Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([CH:19]1[NH:23][C:22](=[O:24])[CH:21]([CH3:25])[NH:20]1)([CH3:18])[CH3:17]>ClCCl.CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:20]1[CH:21]([CH3:25])[C:22](=[O:24])[NH:23][CH:19]1[CH:16]([CH3:18])[CH3:17])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1NC(C(C)C)NC1=O
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)C1NC(=O)C(C)N1C(=O)CNC(=O)OCc1ccccc1

Procedure:
The same procedure of the example 2, starting from N-benzyloxycarbonylglycine and 2-isopropyl-5-methyl-4-imidazolidinone afforded 1-(2-benzyloxycarbonylaminoacetyl)-2-isopropyl-5-methyl-4-imidazolidinone as a diastereoisomeric mixture Rf=0.52 and 0.57 (dichloromethane/methanol 9:1, silica gel plates) then the oily title compound as a diastereoisomeric mixture, Rf=0.24 and 0.27 (dichloromethane/methanol 7:3, silica gel plates). Mass spectrum (E.I., 70 e V, 1.5 mA), m/z=156 (M.+ --C3H7).
Reaction SMILES: [Li]C(C)(C)C.[CH:6]([Si:9]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[C:10]1[O:11][CH:12]=[CH:13][N:14]=1)([CH3:8])[CH3:7].[Sn:21](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1.C(OCC)(=O)C>[CH2:30]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[C:12]1[O:11][C:10]([Si:9]([CH:6]([CH3:8])[CH3:7])([CH:15]([CH3:17])[CH3:16])[CH:18]([CH3:20])[CH3:19])=[N:14][CH:13]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)[Si](c1ncco1)(C(C)C)C(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc([Si](C(C)C)(C(C)C)C(C)C)o1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
tert-BuLi (1.7M, 8.4 mL, 14.3 mmol) was added dropwise over 30 min. to a stirred solution of 2-(triisopropylsilyl)-1,3-oxazole* (3 g, 13 mmol) in THF (75 mL) at −78° C. under argon. The solution was allowed to stir for 20 min. at −78° C. and Bu3SnCl (5.2 mL, 19.5 mmol) was then added over 20 min. The reaction mixture was warmed up to room temperature and stirred for an additional 16 h. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was dissolved in n-pentane, filtered through Celite and the solvent evaporated to give the title compound in quantitative yield as a pale-yellow oily residue, which was used without further purification in the next step. *Prepared according to Ross A, et al. Tetrahedron Letters 2002, 43, 935.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[C:9]([C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C#CCCCCCC
Reactant: O=Cc1cc(Br)cs1
Product: CCCCCCC#Cc1csc(C=O)c1
Yield: 89 %

Procedure:
Reaction of 4-bromo-2-thiophenecarboxaldehyde (3.40 g 2 mmole, prepared by the methods described by D. Chadwick et al, J.C.S. Per 1 1766, 1973), with 1-octyne (4.40 g, 4 mmole) as described in Example 20 gave the title compound as a yellow oil (89.0%); mp 2° C.; νmax 3100, 2260, 1685, 1160, 855, 655, 622; δH(CDCl3) 0.88(3H, t, J=6 Hz), 1.3(8H, m), 2.33(2H, t, J=6 Hz), 7.7(2H, s), 9.9 (1H, s).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:31][CH2:32][CH3:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27](O)=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:30])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:32]([O:31][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=2)=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[O:17])[C:7]1=[O:30])[CH3:33]
Reactant: Cc1ccc(N)cc1
Reactant: CCOC(CN1C(=O)C(CC(=O)O)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Reaction time: 18 h
Yield: 116.5 %

Procedure:
In 100 ml of dichloromethane was dissolved 2.8 g of (+)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one, and 1.20 g of 4-dimethylaminopyridine, 1.90 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 1.10 g of p-toluidine were successively added thereto. The mixture was stirred for 18 hours and concentrated. The concentrate was diluted with ethyl acetate, washed successively with dilute hydrochloric acid and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to yield 3.90 g (81%) of the title compound as a white powder. The resulting compound was found to be optically pure as analyzed by high performance liquid chromatography using an optically active column (CHIRALCEL OD, produced by Daicel Chemical Industries, Ltd.).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17]([NH2:24])[C:16]=2[N:15]=[C:14]1[CH2:25][CH2:26][CH2:27][CH3:28].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(S(O)(=O)=O)C>ClCCl.C(O)(C)C>[NH2:24][C:17]1[C:16]2[N:15]=[C:14]([CH2:25][CH2:26][CH2:27][CH3:28])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:21]=2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=1
Reactant: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCN
Reactant: O=C(Cl)c1ccccc1
Agent: CCS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCNC(=O)c1ccccc1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
Triethylamine (0.07 mL, 0.5 mmol) was added to a solution of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (150 mg, 0.5 mmol) in dichloromethane (150 mL). The reaction mixture was cooled in an ice bath. Benzoyl chloride (0.07 mL, 0.5 mmol) was added and the reaction mixture was removed from the ice bath. The reaction mixture was washed twice with water and then concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with 10% methanol in dichloromethane to provide an oily brown material. This material was dissolved in a minimum amount of isopropanol and then ethanesulfonic acid (55 mg, 0.5 mmol) was added with stirring. The reaction mixture was stirred at ambient temperature for ˜1 hour and then heated briefly in a sand bath until it became homogeneous. The solution was allowed to cool to ambient temperature and then was chilled in an ice bath. The resulting precipitate was isolated by filtration to provide 111 mg of N-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]benzamide as a crystalline solid, m.p. 127.8-128.8° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:15]1[S:16][C:17]([C:20]#[CH:21])=[CH:18][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1.CCN(CC)CC.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CC(=O)OCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)=O.CC#N>[C:1]([NH:5][C:6]1[N:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:15]1[S:16][C:17]([C:20]#[C:21][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[CH:18][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(Br)n1
Reactant: C#Cc1ccc(-c2nc3cnccn3c2NC(C)(C)C)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cccc(C#Cc2ccc(-c3nc4cnccn4c3NC(C)(C)C)s2)n1
Temperature: 50 °C
Yield: 42 %

Procedure:
300 mg (1.0 mmol) of tert-butyl-[2-(5-ethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-amine were dissolved together with 138 μl (1.2 mmol) of 2-bromo-6-methyl-pyridine in DMF (7 ml). 1.4 ml (10.0 mmol) of NEt3, 19 mg (0.1 mmol) of copper(I) iodide and 71 mg (0.1 mmol) bis(triphenylphosphine)-palladium(II) chloride were added to this solution. The reaction mixture was heated to 50° C. for 6 h. The mixture was then diluted with EA and combined with a 1M aq. Na2CO3 solution. The phases were separated and the aq. phase was extracted with EA. The combined organic phases were dried over MgSO4, filtered and evaporated under a vacuum. 166 mg (0.42 mmol, 42%) of N-tert-butyl-2-(5-((6-methylpyridin-2-yl)ethynyl)thiophen-2-yl)imidazo[1,2-a]pyrazin-3-amine were obtained by CC (acetone/MeCN 1:1) of the group.
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)=[CH2:4].[CH3:11][C:12]([Si:15]([CH3:29])([CH3:28])[O:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18](Cl)=[O:19])([CH3:14])[CH3:13]>O1CCCC1.C(Cl)Cl>[CH3:14][C:12]([Si:15]([CH3:28])([CH3:29])[O:16][C@@H:17]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:18]([N:9]1[C@H:5]([CH:3]=[CH2:4])[CH2:6][CH2:7][C:8]1=[O:10])=[O:19])([CH3:11])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](Cc1ccccc1)C(=O)Cl
Reactant: C=CC1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C[C@@H]1CCC(=O)N1C(=O)[C@H](Cc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To 60% sodium hydride (336 mg, 10 mmol, in mineral oil) in tetrahydrofuran (20 mL) at 0° C. was added dropwise a solution of 5-vinylpyrrolidin-2-one (1.0 g, 9.0 mmol) in tetrahydrofuran (10 mL) over a 5 min period. The cooling bath was removed and the solution was allowed to warm to 25° C. to ensure complete anion generation. To the anion at 25° C. was added dropwise a solution of (2S)-2-((1,1-dimethylethyl)dimethylsilyloxy)-3-phenylpropanoyl chloride (4, 2.98 g, 10 mmol) in tetrahydrofuran (10 mL) over a 5 min period. TLC indicated that the reaction was complete upon addition of the acid chloride (silica gel plates; hexane and ethyl acetate, 9:1). The solvent was removed by rotary evaporation affording a thick slug. The slug was dissolved in methylene chloride (75 mL) and washed with water (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and dried (MgSO 4). Concentration and purification by flash chromatography on silica gel (EM 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 4.5 cm diameter×15 cm length) using hexane and ethyl acetate (19:1) afforded 1.54 g (46%) of (5S)-N-((2S)-2-((1,1-dimethylethyl)-dimethylsilyloxy)-3-phenylpropanoyl)-5-ethenylpyrrolidin-2-one (5a) as a white crystalline material: mp 92°-93.5° C.; 1H NMR (CDCl3) δ-0.316 (s,3 H), -0.217 (s,3 H), 0.703 (s, 9 H), 1.94 (t, J=9.6 Hz, 1 H), 2.29 (p, J=11.7 Hz, 1 H), 2.50-2.75 (m, 3 H), 3.11 (d, J=12.8 Hz, 1 H), 4.97-5.13 (m, 1 H), 5.12-5.18 (m, 2 H), 5.45 (d, J=9.8 Hz, 1 H), 5.75-5.86 (m, 1 H); 13C NMR (CDCl3) δ175.1, 174.1, 137.9, 135.4, 130.0, 128.0, 126.4, 115.8, 74.2, 58.1, 41.2, 31.7, 25.5, 24.3, 18.1, -5.50, -5.76.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:10]=1)(=O)CCCCC.[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCOCC>[OH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:13][C:14]=1[C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCc1cccc(OC(=O)CCCCC)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCc1ccc(C(=O)CCCCC)c(O)c1

Procedure:
A 14.28 g portion of hexanoic acid, 3-tetradecylphenyl ester was heated to 90°-100° C., then 9.81 g of aluminum chloride was added in portions over 2 hours. Heating was continued for an additional hour, then the mixture was allowed to cool, diluted with ether and poured onto a mixture of ice and concentrated hydrochloric acid. The ether layer was washed with water, then dried and the solvent removed, giving 7 g of the desired compound, mp 44°-45° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([OH:14])([CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15](Cl)([Cl:17])=[O:16]>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([O:14][C:15]([Cl:17])=[O:16])([CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(O)CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(OC(=O)Cl)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-hydroxy-3-methylpyrrolidine-carboxylic acid tert-butyl ester (200 mg, 1.00 mmol) in THF (4 mL) was slowly treated with phosgene 20% in toluene (0.954 mL). After stirring at rt for 16 h, solvents were removed under reduced pressure and co-evaporate with CH2Cl2. The crude 3-chlorocarbonyloxy-3-methylpyrrolidine-carboxylic acid tert-butyl ester was used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH3:13])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].[Cl-].[NH4+]>CN(C)C=O>[CH2:10]([O:9][C:6]1[C:7]([F:8])=[C:2]([O:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[F:20])[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCOc1ncnc(Cl)c1F
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1ncnc(Oc2ccccc2F)c1F
Temperature: 80 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.1 g of 4-chloro-6-(2-butynyloxy)-5-fluoropyrimidine, 0.1 g of potassium carbonate, and 0.07 g of 2-fluorophenol, followed by stirring at 80° C. for 3 hours. The reaction mixture was left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.11 g of 4-(2-butynyloxy)-6-(2-fluorophenoxy)-5-fluoropyrimidine (the present compound (183)).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:16])=[CH:7][CH:6]=1)([O-])=O.[H][H]>[C].[Pd].CO>[ClH:1].[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@@H:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[OH:16])=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CCNC[C@H](O)c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(CCNC[C@H](O)c2ccccc2)cc1
Temperature: 20 °C
Yield: 94.5 %

Procedure:
A mixture of 11.0 kg of (R)-2-[[2-(4-nitrophenyl)ethyl]amino]-1-phenylethanol monohydrochloride, 110 liters of methanol and 1.20 kg of wet 10% palladium-carbon (wetting rate: 54.2%) was stirred in a hydrogen atmosphere until absorption of hydrogen stopped. The reaction solution was filtered and the filtrate was concentrated in vacuo. Methanol (40 liters) was added to the residue to dissolve at 40° C. and crystallization was conducted by addition of 220 liters of diisopropyl ether thereto followed by stirring at 20° C. throughout one night. The crystals were filtered and washed with 30 liters of diisopropyl ether. They were dried in vacuo to give 9.43 kg of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH3:15])[CH2:10][CH2:9]2)[N:5]=[CH:4][N:3]=1.[C:23]1([OH:34])[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:33])[C:27]=2[CH:26]=[CH:25][N:24]=1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:5]=[CH:4][N:3]=[C:2]([O:33][C:28]4[CH:29]=[CH:30][CH:31]=[C:32]5[C:27]=4[CH:26]=[CH:25][NH:24][C:23]5=[O:34])[CH:7]=3)[CH2:9][CH2:10]2)[CH3:15])=[CH:17][CH:18]=1
Reactant: CC(c1ccc(F)cc1)N1CCN(c2cc(F)ncn2)CC1
Reactant: Oc1cccc2c(O)nccc12
Product: CC(c1ccc(F)cc1)N1CCN(c2cc(Oc3cccc4c(=O)[nH]ccc34)ncn2)CC1

Procedure:
4-Fluoro-6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidine, Example 33(a), (0.074 g, 0.24 mmol) was reacted with 1,5-isoquinolinediol (0.058 g, 0.36 mmol, Sigma) under the conditions of Example 70 to give the title compound. Mp: 249° C. MS (ESI, pos. ion) m/z: 446 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12](=[O:25])[NH:13][CH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.C(Cl)Cl>C(O)(C(F)(F)F)=O>[NH2:7][C@H:8]([CH:9]([CH3:11])[CH3:10])[C:12]([NH:13][CH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)=[O:25]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)NCCc1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H](N)C(=O)NCCc1ccc2c(c1)OCO2
Yield: 83.3 %

Procedure:
[1-(2-Benzo[1,3]dioxol-5-yl-ethylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester (447.1 mg, 1.23 mmol) was dissolved in 1:1 TFA:DCM (6 mL) and stirred at room temperature for 3 hours. After this time, the solvent was removed by vacuum. The crude material was dissolved in DCM (75 mL) and washed with 1M NaOH (aq) (75 mL) to afford the crude product as the freebase. The product was purified by Flash Chromatography (0-10% methanol/DCM gradient) to afford 270.7 mg (83.5%) of the pure product, 2-amino-N-(2-benzo[1,3]dioxol-5-yl-ethyl)-3-methyl-butyramide. [M+H]+ 265.1
Reaction SMILES: [Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][C:10]([N+:16]([O-])=O)=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[S:14][C:13]1[CH:12]=[CH:11][C:10]([NH2:16])=[CH:9][C:8]=1[S:7]2
Reactant: O=[N+]([O-])c1ccc2c(c1)Sc1cccc(Br)c1S2
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)Sc1cccc(Br)c1S2
Yield: 104 %

Procedure:
Zn dust (144.1 g, 2.2 mol) was added to a stirred solution of 1-bromo-7-nitro-thianthrene (125 g, 367.4 mmol) in glacial acetic acid (500 ml at 0° C. (ice bath). After one hour the ice bath was removed and the solution was left to react overnight at room temperature. The mixture was filtered through a pad of Celite and washed with copious amount of dichloromethane and the filtrate was evaporated in vacuo. Water was added (500 ml) to the residue and the pH was adjusted to pH 8 by addition of concentrated ammonia. The solid formed was filtered and dried in a vacuum desiccator to give the title compound (118.5 g) and was used without any further purification. m/z (LC-MS, ESP), RT=4.92, (M++1)=310-312 (1:1, bromine isotope ratio present)
Reaction SMILES: [CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][C:8](B(O)O)=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:22][C:23]1[CH:24]=[C:25](I)[CH:26]=[CH:27][CH:28]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CO.O.C(COC)OC>[Br:22][C:23]1[CH:24]=[C:25]([C:17]2[CH:16]=[C:15]3[C:6](=[C:5]4[C:18]=2[CH:1]=[CH:2][CH:3]=[CH:4]4)[CH:7]=[CH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]3=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1cc2c3ccccc3ccc2c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cc3c4ccccc4ccc3c3ccccc23)c1
Reaction time: 8 h
Yield: 28.4 %

Procedure:
In argon atmosphere, a mixture of 5.00 g (18.37 mmol) of 6-chryseneboronic acid, 5.20 g (18.37 mmol) of 3-bromoiodobenzene, 1.06 g (0.92 mmol) of tetrakis(triphenylphosphine)palladium (0), 30 ml of toluene, 30 ml of dimethoxyethane, and 27.6 g of a 2 M sodium carbonate aqueous solution was refluxed for 8 h under stirring and left standing overnight. The reaction mixture was added with water and stirred at room temperature for one hour. After adding methanol, the solid matter was collected by filtration and purified by silica gel chromatography to obtain 2.00 g (yield: 28.4%) of 6-(3-bromophenyl)chrysene.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[Cl:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1O>C(#N)C>[Cl:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[O:5][CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Oc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c(Cl)c1

Procedure:
A mixture of 1-(diphenylmethyl)-3-azetidinyl methanesulfonate (363.8 g, 1.15 mol), potassium carbonate (330 g, 2.38 mol) and 2-chloro-4-fluorophenol (140 g, 0.96 mol) in acetonitrile (2.5 L) was heated under reflux for 4.5 hours. The cooled reaction mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate (1 L) and water (500 mL). The organic layer was separated, dried over sodium sulfate concentrated in vacuo and the residue was triturated with ethyl acetate/pentane/dichloromethane, 90:10:1, to afford the title compound as a white solid in quantitative yield, 350 g. 1H NMR(400 MHz, CDCl3) δ: 3.19(m, 2H), 3.75(m, 2H), 4.45(m, 1H), 4.78(m, 1H), 6.60(m, 1H), 6.83(m, 1H), 7.14(m, 1H), 7.18-7.50(m, 10H)
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][CH2:23][C:10]2([CH:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:12]([CH3:21])[C:11]2=[O:22])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH:13]2[C:10]3([CH2:23][CH2:24][CH2:25][NH:8][CH2:9]3)[C:11](=[O:22])[N:12]2[CH3:21])=[CH:19][CH:18]=1
Reactant: CN1C(=O)C2(CCCN(C(=O)OC(C)(C)C)C2)C1c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C2(CCCNC2)C1c1ccc(F)cc1

Procedure:
A solution comprising of rac-1-(4-Fluoro-phenyl)-2-methyl-3-oxo-2,6-diaza-spiro[3.5]nonane-6-carboxylic acid tert-butyl ester (830 mg, 2.38 mmol) and TFA (1 ml, 12.98 mmol) in DCM (15 ml) was stirred at RT overnight. The reaction mixture was concentrated in vacuo and the resulting crude product was dissolved with ethyl acetate and washed with a saturated solution of sodium bicarbonate. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to yield a the title compound as a yellow oil;