Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][C@@H:14]([CH3:18])[C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([O:29][C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:23]=2[N:24]=1.[CH3:34][NH:35][CH3:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:34][N:35]([CH3:36])[C:15]([C@@H:14]([NH:13][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:19][C:20]3[S:21][C:22]4[CH:28]=[C:27]([O:29][C:30]([F:31])([F:33])[F:32])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:18])=[O:16]
Reactant: CNC
Reactant: C[C@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C)C(=O)N(C)C
Temperature: 0 °C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((S)-1-dimethylcarbamoyl-ethyl)-amide (46 mg) was prepared by following General Procedure F using (S)-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionic acid (48 mg), dimethyl amine (0.3 ml, 1.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml), with a minor modification of General Procedure F where DIEA was slowly added to the reaction mixture at last while stirring at 0° C. LC/MS: m/z 508. 1H NMR (DMSO-d6, 400 MHz): δ 8.39 (d, 1H), 7.98 (s, 1H), 7.95 (s, 1H), 7.76 (m, 1H), 7.66 (m, 1H), 7.45 (br, 1H), 7.30 (m, 1H), 7.22 (d, 1H), 4.93 (p, 1H), 3.62 (s, 3H), 2.87 (d, 6H), and 1.31 (d, 3H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:40][O:41][CH3:42])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:40][O:41][CH3:42])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Reaction time: 1.25 h
Yield: 87 %

Procedure:
To a suspension of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.3 g) in methylene chloride (40 ml) were added anisole (3.3 g) and trifluoroacetic acid (8.7 g) under ice-cooling with stirring, and the stirring was continued at ambient temperature for 75 minutes. After evaporation of the reaction mixture, to the residue were added water and ethyl acetate, followed by adjusting to pH 7 with a saturated aqueous solution of sodium bicarbonate. To the separated aqueous solution was added ethyl acetate, followed by adjusting to pH 2 with 10% hydrochloric acid. The ethyl acetate layer was separated out, washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then evaporated to dryness to give a residue, which was washed with diethyl ether to obtain 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.45 g).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].O1CCCC1.C([Li])CCC.C([O:20][C:21](=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])C>C(O)(=O)C>[O:20]=[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCCCCCCCCCC(=O)OCC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCCCCCCCC(=O)CP(=O)(OC)OC
Reaction time: 0.5 h

Procedure:
84 g. of dimethyl methylphosphonate were dissolved in 400 ml. of tetrahydrofuran and cooled to -60°C. Under an atmosphere of nitrogen, n-butyllithium (prepared from 14 g. of lithium, 116 g. of n-butyl bromide and 510 ml. of diethyl ether) was added dropwise to the solution while maintaining the temperature below -50°C. and then stirred for 30 minutes. To the solution thus obtained, 38 g. of lauric acid ethyl ester in 140 ml. of tetrahydrofuran were added at below -55°C. and stirred for 16 hours. The reaction mixture was then neutralized with acetic acid, concentrated, dissolved in a small amount of water and extracted with diethyl ether. The extracts were washed with water, dried, concentrated and distilled to give 50 g. of the title compound having the following physical characteristic:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=3)C2)[N:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][NH2:35])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32].O1CCOC[CH2:37]1>C(=O)([O-])[O-].[Na+].[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([N:35]2[CH2:34][CH2:33][C:27]3[C:28](=[CH:29][C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:37]2)[N:5]=[C:4]([NH:9][CH2:18][CH2:17][C:16]2[CH:11]=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[N:3]=1
Reactant: COc1cc2c(cc1OC)CN(c1nc(Cl)nc(Cl)n1)CC2
Reactant: COc1ccc(CCN)cc1OC
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(CCNc2nc(Cl)nc(N3CCc4cc(OC)c(OC)cc4C3)n2)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2,4-Dichloro-6-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-l,3,5-triazine (3.08 g, 9.03 mM) in dioxane (50 mL) and aqueous sodium carbonate solution (50 mL, 10% solution) was treated with 2-(3,4-dimethoxyphenyl)ethylamine (1.64 g, 9.03 mM). After stirring 18 hrs at ambient temperature the mixture was extracted with methylene chloride (3×75 mL). Filtration through a cotton plug and concentration provided a solid which was recrystallized from methylene chloride/ethanol to provide 3.52 g, (80%), mp=152°-153° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:16][C:17]1([C:26]#[N:27])[CH:22]2[CH2:23][CH2:24][CH2:25][CH:18]1[CH2:19][CH2:20][CH2:21]2.C(Cl)Cl.O>O.C1COCC1>[C:26]([C:17]1([NH:16][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:18]2[CH2:19][CH2:20][CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25]2)#[N:27]
Reactant: N#CC1(N)C2CCCC1CCC2
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: N#CC1(NC(=O)c2ccccc2)C2CCCC1CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add a solution of 2.37 g (17.17 mmol) of potassium carbonate in 30 mL of water, then 1.37 mL (11.8 mmol) of benzoyl chloride, to a solution of 1.88 g (11.45 mmol) of 9-aminobicyclo[3.3.1]nonane-9-carbonitrile in 20 mL of THF. Stir the reaction mixture for 1 h at RT, then distribute in 100 mL of a 1:1 mixture of DCM/water. Wash the organic phase with 50 mL of water, dry over Na2SO4 and concentrate under reduced pressure. Solidify the residue obtained in 100 mL of pentane giving, after filtration and washing with pentane, 2.81 g of N-(9-cyanobicyclo[3.3.1]non-9-yl)benzamide in the form of white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[I-].[K+].[CH3:26][CH:27]=[CH:28][CH2:29][NH2:30]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:30][CH2:29][CH2:28][CH:27]=[CH2:26])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: CC=CCN
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Yield: 78.7 %

Procedure:
A stirred mixture of 8-chloro-1-(chloromethyl)-6-phenyl-4-H-s-triazolo[4,3-a][1,4]benzodiazepine (1.37 g., 0.004 mole), potassium iodide (0.67 g., 0.004 mole), methylallylamine (0.84 g., 0.012 mole) and tetrahydrofuran (100 ml.) is kept at ambient temperature (25° C.) for 18 hours and concentrated in vacuo. The residue is mixed with water and extracted with methylene chloride. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is crystallized from ethyl acetate-Skellysolve B hexanes to give 1.19 g of 8-chloro-1-[(allylmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 157°-160° C. The analytical sample has a melting point of 158° -164° C. Anal. calcd. for C21H20ClN5 : C, 66.75; H, 5.33; Cl, 9.38; N, 18.53. Found: C, 66.87; H, 5.46; Cl, 9.42; N, 18.67. Preparation 40 8-Chloro-1-[(allylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [CH3:1][N:2]([CH3:12])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Li]CCCC.CCCCCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>CCOCC>[CH3:1][N:2]([CH3:12])[S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[B:24]([OH:29])[OH:25])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(C)S(=O)(=O)c1ccccc1B(O)O
Temperature: -70 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
A solution of N,N-dimethylbenzenesulfonamide (9.25 g; 50 mmol) in dry Et2O (150 ml) under N2 was cooled to −70° C. and added a solution of 2.5 M n-BuLi in hexane (24 ml; 60 mmol) such that the reaction temperature was kept below −60° C. The cooling bath was removed and the reaction mixture allowed to slowly warm up to +20° C. The reaction mixture was re-cooled to −70° C. and B(Oi-Pr)3 (16.1 ml; 70 mmol) was added. The reaction mixture was left cold and allowed to warm up over night, 1 M HCl (100 ml) was added and stirring was continued at rt. for 1 h. The reaction mixture was then extracted with Et2O (2×50 ml) and the combined organic fractions extracted with 1 M NaOH (4×50 ml). The combined aqueous fractions were neutralized with 1 M HCl and extracted with Et2O (4×100 ml). The combined organic fractions were dried (Na2SO4) and evaporated to dryness, washed with Et2O/hexane to give 3.4 g (30%) product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[C:1]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][O:18][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:15][CH2:16]1)=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(CC[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Product: CN(CC[C@H]1CC[C@H](COS(C)(=O)=O)CC1)C(=O)OC(C)(C)C

Procedure:
In analogy to the procedures described in examples 11.13 and 11.14, trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester (example 11.8) was reacted with methanesulfonyl chloride to give trans-methanesulfonic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester, which was subsequently treated with 4N hydrogen chloride in dioxan to yield trans-methanesulfonic acid 4-(2-methylamino-ethyl)-cyclohexylmethyl ester HCl salt as colorless solid, MS: 250 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11]CC)=[O:10])=[CH:5][CH:4]=1)=[O:2].[OH-].[Na+].O1CCO[CH2:22][CH2:21]1>>[CH2:21]([CH2:15][C:8]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:17][CH:16]=1)([CH3:14])[C:9]([OH:11])=[O:10])[CH3:22]
Reactant: C1COCCO1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCC(C)(Oc1ccc(C=O)cc1)C(=O)O
Temperature: 25 °C
Yield: 99 %

Procedure:
The obtained Compound 97a (1.0 eq.) was dissolved in 1,4-dioxane, and 1 N NaOH (1.4 eq.) was added thereto. The reaction mixture was stirred at room temperature, and after a volatile material was evaporated, the residual was distributed between methylene chloride and water. An water layer was acidified by using a 12 N HCl and extracted by using methylene chloride. An organic layer was evaporated to obtain Compound 97c.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:11]1[CH2:25][CH2:24][C:14]2[N:15]=[C:16]([S:19](=O)(=O)NC)[N:17]=[CH:18][C:13]=2[CH2:12]1.[CH:26]([C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])([CH3:28])[CH3:27].[CH3:36]CN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:26]([C:29]1[CH:30]=[C:31]([NH:32][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH2:25][CH2:24][C:14]4[N:15]=[C:16]([S:19][CH3:36])[N:17]=[CH:18][C:13]=4[CH2:12]3)[CH:4]=2)[CH:33]=[CH:34][CH:35]=1)([CH3:28])[CH3:27]
Reactant: CC(C)c1cccc(N)c1
Reactant: CNS(=O)(=O)c1ncc2c(n1)CCN(c1cc(C(=O)O)ccc1C)C2
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)CCN(c1cc(C(=O)Nc3cccc(C(C)C)c3)ccc1C)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-methyl-3-[2-(methylsulfamyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]benzoic acid (67 mg, 0.212 mmol), 3-isopropylaniline (0.03 ml, 0.212 mmol) and N,N′-diisopropylethylamine (0.18 ml, 1.06 mmol) in DMF (1.0 ml) was treated with HATU (89 mg, 0.233 mmol). After stirring at room temperature for 1.5 hours, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with sat'd NaCl(aq.), dried (MgSO4), filtered, and concentrated. Trituration of the residue with cold MeOH yielded the title compound as a white, crystalline solid (50 mg, 55%).
Reaction SMILES: C([O:8][C:9]1[C:14]([O:15][CH2:16][C:17]2C=CC=CC=2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][NH2:25])C1C=CC=CC=1.C=O.[C:28](O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].C(Cl)[Cl:41]>>[ClH:41].[O:15]1[C:14]2[C:9](=[C:10]3[C:11](=[CH:12][CH:13]=2)[CH2:28][NH:25][CH2:24][CH2:23]3)[O:8][CH2:17][CH2:16]1
Reactant: ClCCl
Reactant: NCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cl
Product: c1cc2c(c3c1CNCC3)OCCO2
Temperature: 25 °C

Procedure:
To 1.3 g (3.9 mmol) 2-(2,3-bis-benzyloxy-phenyl)-ethylamine (Chimie therapeutique 8, 1973, 308) and 0.44 mL (8.8 mmol) formaldehyde (37% solution in water) in 10 mL DCM are added slowly 0.60 mL (7.8 mmol) TFA and the resulting mixture is stirred at r.t. over night. The reaction is neutralised by the addition of a sat. aq. NaHCO3 solution and extracted with DCM. The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH:9]([Zn]C(C)C)([CH3:11])[CH3:10].CC(O)C>O1CCOCC1.C1(C)C=CC=CC=1>[CH:9]([C:4]1[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)[Zn]C(C)C
Reactant: Nc1cccc(Br)n1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CC(C)c1cccc(N)n1
Reaction time: 0.5 h

Procedure:
2-Amino-6-bromopyridine (2 g) was dissolved in dioxane (50 mL), and at 0° C. under an argon athmosphere 1,3-bis(diphenylphosphino)propane nickel (II) chloride (0.627 g) was added followed by diisopropyl zinc (23.12 mL of a 1M solution in toluene, via syringe over 30 minutes). The mixture was allowed to reflux for 15 h, poured into 2-propanol, which was then concentrated in vacuo. The residue was partitioned between AcOEt and saturated aqueous NH4Cl solution, the layers were separated and the organic layer dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (methylene chloride/methanol 95:5) to give 6-isopropyl-pyridin-2-ylamine as light brown oil (0.48 g). MS (EI): 136.1 (M+).
Reaction SMILES: Br[CH:2](C)[C:3]([C:5]1C=CC=CC=1)=[O:4].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[CH2:20][C:21]([OH:23])=[O:22].[CH2:24]1[CH2:34][CH2:33]N2[C:27](=NCCC2)[CH2:26][CH2:25]1.Cl>C(N(CC)CC)C.C(#N)C>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]1[C:21](=[O:23])[O:22][C:3]([OH:4])([CH3:5])[C:2]=1[C:27]1[CH:26]=[CH:25][CH:24]=[CH:34][CH:33]=1
Reactant: O=C(O)Cc1c(F)cccc1F
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(O)OC(=O)C(c2c(F)cccc2F)=C1c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
To a mixture of 2-bromopropiophenone (2.13 g), 2,6-difluorophenylacetic acid (1.81 g) and acetonitrile (25 mL), triethylamine (1.52 g) was added dropwise in a water bath, stirred at room temperature for 4 hours and then allowed to stand still overnight. To the mixture, 4.57 g of 1,8-diazabicyclo[5.4.0]-7-undecene (hereinafter, referred to as DBU) was added dropwise under ice cooling. The mixture was stirred at room temperature for one hour. Thereafter, to the obtained mixture, air was blown in while stirring at room temperature for 5 hours. To the reaction mixture, ice and 1 mol/L hydrochloric acid were added. The mixture was extracted with ethyl acetate. The organic layer was sequentially washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution, dried over an anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 3-(2,6-difluorophenyl)-5-hydroxy-5-methyl-4-phenyl-2(5H)-furanone (2.83 g).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:11])[CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:19]1[CH2:26][CH:25]2[CH2:27][CH:21]([CH2:22][NH:23][CH2:24]2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCO>[C:1]1([NH:7][C:8](=[O:11])[CH2:9][CH2:10][N:23]2[CH2:24][CH:25]3[CH2:27][CH:21]([CH2:20][N:19]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:26]3)[CH2:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=O)Nc1ccccc1
Reactant: c1ccc(CN2CC3CNCC(C3)C2)cc1
Solvent: CCO
Product: O=C(CCN1CC2CC(C1)CN(Cc1ccccc1)C2)Nc1ccccc1
Reaction time: 10 h
Yield: 97 %

Procedure:
N1-Phenylacrylamide (1.0 g; 6.8 mmol; from step (a) above) was added to a stirred solution of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (1.5 g; 6.8 mmol; see Example E above) in EtOH (7 mL). The reaction mixture was stirred for 10 h and concentrated to give the sub-title compound in a 97% yield.
Reaction SMILES: CI.[C:3]([C:6]1[CH:7]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][C:11]=1[OH:12])(=[O:5])[CH3:4].[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:3]([C:6]1[CH:7]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][C:11]=1[O:12][CH3:17])(=[O:5])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1ccc(O)c(C(C)=O)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(NC(C)=O)cc1C(C)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.8 %

Procedure:
Methyl iodide (3.42 ml, 7.81 g, 55 mmol) was added to a stirred mixture of N-(3-acetyl-4-hydroxyphenyl)acetamide (J.Org.Chem. 1995, 60, 4324-4330) (9.65 g, 50 mmol) and potassium carbonate (13.82 g, 100 mmol) in dimethylformamide (50 ml). The mixture was stirred at room temperature for 72 hours, then the solvent was evaporated under reduced pressure. Water (100 ml) was added and the mixture was extracted with ethyl acetate (6×100 ml). The combined organic fractions were dried (MgSO4) and evaporated under reduced pressure to give N-(3-acetyl-4-methoxyphenyl)acetamide as a tan solid (10.34 g, 100%), 1H NMR (d6 -DMSO) δ 9.91 (1H, br. s), 7.76 (2H, m), 7.12 (1H, d, J=9.6 Hz), 3.86 (3H, s), 2.52 (3H, s), and 2.01 (3H, s). m/e (CI+) 208 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[Br:12][C:13]1[C:14]([CH3:20])=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].[CH2:21](OC(OCC)OCC)C>C1COCC1.CCOC(C)=O>[Br:12][C:13]1[C:14]([CH3:20])=[C:15]([N:16]2[C:4](=[O:6])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([F:11])[CH:7]=3)[N:1]=[CH:21]2)[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c(N)cccc1Br
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: CCOC(OCC)OCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Br)cccc1-n1cnc2ccc(F)cc2c1=O
Temperature: 110 °C
Yield: 55.8 %

Procedure:
A mixture of 2-amino-5-fluorobenzoic acid (1.00 g, 6.45 mmol), 3-bromo-2-methylaniline (1.199 g, 6.45 mmol) and triethoxymethane (0.955 g, 6.45 mmol) in THF (2 mL) was heated at 110° C. overnight in a sealed tube. The mixture was cooled to rt and diluted with EtOAc. The solution was washed with NaHCO3 (aq) and water, then was dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 80:20 to 70:30 hexane-EtOAc) to give 3-(3-bromo-2-methylphenyl)-6-fluoroquinazolin-4(3H)-one as a white solid (1.2 g, 56%). 1H NMR (400 MHz, chloroform-d) δ 8.00 (1 H, dd, J=8.4, 3.1 Hz), 7.93 (1 H, s), 7.81 (1 H, dd, J=9.0, 4.8 Hz), 7.74 (1 H, dd, J=6.9, 2.3 Hz), 7.50-7.58 (1 H, m), 7.21-7.26 (2 H, m), 2.25 (3 H, s). Mass spectrum m/z 333, 335 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([O:11]CC)=[O:10])[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Li+]>C1COCC1.CO.O>[C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)=O)on1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1cc(C(=O)O)no1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 29.9 %

Procedure:
Ethyl 5-acetylisoxazole-3-carboxylate (300 mg, 1.638 mmol) was dissolved in THF/methanol mixture (9:1) and 1M lithium hydroxide (3.28 ml, 3.28 mmol) was added slowly. The reaction mixture was stirred at RT for 40 min, diluted with water and pH was adjusted to 3. The reaction mixture was extracted three times with ethyl acetate. Ethyl acetate phases were combined, washed with brine, dried and evaporated to dryness to yield the title compound (29.9%). m/z [155.1+1].
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[CH:14]=2)=[O:7])=[CH:34][CH:35]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C)cc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c1
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cc(C)cc(C)c2)cc1
Yield: 86.4 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3,5-dimethylphenyl)benzamide (382.8 mg, 0.81 mmol) and acetic anhydride (0.092 ml, 0.99 mmol), the procedure of Inventive Example 94 was repeated to obtain 360.9 mg (86.4%) of the title compound in a light brown amorphous form.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C.C(OCC)C>[CH2:17]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cc2cccnc2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1cc2cccnc2n1Cc1ccccc1
Temperature: 20 °C
Yield: 82 %

Procedure:
2 g (10 mmol) of ethyl pyrrolo[2,3-b]pyridine-2-carboxylate (WO2004101563) are added, portionwise, to a suspension of 0.44 g (11 mmol) of sodium hydride in 50 ml of DMF, stirred at 20° C. After stirring at ambient temperature for 1 h, 2.1 g (12 mmol) of benzyl bromide are added, dropwise, and the reaction mixture is stirred at ambient temperature for 20 h. 150 ml of water and 150 ml of ethyl ether are subsequently added with stirring. The aqueous phase is separated and extracted twice with 50 ml of ethyl ether. The organic phases are combined, washed with 100 ml of water, dried over sodium sulphate and then concentrated under reduced pressure. The resulting product is purified by silica column chromatography, elution being carried out with a mixture of heptane and dichloromethane. 2.3 g of the expected product are thus isolated.