Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2.CN(C)[C:18]1[O:19][C:20](=[O:28])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=1>C1(C)C(C)=CC=CC=1>[CH:1]([N:4]1[C:20](=[O:28])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[NH:23][C:18]1=[O:19])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Solvent: Cc1ccccc1C
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)n1c(=O)cc(C(F)(F)F)[nH]c1=O
Reaction time: 3 h
Yield: 53.9 %

Procedure:
Isopropylamine (1.2 g, 20.3 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU, 6 mL) are added to a solution of 2-dimethylamino-4-trifluoromethyl-6H-1,3-oxazin-6-one (4.0 g, 19.2 mmol) in xylene (34 mL). The resultant reaction mixture is held at 100° C. for 3 hours, cooled, washed with 5 wt. % HCl (40 mL), and extracted with ethyl acetate. The combined organic extracts are concentrated and triturated with heptane. The solids are filtered and dried to give the title product as a yellow powder (2.3 g, 54% yield, mp 127°-129° C.) which is identified by 1H NMR (DMSO-d6) δ 6.11 (1H, s), 4.96 (1H, sp), 1.35 (6H, d) ; and 19F NMR δ -68.9 (s).
Reaction SMILES: [N:1]1([C:10](=[O:12])[CH3:11])[CH2:6][CH2:5][CH:4]([C:7](=[O:9])[CH3:8])[CH2:3][CH2:2]1.[Br:13]Br>CO>[C:10]([N:1]1[CH2:6][CH2:5][CH:4]([C:7](=[O:9])[CH2:8][Br:13])[CH2:3][CH2:2]1)(=[O:12])[CH3:11]
Reactant: BrBr
Reactant: CC(=O)C1CCN(C(C)=O)CC1
Solvent: CO
Product: CC(=O)N1CCC(C(=O)CBr)CC1
Reaction time: 3 h

Procedure:
1,1′-(Piperidine-1,4-diyl)diethanone (38.0 g, 225 mmol) was dissolved in methanol (700 mL) and bromine (12.1 mL, 236 mmol) was added. After agitating for 3 hours the solvent was removed. The resulting solid was washed with ethyl acetate, then distributed between ethyl acetate and sodium carbonate. The organic phase was separated, washed with brine, dried and evaporated to give the title compound.
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])[CH:3]1[O:7][C:6](=[O:8])[CH:5]=[C:4]1[O:9][CH3:10].[Br:21]Br>C(#N)C>[Br:21][C:5]1[C:6](=[O:8])[O:7]/[C:3](=[CH:2]\[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])/[C:4]=1[O:9][CH3:10]
Reactant: COC1=CC(=O)OC1C(O)c1ccccc1C(F)(F)F
Reactant: BrBr
Solvent: CC#N
Product: COC1=C(Br)C(=O)O/C1=C\c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 6 %

Procedure:
A stirred solution of 5-{hydroxy-[2-(trifluoromethyl)phenyl]methyl}-4-methoxy-5H-furan-2-one (2.9 g, 10.1 mmol) in acetonitrile at room temperature is treated dropwise with bromine (0.52 ml, 10.1 mmol), stirred for 24 h and concentrated in vacuo. The resultant residue is diluted with CH2Cl2 and triethylamine (4.25 ml), cooled in an ice bath, treated with methane sulfonyl chloride (1.6 ml), stirred for 0.5 h at ice bath temperatures, allowed to warm to room temperature for 2 h and diluted with EtOAc and water. The organic phase is separated, dried over MgSO4 and concentrated in vacuo. This residue is flash chromatographed (SiO2, hexane/EtOAc as eluent) to afford the title product as a white solid, 0.20 g (6% yield), mp 136-138° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:37][CH2:38][CH:39](CO)[OH:40]>>[CH2:1]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH:39]([OH:40])[CH2:38][OH:37])=[O:21])=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OCC(O)CO
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(=O)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A mixture of 2.25 g. of methyl 4-(4-tetradecenylamino)benzoate, 280 mg. of glycerol, and 1.37 g. of p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield the product as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[CH3:29][N:25]1[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=[C:20]([O:1][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([O:11][C:12]4[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=4)=[C:7]([CH:10]=3)[C:8]#[N:9])[CH:30]=[C:24]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: Cc1ccc(Oc2ccc(CO)cc2C#N)cn1
Product: Cc1ccc(Oc2ccc(COc3cc4n(c(=O)n3)CCCN4C)cc2C#N)cn1

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 5-(hydroxymethyl)-2-((6-methylpyridin-3-yl)oxy)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:9]=[C:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]1=[O:23].[NH:24]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([C:33](O)=[O:34])[C:27]=2[CH:26]=[CH:25]1.C1C=CC2N(O)N=NC=2C=1.Cl>O.CN(C=O)C>[C:11]1([CH:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:8]2[CH:7]=[CH:6][C:5](=[O:23])[N:4]([CH2:3][CH2:2][NH:1][C:33]([C:28]3[C:27]4[CH:26]=[CH:25][NH:24][C:32]=4[CH:31]=[CH:30][CH:29]=3)=[O:34])[CH:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: NCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O)c1cccc2[nH]ccc12
Yield: 59 %

Procedure:
To a solution of 1-(2-aminoethyl)-5-(diphenylmethyl)-2(1H)-pyridinone (75.0 mg), a mixture of indole-4-carboxylic acid (39.7 mg), HOBt (36.6 mg) and DMF (3.0 mL) was added WSCD. HCl (52.0 mg) at ambient temperature and the mixture was stirred at the same temperature for 18 hours. The resulting mixture was diluted with water (10.0 mL) and extracted with EtOAc (15 mL). The organic layer was washed successively with 1M HCl aqueous solution, saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:MeOH=90:10) to afford N-{2-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]ethyl}-1H-indole-4-carboxamide (65 mg) as a yellow amorphous powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][CH:17]([C:19]1[O:23][C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:21][C:20]=1[CH:34]([CH3:36])[CH3:35])[CH3:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].I[CH3:40]>O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:40])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][CH:17]([C:19]1[O:23][C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)=[N:21][C:20]=1[CH:34]([CH3:35])[CH3:36])[CH3:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1cc2cc(OCC(C)c3oc(-c4ccc(C(F)(F)F)cc4)nc3C(C)C)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc2cc(OCC(C)c3oc(-c4ccc(C(F)(F)F)cc4)nc3C(C)C)ccc2n1C

Procedure:
5-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-1H-indole-2-carboxylic acid ethyl ester (0.117 g, 0.234 mmol) is stirred with sodium hydride, 60% mineral oil (0.011 g, 0.28 mmol) and NN-dimethyl formamide (12 mL). Iodomethane (16 uL, 0.26 mmol) is added and the mixture is stirred at 80 deg C. 2 hr, and room temperature 18 hr. The mixture is diluted with water (50 mL), and the product is extracted into ethyl acetate (2×50 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered, concentrated, and purified via silica gel chromatography eluting with 8:2 hexanes:ethyl acetate to 6:4 hexanes:ethyl acetate to afford the title compound as a tan solid, 0.062 g, 51%). MS M++1 515. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:22]1[CH:30]=[C:29]([O:31][CH3:32])[C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])(=[O:13])=[O:12].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>O1CCCC1>[CH3:38][O:37][C:35](=[O:36])[CH2:34][N:14]([S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:4]([OH:3])[C:22]1[CH:30]=[C:29]([O:31][CH3:32])[C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1)(=[O:12])=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: COC(=O)CBr
Reactant: COc1cc(C(O)c2ccccc2S(=O)(=O)Nc2ccccc2C)cc2c1OCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CN(c1ccccc1C)S(=O)(=O)c1ccccc1C(O)c1cc(OC)c2c(c1)OCO2
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
Sixty percent sodium hydride suspension in oil (0.422 g, 10.55 mmol) was washed with tetrahydrofuran and was added to tetrahydrofuran (175 mL). To this was added 2-[hydroxy-(7-methoxy-benzo[1,3]dioxol-5-yl)-methyl]-N-o-tolyl-benzenesulfonamide (4.1 g, 9.59 mmol). After stirring for 30 minutes, methyl bromoacetate (1.09 mL, 11.5 mmol) was added followed by stirring at reflux for 18 hours. The mixture was evaporated to an oil in vacuo, and the residue was resuspended in ethyl ether, washed with 1N citric and brine. The solution was dried over anhydrous magnesium sulfate, filtered, and evaporated to a solid. The material was chromatographed on 300 g silica gel eluted with a mixture of ethyl acetate and hexane (35:65). The appropriate fractions were concentrated in vacuo from ethyl ether giving a solid, 4.29 g, 89.5% yield. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21]([O:23]CC)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO>[C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:19])([F:20])[F:18])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21]([OH:23])=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
Ethyl 4-phenyl-8-(trifluoromethyl)quinoline-3-carboxylate (35.96 g, 104.14 mmol) was taken into THF/MeOH (300 mL of 1:1 mixture) along with 2 M NaOH (200 mL) and heated at 70° C. for 20 minutes. The organics were removed and the remaining aqueous layer was cooled to 0° C. and acidified with concentrated HCl. The mixture was concentrated and the resulting material was passed through a silica gel column using CH2Cl2, then 20% MeOH in CH2Cl2. The fractions were combined and the volume was reduced and then diluted to twice the volume with hexane and placed in a freezer overnight. A solid precipitated which was filtered and dried to yield the carboxylic acid as a brown solid (14.03 g). MS (ESI) m/z 318 ([M+H]+); MS (ESI) m/z 316 ([M−H]−).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J33) (228 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow oil (373 mg, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: O=C(Nc1cccnc1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C(=O)Nc2cccnc2)c1
Yield: 86 %

Procedure:
A solution of 3-(3-nitrobenzoylamino)-pyridine (2 g, 8.23 mmol) in ethanol (200 ml) was treated with 10% palladium on charcoal (0.5 g) and hydrogenated at atmospheric pressure for 4 h. Filtration and evaporation afforded the product as a white solid (1.51 g, 86%)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.Br[CH2:27][O:28][C:29](=[O:31])[CH3:30].O>CN(C)C=O>[CH3:27][O:28][C:29](=[O:31])[CH2:30][N:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:25][CH2:24]1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CC(=O)OCBr
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
A solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (60 mg, 0.17 mmol, Example 59) and bromomethylacetate (60 mg, 0.39 mmol, Aldrich) in dimethylformamide (1.5 mL) was stirred at room temperature for 6 hours. The solution was poured into water and extracted into methylene chloride (2×). The combined organic extracts were washed with 5% aqueous sodium bicarbonate. The organic solution was dried (Na2SO4) and solvent was removed under vacuum to give a crude solid. Purification was by silica gel chromatography to give [4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin- 1-yl]-acetic acid methyl ester as a white solid. HRMS, observed: 418.1888; Calcd for M+: 418.1885.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[CH:4]1([Zr+3:9])[CH:8]=[CH:7][CH:6]=[CH:5]1.C(COC)OC.[CH3:16][Si:17]([CH3:27])([CH3:26])[O:18][CH2:19][CH2:20][C-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[K+]>C1(C)C=CC=CC=1>[Cl-:1].[Cl-:1].[CH:4]1([Zr+2:9][C:21]2([CH2:20][CH2:19][O:18][Si:17]([CH3:16])([CH3:27])[CH3:26])[CH:22]=[CH:23][CH:24]=[CH:25]2)[CH:8]=[CH:7][CH:6]=[CH:5]1
Reactant: C[Si](C)(C)OCC[c-]1cccc1
Reactant: [Zr+3]C1C=CC=C1
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: C[Si](C)(C)OCCC1([Zr+2]C2C=CC=C2)C=CC=C1
Reaction time: 12 h
Yield: 27 %

Procedure:
To a suspension of 3.52 g (10 mmol) of an adduct of cyclopentadienyl zirconium trichloride with dimethoxyethane in toluene, a suspension of 2.2 g (10 mmol) of potassium (2-trimethylsiloxy-ethyl)-cyclopentadienide in toluene is added. The addition is carried out at −78° C. An orange-brown suspension is immediately formed; it is maintained under stirring for 12 hours; then it is left settling and it is filtered. The obtained orange solution is concentrated up to 5 ml and hexane is added, so that a brown solid is obtained. (1.1 g, 2.7 mmol. Yield: 27%). 1H-NMR: 6.00 (t, 2H), 5.87 (s, 5H), 5.67 (t, 2H), 3.66 (t, 2H), 2.92 (t, 2H), 0.11 (s, 9H). Mass spectrum. M+-65: (343): 33%.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4].O[Li].O>C1COCC1>[C:21]([O:20][C:18]([N:6]1[CH2:7][C@@H:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH2:9][C@H:5]1[C:3]([OH:4])=[O:2])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)[C@@H]1C[C@H](Nc2cccc(Cl)c2)CN1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](Nc2cccc(Cl)c2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of the (2S,4S)-4-(3-chloro-phenylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (200 mg, 0.58 mmol) in THF (2 ml) was added a solution of LiOH.H2O (73 mg 1.74 mmol), and the reaction stirred at room temperature overnight. The solvent was concentrated in vacuo and the residual aqueous solution washed with DCM (2 ml). The aqueous was then adjusted to pH 5 with saturated aqueous citric acid and re-extracted with DCM (2×10 ml). These combined extracts were dried over MgSO4 and evaporated to give the title compound as a white foam (168 mg, 88%)
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:38])[CH2:35][CH2:36][CH3:37]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCCC(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 62 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, butyryl chloride (0.24 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 1:1) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}butanamide (0.41 g, 62%) as a white solid: mp 121-123° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 8.44 (t, J=5.55 Hz, 1H), 7.87-7.66 (m, 3H), 5.19-5.12 (dd, J=5.1 and 12.4 Hz, 1H), 4.72 (d, J=5.6 Hz, 2H), 2.96-2.85 (m, 1H), 2.63-2.51 (m, 2H), 2.17 (t, J=7.2. Hz, 2H), 2.08-2.04 (m, 1H), 1.63-1.51 (m, 2H), 0.87 (t, J=7.3 Hz, 3H); 13C NMR (DMSO-d6) δ 172.71, 172.47, 169.77, 167.46, 166.92, 139.53, 134.68, 133.11, 131.49, 127.04, 12.1.77, 48.84, 37.55, 37.16, 30.91, 21,96, 18.60, 13.63; Anal. Calcd. For C18H19N3O5: C, 60.50; H, 5.36; N, 11.76. Found: C, 60.46; H, 5.36; N, 11.59.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([CH:9]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:10][C:11]([OH:13])=[O:12])#[N:8].COS(OC)(=O)=O>C(#N)C>[C:7]([CH:9]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:10][C:11]([O:13][CH3:1])=[O:12])#[N:8]
Reactant: N#CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: COC(=O)CC(C#N)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
320 g of potassium carbonate are added to a solution of 260 g of 3-cyano-3-(3,4-dichlorophenyl) propionic acid in 2.7 litres of acetonitrile. The suspension is heated under reflux in adding progressively 110 ml of dimethylsulphate. The mixture is left to return to room temperature after 15 minutes. The reaction mixture is concentrated and then taken up into 2 litres of dichloromethane. The organic phase is washed with water and then concentrated. The residue is taken up into 500 ml of methanol in order to provide the expected ester with a yield of 80%.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[NH:19][CH2:18][CH2:17][NH:16][C:15]=2[N:20]=1)CCC.[OH-].[Na+].Cl>CO>[NH:19]1[CH2:18][CH2:17][NH:16][C:15]2[N:20]=[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:21])=[O:5])[CH:12]=[CH:13][C:14]1=2
Reactant: CCCCOC(=O)CCCCc1ccc2c(n1)NCCN2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCc1ccc2c(n1)NCCN2

Procedure:
A solution of 5-6 (2.93 mmol) and 1.0 N NaOH solution (4.40 mL, 4.40 mmol) in MeOH (15 mL) was stirred overnight. The reaction was neutralized by adding 1.0 N HCl solution (4.40 mL, 4.40 mmol) then concentrated to yield a dark brown foam used as is in the next reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:20][OH:21]>>[CH:20]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][CH2:9]2)=[CH:4][CH:3]=1)=[O:21]
Reactant: Cc1cc(C)c2c(c1C)OCC2c1ccc(Br)cc1
Reactant: CO
Product: Cc1cc(C)c2c(c1C)OCC2c1ccc(C=O)cc1
Yield: 73 %

Procedure:
Using 3-(4-bromophenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained in Reference Example 236, the title compound was synthesized in the same manner as in Reference Example 245. Yield 73%. Melting point: 87-88° C. (methanol).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]1[O:15][C:14]2[CH:13]=[CH:12][C:9]([CH2:10]O)=[CH:8][C:7]=2[O:6]1>C(Cl)(Cl)(Cl)Cl>[CH2:5]1[O:15][C:14]2[CH:13]=[CH:12][C:9]([CH2:10][Br:2])=[CH:8][C:7]=2[O:6]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
Phosphorus tribromide (0.35 mmol) was added to a solution of 3,4-methylenedioxy benzyl alcohol (1 mmol) in 10 ml of carbon tetrachloride at room temperature. The reaction mixture was refluxed for 4 hrs., cooled to room temperature and washed with sodium carbonate solution (10 ml). The organic layer was dried and concentrated under reduced pressure to give the required product which was used as such for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:36]1[CH2:39][CH2:38][CH2:37]1>CN(C=O)C.C(OCC)(=O)C>[CH:36]1([O:1][C:2]2[CH:28]=[CH:27][C:5]3[N:6]=[C:7]([N:9]4[CH2:10][CH2:11][CH:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH3:18])[CH2:13][CH2:14]4)[O:8][C:4]=3[CH:3]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: BrC1CCC1
Reactant: C[C@@H](COC1CCN(c2nc3ccc(O)cc3o2)CC1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COC1CCN(c2nc3ccc(OC4CCC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(6-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (500 mg) in DMF (5 mL) were added cesium carbonate (1.7 g) and bromocyclobutane (265 mg), and the mixture was stirred at room temperature for 15 hr and at 60° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (378 mg).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(O)(=O)C>O1CCCC1>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][C:7]2[S:6][CH:10]=[CH:9][CH:8]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(CBr)cc1
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Cc2cccs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Butyllithium (12.5 ml of 1.6N in hexanes) was added to a stirred solution of thiophene (1.68 g) in dry tetrahydrofuran (80 ml). The mixture was stirred at room temperature for 0.5 h and then a solution of 4-methoxybenzylbromide (2.62 g) in tetrahydrofuran (10 ml) was added dropwise. The mixture was stirred for 1 h and then acetic acid (1.2 ml) was added and the solvent evaporated. The residue was partitioned between ethyl acetate and water, the organic phase was washed with water and brine dried over magnesium sulphate and evaporated. The product was isolated by column chromatography (Kieselgel:hexane). δ(CDCl3) 3.80 (3H, s), 4.10 (2H, s), 6.78-6.94 (4H, m), 7.13-7.20 (3H, m).