Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12]COCCOC)[CH:7]=O)[CH3:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:24][C:25]#[N:26]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[C:24](=[CH:7]/[C:6]2[CH:9]=[CH:10][C:11]([OH:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)/[C:25]#[N:26])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: CCOc1cc(C=O)ccc1OCOCCOC
Reactant: COc1ccc(CC#N)cc1OC
Product: CCOc1cc(/C=C(\C#N)c2ccc(OC)c(OC)c2)ccc1O
Yield: 37.7 %

Procedure:
The hydroxyl group of 3-ethoxy-4-hydroxybenzaldehyde (2.0 g) was protected by use of 2-methoxyethoxymethyl chloride (1.5 g) in accordance with (production process 1), to thereby produce 3-ethoxy-4-methoxyethoxymethoxybenzaldehyde (2.8 g, yield: 91%). The thus-produced 3-ethoxy-4-methoxyethoxymethoxybenzaldehyde (2.8 g) and 3,4-dimethoxybenzyl cyanide (2.0 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (1.35 g, yield: 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]/I)[CH3:12].O>C(N(CC)CC)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.[Cu]I>[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]/[C:9]#[C:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([Cl:10])[CH:5]=1)[CH3:12]
Reactant: CCOC(=O)/C=C/I
Reactant: C#Cc1cc(Cl)cc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)/C=C/C#Cc1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 1,3-dichloro-5-ethynyl-benzene (1.52 g, 8.9 mmol) in triethylamine (32.4 mL) was added PdCl2(PPh3)2 (57.15 mg, 0.08 mmol), (E)-3-iodo-prop-2-enoic-acid ethyl ester (1.84 g, 8.1 mmol) and copper(I)iodide (7.7 mg, 0.04 mmol). The reaction mixture was stirred for 2 h at 50° C., whereafter the reaction mixture was cooled to room temperature, water (30 mL) added and the mixture extracted with diethyl ether (3×20 mL). The combined and dried organic phases were evaporated to give crude (E)-5-(3,5-dichlorophenyl)-pent-2-en-4-ynoic acid ethyl ester in 1.1 g yield.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C@@H:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:4]([CH2:5][CH2:6]2)[CH:3]1[C:17]([O:19][CH3:20])=[O:18].[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH2:8][C@@H:7]2[N:9]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@@H:4]([CH2:5][CH2:6]2)[CH:3]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1C(=O)C[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1C(O)C[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.1 %

Procedure:
(1S,5R)-8-Tert-butyl 2-methyl 3-oxo-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate (2 g, 7.04 mmol) was dissolved in MeOH (26 mL), sodium borohydride (280 mg, 7.39 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 1.5 hours. After evaporation, the crude mixture was dissolved in EtOAc, washed with saturated NaHCO3 and water. Dried and concentrate to give 1.75 g of crude product. The crude was carried over the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:8]([C:19](=[O:21])[CH3:20])=[C:7]([CH3:22])[NH:6][C:5]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)(=[O:3])[CH3:2].[I-].[Na+].[ClH:32].[C:33]1([C:39]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C.C(OCC)C>[ClH:32].[C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:8]([C:19](=[O:21])[CH3:20])=[C:7]([CH3:22])[NH:6][C:5]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:42]1[CH2:43][CH2:44][C:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:40][CH2:41]1)(=[O:3])[CH3:2]
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: CC(=O)C1=C(C)NC(CCCCCCBr)=C(C(C)=O)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(=O)C1=C(C)NC(CCCCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)=C(C(C)=O)C1c1cccc([N+](=O)[O-])c1

Procedure:
3.5 g (7.8 mmol) 3,5-diacetyl-1,4-dihydro-2-(6-bromohexyl)6-methyl-4-(3-nitrophenyl) -pyridine are reacted first with 2.3 g (15.6 mmol) sodium iodide, as described for starting compound B, and then with 4.3 g (15.6 mmol)4,4-diphenylpiperidine hydrochloride. Working up is carried out as described for starting compound B. The crude product is chromatographed with toluene/acetone=8/2. The product thus obtained is taken up in 5 ml acetonitrile and the mixture is diluted with 5 ml diethyl ether. The title compound is precipitated by addition of ethereal hydrochloric acid. Yield: 3 g (61%). M.p. 166°-167° C. (acetonitrile).
Reaction SMILES: [C:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=[O:5])[CH2:2][CH2:3][CH3:4].[ClH:19].[H][H].CC(C)=O>O1CCOCC1.[Pd]>[ClH:19].[C:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Oc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CCCC(=O)Oc1ccc(N)cc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
10 g of 2-butanoyloxy-5-nitro-benzoic acid, 8.5 ml of dioxane, 1.5 ml of HCl 4M solution in dioxane and 1.0 g of Pd/C at 5% were loaded into a 300 ml reactor at 16±2° C. After two vacuum-nitrogen cycles, the reactor was saturated with hydrogen at 10 bar and kept at 16±2° C. for 6 hours. At the end, nitrogen atmosphere was restored in the reactor and the reaction mixture was added with 125 ml of acetone at 25° C. The suspension was stirred at 25° C. for 30 minutes to obtain the dissolution of the undissolved product and the carbon suspension was filtered on a celite panel which was then washed with 60 ml of acetone. The resultant solution was then evaporated under vacuum at 30° C. and the solid residue was dried under vacuum at 35° C. for 4 hours to obtain 10 g of the expected product (99% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:13][C@@H:12]([C:14]([O:16]C(C)(C)C)=[O:15])[N:11]([C:21](=[O:34])[C@H:22]([CH3:33])[CH2:23][S:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]1=[O:35]>C1(C)C=CC=CC=1>[CH3:8][N:9]1[CH2:13][C@@H:12]([C:14]([OH:16])=[O:15])[N:11]([C:21](=[O:34])[C@H:22]([CH3:33])[CH2:23][S:24][C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]1=[O:35]
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)N1C(=O)N(C)C[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1C(=O)N(C)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
15 ml of trifluoroacetic acid are added to 4.0 g of tert.-butyl (4S)-1-methyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylate, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is condensed under reduced pressure. Toluene is added to the residue, and said mixture is again condensed under reduced pressure. The residue thus obtained is recrystallized from a mixture of ethyl acetate and n-hexane. 3.2 g of (4S)-1-methyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylic acid is thereby obtained as colorless syrup. The physico-chemical properties of this product are identical with those of the sample obtained in Example 1-(5).
Reaction SMILES: [C:1]([C:4]1[S:5]C(Cl)=C[CH:8]=1)(=O)[CH3:2].[Cl:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.N1CCOCC1.[S]>CC(=O)CC>[NH2:20][C:19]1[S:5][C:4]([CH3:8])=[C:1]([CH3:2])[C:18]=1[C:16]([C:14]1[S:15][C:11]([Cl:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: N#CCC(=O)c1ccc(Cl)s1
Reactant: CC(=O)c1ccc(Cl)s1
Agent: [S]
Solvent: CCC(C)=O
Solvent: C1COCCN1
Product: Cc1sc(N)c(C(=O)c2ccc(Cl)s2)c1C
Yield: 46 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-chlorothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-chlorothiophene-2-carbonyl)acetonitrile (Steps A and B). 2-Butanone (Aldrich), 2-(5-chlorothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 46%; IR (KBr) cm−1: 3377, 3259, 2918, 1551, 1424, 1326, 1266, 1003, 764; 1H NMR (CDCl3):δ 1.90 (s, 3H), 2.17 (s, 3H), 5.77 (bs, 2H), 6.89 (d, 1H, J=4 Hz), 7.16 (d, 1H, J=4 Hz); red solid, mp: 125–127° C. (petroleum ether).
Reaction SMILES: [BrH:1].[N:2]1[N:9]2[C:5]([S:6][C:7]3[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[C:8]=32)=[N:4][CH:3]=1.BrBr>C(O)(=O)C>[BrH:1].[Br:1][CH:11]1[C:10](=[O:14])[C:8]2[N:9]3[N:2]=[CH:3][N:4]=[C:5]3[S:6][C:7]=2[CH2:13][CH2:12]1
Reactant: O=C1CCCc2sc3ncnn3c21
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C1c2c(sc3ncnn23)CCC1Br
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
2-Bromo-1,3-cyclohexadione (4.4 g) prepared in Example 1, Route 1 (A) and 1H-1,2,4-triazole-3-thiol (2.32 g) were dissolved into absolute ethanol (50 ml), and the reaction mixture was heated to reflux for 5 hours. After completion of the reaction, the reaction mixture was cooled and filtered to give 5,6-dihydro[1,2,4]triazolo[5,1-b]benzothiazole-8(7H)-one hydrobromide (2.84 g, compound (IIc) of Reaction Scheme II). The hydrobromide was dissolved into anhydrous acetic acid (20 ml) and an equivalent amount of bromine was added dropwise thereto at a temperature of 100° C., and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was cooled to give the titled compound (95%) as solids.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:23]([CH3:22])(=[O:25])=[O:24])=[CH:6][CH:7]=1
Reactant: Clc1ccc(NCc2cccnc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccc(Cl)cc1

Procedure:
A 5.5 g. portion of 3-(4-chlorophenylaminomethyl)pyridine was dissolved in 50 ml. of dichloromethane and 3.8 g. of potassium carbonate was added. To it was added, dropwise with stirring, 2.4 ml. of methanesulfonyl chloride. The mixture was stirred at ambient temperature for several days, and it was then washed twice with water, dried and concentrated to a solid. It was triturated with petroleum ether and dried to obtain 7.1 g. of the desired product, m.p. 137.5°-140.5°. It was further triturated with diethyl ether and dried to obtain 7.0 g. of purified product, m.p. 137°-141°.
Reaction SMILES: [OH-].[Na+].CO.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=O)=[CH:19][CH:18]=2)=[CH:15][CH:14]=[N:13]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]C#N)=[CH:29][CH:28]=1>O>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:25][N:23]=[C:20]3[CH:21]=[CH:22][C:17]([C:16]4[N:12]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=5[F:5])[N:13]=[CH:14][CH:15]=4)=[CH:18][C:19]=23)=[CH:29][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2F)cc1
Reactant: N#CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Fc1ccc(-c2onc3ccc(-c4ccnn4-c4ccccc4F)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A mixture of sodium hydroxide (282 mg, 7.06 mmol) and MeOH (2.5 ml) was allowed to stir for 1 h at room temperature, 1-(2-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate B) (200 mg, 706 μmol) and commercially available 2-(4-fluoro-phenyl)-acetonitrile (143 mg, 127 μl, 1.06 mmol) were added, and the reaction mixture was allowed to stir for 2 h at 60° C. The reaction mixture was poured into water (20 ml) and extracted with diethyl ether (2×40 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (toluene/ethyl acetate 95:5) followed by crystallization (ethyl acetate/heptane) to yield the title compound as a light yellow solid (184 mg, 70%), MS (ISP) m/z=374.1 [(M+H)+], mp 171° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)[NH2:21]>C(O)(C)C.C(=O)([O-])O.[Na+]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:10]1[C:3]2[C:2]([NH:21][C:20]3[CH:22]=[CH:23][C:24]([O:25][C:26]4[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=4)=[C:18]([CH3:17])[CH:19]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)[CH3:16]
Reactant: CCOC(=O)Cn1ccc2ncnc(Cl)c21
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)Cn1ccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c21
Temperature: 110 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of ethyl (4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate (140 mg) in isopropyl alcohol (0.6 mL) was added 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (188 mg), and the mixture was stirred in an oil bath at a temperature of 110° C. for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (25 mL×3). The organic layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=10/0→9/1). The object fraction was concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (210 mg) as white powder crystals.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]OC)[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[Cl-].C[Al+]C>C1(C)C=CC=CC=1>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:30]([C:29]3[CH:31]=[CH:32][C:26]([O:25][C:24]([F:23])([F:33])[F:34])=[CH:27][CH:28]=3)[CH2:20][CH2:19]2)[CH2:11][CH2:10]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(Cc2ccccc2)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(Cc1ccccc1)CC2
Temperature: 25 °C

Procedure:
To a solution of 1-benzyl-4-(2-methoxyethyl)-piperidine-4-carboxylic acid ethyl ester (5.2 g, 0.017 mol) and 4-(trifluormethoxy)aniline (4.57 ml, 0.034 mol) in toluene (200 ml) under an argon atmosphere at room temperature, was added dimethylaluminium chloride (0.9M solution in heptane, 37 ml, 0.034 mol) and the mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature and quenched was sat. Na2SO4 (aq) solution and the mixture was filtered through Celite® and evaporated under reduced pressure. The crude residue was purified by flash column chromatography (1:3 AcOEt/heptane) to give 8-benzyl-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one as a white solid. MS (ESI): 405.4 (MH+).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:3]1([CH3:8])[CH:4]=[CH:5][C:6]([O:7][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:1][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(C)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a mixture of p-cresol (500 mg, 4.63 mmol) and ethyl 2-bromoacetate (928 mg, 5.56 mmol) in CH3CN (10 mL) was added K2CO3 (3 g, 21.7 mmol). The reaction mixture was stirred at 80° C. for 4 h. The solid was removed by filtration and the filtrate was concentrated to give the title compound which was used in the next step without further purification.
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([C:12](Cl)=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.C(OC([N:22]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[C:31]([C:36](=[O:46])[NH:37][CH2:38][C:39](=[O:45])[NH:40]C(C)(C)C)[CH:30]=2)[CH2:24][CH2:23]1)=O)(C)(C)C.C(N(CC)CC)C.C[Si](Cl)(C)C>C1COCC1.CCOC(C)=O>[CH:7]1([C:12]2[N:37]([CH2:38][C:39]([NH2:40])=[O:45])[C:36](=[O:46])[C:31]3[C:32](=[CH:33][CH:34]=[C:29]([N:25]4[CH2:26][CH2:27][CH2:28][NH:22][CH2:23][CH2:24]4)[CH:30]=3)[N:35]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CC(C)(C)NC(=O)CNC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: NC(=O)Cn1c(C2CCCC2)nc2ccc(N3CCCNCC3)cc2c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
Pyridine (21 mg, 0.022 mL, 0.268 mmol) and cyclopentanecarbonyl chloride (30 mg, 0.223 mmol) were added to an ice-water cooled solution of 4-{4-amino-3-[(tert-butylcarbamoylmethyl)carbamoyl]phenyl}perhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (INTERMEDIATE V.38) (100 mg, 0.223 mmol) in THF (1 mL) and the reaction mixture stirred for 15 min. Solvent was removed in vacuo and the residue partitioned between DCM (10 mL) and water (10 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude material was dissolved in 1,2-dichloroethane (5 mL) and triethylamine (1.04 g, 1.39 mL, 10.28 mmol) and trimethylsilyl chloride (364 mg, 0.428 mL, 3.35 mmol) added. The reaction mixture was heated at reflux temperature for 3 h. The reaction mixture was diluted with EtOAc (10 mL), washed with 1M HCl (aq.) and sodium bicarbonate (aq.) solution. The organic phase was dried (MgSO4) and solvent removed in vacuo. Crude product was purified by chromatography on silica gel with a gradient of DCM to DCM:EtOAc (1:4, v/v) as eluent. The product was dissolved in DCM (5 mL), TFA (0.5 mL) added and the reaction stirred at room temperature for 2 h. The solution was poured directly onto an SCX cartridge and product eluted with 2N NH3/MeOH. Solvent was removed under reduced pressure to afford N-tert-butyl-2-(2-cyclopentyl-4-oxo-6-perhydro-1,4-diazepin-1-yl-4H-quinazolin-3-yl-acetamide (EXAMPLE 7a) (35 mg, 0.082 mmol, 37%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][N:15]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: Clc1ncnc2cc(Br)ccc12
Product: FC(F)(F)c1ccc(Nc2ncnc3cc(Br)ccc23)nc1

Procedure:
Heat a mixture of 7-bromo-4-chloro-quinazoline (200 mg, 0.821 mmol) and 2-amino-5-trifluoromethyl-pyridine (239 mg, 1.48 mmol) at 230° C. for 2 minutes. Cool and partition the solid residue between EtOAc and 10% NaOH. Dry the EtOAc layer (Na2SO4), remove the solvent under reduced pressure, and purify via flash chromatography to yield (7-bromo-quinazolin-4-yl)-(5-trifluoromethyl-pyridin-2-yl)-amine as a yellow solid.
Reaction SMILES: [O:1]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)COc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)Oc1ccccc1
Reaction time: 4 h

Procedure:
Methyl phenoxyacetate (5.0 g, 30 mmol), N-bromosuccinimide (5.4 g, 30 mmol), a few crystals (0.2 to 0.5 g) of benzoyl peroxide, and 50 mL of carbon tetrachloride were placed in a 100 ml flask and heated at reflux with stirring for about 4 hr. The mixture was then allowed to cool, was filtered, and was concentrated by evaporation under reduced pressure to obtain 6.6 g (90 percent of theory) of the title compound as a red oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH:21]([NH2:23])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH:21]([NH:23][C:26](=[O:28])[CH3:27])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1
Solvent: c1ccncc1
Product: CC(=O)NC(C)CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1

Procedure:
A solution of 1-({trans-4-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]cyclohexyl}oxy)propan-2-amine (172 mg) and acetic anhydride (0.24 mL) in pyridine (4 mL) was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (NH, hexane/ethyl acetate). The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (95 mg) as white crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:17]([O:19][C:20](=O)[C:12]=12)=[O:18]>C(O)(=O)C>[O:18]=[C:17]1[C:13]2[C:12](=[N:11][CH:16]=[CH:15][CH:14]=2)[C:20](=[O:19])[N:1]1[CH:2]([CH2:3][CH2:4][C:5]([NH2:6])=[O:7])[C:8]([OH:10])=[O:9]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C1OC(=O)c2ncccc21
Solvent: CC(=O)O
Product: NC(=O)CCC(C(=O)O)N1C(=O)c2cccnc2C1=O
Yield: 25.7 %

Procedure:
A stirred suspension of (S)-glutamine (14.6 g, 100 mmol) and 2,3-pyridinedicarboxylic anhydride (14.9 g, 1 00 mmol) in 100 mL of acetic acid is heated and refluxed for 1 hour. The reaction solution is cooled to form a solid. The solid is removed by filtration and washed with acetic acid to yield 7.11 g (26%) of 2-(1,3-dioxo-4-azaisoindolin-2-yl)glutaramic acid. The pro duct can be further purified by slurring in 700 mL of refluxing ethanol, cooling, filtering, and drying to produce a white powder with a melting point of 222-226° C.; 1H NMR (DMSO-d6)δ 13.25 (br s, 1H, COOH), 9.04 (dd, 1H, J=1.2, 4.9 Hz, pyr), 8.37 (dd, 1H, J=1.2, 7.8 Hz, pyr), 7.85 (dd, 1H, J=4.9, 7.8 Hz, pyr), 7.20 (s, 1--H, CONH2), 6.73 (s, 1H, CONH2), 4.83 (dd, 1H, J=10.2, 4.8 Hz, CHN), 2.55-1.90 (m, 4H, CH2CH2); 13C NMR (DMSO-d6)δ 1173.22, 170.21, 165,8, 165.7, 155.4, 150.9, 131.7, 128.3, 126.9, 51.5, 31.4, 24.0.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)[NH2:3].[Cl:13][CH:14]([C:18](=O)[CH3:19])[C:15](=O)[CH3:16]>>[Cl:13][C:14]1[C:15]([CH3:16])=[N:3][N:2]([C:4]2[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=2)[C:18]=1[CH3:19]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: NNc1ccc(CCO)cc1
Agent: Cl
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1Cl

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 2-(4-hydrazinophenyl)ethanol hydrochloride and 3-chloropentane-2,4-dione: MS (ESI) m/z 251 [M+H]+, 1H-NMR (CDCl3) δ 7.32-7.25 (4H, m), 3.76 (2H, t, J=6.7 Hz), 2.85 (2H, t, J=6.7 Hz), 2.32 (1H, br.s), 2.28 (3H, s), 2.27 (3H, s).