Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]1(B(O)O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>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.O>[C:18]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccccc1Br
Reactant: OB(O)c1cccc2ccccc12
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: C1CCOC1
Product: O=Cc1ccccc1-c1cccc2ccccc12
Yield: 79.9 %

Procedure:
Into a 200-mL eggplant type flask were introduced 6.45 g (34.9 mmol) of 2-bromobenzaldehyde, 5.0 g (29.1 mmol) of 1-naphthylboronic acid, 0.15 g of tetrakis(triphenylphosphine)palladium, 60 mL of tetrahydrofuran, 10 g (73 mmol) of potassium carbonate, and 20 mL of water. This reaction mixture was heated with refluxing overnight. After washing with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution and drying with anhydrous magnesium sulfate, the extract was concentrated to obtain yellow crystals. These crystals were purified by silica gel chromatography (solvent: hexane/toluene) to obtain 5.4 g of 2-(1-naphthyl)benzaldehyde (yield, 81%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][N:6]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:7].[C:16](Cl)(=[O:19])[CH2:17][CH3:18].[OH-].[Na+]>C(=S)=S.O>[CH3:5][N:6]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][CH:11]=1)[CH3:7]
Reactant: CCC(=O)Cl
Reactant: CN(C)CCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: S=C=S
Solvent: O
Product: CCC(=O)c1ccc(CCN(C)C)cc1
Reaction time: 1 h
Yield: 81.3 %

Procedure:
Anhydrous aluminium chloride (66 g) was added to a solution of N,N-dimethylphenethylamine (22.358 g) in dried carbon disulfide (225 ml). Then, propionyl chloride (15.27 g) was added dropwise to the solution at 50° to 60° C. with stirring over a period of about 1 hour and the solution was refluxed with stirring for 4.5 hours. Cold water was added to the solution to decompose the aluminium chloride. The solution was adjusted to weak alkaline with sodium hydroxide solution and extracted with ethyl ether. The ethereal extract was dried over anhydrous sodium sulfate, concentrated and distilled under reduced pressure to give p-N,N-dimethylaminoethylpropiophenone (25 g, 81%) as a fraction boiling at 115°-117° C./1-2 mmHg.
Reaction SMILES: [C:1]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[C:17](#[N:20])[CH:18]=[CH2:19]>O1CCCC1>[C:1]([C:4]1([CH2:19][CH2:18][C:17]#[N:20])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2]
Reactant: C=CC#N
Reactant: NC(=O)C1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Product: N#CCCC1(C(N)=O)c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
One hundred g. of 9-carbamoylfluorene was slurried in 3375 ml. of tetrahydrofuran in a 5-liter flask. The mixture was heated to 45° with stirring, and to it was added 10 ml. of Triton B. The mixture was stirred for 15 minutes at constant temperature, and 26.2 g. of acrylonitrile was then added in one portion. The mixture was stirred at the reflux temperature for 3 hours, and was then allowed to cool to room temperature. The mixture was then concentrated under vacuum to a solid, which was purified as described in Example 1 above to obtain 110 g. of product, analytically identical to the product of Example 1.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][CH:14]([OH:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C.C([O-])(=O)C.[Na+].[H][H]>[Pd].CO.C(O)(=O)C>[OH:21][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][NH:12][C:6]1[C:5]2[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: OC(CNc1ccnc2cc(Cl)ccc12)c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC(CNc1ccnc2ccccc12)c1ccccc1

Procedure:
A mixture of 7-chloro-N-(2-hydroxy-2-phenylethyl)-4-quinolinamine (10 g), 0.8 g of palladium on powdered charcoal (10%), 5 ml of acetic acid, 7 g of sodium acetate 3H2O and 200 ml of methanol was hydrogenated at room temperature with shaking at 30-50 psi until completion of hydrogen uptake. The catalyst was filtered and the solvent evaporated. The oil residue was dissolved in 20 ml of water and the solution made alkaline (pH=10) with and NaOH solution. The crystalline compound was filtered and recrystallized from isopropanol. The yield was 7.5 g, mp 289°-290° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[N:17]3[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=1)=[CH:7][CH:6]=2.[CH:23](B(O)O)=[CH2:24].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([CH2:12][C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]=[CH:3][C:2]([CH:23]=[CH2:24])=[CH:11]4)=[N:14][N:15]=2)[N:18]=1
Reactant: Cc1ccc2nnc(Cc3ccc4ncc(Br)cc4c3)n2n1
Reactant: C=CB(O)O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=Cc1cnc2ccc(Cc3nnc4ccc(C)nn34)cc2c1
Yield: 35 %

Procedure:
To a microwave vessel was added 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline (500 mg, 1.41 mmol, 1 equiv), vinyl boronic acid (299 uL, 1.76 mmol, 1.25 equiv), K2CO3 (390 mg, 2.82 mmol, 2.0 equiv) followed by 1,4-dioxane (10 mL) and water (5 mL). The solution was degassed with nitrogen for 10 min and then dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (51 mg, 0.07 mmol, 0.05 equiv) was added. The microwave vessel was capped and reacted in a microwave reactor at 130° C. for 30 min. The microwave vessel was cooled and then the mixture was extracted into dichloromethane and washed with water. The volatiles were removed in vacuo and the residue absorbed onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-80:20) to obtain the title compound as a brown oil (35% yield). Analytical data presented in Table 1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][CH2:12][C:13]2([OH:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]([CH3:20])=[C:4]([CH3:21])[N:3]=1>[Pt].C(OCC)(=O)C>[NH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH3:21])=[C:5]([CH3:20])[C:6]=1[NH:11][CH2:12][C:13]1([OH:19])[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCC2(O)CCOCC2)c1C
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c(N)c(NCC2(O)CCOCC2)c1C

Procedure:
4-{[(2-Chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol (8.74 g, 27.7 mmol), 10% platinum on carbon (874 mg), and ethyl acetate (185 mL) were combined and placed under hydrogen pressure (50 psi, 3.4×105 Pa) on a Parr apparatus for 4 hours. The reaction mixture was filtered through a layer of CELITE filter aid and the filter cake was washed with 1:1 ethyl acetate:methanol. The filtrate was concentrated under reduced pressure to provide crude 4-{[(3-amino-2-chloro-5,6-dimethylpyridin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].Br[CH2:34][CH2:35][CH2:36][OH:37].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:34][CH2:35][CH2:36][OH:37])[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: OCCCBr
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCO)C[C@H]1Cc1c[nH]c2ccccc12
Reaction time: 9 h
Yield: 77.3 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (5 g) and 3-bromopropanol (1.68 g) in N,N-dimethylformamide (40 ml) was heated at 60° C. in the presence of potassium carbonate (4.55 g). After 9 hours, the reaction mixture was poured into water (400 ml) and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the obtained residue was purified by column chromatography on silica gel using dichloromethanemethanol (30:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-hydroxypropyl)-2-(1H-indol-3-ylmethyl)piperazine (4.36 g) as a powder.
Reaction SMILES: [C:1]([NH:7][CH:8]([C:15]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)=[O:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl>[CH2:2]([C:1]1[O:16][C:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[C:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)NC(CC(=O)OCC)C(=O)c1ccco1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CCCCc1nc(CC(=O)OCC)c(-c2ccco2)o1
Yield: 85.2 %

Procedure:
To a solution of 5.0 g of ethyl 3-pentanoylamino-3-(2-furylcarbonyl)propionate in 50 ml of methylene chloride is added a mixture of 10 g of phosphorus pentoxide and 10 g of diatomaceous earth. The mixture is refluxed for 6 hours under stirring. After the reaction is completed, the mixture is treated in the same manner as described in Example 2. 4.0 g of ethyl 2-[2-n-butyl-5-(2-furyl)-4-oxazolyl]acetate are thereby obtained as an oil. Yield: 85.1%
Reaction SMILES: [CH:1](OCC)=[O:2].[CH2:6]([NH:9][CH2:10][CH:11]=[CH2:12])[CH:7]=[CH2:8].N#N>>[CH2:6]([N:9]([CH2:10][CH:11]=[CH2:12])[CH:1]=[O:2])[CH:7]=[CH2:8]
Reactant: C=CCNCC=C
Reactant: CCOC=O
Agent: N#N
Product: C=CCN(C=O)CC=C
Temperature: 120 °C
Yield: 95 %

Procedure:
Ethyl formate (55.6 g, 750 mmole) and 37.5 g (385 mmole) of N,N-diallyl amine were combined in a 250 mL 3-neck flask equipped with mechanical stirrer, Friedrich condenser, and N2 blanket. The reaction mixture was stirred at reflux temperature (120° C. oil bath) for 24 hours and then sampled by GC to determine if all the N,N-diallylamine was reacted, RT of 0.4 mm. The product was vacuum distilled using a 1-piece apparatus with a fractionation column. The first fraction distilled at 30° C./16 torr. The second fraction N,N-diallylformamide (NDF), distilled at 88°-90° C./10-14 torr. The yield was 95%. Structure was confirmed by NMR.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH:10]([CH2:12][C:13](=O)[CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11].C([BH3-])#N.[Na+].C(N(CC)CC)C>CO.CCCCCC.C(OC(=O)C)C>[CH2:1]([NH:8][CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH:10]([CH3:11])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(=O)CC(C)C
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCC(CC(C)C)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
Benzylamine (3.1 ml, 28 mmol) was added to a stirred mixture of 2-methyloctan-4-one (4.0 g, 28 mmol) and 3 Å molecular sieves in dry methanol (40 ml) under argon. The mixture was stirred at room temperature overnight. Sodium cyanoborohydride (1.77 g, 28 mmol) was added and the mixture stirred overnight. Stirring was stopped and the solution was decanted, from the molecular sieves, into saturated aqueous ammonium chloride. The mixture was filtered, concentrated, ethyl acetate added and the mixtures washed with water. The organics were dried over anhydrous magnesium sulphate, filtered and concentrated to give a yellow oil. Chromatography (silica: 1% triethylamine and 10% ethylacetate in hexane) gave N-benzyl-2-methyl-4-aminooctane (3.0 g, 46%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:34][C:33](=[O:35])[NH:32][N:31]=2)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[NH:31][N:32]=[C:33]([O:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:34]=2)=[CH:28][CH:29]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCS(C)(=O)=O
Reactant: COc1ccc(C2=NNC(=O)C2)cc1
Product: COc1ccc(-c2cc(Oc3ncnc4cc(OCCCS(C)(=O)=O)c(OC)cc34)n[nH]2)cc1
Yield: 0.1 %

Procedure:
Using a procedure analogous to that described in Example 34, 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (150 mg, 0.45 mol) was reacted with 3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (105 mg, 0.54 mol), (prepared as described for the starting material in Example 10), to give 4-(5-(4-methoxyphenyl)pyrazol-3-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (220 mg, 91%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:21])=[CH:18][N:17]=3)[C:13]=2[O:14]C)=[C:5]([CH3:32])[CH:4]=1)#[N:2].[Cl-].[Li+]>CC(N(C)C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:21])=[CH:18][N:17]=3)[C:13]=2[OH:14])=[C:5]([CH3:32])[CH:4]=1)#[N:2]
Reactant: COc1c(-c2ccc(C#N)cc2C)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCOCC3)cn2)c1O
Temperature: 50 °C
Reaction time: 14 h
Yield: 31.2 %

Procedure:
Combined 6-(4-(4-cyano-2-methylphenyl)-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (27.3 mg, 0.063 mmol) and lithium chloride (13.41 mg, 0.316 mmol) in DMA (0.5 mL) then heated at 50° C. using a heating block for 24 hours. Additional portion of lithium chloride (8.05 mg, 0.190 mmol) was added and the reaction mixture was stirred at 50° C. for an additional 14 hours. The reaction mixture was cooled to 23° C., filtered through a Hydrophilic PTFE 0.45 um filter (Millipore Millex™-LCR), rinsed with DMSO (2×0.5 mL), and purified via preparative HPLC (SunFire™ C18, 5 μm, ID 30 mm×75 mm) using a gradient of 30-60% ACN (with 0.035% TFA) in water (with 0.05% TFA). The product containing fractions were combined and concentrated via rotary evaporation to furnish an off-white solid which was collected by filtration, rinsed with water (5×2 mL), and dried in vacuo to give the title compound (8.2 mg, 31.0% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.28 (m, 2 H) 1.58-1.67 (m, 2H) 1.75-1.86 (m, 1 H) 2.43 (s, 3 H) 3.20 (t, J=6.32 Hz, 2 H) 3.27 (td, J=11.75, 2.02 Hz, 2 H) 3.81-3.90 (m, 2 H) 7.60-7.69 (m, 1 H) 7.73 (s, 1 H) 7.78 (br. s., 1 H) 8.05-8.25 (m, 1 H) 8.35-8.45 (m, 1 H) 8.69-8.80 (m, 1 H) 8.89-8.95 (m, 1 H) 13.21 (br. s., 1 H). MS m/z [M+H]+ 418.5.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[C:3]1=[O:25].C(N(C(C)C)CC)(C)C.[C:35]([C:39]1[CH:43]=[C:42]([C:44](O)=[O:45])[N:41]([CH3:47])[N:40]=1)([CH3:38])([CH3:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:35]([C:39]1[CH:43]=[C:42]([C:44]([NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C@H:7]3[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]3[CH2:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[C:3]2=[O:25])=[O:45])[N:41]([CH3:47])[N:40]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Reactant: Cn1nc(C(C)(C)C)cc1C(=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: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)c3cc(C(C)(C)C)nn3C)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (40 mg, 0.08 mmol) in DMF (2 mL) was added diisopropylethylamine (0.1 mL, 0.6 mmol), 3-tert-butyl-1-methyl-1H-pyrazole-5-carboxylic acid (18 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol). The reaction was stirred at RT for 14 h, partially concentrated, and purified by RP-HPLC to affor 20 mg of the title compound. MS found: (M+H)+=538.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1)N.[CH2:19]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[CH2:20][CH3:21].Cl>C(O)(C)C>[CH2:19]([N:22]1[CH2:27][CH2:26][C:25]2[NH:2][C:4]3[C:18]([C:24]=2[CH2:23]1)=[C:8]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3)[CH2:20][CH3:21]
Reactant: CCCN1CCC(=O)CC1
Reactant: NNc1ccc2scc(-c3ccccc3)c2c1
Agent: Cl
Solvent: CC(C)O
Product: CCCN1CCc2[nH]c3ccc4scc(-c5ccccc5)c4c3c2C1

Procedure:
The compound is formed analogously to that described in Example 40, from 13.8 g of 5-hydrazino-3-phenylbenzothiophene hydrochloride and 7.5 g of 1-propyl-4-piperidone by boiling the starting materials in 120 ml of isopropanol containing hydrogen chloride for 4 hours. Melting point: 187°-188° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:18][CH2:19][CH2:20][N:21]([CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([Cl:32])[CH:23]=1)[CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1)=[O:8].[ClH:43]>O1CCOCC1.O>[ClH:32].[ClH:43].[CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:18][CH2:19][CH2:20][N:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[C:24]([Cl:32])[CH:23]=1)[CH2:5][CH2:6][C:7]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:13][CH2:14]2)[C@H:11]([OH:17])[CH2:10]1)=[O:8]
Reactant: COC(=O)[C@H](CCC(=O)N1CCC2(CC2)[C@H](O)C1)NCCN(CCC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H](CCC(=O)N1CCC2(CC2)[C@H](O)C1)NCCN(CCC(=O)O)c1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 184.5 %

Procedure:
A solution of 0.47 g (0.8 mmol) of (S)-2-{2-[(2-tert-butoxycarbonyl-ethyl)-(3-chloro-4-trifluoromethyl-phenyl)-amino]-ethylamino}-5-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-5-oxo-pentanoic acid methyl ester in 2.2 ml of dioxan was cooled (10° C.), treated with 1.9 ml (7.6 mmol) of HCl solution (4 M in dioxane), 2 drops of water and stirred at RT for 22 h. The solution was evaporated, suspended in acetonitrile and evaporated (3×) to yield 0.47 g (92%) of the title compound as light yellow foam. MS (LC/MS): 564 (MH+, Cl).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([NH:8][C:9]([O:11]CC2C=CC=CC=2)=O)[CH2:6][CH:5]([O:19][C:20](=[O:22])[CH3:21])[C:4](=[O:23])[NH:3]1.[N+:24]([C:27]1[CH:37]=[CH:36][CH:35]=[C:29]2C([O:32][C:33](=O)[C:28]=12)=O)([O-:26])=[O:25]>C(O)(=O)C.[Pd]>[N+:24]([C:27]1[CH:37]=[CH:36][CH:35]=[C:29]2[C:28]=1[C:33](=[O:32])[N:8]([CH:7]1[CH2:6][CH:5]([O:19][C:20](=[O:22])[CH3:21])[C:4](=[O:23])[NH:3][C:2]1=[O:1])[C:9]2=[O:11])([O-:26])=[O:25]
Reactant: CC(=O)OC1CC(NC(=O)OCc2ccccc2)C(=O)NC1=O
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)OC1CC(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)NC1=O

Procedure:
A solution of 2,6-dioxo-3-benzyloxycarbonylamino-5-acetoxypiperidine (9 g, 28.2 mmol) and Pd/C (10%, 0.9 g) in acetic acid (90 mL) is shaken under hydrogen (50-60 psi) for 3 hours. The suspension is filtered through a pad of Celite and washed with acetic acid. To the filtrate is added 3-nitrophthalic anhydride (5.4 g, 28.2 mmol), this mixture is heated at reflux for 18 hours, and the solvent is then removed in vacuo to give 3-(4-nitro-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine which can be further purified by column chromatography.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:37])=[C:5]([C:28]([O:35]C)=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:32][O:31][C:30]1[C:3](=[O:2])[C:4]([CH3:37])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])[C:28](=[O:35])[C:29]=1[O:33][CH3:34]
Reactant: COc1c(C)c(Cc2ccc(Oc3cccnc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3cccnc3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 57.7 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyloxy)benzoyl]morpholine (0.022 g, 0.0435 mmol) was dissolved in a mixed solution of acetonitrile (6 ml) and water (2 ml) and after adding thereto CAN (0.060 g, 0.109 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.012 g, 0.0251 mmol, 58%).
Reaction SMILES: C[C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1.C[CH:11]1[CH2:17][C:16](C)(C)C[C:13](=[O:14])[CH2:12]1>>[CH:17]1[CH:16]=[C:9]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)[C:13]([OH:14])=[CH:12][CH:11]=1
Reactant: CC1(C)CCCC(=O)C1
Reactant: CC1CC(=O)CC(C)(C)C1
Product: Oc1cccc(-c2ccccc2O)c1

Procedure:
Following the same procedure as in Example A.2 3 mol of 3,3-dimethylcyclohexanone are used instead of 3 mol of dihydroisophorone. The product had a melting point of 190°-201° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1>ClCCl>[C:11]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1)(=[O:18])[CH2:10][CH2:9][CH3:8]
Reactant: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Solvent: ClCCl
Product: CCCC(=O)Nc1ccc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
To a stirred solution of 15 g. (0.0504 mole) of 4-(4'-aminophenyl)-2,6-di(t-butyl)phenol in 75 ml. of dichloromethane is added dropwise 5.37 g. (0.0504 mole) of n-butyroyl chloride. The reaction is immediate. The solvent is removed by evaporation, and the solid residue is recrystallized, first from aqueous ethanol, then from heptane to provide 4-(4'-butyramidophenyl)-2,6-di(t-butyl)phenol, m.p. 180°-181° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(O[Cl:15])(C)(C)C>CC(O)=O>[Cl:15][C:3]1[C:2]([OH:1])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)OCl
Solvent: CC(=O)O
Product: O=Cc1cccc(O)c1Cl
Yield: 55 %

Procedure:
To a suspension of 3-hydroxybenzaldehyde (20.12 g, 160 mmol) in HOAc (40 mL) was added carefully tBuOCl (20 mL, 176 mmol) with stirring. The reaction became a clear solution and strongly exothermic. It was allowed to cool and stirred for 16 hours, resulting in a white precipitate. The solid was filtered, washed with H2O and dried to give 2-chloro-3-hydroxybenzaldehyde (13.77 g, 55%), GCMS (EI) m/z 156, 158 (M+).