Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([Li])CCC>CCCCCC.O1CCCC1>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: C1CCNC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCCC1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), pyrrolidine (3 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (25 ml) as the starting materials. After recrystallisation from ethanol, 1-[(2-phenylquinazolin-4-yl)-carbonyl]-pyrrolidine (2.1 g), melting at 153° C., is obtained.
Reaction SMILES: [K].C[O:3][C:4](=[O:11])[CH2:5][CH2:6][C:7]([O:9]C)=[O:8].[C:12]1([CH:22]=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.Cl.[C:25](O)(C)(C)C>>[CH3:25][C@@:5]([CH2:22][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)([CH2:6][C:7]([OH:9])=[O:8])[C:4]([OH:3])=[O:11]
Reactant: COC(=O)CCC(=O)OC
Reactant: O=Cc1cccc2ccccc12
Reactant: CC(C)(C)O
Agent: Cl
Agent: [K]
Product: C[C@](CC(=O)O)(Cc1cccc2ccccc12)C(=O)O
Temperature: 0 °C

Procedure:
To solution of potassium (2.15 gm) in t-butanol (45 ml) at room temperature was added dropwise a solution of dimethylsuccinate (14 ml) and 1-naphthaldehyde (7.5 ml). The reaction mixture was then heated to reflux for a period of 30 min. whereupon, it was cooled to 0° C. The reaction mixture was made acidic with HCl (6N, 10 ml) and evaporated in vacuo. The reaction mixture was partitioned between water and diethyl ether and the combined organic fractions were extracted with NH4OH (1N) four times. The combined basic fractions were washed with diethyl ether, and acidified with HCl (3N), and extracted thoroughly with methylene chloride. The combined organic fractions were dried over Na2SO4, filtered and evaporated in vacuo. Without purification the crude methyl-4-carboxy-2-(1-naphthylmethylene)-propionate was dissolved in methanol (100 ml) and to this solution at 0° C. slowly added magnesium turnings (2.3 gm) over a 3 hr period. When all the magnesium had been consummed, the reaction mixture was poured into HCl (carefully, 3N, 150 ml). The reaction mixture was extracted with diethyl ether, dried over Na2SO4, filtered and evaporated in vacuo to give the title compound in its racemic form. This material has been resolved with (+) methylbenzylamine in diethyl ether. Thus 5.2 gm of racemic material has been converted to 2.2 gm of pure R(+) title compound. [α]D =+48.56(EtOAc). NMR (CDCl3) 2.4-2.5(dd,1H), 2.7-2.85(2d,1H), 3.05-3.15(ABq,1H), 3.55-3.7(m,1H), 3.7(S,3h), 7.27(d,1H), 7.3-7.4(t,1H), 7.45-7.6(m,2H), 7.75(d,1H), 7.85(d,1H), 8.05(d,1H).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=O.S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].[CH:30]1([NH2:33])[CH2:32][CH2:31]1>FC(F)(F)S(O)(=O)=O>[CH:30]1([NH:33][C:13](=[O:15])[C:12]2[CH:16]=[C:17]([I:1])[C:18]([CH3:19])=[C:10]([F:9])[CH:11]=2)[CH2:32][CH2:31]1
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: NC1CC1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
N-Iodosuccinimide (3.31 g, 20 mmol) was added in portions over 3 hours to a solution of 3-fluoro-4-methylbenzoic acid (2.27 g, 20 mmol) in trifluoromethanesulphonic acid (15 mL) kept at 0° C. Subsequently, the mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was poured into ice/water and the precipitate that formed was collected by filtration and washed with water. The solid was dissolved in ethyl acetate, the organic layer was washed with saturated aqueous sodium thiosulphate solution and brine, dried (MgSO4) and the solvent was removed under vacuum. The residue obtained was treated with thionyl chloride (20 mL) and heated at 100° C. for 2.5 hours. Excess thionyl chloride was removed in vacuo and the residue was dissolved in dichloromethane (20 mL). Sodium carbonate (3.70 g, 35 mmol) and cyclopropylamine (1.90 mL, 27 mmol) were added to the solution and the mixture was stirred at room temperature for 72 hours. The mixture was then filtered and the residue was washed with dichloromethane and ethyl acetate. The combined filtrate and washings were concentrated under vacuum and the residue was purified by flash chromatography (10:1 to 5:1 hexanes/ethyl acetate) to give the title compound (2.13 g, 45%) as a white solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CCCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl E-7-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-7-phenylheptanoate (730 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-7-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-7-phenylheptanoic acid (569 mg, yield 82%) as colorless crystals. m.p. 84-85° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:5]=1[C:6](OC)=[O:7])(=O)[CH3:2].O.[NH2:17][NH2:18]>CO.O>[CH3:15][O:14][C:12]1[CH:13]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[NH:18][N:17]=[C:1]2[CH3:2]
Reactant: COC(=O)c1ccc(OC)cc1C(C)=O
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1ccc2c(=O)[nH]nc(C)c2c1
Temperature: 95 °C
Reaction time: 6 h
Yield: 94.4 %

Procedure:
To a solution of methyl 2-acetyl-4-methoxybenzoate (5) (2.47 g, 11.86 mmol) in methanol (14.5 mL) is added hydrazine monohydrate (1.78 g, 35.60 mmol). The mixture is stirred at 95° C. under argon for 6 h, the cooled to room temperature, diluted with H2O (50 mL), and extracted with CHCl3 (2×100 mL) and ethyl acetate (100 mL, 2×50 mL, and 2×40 mL). The extracts were washed (brine) and dried. After solvent removal at reduced pressure, the residue is suspended in ethyl acetate (30 mL), heated, cooled, and filtered to give 2.13 g (94%) of 6 as a white solid, mp 252-254° C. IR 3298, 2941, 1732, 1055 cm−1; 1H NMR (CDCl3) δ 2.58 (s, 3H, CH3), 4.00 (s, 3H, CH3O), 7.12 (d, J=1.6 Hz, 1H, 5-PhthH), 7.35 (dd, J=5.6, 1.6 Hz, 1H, 7-PhthH), 8.41 (d, J=5.6 Hz, 1H, 8-PhthH), 10.12 ppm (s, 1H, NH).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:20])[O:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([OH:19])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[CH3:22][N:23]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:24](N1C=C[N+](C)=C1)=[O:25]>>[CH2:1]([C:8]1[C:9](=[O:20])[O:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([O:19][C:24](=[O:25])[N:23]([CH3:22])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Cc2ccccc2)c(=O)oc2cc(O)ccc12
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: Cc1c(Cc2ccccc2)c(=O)oc2cc(OC(=O)N(C)c3ccccc3)ccc12

Procedure:
The title compound was prepared from 3-benzyl-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(methyl-phenyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=400 (M+1), Rt: 4.90 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[CH:6]=1)[CH3:2].CN1C(=O)CCC1.[CH2:20]([Mg]Br)[CH:21]([CH3:23])[CH3:22]>C1COCC1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CC(C)C[Mg]Br
Reactant: CCOC(=O)c1ccnc(Cl)c1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccnc(CC(C)C)c1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-isonicotinic acid ethyl ester (10.0 g, 63.3 mmol) in THF (150 mL), NMP (8.78 g, 88.6 mmol) and Fe(acac)3 (2.46 g, 6.96 mmol) is added under argon. The mixture is cooled to −74° C. before isobutylmagnesium bromide (47 mL of a 2 M solution in THF, 94.9 mmol) is added. The temperature rises to −65° C. The mixture is stirred at −75° C. for 1 h, then warmed to rt and carefully quenched with water. The mixture is extracted with EA, the org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-isobutyl-isonicotinic acid ethyl ester (3.00 g) as an oil, LC-MS: tR=0.74 min, [M+1]+=208.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:48]1[CH2:52][CH2:51][CH:50]([C:53]2[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=2)[CH2:49]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([C:14]([N:48]3[CH2:52][CH2:51][CH:50]([C:53]4[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=4)[CH2:49]3)=[O:16])=[CH:12][O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1
Reactant: c1cncc(C2CCNC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC(c3cccnc3)C2)cc1
Yield: 85.9 %

Procedure:
A solution of 3-(4-methoxyphenyl)isoxazole-4-carboxylic acid (7 mg, 0.03 mmol), N-ethyl-N-isopropylpropan-2-amine (16 μL, 0.09 mmol, 3 equ.) and TBTU (12 mg, 0.036 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-pyrrolidin-3-ylpyridine (4 mg, 0.03 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (9 mg). MS (ESI, pos. ion) m/z: calcd for C20H19N3O3: 349.1426, found 349.1427.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:16]([C:14]1[S:15][C:11]([C:3]2[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: Nc1ccccc1Cl
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Product: Cc1c(-c2ccc(C(=O)Nc3ccccc3Cl)s2)noc1C(F)(F)F
Yield: 43 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 2-chloroaniline by the method described in Example 2 Method B. The reaction mixture was evaporated in vacuo, triturated and filtered with the aid of water, then washed with an aqueous 1 N hydrochloric acid solution followed by water. The crude solid was then chromatographed on silica gel with EtOAc/hexanes (10 then 15%) as eluant to afford product as a colorless solid (42 mg, 43%). 1H NMR (CDCl3) 2.39 (d, J=1.3, 3H), 7.10 (td, J=7.9, 1.3, 1H), 7.33 (td, J=7.9, 1.3, 1H), 7.42 (dd, J=8.3, 1.8, 1H), 7.56 (d, J=4.0, 1H), 7.69 (d, J=4.0, 1H), 8.34 (s, 1H), 8.46 (dd, J=1.3, 1H). 13C NMR 8.0, 114.8, 118.7 (q, J=271), 123.2, 125.4, 128.2, 129.0, 129.3, 134.0, 134.3, 141.7, 155.5 (q, J=40), 157.8, 159.0. 19F NMR −63.1. LC/MS 7.19 min, [M+1]+ 387.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:48][CH2:49][C:50]2[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=2[CH3:56])=[O:16])=[CH:17][CH:18]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(C2Cc3ccccc3O2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C3Cc4ccccc4O3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.8 %

Procedure:
To a solution of 4-(2,3-dihydrobenzofuran-2-yl)benzoic acid (0.02 g, 0.08 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.04 g, 0.2 mmol) and N-hydroxybenzotriazole (0.02 g, 0.15 mmol) in dichloromethane (10 mL) was added triethylamine (0.10 g, 1.0 mmol). The reaction mixture was stirred for 15 minutes at room temperature, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.03 g, 0.2 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water. The organic phase was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give pure product as a white solid 4-(2,3-dihydrobenzofuran-2-yl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (Compound I-51) (0.02 g, 66%). LRMS (M+H+) m/z: calcd 374.16. found 374. 1H NMR (300 MHz, CD3OD): δ 7.80-7.77 (m, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.18-7.12 (m, 2H), 6.87-7.80 (m, 2H), 6.09 (s, 1H), 5.79 (t, J=9.0 Hz, 1H), 4.49 (s, 2H), 3.73-3.64 (m, 1H), 3.14-3.06 (m, 1H), 2.36 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: Cl(=O)=O.[S:4](=[O:8])(=[O:7])([OH:6])[O-:5].[Na+:9]>O>[S:4]([OH:8])([OH:7])(=[O:6])=[O:5].[Na+:9].[S:4]([O-:8])([O-:7])(=[O:6])=[O:5].[S:4]([OH:8])([OH:7])(=[O:6])=[O:5].[Na+:9]
Reactant: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)O
Product: O=S(=O)([O-])[O-]

Procedure:
recycling the first stage acidic filtrate back to said chlorine dioxide generator and dissolving said first stage sodium bisulfate crystals in H2O to create a second stage solution for a second stage evaporator/crystallizer and heating said second stage solution to a prescribed temperature under a partial vacuum for a predetermined period of time to reduce the solution volume and then cooling said solution in the crystallizer to produce second stage sodium sesquisulfate crystals from which the second stage acidic filtrate is separated and recycled to said first stage evaporator/crystallizer, and
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]=2[NH:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O>[N+](C1C=CC=CC=1)([O-])=O>[C:18]1([C:17]2[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:7]3[NH:11][N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]=3[N:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Nc1c(C(F)(F)F)n[nH]c1-c1ccccc1)c1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Temperature: 185 °C
Reaction time: 6 h

Procedure:
A mixture of 1.02 g of N-(5-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-benzamide in 10 mL of nitrobenzene was treated with 0.41 mL of phosphorous oxychloride and stirred at 185° C. for 6 h. The solvent was distilled off under high vacuum and the residue was partitioned between ethyl acetate and water. The organic portion was washed with saturated sodium bicarbonate, water and brine and dried over magnesium sulphate. Concentration and purification by MPLC, eluting with 1/3 ethyl acetate/heptane, gave the title compound as a white solid, melting point 264–265° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].N1C=CC=CC=1.CO>C(Cl)Cl>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:19][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:24]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccccc1F
Reaction time: 0.5 h

Procedure:
2-Methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine (1.52 g, 5.84 mmol) was dissolved in DCM (30 mL). To this solution was transferred a solution of 2-fluorobenzoyl chloride in DCM (2 mL), followed by pyridine (7.5 mL). The solution was stirred at r.t. for 2 h when TLC (10% MeOH in DCM) and LC/MS showed that the reaction was complete. The reaction was quenched with polymer bounded diethylenetriamine (4 mmol/g, 1.5 g) and the suspension was stirred for 30 min. Then, 10 mL of DCM was added to the suspension and the suspension was filtered through a Celite pad, rinsed with DCM and 10% MeOH in DCM. The crude product was purified on a silica gel column eluted with 2%, 5% and 7.5% MeOH in DCM to obtain the title compound as a yellow solid, 1.79 g (80%). LCMS: RT=1.53 minutes, MS: 382 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][CH:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:38][O:39][C:40](=[O:44])[CH2:41][CH2:42]Br>C1COCC1.ClCCl>[CH3:38][O:39][C:40](=[O:44])[CH2:41][CH2:42][N:21]1[CH2:22][CH2:23][CH2:24][CH:19]([O:18][C:16]2[C:17]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[C:10]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:11][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:20]1
Reactant: COC(=O)CCBr
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC4CCCNC4)c23)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCN1CCCC(Oc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)C1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Dissolve 200 mg (0.5 mmol) of (+/−)-5-(4-methoxyphenyl)-6-phenyl-4-(piperidin-3-yloxy)furo-[2,3-d]pyrimidine (Example 37A) in 1 ml of THF and add 69 μl (0.5 mmol) of triethylamine. After adding 54 μl (0.5 mmol) of 3-bromopropionic acid methyl ester, stir the mixture at 20-40° C. for approx. 8 h. In the meantime, add triethylamine (total of approx. 1.2 mmol) and 3-bromopropionic acid methyl ester (total of approx. 1.2 mmol) twice more. After diluting with dichloromethane, wash the mixture with saturated sodium hydrogencarbonate solution and concentrate under reduced pressure. Purify the crude product by means of preparative RP-HPLC (eluent: acetonitrile/water gradient). 118 mg (45.7% of theory) of the target product are obtained.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15](/[C:22]2[CH:27]=[CH:26][CH:25]=[C:24](OC)[CH:23]=2)\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1.[O:42]1CCC[CH2:43]1>>[CH3:43][O:42][C:27]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1/[C:15](/[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]1[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=1)=[O:30]
Reactant: C1CCOC1
Reactant: NCCCCc1cccnc1
Reactant: COc1cccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)c1
Product: COc1ccccc1/C(=C/C=C/C(=O)NCCCCc1cccnc1)c1ccccc1

Procedure:
As in Example 134, a solution of (2E,4E)-5-(3-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid 4-nitrophenyl ester (2.96 g) and 3-pyridinebutanamine (1.107 g) in tetrahydrofuran (15 mL) was stirred for 1 hour at room temperature. After the usual work up, the crude amide was purified by HPLC (ethyl acetate) and then crystallized from ethyl acetate-hexane to provide 2.5 g of (2E,4E)-5-(methoxyphenyl)-5-phenyl-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 66°-68° C. Anal. Calculated for C28H28N2O2 : C, 78.61; H, 6.84; N. 6.79 Found: C, 78.42; H, 6.88; N, 6.79.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:40])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=2)[CH2:23][NH:24][C:25](=[O:36])OC2C=CC([N+]([O-])=O)=CC=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH3:41][NH:42][CH3:43]>ClCCl.O1CCCC1>[Br:1][C:2]1[C:3](=[O:40])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=2)[CH2:23][NH:24][C:25](=[O:36])[N:42]([CH3:43])[CH3:41])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CNC
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccc(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccc(CNC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
To a reaction vessel (borosilicate culture tube) was added 4-nitrophenyl 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzylcarbamate (from step 1) (0.350 g, 0.570 mmol) dissolved in dichloromethane (6.0 mL). The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. A stock solution of N,N-dimethylamine in tetrahydorfuran (0.427 mL, 2.0 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) which afforded an off white solid (0.226 g, 63.3%). 1H NMR (400 MHz, DMF-d6) δ 7.81 (app q, J=7.92 Hz, 1H), 7.40-7.19 (m, 5H), 7.06 (d, J=7.45 Hz, 1H), 6.88 (app t, J=5.84 Hz, 1H), 6.68 (s, 1H), 5.45 (s, 2H), 5.42 (s, 1H), 4.35 (d, J=5.84 Hz, 1H), 2.92 (s, 6H), 2.44 (s, 3H). ES-HRMS m/z 520.1065 (M+H C24H24BrF2N3O3 requires 520.1042).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=O)=[C:12]([CH3:21])[CH:11]=1.Cl.[CH3:24][C:25]([CH3:35])([CH3:34])[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([N:31]2[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[CH3:24])[CH2:29][CH2:30]2)=[O:20])=[C:12]([CH3:21])[CH:11]=1
Reactant: COC(=O)c1ccc(CCC(=O)O)c(C)c1
Reactant: CC(C)(C)CCN1CCNCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(CCC(=O)N2CCN(CCC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Oxalyl chloride (2.6 ml, 30 mmol) was added slowly to a solution of 4-(2-carboxy-ethyl)-3-methyl-benzoic acid methyl ester from Example E30.3 (5.33 g, 24 mmol) in di-chloromethane (60 ml) and few drops of DMF at 0° C. The mixture was stirred for 2 h at room temperature then concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (30 ml) and added to a solution of 1-(3,3-dimethyl-butyl)-piperazine hydrochloride from Example E4 (6.3 g, 26 mmol) in dichloromethane (45 ml) and DIEA (17 ml, 96 mmol) at 0° C. The mixture was stirred for 1 h at room temperature then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane) to yield the title compound (8.5 g, 96%).