/C=C\CC=C=CCCC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCC/C=C\CC=C=CCCC(=O)[O-]
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of 160 mg of methyl 4,5,8Z-eicosatrienoate in 20 ml of ethanol was treated 0.5 ml of 1.0N aqueous potassium hydroxide and the reaction mixture was stirred under nitrogen at room temperature for 7 hours. The solvents were removed under reduced pressure and the resulting oil was dried for several hours at 0.02 mn and 25° C. to give 168 mg of potassium 4,5,8Z-eicosatrienoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N:12]([O-:14])=[O:13].[Na+].[N+]([O-])(O)=O.[OH-].[NH4+]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=N[O-]
Reactant: Brc1ccc2ncccc2c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1c(Br)ccc2ncccc12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 2325.8 %

Procedure:
A solution of 6-bromoquinoline (2.0 g, 9.61 mmol) in concentrated sulfuric acid (10 mL) was cooled to 0° C. Sodium nitrite (27 mg, 0.384 mmol) was added, followed by dropwise addition of concentrated nitric acid (0.8 mL). The reaction mixture was stirred at 0° C. for 45 min. then at room temperature for 1 h, before pouring onto ice, resulting into a yellow precipitate. The mixture was neutralized to pH 7 with ammonium hydroxide. The precipitate was filtered, washed with water and dried in vacuo to yield 2.26 g of 6-bromo-5-nitro-quinoline as a light green solid (93% yield):): 1H NMR (CDCl3) δ 7.62 (dd, 1H), 7.94 (d, 1H), 8.07 (d, 1H), 8.17 (d, 1H), 9.06 (dd, 1H); MS (m/z) 253, 255 [M+H+]+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([OH:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:40](OC(=O)C)(=[O:42])[CH3:41].N1C=CC=CC=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([O:38][C:40](=[O:42])[CH3:41])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](O)[C@H]2[C@@H](CC[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2C[C@@H]3O[C@]4(CC[C@@H](C)CO4)[C@@H](C)[C@@H]3[C@@]12C

Procedure:
(3β,5α,11β,12β,25R)-3-(t-butyldimethylsilyloxy)spirostan-11,12-diol was selectively acetylated with acetic anhydride, pyridine and dimethylaminopyridine in methylene chloride to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:18]([Cl:19])=[CH:17][C:16]2[C:4](=[C:5]3[C:14]([N:15]=2)=[C:13](C(O)=O)[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]3)[CH:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[C:18]([Cl:19])=[CH:17][C:16]2[C:4](=[C:5]3[C:14]([N:15]=2)=[CH:13][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]3)[CH:3]=1
Reactant: O=C(O)c1c2nc3cc(Cl)c(Br)cc3c-2[nH]c2ccccc12
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Clc1cc2nc3cc4ccccc4[nH]c-3c2cc1Br
Yield: 94 %

Procedure:
7-Bromo-8-chloroquindoline-11-carboxylic acid from Example 74 (3.00 g, 7.99 mmol) was refluxed at 250° C. in diphenyl ether (30 mL) for 4 hours in an oversize flask. The mixture was cooled, diluted with petroleum ether (30 mL), and filtered. The filter cake was washed with petroleum ether (100 mL) and dried under high vacuum to yield 2.49 g (94%) of the title compound as a greenish solid, mp >246° C.; 1H NMR (DMSO-d6) δ 11.70 (s, 1H), 8.62 (s, 1H), 8.36 (s, 1H), 8.18 (d, J=8.4, 1H), 8.12 (d, J=8.4, 1H), 7.84 (s, 1H),7.69 (t, J=6.8, 1H), 7.59 (t, J=7.2, 1H); 13C NMR (DMSO-d6) δ 143.65, 143.15, 133.39, 132.95, 128.65, 127.66, 127.97, 126.75, 125.51 (two signals), 121.53, 114.34, 113.10, 111.11; MS (EI, m/z) 331.9 (M+2+).