Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:24]=[N:25][C:26](Cl)=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Br-].[CH2:31]([Zn+])[CH2:32][CH3:33]>C1(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)C=CC=CC=1.C1COCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:24]=[N:25][C:26]([CH2:31][CH2:32][CH3:33])=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CCC[Zn+]
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(Cl)nc3)c2C#N)CC1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCc1ccc(Nc2ncnc(OC3CCN(C(=O)OC(C)C)CC3)c2C#N)cn1

Procedure:
In a 25 mL round-bottomed flask fitted with a condenser and N2 inlet was placed 4-[6-(6-chloro-pyridin-3-ylamino)-5-cyano-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (100 mg, 1.3 mmol), n-propylzinc bromide (0.5M in THF, 0.72 mL), tetrakis (triphenylphosphino)palladium (28 mg, 0.024 mmol), and THF (3.5 mL). The reaction mixture was refluxed overnight under N2 atmosphere. The product was purified by preparative HPLC. 1H NMR (CDCl3, 400 MHz) δ 1.03 (t, 3H), 1.26 (d, 6H), 1.85 (m, 4H), 1.98 (m, 2H), 3.04 (t, 2H), 3.44 (m, 2H), 3.77 (m, 2H), 4.94 (m,1H), 5.46 (m, 1H), 7.57 (d, 1H), 8.34 (s, 1H), 8.51 (s, 1H), 8.56 (d,1H),9.42 (s, 1H). Exact mass calculated for C22H28N6O3 424.22, found 425.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:12]2[CH2:11][N:10]([C:13](=[O:15])[CH3:14])[CH2:9][CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=1.Cl.O1CCOCC1>COCCO>[C:13]([N:10]1[CH2:11][C:12]2[C:2]([NH:1][C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=4[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:34])=[CH:19][N:18]=3)=[CH:3][CH:4]=[CH:5][C:6]=2[NH:7][CH2:8][CH2:9]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCNc2cccc(N)c2C1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cccc3c2CN(C(C)=O)CCN3)ncc1Cl
Yield: 3.8 %

Procedure:
1-(6-Amino-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-ethanone (35 mg, 0.17 mmol) was dissolved in 2-methoxyethanol (3 mL) and the mixture was treated with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (25 mg, 0.084 mmol) and 4N HCl/dioxane (0.05 mL, 0.17 mmol). The reaction was then irradiated at 140° C. for 20 minutes. The mixture was then reduced en vacuo and the crude mixture was purified by prep HPLC to afford 1.47 mg of 2-[2-(4-Acetyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzamide as a light brown foam. LC/MS (ESI)=466.37 (M+H). 1H NMR (400 MHz, MeOD, d4) δ 8.80 (m, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 7.79 (m, 3H), 7.64 (m, 3H), 7.35 (m, 1H), 6.97 (m, 1H), 6.49 (m, 1H), 3.64 (m, 2H), 3.35 (m, 2H), 3.21 (m, 2H), 2.98 (s, 3H), 1.94 (d, 3H, J=7.07 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.[C:19](Cl)(Cl)=[O:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:19](=[O:20])[O:14][C:12](=[O:13])[C:11]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]23)=[CH:7][CH:8]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(Nc2ccccc2C(=O)O)cc1
Product: COc1ccc(-n2c(=O)oc(=O)c3ccccc32)cc1

Procedure:
The starting material, N-(4-methoxyphenyl)isatoic anhydride was prepared from 2-(4-methoxyphenylamino)benzoic acid and phosgene according to the procedure of Example 1, part (b).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1>CN(C)C=O>[N:1]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCc1ccc(CBr)cc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(CN2CCCC2)cc1

Procedure:
0.446 mL (5.44 mmol) of pyrrolidine and 1.366 g (9.882 mmol) of potassium carbonate are added to 20 mL of dimethylformamide. 1.038 g (4.941 mmol) of (4-bromomethyl-phenyl)-acetonitrile are added with stirring and the mixture is stirred for 12 hours at RT. The reaction mixture is evaporated down in the rotary evaporator and the residue is extracted with EtOAc and water. The organic phase is dried over magnesium sulphate and the solvent is removed using the rotary evaporator.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][OH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[Si:1]([O:18][CH2:19][CH2:20][CH:21]=[O:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCCCO)(c1ccccc1)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-(tert-butyl-diphenylsilyloxy)-1-propanol (1 mmole) in methylene chloride (7 mL) was treated with powder molecular sieves (4 A, 0.5 equiv. wt/wt) and pyridinium chlorochromate (1.5 mmole) at 0° C. The resulting mixture was stirred at room temperature for 2 h, and diluted with diethyl ether (7 mL) and stirred at room temperature for.another 30 min. Filtration, evaporation and chromatography gave 3-(tert-butyldiphenylsilyloxy)-1-propanal as a clear oil.
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[O:12][C@@:11]1([F:34])[CH2:25]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.N.C[OH:37]>>[F:16][C@:14]1([CH3:15])[C@H:10]([OH:9])[C@@:11]([F:34])([CH2:25][OH:37])[O:12][C@H:13]1[N:17]1[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]1=[O:24]
Reactant: CO
Reactant: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@@](F)(CC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: N
Product: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@](F)(CO)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Chiral (2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,4-difluor-O-2-benzoylmethyl-4-methyl-tetrahydrofuran-3-yl benzoate (0.34 g, 0.7 mmol) was dissolved into methanol, and a solution of ammonia in methanol (7 N, 20 mL) was added. The reaction mixture was stirred at room temperature for overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH=20:1) and pre-HPLC to afford the title compound as a white solid (0.074 g, 38%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCCCc1ccccc1
Reaction time: 18 h
Yield: 57 %

Procedure:
To a solution of 5-phenylpentanol (15.0 g, 91 mmol) in methylene chloride was added pyridinium chlorochromate (24.6 g, 114 mmol) under an atmosphere of dry nitrogen at room temperature. After 18 hours, the mixture was filtered through a bed of Celite®, and purified by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane to give the aldehyde in 57% yield.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:3]1.[NH2-].[Na+].Cl[CH2:22][CH2:23][N:24]([CH3:28])[CH2:25][CH2:26]Cl>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=3)[N:2]([N:1]3[CH2:26][CH2:25][N:24]([CH3:28])[CH2:23][CH2:22]3)[CH:3]=2)=[CH:13][CH:14]=1
Reactant: Cc1ccc2c(c1)c(-c1ccc(F)cc1)cn2N
Reactant: CN(CCCl)CCCl
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c(-c1ccc(F)cc1)cn2N1CCN(C)CC1
Temperature: 25 °C

Procedure:
To a mixture of 1-amino-3-(4-fluorophenyl)-5-methyl-1H-indole 19a (1 g) and toluene (20 ml) was added a 50% suspension of sodium amide in xylene (1.0 ml). After reaction for 15 min at room temperature a solution of N,N-bis(2-chloroethyl)methylamine (0.8 g) in toluene was added slowly and the mixture was refluxed for 3 h. After cooling to room temperature, the solvents were evaporated in vacuo and water (100 ml) was added. The mixture was extracted with ethyl acetate (2×50 ml) and the combined organic phases were dried (Na2SO4). Evaporation of the solvents in vacuo afforded the title compound, which was purified by column chromatography on silica gel (eluted with ethyl acetate/ethanol 4:1 containing 4% triethylamine) and crystallized from heptane. Yield: 0.5 g, mp 105°-107° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CN1CCN(c2cc(Cl)ncn2)CC1
Reaction time: 18 h
Yield: 84.2 %

Procedure:
4,6-dichloropyrimidine, (2 g, 13.4 mmol), and N-methylpiperazine, (1.5 mL, 13.4 mmol), were dissolved in 20 mL THF along with TEA (1.9 mL, 13.4 mmol) and stirred for 18 h. The THF was evaporated and 10 mL water was added and then extracted with DCM. The DCM was dried with sodium sulfate, filtered and evaporated affording 2.4 g of 4-Chloro-6-(4-methyl-piperazin-1-yl)-pyrimidine as a yellow waxy solid which was used without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11]([NH2:14])(=[O:13])=[O:12].C1([O:21][C:22](=O)[NH:23][C:24]2[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([CH3:32])[N:25]=2)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl>C(#N)C.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11]([NH:14][C:22]([NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([CH3:32])[N:25]=1)=[O:21])(=[O:13])=[O:12]
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Reactant: NS(=O)(=O)c1sccc1C1OCCO1
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2sccc2C2OCCO2)n1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To 0.47 g of 3-(1,3-dioxolan-2-yl)thiophene-2-sulfonamide in 20 ml of acetonitrile was added 0.52 g of phenyl(4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate and 0.3 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). After stirring at ambient temperatures for two hours the solution was diluted to 50 ml with water and the pH was adjusted to 3 by the addition of hydrochloride acid. The resultant solution was extracted with methylene chloride and the methylene chloride phase was dried over magnesium sulfate, filtered and evaporated. Trituration of the residue with butyl chloride yielded 0.6 g of the product, m.p. 164°-166°. Infrared absorption spectra showed peaks at 1700, 1600 and 1550 cm-1, consistent for the desired structure. ##STR27##
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[C:12](=[O:18])[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:3]([N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[C:12](=[O:18])[C:13](=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCC2CCC1N2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CC2CCC1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100.9 %

Procedure:
A 5N sodium hydroxide solution (1.62 mL, 0.5 equiv.) was added to (±)-8-benzyl-8-aza-bicyclo[3.2.1]octan-2-one (3.49 g, 16.2 mmol), followed by a solution of benzaldehyde (2.59 mL, 2.69 g, 16.2 mmol) in ethanol (160 mL). The solution was stirred at ambient temperature for 4.5 h. The solution was concentrated under reduced pressure, and the residue was taken up in dichloromethane (160 mL). The mixture was washed with water (160 mL) and brine (160 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give crude product (4.96 g, theoretical yield 4.92 g) as an orange oil.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1F)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH2:3][Cl:2])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: ClCc1ncc[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-n2ccnc2CCl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(Chloromethyl)imidazole hydrochloride (920 mg) was dissolved in 5 ml of acetonitrile. To this solution was added 830 μL of 2,4-dinitrofluorobenzene and 2.5 g of potassium carbonate. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried (sodium sulfate) and concentrated. The crude reaction product was purified by flash silica gel chromatography (1:1 ethyl acetate-hexane elution) to give 710 mg of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:18]2)=[C:5]2[CH:13]=[N:12][N:11]([CH2:14][CH3:15])[C:6]2=[N:7][C:8]=1[CH2:9][CH3:10].C(N(CC)CC)C.[Br:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](Cl)=[O:48])=[CH:45][CH:44]=1.O>ClCCl>[Br:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][C:46]([C:47]([NH:1][CH2:2][C:3]2[C:4]([NH:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:18]3)=[C:5]3[CH:13]=[N:12][N:11]([CH2:14][CH3:15])[C:6]3=[N:7][C:8]=2[CH2:9][CH3:10])=[O:48])=[CH:50][CH:51]=1
Reactant: O=C(Cl)c1ccc(CCCCOCCCCBr)cc1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCN(C(N)=O)CC2)c1CN
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCN(C(N)=O)CC2)c1CNC(=O)c1ccc(CCCCOCCCCBr)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
A solution of 4-{[5-(aminomethyl)-1,6-diethyl-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}-1-piperidinecarboxamide (0.21 g, 0.6 mmol, e.g. which can be as prepared in Intermediate 17) and triethylamine (0.21 ml, 1.52 mmol, 2.5 equivalents) in dichloromethane (20 ml) was stirred and cooled in an ice/water bath under an atmosphere of nitrogen. 4-{4-[(4-Bromobutyl)oxy]butyl}benzoyl chloride (0.32 g, 0.91 mmol, 1.5 equivalents, e.g. which can be as prepared in Intermediate 26) was added portion-wise over 2 minutes, and the mixture was stirred at 0° C. for 10 minutes and then at room temperature overnight. Iced water was added to the reaction mixture and the organic phase was separated and collected through a hydrophobic frit. The aqueous phase was extracted with dichloromethane (50 ml), and the combined organic extracts were evaporated to dryness to give a whitish foam. The residue was purified by passing through a 20 g silica column, eluting with a gradient of cyclohexane/ethyl acetate followed by a gradient of ethyl acetate/methanol. The fractions containing the product (obtained from 9:1 ethyl acetate/methanol) were pooled and evaporated to dryness to give the title compound as a pale yellow foam (0.27 g). LCMS showed MH+=656/658 (Bromine isotope pattern); TRET=2.88 min.
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])([CH3:10])([CH3:9])[CH3:8].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[CH2:18]([O:17][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][C:11]=1[C:7]([CH3:10])([CH3:9])[CH3:8])[C:1](=[O:5])[CH:2]([CH3:4])[CH2:3]2)[CH:19]([CH3:21])[CH3:20]
Reactant: C=C(C)C(=O)O
Reactant: CC(C)COc1ccccc1C(C)(C)C
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: CC(C)COc1cc2c(cc1C(C)(C)C)C(=O)C(C)C2
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
A mixture of 75.1 g (0.872 mol) of methacrylic acid and 90.0 g (0.436 mol) of 1-tert-butyl-2-isobutoxybenzene was added dropwise to Eaton's reagent (prepared from 119 g of P4O10 and 600 ml of MeSO3H) for 2 h at 50° C. The resulting mixture was stirred at 50° C. for 30 min, then cooled to room temperature, and poured into 1 liter of cold water. The crude product was extracted with 3×200 ml of dichloromethane. The organic extract was washed with aqueous K2CO3, dried over Na2SO4, and then passed through a pad of silica gel (40-63 um). The silica gel pad was additionally washed by 100 ml of dichloromethane. The combined elute was evaporated to dryness. The residue was distilled in vacuum, b.p. 155-170° C./5 mm Hg. The product was purified by flash chromatography on silica gel 60 (40-63 um; eluent: n-hexane-dichloromethane-ether=25:25:1, vol.) to give 91.9 g (76%) of the title indanone.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:17][C:18]1C=CC(CC(O)=O)=C[CH:19]=1.C(Cl)(=O)C>N1C=CC=CC=1>[C:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1)(=[O:17])[CH3:19]
Reactant: O=C(O)C1(c2ccc(O)cc2)CCCCC1
Reactant: O=C(O)Cc1ccc(O)cc1
Solvent: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C2(C(=O)O)CCCCC2)cc1
Reaction time: 0.25 h
Yield: 23.6 %

Procedure:
To a solution of 1-(4-hydroxyphenyl)cyclohexanecarboxylic acid (10) (1.264 g crude material, obtained from 1.000 g (6.57 mmol) of 9) in pyridine (5 ml) under argon atmosphere at 0° C. acetyl chloride (0.541 g, 7.61 mmol) slowly (ca. over 10 minutes) was added and the mixture was stirred for 15 minutes at this temperature. The ice bath was removed and the reaction mixture was stirred at ambient temperature for 3 hours, then the content was poured into ice water (30 ml) and the pH of the medium was brought to 1-2 by adding conc.HCl. The mixture was extracted with ethyl acetate (2×40 ml), the organic extract was washed successively with water (30 ml), brine (15 ml), and dried (Na2SO4). The solvent was evaporated, the residue was dissolved in toluene and chromatographed on silica gel (100 g) with petroleum ether-dioxane-acetic acid (8:2:0.1) as eluent affording the title compound (0.406 g, 23.5% based on 9) as a white solid. 1H NMR (CDCl3, HMDSO) δ: 1.06-1.98 (8H, m); 2.28 (3H, s); 2.30-2.63 (2H, m); 7.09 (2H, d, J=8.6 Hz); 7.46 (2H, d, J=8.6 Hz); 10.49 (1H, br s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:13][CH2:12]1)[CH3:9])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C[C@H]1CC[C@H](CCC(=O)O)CC1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CN(C[C@H]1CC[C@H](CCCO)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.898 g (3.0 mmol) of trans-3-{4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-cyclohexyl}-propionic acid dissolved in 10.0 ml of tetrahydrofuran were added slowly and at 0° C. to 4.5 ml of an 1M solution of boran-tetrahydrofuran-complex in tetrahydrofuran. The reaction mixture was then stirred at room temperature for 1 hour. Subsequently, 10 ml of methanol were added and the reaction mixture evaporated. It was then poured into 50 ml of an ice/water/aqueous sodium hydrogen carbonate mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 4:1 v/v mixture of dichloromethane and ether as the eluent giving 0.690 g (80.6%) trans-[4-(3-hydroxy-propyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester as colorless viscous oil, MS: 286 (MH+).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:15]COCCOC)=[CH:7][C:8]([CH3:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.[CH3:27]O>>[CH3:27][O:12][C:10](=[O:11])[C:9]1[CH:13]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[CH:7][C:8]=1[CH3:14]
Reactant: CO
Reactant: COCCOCOc1cc(C)c(C(=O)O)cc1C(C)(C)C
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C(C)(C)C)c(O)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-tert-butyl-4-(2-methoxy-ethoxymethoxy)-2-methyl benzoic acid from Example AAA (20.9 g, 70.5 mmol), MeOH (150 mL), and H2SO4 (10 mL) was refluxed for 5 hours and stirred overnight at room temperature. The mixture was concentrated by half, diluted with H2O, and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give the title compound. 1H NMR (CDCl3) δ 1.36 (s, 9 H), 2.48 (s, 3 H), 3.82 (s, 3 H), 6.48 (s, 1 H), 7.87 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl>C1(C)C(C)=CC=CC=1>[N:1]1([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: ClCCNCCCl
Reactant: CCOC(=O)c1cccc(N)c1
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cccc(N2CCNCC2)c1
Reaction time: 48 h
Yield: 68.4 %

Procedure:
Ethyl 3-aminobenzoate (1.65 g) was dissolved in xylene (20 ml), and bischloroethylamine hydrochloride (1.79 g) was added to the solution. The mixture was heated under reflux with stirring for two days. The solvent was removed from the reaction solution by distillation under the reduced pressure. Water and a saturated aqueous sodium hydrogencarbonate solution were added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=9:1−5:1) to give 1.60 g (70.0%) of ethyl 3-piperazin-1-yl-benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(Cl)Cl.[C:14](Cl)(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(N(CC)CC)C>[C:14]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Nc1ccc2cc[nH]c2c1
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)Nc1ccc2cc[nH]c2c1
Reaction time: 1 h

Procedure:
A solution of 4.24 g. 6-aminoindole in 300 ml. methylene chloride was stirred at 0° C. and 5.4 ml triethylamine followed by 4.2 ml. hexanoyl chloride was then added. The dark mixture was stirred for 1 hour and then filtered to remove a white precipitate. The filtrate was diluted with methylene chloride; washed sequentially with 10% w/v sodium hydrogen sulphate water, and brine; dried (MgSO4); and evaporated. The residue was crystallized from ethyl acetate and hexane to give 6-hexanamidoindole (E) as a white solid. Partial evaporation of the mother liquor gave a second crop of solid giving a combined yield of 4.5 g. (65%); NMR: 0.9 (t, 3H, CH3), 1.4 (m, 4H, CH3CH2CH2), 1.8 (m, 2H, CO.CH2CH2), 2.4 (t, 2H, CO.CH2), 6.5 (m, 1H, H3), 6.8 (dd, 1H, H5), 7.2 (m, 2H, CO.NH+H2), 7.5 (d, 1H, H4), 8.1 (bs, 1H, H7), 8.3 (br, 1H, NH).