Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19]C)=[O:17])=[N:11][C:10]([OH:21])=[C:9]([OH:22])[C:8]=2[C:7]1=[O:23].[CH3:28][O-].[Mg+2].C[O-]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]([CH3:28])[C:12]=2[C:16]([O:18][CH3:19])=[O:17])[C:7]1=[O:23]
Reactant: CCOC(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: C[O-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of ethyl 6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (40 g) in DMF (200 mL) was added magnesium methoxide in methanol (100 mL). The mixture heated at 40-50° C. for 3 hours. The excess methanol distilled off, and methyl tosylate (18 mL) was added. The reaction mixture was heated at 50° C. overnight, then cooled to 25° C., and then quenched into 1N HCl (100 mL). The suspension stirred for 1 hour at ambient temperature. The product was isolated by filtration, and the filter cake washed with water (2×100 mL) and then dried on the filter under an atmosphere of nitrogen. The crude product was suspended in methanol (460 mL), heated at reflux temperature for 1 hour, and then allowed to cool to ambient temperature. The product was isolated by filtration and the filter cake washed with cold methanol (2×40 mL) and dried to give the title product.
Reaction SMILES: C[C@@H]1[O:7][C@@H](O[C@@H:9]2[C:14]3=C(O)[C:16]4C(=O)C5C(=CC=CC=5OC)C(=O)[C:17]=4[C:18](O)=[C:13]3[CH2:12][C@@:11](O)(C(CO)=O)[CH2:10]2)C[C@H](N)[C@@H]1O.Cl.C[C@@H]1O[C@@H](O[C@@H]2C3=C(O)C4C(=O)C5C(=CC=CC=5OC)C(=O)C=4[C:58]([OH:59])=[C:53]3[CH2:52][C@@:51]([OH:77])([C:73]([CH2:75][OH:76])=[O:74])C2)C[C@H](N)[C@@H]1O.C#CCCCCCC#C.[OH2:89]>CS(C)=O>[CH:14]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:18][C:17]#[CH:16].[O:89]=[C:75]1[O:76][C@H:52]([C@H:53]([CH2:58][OH:59])[OH:7])[C:51]([OH:77])=[C:73]1[OH:74]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Reactant: O
Agent: C#CCCCCCC#C
Agent: Cl
Solvent: CS(C)=O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
100 mg of product 1 are dissolved in 1.1 ml of distilled water; a solution of 200 μl of 1,8-Nonadiyne in 11.23 ml of DMSO are prepared separately, whereas 23.2 mg of doxorubicin hydrochloride are dissolved in 0.5 ml of distilled water. The solution of hyaluronic acid is mixed with that of doxorubicin and with 0.2 ml of that of 1,8-Nonadiyne; 0.1 ml of an aqueous solution obtained with 50 mg of CuSO4.5H2O in 1 ml of H2O and 0.1 ml of an aqueous solution of 20 mg of ascorbic acid are then added. The mixture is stirred vortically for a few minutes. The rapidly formed gel (see FIG. 31) incorporates the doxorubicin hydrochloride inside.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH3:10][CH:11]([CH2:14][CH3:15])[CH2:12]O>>[CH3:10][CH:11]([CH2:14][CH3:15])[CH2:12][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH2:10][CH:11]([CH3:12])[CH2:14][CH3:15])=[O:6])[OH:3]
Reactant: CCC(C)CO
Reactant: O=C(O)CC(O)C(=O)O
Product: CCC(C)COC(=O)CC(O)C(=O)OCC(C)CC
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
Di(2-methylbutyl)-DL-malate was prepared using a procedure similar to that in Example 4. To the reaction flask, DL-malic acid (100.56 g), 2-methyl-1-butanol (325 mL) and Amberlyst®15 ion exchange resin (15.1 g) were added. The mixture was placed under nitrogen and heated to reflux. At 108° C., two phases started to collect in the Dean-Stark trap. After 1.5 hr, the reaction temperature was increased to 115° C. for 20 minutes and 120° C. for 20 minutes. Once water ceased to collect in the Dean-Stark trap, the product was diluted with diethyl ether, collected via filtration over a short bed of silica, washed 4 times with saturated sodium bicarbonate, once with water and dried over magnesium sulfate. The diethyl ether was removed via rotary evaporation. Di-(2-methylbutyl)-DL-malate was obtained as a low viscosity, clear, very light yellow liquid with no detectable odor (139.8 g, 68% yield) after removing residual 2-methyl-1-butanol via vacuum distillation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]2.[C:14]([O:17][C:18](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][O:17][CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2cc(Br)ccc2C(=O)N1
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Product: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Temperature: 125 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-bromo-4H-isoquinoline-1,3-dione (2.4 g, 10 mmol) in 25 mL of a 4:1 mixture of acetic anhydride and N,N-dimethylformamide, respectively, is added trimethylorthoformate (2.2 mL, 20 mmol). The reaction mixture is shaken in a heating block at 125° C. for 1 hour. Upon cooling to room temperature, the product precipitated out. The precipitate is then filtered off, rinsed with copious amounts of ether, and dried to yield 2.4 g of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione.
Reaction SMILES: Br[C:2]1[C:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[CH2:5][CH2:6]2.C1[CH2:26][O:25]CC1.[OH2:27]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(N(CC)CC)C>[O:21]=[C:4]1[C:3]2[C:2]([C:26]([OH:25])=[O:27])=[C:10]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5]1
Reactant: C1CCOC1
Reactant: O
Reactant: O=C1CCc2ccc(NS(=O)(=O)c3ccccc3)c(Br)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1CCc2ccc(NS(=O)(=O)c3ccccc3)c(C(=O)O)c21
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A solution of Example 129D (0.1112 g, 0.303 mmol) in 4:1 THF/H2O in a Parr bomb was treated with triethylamine (92 μL) and PdCl2(dppf) (24.8 mg). The bomb was charged to 700 psi with CO, stirred for 24 hours at 120° C., and concentrated. The concentrate was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (ESI(+)) m/e 332 (M+H)+, 349 (M+NH4)+, 354 (M+Na)+; MS (ESI(−)) m/e 330 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.72 (m, 1H), 7.52 (m, 4H), 7.33 (d, 1H), 7.22 (d, 1H), 2.99 (m, 1H), 2.88 (m, 1H), 2.73 (m, 1H), 2.27 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:52])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:51])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:50])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:49])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:48])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:47])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:46])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:45])[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])[CH2:3][C:4](O)=[O:5].[NH3:53].C1C=CC=CC=1.C(OCC)(=O)C>C(Cl)Cl>[CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:52])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:51])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:50])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:49])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:48])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:47])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:46])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:45])[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])[CH2:3][C:4]([NH2:53])=[O:5]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)CC(=O)O
Reactant: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)CC(N)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
20 g of 3,7,11,15,19,23,27,31,35,39-decamethyl-6,10,14,18,22,26,30,34,38-tetracontanonaenic acid are dissolved in 100 ml of methylene chloride. To this solution, 6.9 g of N,N-dicyclohexylcarbodiimide are added with cooling at 0° C., and stirred for 1.0 hour. Ammonia gas is blown little by little into this solution during an hour. Stirring for 3.0 hours is performed at room temperature after the end of addition of ammonia. Mother liquor is condensed after filtering off N,N-dicyclohexylurea formed. The residue is subjected to silica gel column chromatography using benzene/ethyl acetate mixture for eluting solvent. The desired product was obtained as an oily substance light yellow in color (yield: 12.3 g). This oily substance was dissolved in 50 ml of acetone and left overnight in a refrigerator. The white crystals deposited were filtered off, dried and thus yielded 8.5 g of desired final product, acid amide derivative.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:21])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][CH:10]=1)[CH3:7])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.CS(O)(=O)=O.[F:33][C:34]1[CH:35]=[C:36]([CH2:41][N:42]([C:44]([NH2:46])=[O:45])[NH2:43])[CH:37]=[C:38]([F:40])[CH:39]=1.N1C=CC=CC=1>C(OCC)(=O)C.CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:43][N:42]([CH2:41][C:36]2[CH:37]=[C:38]([F:40])[CH:39]=[C:34]([F:33])[CH:35]=2)[C:44]([NH2:46])=[O:45])=[O:20])=[CH:13][CH:14]=1)[CH3:21])=[O:5])[CH3:2]
Reactant: NC(=O)N(N)Cc1cc(F)cc(F)c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)NN(Cc2cc(F)cc(F)c2)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To 4-[4-(1Ethoxycarbonyl-1-methylethoxy)phenyl]butyric acid (1.0072 g, 3.42 mmol) in ethyl acetate (10 mL) at rt was added DMF (1 pipette drop), followed by oxalyl chloride (0.728 g, 5.73 mmol) dropwise over 5 min. The resulting solution was stirred for 30 min at rt, then concentrated to an oil. The oil was twice reconstituted into toluene (20 mL) and concentrated to an oil, then dissolved in ethyl acetate (3 mL). 1-(3,5-Difluorophenylmethyl)hydrazine carboxamide methanesulfonate (1.025 g, 3.45 mmol) was suspended in ethyl acetate (10 mL) at 0° C., and pyridine (0.65 mL, 636 mg, 8.04 mmol) was added. The solution of acid chloride in ethyl acetate was then added dropwise over 15 min, and the resulting mixture stirred for 30 min at 0° C. The mixture was then diluted with ethyl acetate and washed with 1 N HCl (2×) followed by sat'd aq. NaCl. It was then dried (MgSO4), filtered and concentrated to an oil, which was chromatographed on silica gel (ethyl acetate) to afford the title compound as a solid (1.1436 g, 70%): mp 108.1-109.4° C.; 1H NMR (DMSO-d6, 60° C.) δ 9.73 (s, 1 H), 7.00 (m, 5 H), 6.70 (d, 2 H, J=6.5 Hz), 6.03 (s, 2 H), 4.54 (br s, 2 H), 4.15 (q, 2 H, J=7 Hz), 2.45 (m, 2 H), 2.09 (m, 2 H), 1.74 (m, 2 H), 1.48 (s, 6 H), 1.17 (t, 3 H, J=7 Hz); 13C NMR (DMSO-d6) δ 174.0, 172.0, 162.5 (dd, J=244, 13 Hz), 159.2, 153.8, 144.1, 135.8, 129.7, 119.4, 111.3 (d, J=25 Hz), 102.8 (t, J=26 Hz), 79.2, 51.1, 47.3, 34.3, 33.1, 27.0, 25.7, 14.6; IR (KBr) 3456, 3324, 1726, 1643, 1509, 1445 cm−1; Anal. Calcd. for C24H29N3O5F2: C, 60.37; H, 6.12; N, 8.80; F, 7.96. Found: C, 60.48; H, 6.28; N, 8.67; F, 7.75.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][CH:10]=O.Br[Si](C)(C)C.[NH2:18][C:19]1[N:24]=[C:23]([OH:25])[CH:22]=[C:21]([NH:26][CH3:27])[N:20]=1>O.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.C(#N)C>[NH2:18][C:19]1[NH:24][C:23](=[O:25])[C:22]2[C:9]([C:2]3[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=3[CH3:12])=[CH:10][N:26]([CH3:27])[C:21]=2[N:20]=1
Reactant: Cc1cc(C)c(CC=O)c(C)c1
Reactant: CNc1cc(O)nc(N)n1
Agent: C[Si](C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC#N
Product: Cc1cc(C)c(-c2cn(C)c3nc(N)[nH]c(=O)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of dimethylsulfoxide (468 mg, 6.00 mmol) and acetonitrile (8 ml) was added to a mixture of mesitylacetoaldehyde (904 mg, 5.57 mmol), bromotrimethylsilane (919 mg, 6.00 mmol) and acetonitrile (8 ml) at 0° C. After stirring at room temperature for 0.5 hour, the mixture was diluted with water (70 ml) and extracted with ethyl acetate (100 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. A mixture of the residue, 2-amino-6-(methylamino)pyrimidin-4-ol (1.69 g, 6.00 mmol), potassium carbonate (50 mg) and dimethylsulfoxide (3 ml) was heated at 100° C. for 1 hour. After cooling, the mixture was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extracts were combined, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (1:1) to give 1.07 g (68%) of the title compound.
Reaction SMILES: [Cl-].[C:2]([CH2:5][N+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])(O)=O.[C:13](#[N:16])[CH:14]=C.CCN(CC)CC>C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:12][C:7]1[N:6]2[C:11]([CH:10]=[CH:9][CH:8]=1)=[C:14]([C:13]#[N:16])[CH:2]=[CH:5]2
Reactant: C=CC#N
Reactant: Cc1cccc[n+]1CC(=O)O
Agent: O=[Mn]=O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc2c(C#N)ccn12
Reaction time: 12 h

Procedure:
To a solution of crude 1-Carboxymethyl-2-methyl-pyridinium chloride (7 g, 0.037 mol) in toluene (50 mL) were added acrylonitrile (7.4 mL, 0.11 mol), MnO2 (6.5 g, 0.075 mol) and Et3N (2 mL) at room temperature under nitrogen atmosphere. The solution was heated to 90 C and was stirred at the same temperature for 12 hours. The solution was cooled down and was filtered to remove the excess MnO2. The filtrate was concentrated and the residue was purified by CombiFlash with 10% EtOAc in Hexane to afford the desirable product 5-Methyl-indolizine-1-carbonitrile, CAS: 5-Methyl-indolizine-1-carbonitrile (3 g, 52%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[N+:13]([O-])([OH:15])=[O:14]>C(OC(=O)C)(=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cccc(Cl)c2N1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1CCc2cc([N+](=O)[O-])cc(Cl)c2N1
Reaction time: 6 h
Yield: 60.4 %

Procedure:
To a solution of 8-chloro-3,4-dihydro-2(1H)-quinolinone (5.08 g) in acetic anhydride (50 ml) was dropwise added a solution of nitric acid (d=1.40, 2.97 g) in acetic acid (20 ml) over the period of 10 minutes with stirring under ice-cooling. The mixture was stirred for 2 hours at ambient temperature and then for 6 hours at 50° C., and was allowed to stand for 60 hours at ambient temperature. The resulting precipitates were collected, washed with acetic anhydride and ethyl acetate successively and dried to give 8-chloro-6-nitro-3,4-dihydro-2(1H)-quinolinone (3.83 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].BrC[CH:17]=[C:18]([CH3:20])[CH3:19].O1CCC[CH2:22]1>>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:22])([CH2:11][CH:17]=[C:18]([CH3:20])[CH3:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(CC=C(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
A solution of 2-methyl-malonic acid diethyl ester (20.0 g, 115 mmol) in tetrahydrofuran (50 mL) was added dropwise over 15 min to a suspension of sodium hydride (2.89 g, 120 mmol) in tetrahydrofuran (100 mL) at 0° C. The clear reaction mixture was stirred for 5 min at 0° C., then a solution of 1-bromo-3-methyl-but-2-ene (18.8 g, 126 mmol) in tetrahydrofuran (30 mL) was added over 10 min. The reaction mixture was allowed to warm to 25° C. and was stirred at that temperature for 22 h. After quenching with 1.0 M aqueous hydrochloric acid solution (20 mL), the mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (self packed glass column, gradient elution: 5-20% ethyl acetate in hexanes) to afford rac-2-methyl-2-(3-methyl-but-2-enyl)-malonic acid diethyl ester (22.15 g, 91.4 mmol, 79%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.25 (6H, t, J=7.0 Hz), 1.37 (3H, s), 1.62 (3H, s), 1.69 (3H, s), 2.57 (2H, d, J=7.0 Hz), 4.17 (4H, q, J=7.0 Hz), 4.99-5.03 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:23])[CH:8]=2)[N:3]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.[OH-].[Na+]>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:23][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]3[N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)=[CH:28][CH:27]=1
Reactant: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(N)ccc2n1
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CNc2ccc3nc(C)cc(N4CCC(c5ccccc5)C4)c3c2)cc1
Yield: 9 %

Procedure:
2-Methyl-6-amino-4-(3-phenylpyrrolidin-1-yl)quinoline (0.08 g; see Example 45 below), 4-methoxybenzaldehyde (0.071 g), sodium triacetoxyborohydride (0.165 g) and acetic acid (0.05 mL) in 1,2-dichloroethane (5 mL) was refluxed for 4 hours. The reaction mixture was diluted with 1 N sodium hydroxide and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with a mixture of dichloromethane, and methanol. The desired fractions were concentrated and the sample evaporated to dryness. Trituration from ether gave the title compound as a white powder (0.01 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccncc2)c1
Yield: 71.1 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(pyridin-4-yl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), pyridin-4-ylboronic acid (0.025 g; 0.177 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.047 g (71%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(pyridin-4-yl)benzamide as a white solid.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:17][NH:18][C:19]([NH2:21])=[O:20].C([O-])(=O)C.[Na+]>C(O)C.O>[CH:1]1([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[N:17][NH:18][C:19]([NH2:21])=[O:20])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NNC(N)=O
Reactant: O=Cc1ccc(OC2CCCCC2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)NN=Cc1ccc(OC2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a solution of 4-cyclohexyloxybenzaldehyde (2.1 g) in ethanol (50 mL) was added a solution of semicarbazide hydrochloride (1.24 g) and sodium acetate (0.87 g) in water (20 mL) at room temperature. The mixture was stirred for 30 min, and the resulting solid was collected by filtration, washed with water (3×50 mL) and dried in vacuo to yield the title compound as a white solid (2.2 g, 72%), mp: 215 -217° C. 1H NMR (DMSO-d6): δ 10.08 (s, 1H), 7.61 (d, J=8.5, 2H), 6.92 (d, J=8.5, 2H), 6.41 (s, 2H), 4.38 (m, 1H), 1.91-1.24 (m, 10H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.[OH-].[Ba+2].[OH-].COCCOC>O>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: OB(O)c1ccccn1
Reactant: Nc1ncc(Br)cn1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: Nc1ncc(-c2ccccn2)cn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 2-amino-5-bromopyrimidine (0.299 g, 1.72 mmol), 2-pyridylboronic acid (1.57 g, 12.79 mmol), barium hydroxide (0.813 mg, 2.58 mmol), DME (8 mL) and water (1.5 mL) is purged with dry argon. Tetrakis(triphenylphosphine) palladium(0) (99.0 mg, 0.086 inmol) is added, and the resultant solution is stirred at 80° C. for 4 hours. The solvents are evaporated in vacuo, and the residue is partitioned between EtOAc and water. The aqueous extract is separated, and extracted with EtOAc. The organic extracts are combined, washed with sat. aq. NaHCO3 and 5% aq. Na2S2O3, dried, (Na2SO4) and the solvent is evaporated in vacuo. The residue is purified by chromatography to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[C:36]([O:40][C:41](=[O:48])[C@H:42]([CH2:44][CH:45]([CH3:47])[CH3:46])[NH2:43])([CH3:39])([CH3:38])[CH3:37]>C1COCC1.CCOC(C)=O>[C:36]([O:40][C:41](=[O:48])[C@H:42]([CH2:44][CH:45]([CH3:46])[CH3:47])[NH:43][C:17](=[O:19])[C@@H:12]1[CH2:13][CH2:14][C:15](=[O:16])[N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: -15 °C

Procedure:
To a solution of N-benzyloxycarbonyl-L-pyroglutamic acid (1.6 g, 6.0 mmols) and N-methylmorpholine (0.66 ml, 6.0 mmols) in anhydrous THF (10 ml), cooled at −15° C. was added dropwise under stirring an equivalent quantity of isobutylchloroformate (0.82 ml, 6.0 mmols). After 10 minutes a solution of L-leucine tertbutylester hydrochloride (1.34 g, 6.0 mmols) and N-methylmorpholinee (0.66 ml, 6.0 mmols) in anhydrous THF (9 ml) was slowly added maintaining the temperature at −15° C. for 2 hours. The reaction mixture was diluted with EtOAc (70 ml) and washed with saturated NaCl solution (20 ml), KHSO4 1M (20+10 ml), saturated NaHCO3 solution (20+10 ml) and saturated NaCl solution (20 ml). The organic phase was dried on Na2SO4 and the solvent was removed at reduced pressure. The crystallization of raw material from EtOAc/n-hexane gave N-benzyloxycarbonyl-L-pyroglutamyl-L-leucine tertbutylester as white crystals: 2.0 g (77%); m.p. 130-1° C.; [a]D22=−70° (1, methanol); IR (CHCl3); 3420, 2958, 1794, 1723, 1514, 1303, 1152 cm−1; 1H-NMR (CDCl3): d 0.8-0.91 [m, 6, CH2CH(CH3)2], 1.20-1.67 [m, 3, CH2CH(CH3)2 and 1.43 (s, 9, OC(CH3)3], 2.00-2.93 (m, 4, CH2CH2 of pGlu), 4.27-4.61 (m, 2, 2 aCH), 5.22 (s, 2, CH2 benzylico), 6.24 (d, 1, NH, J=8 Hz), 7.28 (s, 5, benzylic aromatics). Calculated for C23H32N2O6: C, 63.87; H, 7.46; N, 6.48; Found C, 64.20; H, 7.60; N, 6.48%.