Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[C:2]([O:6][CH2:7][CH2:8][N:9]([CH3:14])[CH:10](SC)[CH3:11])([CH3:5])([CH3:4])[CH3:3].Cl.C(OCCN)(C)(C)C.[NH2:24][C:25]1[CH:33]=[C:32]2[C:28]([CH2:29][C@@H:30]([OH:49])[C@@H:31]2[NH:34][C:35]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)=[O:36])=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:2]([O:6][CH2:7][CH2:8][N:9]([CH3:14])[C:10](=[N:24][C:25]1[CH:33]=[C:32]2[C:28]([CH2:29][C@@H:30]([OH:49])[C@@H:31]2[NH:34][C:35]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[CH:39][CH:38]=2)=[O:36])=[CH:27][CH:26]=1)[CH3:11])([CH3:5])([CH3:4])[CH3:3]
Reactant: CSC(C)N(C)CCOC(C)(C)C
Reactant: Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3)cc1)[C@H](O)C2
Agent: CC(C)(C)OCCN
Agent: Cl
Agent: I
Solvent: c1ccncc1
Product: CC(=Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3)cc1)[C@H](O)C2)N(C)CCOC(C)(C)C
Reaction time: 18 h
Yield: 22 %

Procedure:
Dissolve the crude HI salt of (2-tert-butoxyethyl)methyl-(1-methylsulfanylethyl)amine (obtained using the crude HCl salt of 2-tert-butoxyethylamine, referenced in Example 9-1, using the methodology detailed in Example 6-1) (297.1 mg, 0.897 mmol) in 20 mL pyridine and add biphenyl-4-carboxylic acid (R)-(6-amino-2(R)-hydroxyindan-1-yl)amide (290.7 mg, 0.844 mmol). Allow the reaction to stir for 18 hours. Remove the solvent in vacuo and dissolve the residue in methylene chloride and wash with saturated aqueous sodium hydrogen carbonate. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to afford 248.7 mg of crude product. Purify the residue by Biotage chromatography (10% MeOH/EtOAc to 25% MeOH/EtOAc) to afford 91.7 mg of the titled product (22% yield). MS (ES): m/z 500.5 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:11]=[C:10]([O:26][CH3:27])[CH:9]=1)=[O:7].[CH2:28](OCC)[CH3:29].C([Mg]I)C.[Cl-].[NH4+]>O1CCCC1>[OH:7][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:11]=[C:10]([O:26][CH3:27])[CH:9]=1)[CH2:28][CH3:29]
Reactant: CCOCC
Reactant: COc1cc(OCc2ccc3ccccc3c2)cc(C(=O)c2nccs2)c1
Agent: CC[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(c1cc(OC)cc(OCc2ccc3ccccc3c2)c1)c1nccs1
Yield: 55 %

Procedure:
A solution of the ketone so obtained (1.2 g) in tetrahydrofuran (20 ml) was added to a diethyl ether solution of ethylmagnesium iodide [prepared from iodoethane (0.6 ml) and magnesium turnings (0.154 g) under diethyl ether (10 ml)] and the mixture was heated to reflux for 15 minutes. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3×15 ml). The combined extracts were washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride/ethyl acetate (17/3 v/v) to give 2-[1-hydroxy-1-[3-methoxy-5-(naphth-2-ylmethoxy) phenyl]propyl]thiazole (0.72 g, 55%), m.p. 105° C. (recrystallised from a mixture of petrol (b.p. 60°-80° C.) and ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:42][S:43][CH2:44][C:45](O)=[O:46]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:45](=[O:46])[CH2:44][S:43][CH3:42])=[N:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CSCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSCC(=O)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 20.7 %

Procedure:
(1 g, 5.78 mmol) 5-Bromopyridin-2-amine was dissolved in DMF (40 ml) and HATU (2.64 g, 6.94 mmol, 1.2 equiv.) was added. After 15 minutes at room temperature Hunig's Base (6.0 ml, 34.7 mmol, 6 equiv.) and 2-(methylthio)acetic acid (736 mg, 6.94 mmol, 1.2 equiv.) were added. The mixture was stirred for 72 hours at room temperature. The reaction mixture was evaporated and extracted three times with saturated Na2CO3 solution and three times with ethyl acetate. The organic layers were extracted three times with 1N HCl solution and evaporated to dryness. The crude product was suspended in pentane, filtered and the solid evaporated to dryness. The desired N-(5-bromo-pyridin-2-yl)-2-methylsulfanyl-acetamide (312 mg, 21% yield) was obtained as a yellow solid, MS: m/e=258.9/260.8 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.O>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[C:28]([F:39])([F:38])[F:27])=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
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: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccccc2C(F)(F)F)CC1
Temperature: 115 °C
Yield: 29.8 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (1.00 g, 3.35 mmol) in N,N-dimethylacetamide (purged with nitrogen) (12 mL). Add potassium carbonate (1.11 g, 8.04 mmol) and 2-trifluoromethylbenzeneboronic acid (764 mg, 4.02 mmol) then purge with nitrogen for 15 min. Add deoxygenated water (6 mL) and tetrakis(triphenylphosphine)palladium(0) (0.039 g, 0.034 mmol) and purge with nitrogen for 15 min. Heat at 115° C. for 21 hr. under nitrogen. Cool to room temperature, add water (20 mL) and extract with DCM (4×20 mL). Concentrate the DCM extracts and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:isohexane), to give 3′-(2-trifluoromethylphenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (408 mg, 29%). MS (ES): m/z=409 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[I-].C([N+]1(C)[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)C1C=CC=CC=1>C(O)C.O>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([N:1]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)=[CH:3][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: C[N+]1(Cc2ccccc2)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N2CCC(=O)CC2)cn1
Reaction time: 0.75 h
Yield: 74 %

Procedure:
To a solution of 5-amino-2-methoxypyridine (375 mg, 3.02 mmol) and K2CO3 (49 mg, 0.355 mmol) in ethanol (7 mL) at 80° C. was added a slurry of 1-benzyl-1-methyl-4-oxopiperidinium iodide in water (5 mL) over a 10 minute period. After 45 minutes, the reaction mixture was cooled and partitioned between dichloromethane (10 mL) and water. The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (1:1 Hexanes:EtOAc) to afford 1-(6-methoxypyridin-3-yl)piperidin-4-one (459 mg, 74%) as a light orange solid. 1H NMR (CDCl3) δ: 2.56 (t, J=5.7 Hz, 4H), 3.42 (t, J=5.7 Hz, 4H), 3.87 (s, 3H), 6.69 (d, J=9.3 Hz, 1H), 7.32 (dd, J=9.0, 3.0 Hz, 1H), 7.85 (d, J=3.0 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][OH:23])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:28]=[C:29]=[O:30])(=O)=O.O>C(Cl)Cl>[C:29]([O:23][CH2:22][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)(=[O:30])[NH2:28]
Reactant: CC(C)(C)OC(=O)NC(CO)COc1noc2ccc(Cl)cc12
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC(COC(N)=O)COc1noc2ccc(Cl)cc12
Yield: 85.5 %

Procedure:
To a suspension of 3.43 g of 3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-5-chloro-1,2-benzoisoxazole in 34 ml of methylene chloride is added 1.70 g of chlorosulfonyl isocyanate at -45° to -40° C., and the temperature thereof is elevated to 0° C., after which they are subjected to reaction at the same temperature for one hour. To the reaction mixture is added 10 ml of water and they are subjected to reaction at 20°-25° C. for one hour, after which methylene chloride is removed by distillation under reduced pressure. The crystals obtained are collected by filtration, to obtain 3.30 g of 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-chloro-1,2-benzoisoxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](=[O:15])[NH:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][O:10][CH2:11][C:12]([NH:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[C:33]=2[N:32]=[CH:31][CH:30]=[CH:29]3)=[O:21])=[O:14])=[O:15])=[CH:16][CH:17]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Reactant: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(4-chlorobenzyl)ureidooxy)acetic acid (Compound VI-11) 108 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)-propanamide (Compound IV-11) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[C:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH:9][C:10]=1[CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[O:5])[CH3:2].CO.[OH-].[Li+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[C:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH:9][C:10]=1[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCc1[nH]c(C(=O)OC(C)(C)C)c(C)c1C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1c(CCC(=O)O)[nH]c(C(=O)OC(C)(C)C)c1C
Reaction time: 1 h
Yield: 110.4 %

Procedure:
5-(2-Ethoxycarbonyl-ethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1d (23.6 g, 66.8 mmol) was dissolved in 190 ml of tetrahydrofuran and 90 ml of methanol under stirring, and added with aqueous lithium hydroxide solution (80 ml, 10 mol/L, 0.8 mol) at room temperature. The color of the reaction solution gradually turned from light yellow to cyan, and stirred for another 1 hour. After thin lay chromatography showed the disappearance of starting materials, the resulting mixture was concentrated under reduced pressure to evaporate organic solvent. The residue was adjusted pH to 2 with hydrochloric acid solution (2 mol/L) in an ice-water bath under stirring. White precipitates were formed. The mixture was filtered, and the filter cake was dried to obtain the title compound 5-(2-carboxy-ethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1e (24 g, yield 98%) as a white solid.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[CH3:12][NH2:13]>C(O)C.O>[CH3:12][NH:13][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNCC(O)COc1ccccc1

Procedure:
To a solution of 1,2-epoxy-3-phenoxypropane (15 g), in ethanol (50 ml) was added 25-30% methylamine in water (50 ml) and the mixture heated under reflux for 1 h. The ethanol was removed in vacuo and the residue acidified with 2 N hydrochloric acid. The aqueous solution was extracted with ethyl acetate then made alkaline with 2 N sodium hydroxide and extracted into ether. The combined ethereal extracts were dried (Na2SO4), filtered and evaporated to give a semi-solid (14.8 g). The product was distilled in vacuo to give the title compound as white crystals b.p. 110°/0.07 mm, m.p. 74°-77° (9 g).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[F:11][C:12]1[C:13]([NH2:22])=[C:14]([NH2:21])[C:15]([F:20])=[C:16]([F:19])[C:17]=1[F:18]>>[F:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]2[C:13]=1[NH:22][C:2](=[O:4])[C:1](=[O:8])[NH:21]2
Reactant: Nc1c(N)c(F)c(F)c(F)c1F
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2c(F)c(F)c(F)c(F)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound (Allison, et al., J. Fluorine Chem. 1: 59 (1971)) was prepared using an adaptation of the method of Cheeseman (Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (2.86 mL, 4.1 mmol) and 3,4,5,6-tetrafluoro-1,2-diaminobenzene (380 mg, 2.11 mmol) was heated to reflux with stirring under N2 for 8 h. The reaction was cooled to room temperature and a small amount of purple precipitate was observed. The excess diethyl oxalate was evaporated and the resulting solid was suspended in 20 ml hexanes, vacuum filtered and the solid rinsed with hexanes (20 mL) and ethyl acetate (10 mL). The solid was air dried to yield 244.8 mg (49.9%). mp 330°-331° C. (lit. ca. 300° C. dec.). 1H NMR (d6-DMSO) δ 12.33 (br s, NH). 19F NMR (C6F6 external standard, δ -162.9), δ -157.7(m), -167.9(m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:12])[C:7]([OH:11])=[CH:8][C:9]=1[CH3:10])([O-:3])=[O:2].Br[CH2:14][CH2:15][CH2:16][C:17]([CH3:23])([CH3:22])[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:12][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]([CH3:10])=[CH:8][C:7]=1[O:11][CH2:14][CH2:15][CH2:16][C:17]([CH3:23])([CH3:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1O
Reactant: COC(=O)C(C)(C)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)(C)CCCOc1cc(C)c([N+](=O)[O-])cc1C
Yield: 58.8 %

Procedure:
A mixture of 16.7 g (100 mmol) of 4-nitro-2,5-xylenol, 24.5 g (110 mmol) of 5-bromo-2,2-dimethylvaleric acid, methyl ester (U.S. Pat. No. 4,665,226) and 15.3 g (110 mmol) of anhydrous potassium carbonate in 200 mL of acetonitrile is stirred at reflux for 18 hours overnight. The inorganic solid is removed, washed thoroughly with fresh acetonitrile and the filtrate is evaporated. The solid residue is stirred with a mixture of diethyl ether and 100 mL of 2N potassium hydroxide solution. The aqueous layer is removed and the organic layer washed with 50 mL of 2N potassium hydroxide solution, brine, dried, and evaporated. The crystalline residue is taken up in hexane (hot), treated with charcoal to assist in removal of some insoluble material, concentrated to 200 mL, and cooled to afford 18.2 g of the title compound as pale yellow needles; mp 73°-75° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[C:18]([CH3:24])[N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.C[Si](C)(C)N[Si](C)(C)C.C[N:35]([CH:37]=[O:38])C>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>[CH3:24][C:18]1[N:17]=[C:16]([C:10]2[N:11]=[C:12]3[N:8]([CH:9]=2)[CH2:7][CH2:6][O:5][C:4]2[C:13]3=[CH:14][CH:15]=[C:2]([C:37]([NH2:35])=[O:38])[CH:3]=2)[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=1
Reactant: CN(C)C=O
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C(N)=O)cc2OCC3)n(C(C)C)n1
Temperature: 80 °C
Yield: 95 %

Procedure:
A mixture of 12-bromo-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (1.0 g, 2.6 mmol), hexamethyldisilazane (3.0 mL, 14 mmol), and Pd(PPh3)2Cl2 (0.09 g, 0.13 mmol) in dry DMF (10 mL) was heated under CO atmosphere at 80° C. overnight. Most of the solvent was removed and water (20 mL) was added. The solid was collected by filtration, washed with water, and dried in vacuo to afford 4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-12-carboxamide (1.3 g, 95% yield) as a gray solid. LCMS (ESI) m/z: 353.3 [M+H+].
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][CH2:26][CH2:27][S:28]([N:31]([CH3:33])[CH3:32])(=[O:30])=[O:29]>>[CH3:32][N:31]([CH3:33])[S:28]([CH2:27][CH2:26][CH2:25][O:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:30])=[O:29]
Reactant: O=C(NC1=Nc2c(O)cccc2C2=NCCN12)c1cccnc1
Reactant: CN(C)S(=O)(=O)CCCCl
Product: CN(C)S(=O)(=O)CCCOc1cccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from N-(7-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Intermediate C) and 3-chloro-N,N-dimethylpropane-1-sulfonamide (Intermediate F). High vacuum drying at 60° C. gave the title compound (44 mg, 39%): HPLC MS RT=0.68 min, MH+=457.3; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.27 (2H, bs), 2.84 (6H, s), 3.36-3.37 (2H, m), 4.31 (2H, bs), 4.43 (2H, bs), 4.62 (2H, bs), 7.59-7.61 (1H, m), 7.71 (1H, bs), 7.83-7.86 (1H, m), 7.97-7.98 (1H, m), 8.89 (1H, bs), 9.00 (1H, m), 9.47 (1H, bs).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@:2]1([CH3:9])[C:3]([OH:5])=[O:4].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[OH-].[Na+].Cl>O1CCOCC1.O>[CH2:14]([O:13][C:11]([N:1]1[CH2:8][CH2:7][CH2:6][C@@:2]1([CH3:9])[C:3]([OH:5])=[O:4])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@]1(C(=O)O)CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@]1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To the solution prepared by dissolving 500 mg of H-α-Me-Pro-OH (commercially available from Chem-Impex International Inc.) and 693 mg of benzyl chloroformate in 10 mL of 1,4-dioxane and 5 mL of water, a 1 M aqueous sodium hydroxide solution was added at room temperature so as to keep pH 10, and the solution was stirred at room temperature for 30 minutes. To the reaction solution, 5 M HCl was added so as to adjust the pH to 2, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure to obtain 842 mg of 1-[(benzyloxy)carbonyl]-2-methyl-L-proline [63-1] (hereinafter, referred to as the compound [63-1]).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:24][C@H:25]([C:31]([NH:33][C:34]1[CH:43]=[C:42]2[C:37]([C:38]([CH3:45])=[CH:39][C:40](=[O:44])[O:41]2)=[CH:36][CH:35]=1)=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[NH2:29])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56]>C1(C)C=CC=CC=1>[NH2:1][C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:24][C@H:25]([C:31]([NH:33][C:34]1[CH:43]=[C:42]2[C:37]([C:38]([CH3:45])=[CH:39][C:40](=[O:44])[O:41]2)=[CH:36][CH:35]=1)=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[NH2:29])=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[F:53][C:54]([C:55]([OH:57])=[O:56])([F:59])[F:58]
Reactant: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@@H](N)Cc3ccccc3)ccc12

Procedure:
Boc-Phe-Gly-Leu-Gln-AMC (0.63 g) was deblocked by treatment with trifluoroacetic acid at about 23°. Toluene was added to the resulting reaction mixture, and then the combined solvents were evaporated at reduced pressure , leaving a residue. This residue was redissolved in toluene, and the solvent was then evaporated again to leave a residue, which was dried in vacuo overnight over solid potassium hydroxide to provide 0.69 g of white, solid H-Phe-Gly-Leu-Gln-AMC trifluoroacetate. TLC with 1-butanol:acetic acid: water (4:1:1) showed two spots, Rf 0.58 and Rf 0.51.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:16])([CH3:17])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCOC(=O)C(C)(C)c1ccc(C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOC(=O)C(C)(C)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 101.5 %

Procedure:
To a solution of t butyl 2-(4-methylphenyl)-2,2-dimethylacetate (19.4 g, 83 mmol) in carbon tetrachloride (350 mL) was added N-bromosuccinimide (16.2 g, 92 mmol) and benzoyl peroxide (0.5 g). The mixture was heated under reflux for 1 hour. The mixture was cooled to rt, and the precipitate was removed by filtration. The filtrate was washed with 10% NaHCO3 and brine, dried (Na2SO4), and evaporated to give t butyl 2-(4-bromomethylphenyl)-2,2-dimethylacetate as a light yellow oil (26.4 g, 100%).
Reaction SMILES: [Li].[CH:2](/Cl)=[CH:3]\[CH3:4].C(/[Li])=C\C.[C:10]1([C:16](=[O:21])[C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CCCCCC.CCOCC>[C:10]1([C:16](/[CH:2]=[CH:3]/[CH3:4])([OH:21])[C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(=O)c1ccccc1
Reactant: C/C=C/Cl
Agent: Cl
Agent: [Li]
Agent: [Li]/C=C/C
Solvent: CCOCC
Solvent: CCCCCC
Product: C/C=C/C(O)(C(=O)OC)c1ccccc1
Reaction time: 1 h

Procedure:
Lithium ribbon (1.0% Na content) 6.9 g., 1.0 g. at.) was cut into strips (1.0 cm.=0.089 g.), degreased in hexane and cut into thin strips into ether (200 ml.) under helium. The reaction flask was equipped with dry-ice condenser and trans-propenyl chloride (25.5 g., 0.30 mole) was introduced dropwise during 60 minutes to the rapidly stirred suspension. The reaction was exothermic and was controlled by the addition of the halide. After addition the mixture was stirred for an additional 60 minutes. The trans-propenyllithium slurry was subsequently siphoned (in spurts during 30 minutes by He.pressure) into a stirred solution containing methyl phenylglyoxylate (55.0 g., 0.3 mole) in ether which was cooled to -78°. After 30 minutes of additional stirring, the reaction was warmed to -10° and poured onto 30 ml. of concentrated HCl and ca. 200 g. of ice. The ether layer was separated and the aqueous layer was further extracted with 3×50 ml. of ether. All ether layers were combined and dried over Drierite for 18 hours. After the solvent was stripped, the crude product weighting 58.1 g. (94%) was obtained which on distillation afforded 35 g. (57%) of pure material, b.p. 100° (0.05 mm.).