Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.[Cl:34][CH2:35][C:36](Cl)=[O:37]>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:36](=[O:37])[CH2:35][Cl:34])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CCl)sc4n3)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.415 mmol) in N,N-dimethylacetamide (3.0 mL) was added chloroacetyl chloride (52.8 μL, 0.664 mmol), and the mixture was stirred at room temperature for 4 hr. Chloroacetyl chloride (26.4 μL, 0.332 mmol) was further added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (15 mL), 5% aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (15 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[4-chloro-5-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]-3-(1-cyano-1-methylethyl)benzamide as an oily residue.
Reaction SMILES: [CH2:1]1[C@@H:5]2[C@@H:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[C@@H:7]3[C@H:2]1[CH:3]=[CH:4]2.C1(C)C=CC=CC=1.COC1C=CC2N=CC=C([C@H](O)[C@@H]3N4C[C@H](C=C)C(CC4)C3)C=2C=1.[CH3:44][OH:45]>C(Cl)(Cl)(Cl)Cl>[CH3:44][O:45][C:11]([C@H:6]1[C@H:5]2[CH2:1][C@H:2]([CH:3]=[CH:4]2)[C@H:7]1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: O=C1OC(=O)[C@H]2[C@@H]1[C@@H]1C=C[C@H]2C1
Reactant: CO
Agent: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1[C@H](C(=O)O)[C@H]2C=C[C@@H]1C2
Temperature: -55 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
The starting material (a) was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. cis-5-Norbornene-exo-2,3-dicarboxylic anhydride (5 g, 30.45 mmol) was suspended in a 1:1 mixture of toluene and carbon tetrachloride (150 mL). The mixture was stirred for 10 min. Quinidine (10.9 g, 33.5 mmol) was added and the flask was degassed and backfilled with nitrogen. The solution was cooled to −55° C. While stirring, methanol (3.7 mL, 91.35 mmol) was added. The mixture was stirred at −55° C. for 16 h. Upon warming to 25° C., the mixture was concentrated in vacuo to a foam. The foam was dissolved in a mixture of ethyl acetate (400 mL) and 1.0 M aqueous hydrochloric acid solution (400 mL). The layers were separated and the organic layer was further washed with 1.0 M aqueous hydrochloric acid solution (2×100 mL), saturated aqueous brine solution (100 mL) and dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1R,2R,3S,4S)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (5.92 g, 30.2 mmol, 99%), as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (1H, d, J=10.2 Hz), 1.96 (1H, d, J=8.6 Hz), 2.47-2.49 (2H, m), 2.93-2.94 (2H, m), 3.51 (3H, s), 6.15-6.20 (2H, m), 12.15 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[NH:3]1.[CH3:19]C(C)=O.C(=O)([O-])[O-].[K+].[K+].CI>CCOCC>[CH3:19][N:3]1[C:4]2[C:9](=[CH:8][C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]1([CH3:18])[CH3:1]
Reactant: CC(C)=O
Reactant: COC(=O)C(C)c1ccc2c(c1)C=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Product: COC(=O)C(C)c1ccc2c(c1)C=CC(C)(C)N2C

Procedure:
1.9 g of methyl 2-(1,2-dihydo-2,2-dimethylquinolin-6-yl)propionate (Compound 7) were added to 40 ml of acetone. 2.0 g of potassium carbonate and 2.0 ml of methyl iodide were added to the solution, and the mixture was heated and refluxed for 17 hours. After the mixture was cooled, the mixture was diluted with ether. Then the precipitate was filtered off, and the solvent was distilled off to give 1.9 g of methyl 2-(1,2-dihydro-1,2,2-trimethylquinolin-6-yl)propionate (Compound 16).
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].Cl(O)(=O)(=O)=O.[CH3:13][C@:14]12[CH2:22][CH2:21][C@@H:20]3[C:23]4[CH2:24][CH:25]=[C:26]([O:31]C)[CH2:27][C:28]=4[CH2:29][CH2:30][C@H:19]3[C@@H:18]1[CH2:17][CH2:16][C@:15]2([C:34]#[CH:35])[OH:33].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:13][C@:14]12[CH2:22][CH2:21][C@@H:20]3[C@@H:23]4[C:28]([CH2:29][CH2:30][C@H:19]3[C@@H:18]1[CH2:17][CH2:16][C@:15]2([C:34]#[CH:35])[OH:33])=[CH:27][C:26](=[O:31])[CH2:25][CH2:24]4.[C:1]([O-:4])(=[O:3])[CH3:2]
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=C(CC=C(OC)C4)[C@H]3CC[C@@]21C
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Product: CC(=O)[O-]
Reaction time: 0.03 h

Procedure:
Prepare a fresh solution of acetic anhydride (4.8 ml.) and 70% aqueous perchloric acid (0.01 ml.) in ethyl acetate (50 ml.) then add dl-13-methyl-17α-ethynyl-3-methoxygona-2,5(10)-dien- 17-Ol (0.5 g.) as a solid, swirl for 1.5 minutes then quench the reaction by adding saturated aqueous sodium bicarbonate solution. Wash the ethyl acetate layer with saturated bicarbonate, brine and dry over anhydrous sodium sulfate. Filter, evaporate in vacuo then add methanol with a trace of pyridine and let stand for 2 hours. Evaporate in vacuo, pump dry then treat the residue in ether with decolorizing charcoal. Filter, evaporate and crystallize the residue from methanol to obtain dl-13-methyl-17α-ethynyl-17-hydroxygon-4-en-3-one, acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]=[N+:16]=[N-:17])[C@H:10](O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCN(S(F)(F)F)CCOC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([CH2:14][N:15]=[N+:16]=[N-:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN=[N+]=[N-])[C@H](O)C1
Agent: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(CN=[N+]=[N-])CC1

Procedure:
To a solution of cis (±)-4-azidomethyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.95 mmol, 0.5 g) was added bis(2-methoxyethyl)aminosulfur trifluoride (2.34 mmol, 0.52 g) slowly and stirred for 12. The reaction mixture was diluted with DCM (10 mL), washed with aq.NaHCO3 solution, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using ethyl acetate:hexanes (2:8) to get 4-azidomethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])=[N:11][N:10]=1.Cl[C:24]1[N+:29]([O-:30])=[CH:28][C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>CC(O)(CC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:24]3[N+:29]([O-:30])=[CH:28][C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)=[O:15])=[N:11][N:10]=1
Reactant: O=C(NC1CCNCC1)c1nnc(Nc2ccccc2F)o1
Reactant: COC(=O)Cc1ccc(Cl)[n+]([O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)(C)O
Product: COC(=O)Cc1ccc(N2CCC(NC(=O)c3nnc(Nc4ccccc4F)o3)CC2)[n+]([O-])c1
Yield: 32.2 %

Procedure:
5-[(2-Fluorophenyl)amino]-N-piperidin-4-yl-1,3,4-oxadiazole-2-carboxamide (Intermediate 101) (100 mg, 0.33 mmol) and methyl (6-chloro-1-oxidopyridin-3-yl)acetate (67 mg, 0.33 mmol) were heated with sodium hydrogen carbonate (56 mg, 0.66 mmol) in 2-methyl-2-butanol (4 mL) at 100° C. for 22 h. The reaction mixture was concentrated by evaporation and the residue was dissolved in DMSO then filtered and purified by preparative HPLC to give the title compound (50 mg, 32%) as a gum; 1H NMR δ 1.94-1.74 (m, 4H), 2.58-2.43 (m, 2H), 2.95-2.84 (m, 2H), 3.65 (s, 3H), 4.07-3.93 (m, 3H), 7.21-7.12 (m, 2H), 7.35-7.23 (m, 2H), 7.45-7.40 (m, 1H), 8.06-7.98 (m, 1H), 8.25-8.20 (m, 1H), 9.13 (d, 1H), 10.64 (s, 1H); MS m/e MH+ 471.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][N:15]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:14]([CH3:13])=[N:15][CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68316.4 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (250 mg, 1.09 mmol), 6-methylnicotinic acid (313 mg, 2.28 mmol), BOP-Cl (581 mg, 2.28 mmol), and triethylamine (0.757 mL, 5.43 mmol) in DCM (5 mL) was stirred at room temperature for 30 minutes. 3M LiOH (3 mL) was then added. The reaction was stirred for an additional 10 minutes and then poured into water. The mixture was then filtered, washed with DCM, washed with 10:1 DCM:MeOH and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-methylnicotinamide (260 g, 68.5% yield) as a solid
Reaction SMILES: C([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([OH:6])=[O:5])C.O.[Ni:12].[CH3:13][C:14](C)=O>[Cl-].C([N+](CC)(CC)CC)C>[CH3:13][CH2:14][CH2:10][CH2:9][CH2:8][CH2:7][CH2:3][C:4]([O-:6])=[O:5].[CH3:13][CH2:14][CH2:10][CH2:9][CH2:8][CH2:7][CH2:3][C:4]([O-:6])=[O:5].[Ni+2:12]
Reactant: [Ni]
Reactant: CC(C)=O
Reactant: CCCCC(CC)C(=O)O
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: O
Product: CCCCCCCC(=O)[O-]
Product: [Ni+2]

Procedure:
To a reaction flask equipped with a mechanical stirrer and thermometer was charged 10.0 g (0,069 mole) of 2-ethylhexanoic acid, 10.0 g mineral spirits, 80.0 g water and 0.45 g of tetraethylammonium chloride. The electrical connections were then made and 11,416 coulombs of direct current were passed. 3.30 g (0,056 mole) of nickel was consumed. After removal of the aqueous layer, a greenish semi-solid was obtained. This material was tertiurated with acetone and gave a green solid containing 7.30% nickel. The filtrate was dried and the acetone was stripped off on a rotary evaporator under reduced pressure. This resulted in a green solution of nickel octoate in mineral spirits containing 10.9% nickel.
Reaction SMILES: Cl.C(O[C:7]([N:9](C)[S:10]([NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:12])=[O:11])=O)CCC>CO>[CH3:7][NH:9][S:10]([NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:12])=[O:11]
Reactant: CCCCOC(=O)N(C)S(=O)(=O)NCC(=O)OCC
Agent: Cl
Solvent: CO
Product: CCOC(=O)CNS(=O)(=O)NC
Reaction time: 3 h

Procedure:
To a solution of HCl in methanol (2 M) is added ethyl 2-((N-(butyloxycarbonyl)-N-methylsulfamoyl)amino)acetate from the previous step (5.0 mmol) in portions at RT and the mixture is stirred for 3 h. After the solvent is removed in vacuo, the residue is washed with diethyl ether to afford ethyl 2-((N-methylsulfamoyl)amino)acetate.
Reaction SMILES: [Na+].[CH3:2][S:3]([O-:5])=[O:4].Br[C:7]1[CH:8]=[C:9]([CH2:14][OH:15])[CH:10]=[C:11]([F:13])[CH:12]=1>CS(C)=O.CCOC(C)=O.[Cu]I>[F:13][C:11]1[CH:10]=[C:9]([CH2:14][OH:15])[CH:8]=[C:7]([S:3]([CH3:2])(=[O:5])=[O:4])[CH:12]=1
Reactant: OCc1cc(F)cc(Br)c1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cc(F)cc(CO)c1
Temperature: 90 °C
Reaction time: 72 h
Yield: 48.2 %

Procedure:
Methanesulphinic acid sodium salt (748 mg, 7.33 mmol) was added to (3-bromo-5-fluorophenyl)methanol (501 mg, 2.44 mmol) and copper(I) iodide (0.248 mL, 7.33 mmol) in DMSO (12 mL) under nitrogen. The resulting mixture was stirred at 90° C. for 3 days. The reaction mixture was diluted with EtOAc (300 mL), then filtered. The filtrate was washed sequentially with water (200 mL) and saturated brine (2×200 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 70 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford [3-fluoro-5-(methylsulfonyl)phenyl]methanol (240 mg, 48.1%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][CH:9]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O>[C:17]([N:1]1[CH:6]=[CH:5][CH:4]([C:12]2[C:11]3[C:15](=[CH:16][C:8]([F:7])=[CH:9][CH:10]=3)[NH:14][CH:13]=2)[CH:3]=[CH:2]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccncc1
Reactant: Fc1ccc2cc[nH]c2c1
Agent: Cl
Solvent: O
Product: O=C(c1ccccc1)N1C=CC(c2c[nH]c3cc(F)ccc23)C=C1
Reaction time: 2 h

Procedure:
To a stirred mixture of 250 parts of pyridine and 39 parts of 6-fluoro-1H-indole are added dropwise 42 parts of benzoyl chloride at 22° C. Upon completion, stirring is continued for 2 hours at room temperature. The reaction mixture is diluted with water and a hydrochloric acid solution 2N is added. The product is extracted twice with 350 parts of 1,1'-oxybisethane. The combined extracts are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 95 parts of 1-benzoyl-4-(6-fluoro-1H-indol-3-yl)-1,4-dihydropyridine as an oily residue.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:26][CH2:27][CH:28]4[CH2:32][CH2:31][CH2:30][N:29]4[C:33]([O:35]C(C)(C)C)=O)[CH:23]=[CH:24][CH:25]=3)[CH2:14][CH2:13]2)[N:3]=1.Cl.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(NC(C)C)(C)C>CO.CCOCC>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([N:26]4[CH2:27][C@H:28]5[CH2:32][CH2:31][CH2:30][N:29]5[C:33]4=[O:35])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(NCC5CCCN5C(=O)OC(C)(C)C)c4)CC3)cccc2n1
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CO
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5C[C@H]6CCCN6C5=O)c4)CC3)cccc2n1
Reaction time: 0.5 h

Procedure:
A solution of (R)-(1,1-dimethylethyl 2-{[(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)amino]methyl}-1-pyrrolidinecarboxylate in methanol was treated with a solution of hydrogen chloride in ether (1M). The resulting mixture was stirred 30 minutes then concentrated under vacuum and then loaded onto an ion-exchange cartridge (SCX-2) and eluted with methanol followed by ammonia in methanol (1 M). The combined basic fractions were concentrated under vacuum. The residue, (10 mg) was then dissolved in DCM (1 mL) and treated with triphosgene (23 mg, 0.3 eq.), diisopropylamine (4 uL, 3 eq.). The mixture was stirred for 1 h then concentrated under vacuum and purified by preparative mass-directed hplc to afford the title compound (3.1 mg).
Reaction SMILES: [O:1]1[C@H:3]2[CH:4]=[C:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][CH2:33][NH2:34].C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]3)=[CH:4][C@H:3]2[NH:30][CH2:31][CH2:32][CH2:33][NH2:34]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: NCCCN
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H](NCCCN)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 65.8 %

Procedure:
5,6α-epoxicholest-7-en-3β-ol (8.9 g, 22.1 mmol, 1 eq) and 1,3-diaminopropane (3.3 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-(3-aminopropylamino)-cholest-7-en-3β-ol as a white solid (6.9 g, 66%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 21% yield.
Reaction SMILES: [CH:1]12[O:6][CH:2]1[CH2:3][CH2:4][CH2:5]2.[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOC(C)=O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:7]([NH:14][C@@H:2]1[CH2:3][CH2:4][CH2:5][C@H:1]1[OH:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CC2OC2C1
Reactant: NCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOC(C)=O
Product: O[C@@H]1CCC[C@H]1NCc1ccccc1

Procedure:
Cyclopentene oxide (5.0 g, 59.1 mmol), benzylamine (7.0 g, 65.3 mmol) and titanium isopropoxide (3.40 g, 12.0 mmol) were taken in a microwave vial and microwaved at 150° C. for 3 hours. The reaction mixture was then cooled and diluted with EtOAc (100 mL). The organic layer was washed with water and dried over anhydrous Na2SO4. Evaporation of the solvent in vacuo and purification on a silica gel column (0 to 20% MeOH/CH2Cl2) afforded trans-2-(benzylamino)cyclopentanol. MS APCI calc'd for C12H17NO [M+H]+ 192. found 192.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:12](CC)CC)C.Cl.[Cl:18][CH2:19][C:20]1[N:21]([CH2:33][CH2:34][CH2:35]N)[C:22]2[C:31]3[N:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[CH:24][C:23]=2[N:32]=1>ClCCl>[Cl:18][CH2:19][C:20]1[N:21]([CH2:33][CH2:34][CH2:35][N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH2:12])=[O:9])[C:22]2[C:31]3[N:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[CH:24][C:23]=2[N:32]=1
Reactant: O=C=NC1CCCCC1
Reactant: CCN(CC)CC
Reactant: NCCCn1c(CCl)nc2cnc3cccnc3c21
Agent: Cl
Solvent: ClCCl
Product: NC(=O)N(CCCn1c(CCl)nc2cnc3cccnc3c21)C1CCCCC1
Reaction time: 8 h
Yield: 75.8 %

Procedure:
Cyclohexyl isocyanate (0.70 mL, 5.50 mmol) and triethylamine (1.74 mL, 12.5 mmol) were added to a stirred suspension of 3-[2-(chloromethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propan-1-amine hydrochloride (prepared as described in Parts A-E of Example 92, 1.56 g, 5.00 mmol) in dichloromethane (25 mL). A solution eventually formed from which a solid precipitated. The mixture was allowed to stand at room temperature overnight, then the solid was isolated by filtration and washed with a minimal amount of dichloromethane to afford 1.52 g of N-{3-[2-(chloromethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propyl}-N-cyclohexylurea as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](I)[CH:7]=1.[F:11][C:12]1[C:13]([C:20]([O:22][CH3:23])=[O:21])=[C:14]([Zn]I)[CH:15]=[CH:16][CH:17]=1>C1COCC1>[C:9]([C:3]1[N:4]=[CH:5][C:6]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[C:13]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:7][C:2]=1[F:1])#[N:10]
Reactant: COC(=O)c1c(F)cccc1[Zn]I
Reactant: N#Cc1ncc(I)cc1F
Solvent: C1CCOC1
Product: COC(=O)c1c(F)cccc1-c1cnc(C#N)c(F)c1

Procedure:
A solution of 3-fluoro-5-iodopyridine-2-carbonitrile (1.08 g, 3.87 mmol) in 10 mL of THF and palladium tetrakistriphenylphosphine (0.18 g, 0.16 mmol) was added to a solution of [3-fluoro-2-(methoxycarbonyl)phenyl](iodo)zinc (prepared from methyl 2-fluoro-6-iodobenzoate and Reike Zinc) in 20 mL of THF via cannula. The mixture was heated to reflux for one hour, cooled, and partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0–20% ethyl acetate in hexanes to provide methyl 2-(6-cyano-5-fluoropyridin-3-yl)-6-fluorobenzoate that gave proton NMR spectra consistent with theory.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:15])=[C:6]([C:8](=[O:14])[CH2:9]N(OC)C)[CH:7]=1.Br[Mg]C1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:15])=[C:6]([C:8]([C:9]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:14])[CH:7]=1
Reactant: FC(F)(F)Oc1ccc([Mg]Br)cc1
Reactant: CON(C)CC(=O)c1cc(Br)ccc1Cl
Solvent: C1CCOC1
Product: O=C(c1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 41.1 %

Procedure:
To the solution of 1-(5-bromo-2-chlorophenyl)-2-[methoxy(methyl)amino]ethanone 15b (0.74 g, 2.65 mmol) in dry tetrahydrofuran (10 mL) was added bromo-[4-(trifluoromethoxy)phenyl]magnesium 15d afforded from the last step at 0° C. under N2. The resulting mixture was stirred at 0° C. for 4 hours. The reaction mixture was quenched with 20 mL of saturated brine, and then 20 mL of water and 40 mL of ethyl acetate were added in turn. The mixture was partitioned. The aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=50/1 to give the title compound 15e as a white solid (415 mg, 41.1%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ (ppm): 7.88 (d, 2H), 7.60 (dd, 1H), 7.53 (d, 1H), 7.37 (d, 1H), 7.33 (d, 2H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=[O:11].[Br:12]Br.O>C(O)(=O)C>[Br:12][C:8]1[CH:9]=[C:10]2[C:5]([N:4]=[CH:3][C:2](=[O:11])[NH:1]2)=[CH:6][CH:7]=1
Reactant: O=c1cnc2ccccc2[nH]1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=c1cnc2ccc(Br)cc2[nH]1
Reaction time: 18 h
Yield: 66.2 %

Procedure:
To a stirred solution of 1H-quinoxalin-2-one (50 g, 342.5 mmol) in glacial acetic acid (2500 mL) was added bromine (54.7 g, 342.5 mmol in 120 mL acetic acid) over a period of 1.5 h at rt. After 18 h stirring, the mixture was slowly poured into 2000 mL water and stirred for 1 h at rt. The precipitate was filtered and the residue was washed with water and dried to give 7-bromo-1H-quinoxalin-2-one as an off-white solid (51 g, 66%): 1H-NMR (300 MHz, d6-DMSO): δ=12.42 (1H, s), 8.19 (1H, s), 7.75 (1H, d), 7.44 (2H, m) ppm.