Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][CH2:20][O:21][C:12]3=[CH:11][C:10]=2[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br.Br[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][CH2:20][O:21][C:12]3=[CH:11][C:10]=2[N:9]([CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:8]=1)=[O:6]
Reactant: BrCc1cccnc1
Reactant: Cc1ccc(C(=O)c2c[nH]c3cc4c(cc3c2=O)OCCO4)cc1C
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccnc3)c3cc4c(cc3c2=O)OCCO4)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 58 mg (0.17 mmol) of 8-(3,4-dimethyl-benzoyl)-2,3-dihydro-6H-[1,4]dioxino[2,3-g]quinolin-9-one, 18 mg of 60% sodium hydride, 57 mg of 3-bromomethylpyridine hydrobromide and 1.2 mL of N,N-dimethylformamide. Yield: 55 mg of a white solid: LC-MSD, m/z for C26H22N2O4 [M+H]+=427.5; HPLC retention time: 1.6 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([CH2:13][CH3:14])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27].[OH-].[K+]>CN(C)C=O.CO.O>[O:12]=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([O:15][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:2]([Cl:1])[C:10]=2[Cl:11])[CH2:6][CH:7]1[CH2:13][CH3:14]
Reactant: CCC1Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCC1Cc2cc(OCCCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
6,7-Dichloro-2-ethyl-5-hydroxy-1-indanone (24.5 g., 0.1 mole) and anhydrous potassium carbonate (15.2 g., 0.11 mole) is stirred in dimethylformamide (100 ml.) while ethyl 4-bromobutyrate (21.4 g., 0.1 mole) is added dropwise. The mixture is stirred and heated at 55°-60° C. for two hours. Potassium hydroxide (7.92 g., 0.141 mole) in methanol (60 ml.) is then added. The solid mass that forms is broken up and the mixture is stirred at 80°-85° C. for 11/2 hours and poured into water (500 ml.). The aqueous mixture is heated to boiling, filtered and acidified (6N HCl). The solid that separates is collected, washed with water, air-dried and recrystallized from ethylacetate to obtain 25.6 g. of 4-(1(1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)butyric acid, m.p. 146°-148° C.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C(N(CC)CC)C.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[CH2:1]([NH:4][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]#[CH:3]
Reactant: C#CCN
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCNC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of propargylamine (6 g, 109 mmol) and triethylamine (15 mL, 109 mmol) in dichloromethane (125 mL) was added dropwise benzoyl chloride (10.5 mL, 90 mmol) at about 0° C. The ice-bath was removed and stirring was continued for about 30 min. Then the reaction mixture was concentrated under vacuum, the residue was diluted with water and was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated under vacuum to provide Example 643. MS (APCI): m/z 160 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+]([O-])=O)[C:4]=1[C:5]#[N:6].[OH-:18].[K+]>FC(F)(F)CO.O>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([O:18][CH2:9][C:11]([F:14])([F:13])[F:12])[C:4]=1[C:5]#[N:6]
Reactant: [OH-]
Reactant: COc1cc(C(F)(F)F)cc([N+](=O)[O-])c1C#N
Agent: [K+]
Solvent: OCC(F)(F)F
Solvent: O
Product: COc1cc(C(F)(F)F)cc(OCC(F)(F)F)c1C#N
Temperature: 25 °C
Yield: 93.1 %

Procedure:
To a solution of 200 mg (0.804 mmol) 2-methoxy-6-nitro-4-trifluoromethyl-benzonitrile in 2.4 ml 2,2,2-trifluoroethanol under argon at 0° C. was added dropwise a solution of 81.3 mg (1.246 mmol) potassium hydroxide in 600 ul water. The mixture was refluxed for 2 days then cooled to room temperature and poured into ice/water. The resulting suspension was filtered and dried in vacuo to provide 112 mg (47%) of the title compound as a white solid. MS (m/e): 317.2 (M+H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]([CH:18]([CH3:20])[CH3:19])[C:7]([C:9]1[N:10]=[C:11]([N:14]2[CH2:17][CH2:16][CH2:15]2)[S:12][CH:13]=1)=[O:8])=[N+]=[N-].[Si:21]([O:38]C1CNC1)([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[N+:43]([C:46]1[CH:56]=[CH:55][C:49]([CH2:50][O:51][C:52](Cl)=[O:53])=[CH:48][CH:47]=1)([O-:45])=[O:44].C(N(CC)CC)C>CO.[OH-].[OH-].[Pd+2]>[Si:21]([O:38][CH:16]1[CH2:17][N:14]([C:11]2[S:12][CH:13]=[C:9]([C:7](=[O:8])[N:6]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:4][NH:1][C:52]([O:51][CH2:50][C:49]3[CH:48]=[CH:47][C:46]([N+:43]([O-:45])=[O:44])=[CH:56][CH:55]=3)=[O:53])[N:10]=2)[CH2:15]1)([C:34]([CH3:37])([CH3:35])[CH3:36])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)N(CCN=[N+]=[N-])C(=O)c1csc(N2CCC2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)N(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reaction time: 1 h
Yield: 55.6 %

Procedure:
A solution of 1-{4-[N-(2-azido-ethyl)-N-isopropyl-carbamoyl]-1,3-thiazol-2-yl}azetidine-3-t-butyldiphenylsilyloxyazetidine (1.33 g, 2.42 mmol) (obtained as described in Reference Example 60(1)) in methanol (65 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide on charcoal (1.33 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. To a solution of the obtained crude product in methylene chloride (63 ml) were added chloroformic acid p-nitrobenzyl ester (627 mg, 2.90 mmol) and triethylamine (0.41 ml, 2.90 mmol) in an ice bath, and the mixture was stirred for 1 hour under the same conditions. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate ethyl acetate:methanol (10:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-{N-isopropyl-N-[2-(p-nitrobenzyloxycarbonylamino)ethyl]-carbamoyl}-1,3-thiazol-2-yl)azetidine (945 mg, yield 56%) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:2]2[C:3]3[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]4[O:18][C:14]([CH3:13])=[CH:15][CH:16]=4)=[N:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:24][CH:23]=1
Reactant: Clc1ccc2c(Br)cccc2n1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(NCc4ccc(F)cc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=362.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-bromo-2-chloroquinoline, 5-methyl-2-furanmethanamine and 4-fluorobenzylamine.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:21][CH2:20][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:14][CH2:13]3)[CH2:9]2)C=CC=CC=1.[Cl:28]C(OC(Cl)C)=O.CO>C(Cl)Cl>[ClH:28].[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:13][CH2:14][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:20][CH2:21]2)[CH2:9]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: c1ccc(C(c2ccccc2)N2CC(N3CCC4(CC3)OCCO4)C2)cc1
Solvent: ClCCl
Solvent: CO
Product: C1COC2(CCN(C3CNC3)CC2)O1
Product: Cl
Reaction time: 1.5 h
Yield: 71.5 %

Procedure:
8-[1-(Diphenylmethyl)azetidin-3-yl]-1,4-dioxa-8-azaspiro[4.5]decane (0.5 g, 1.4 mmol) was dissolved in dry CH2Cl2 under nitrogen and to the resultant solution was added 1-chloroethyl chloroformate (0.45 mL, 4.1 mmol) at 0° C. The mixture was stirred for 1.5 h and then methanol was added. The solution was heated to reflux for 20 min and then the solvent was removed by evaporation. The residue was triturated with acetone and the precipitate was then recrystallised from isopropyl alcohol. There was obtained 235 mg (73%) of 8-azetidin-3-yl-1,4-dioxa-8-azaspiro[4.5]decane hydrochloride as a solid. LCMS: m/z 199 (M+1)+.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:27])=[O:22])[CH3:26])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-alanine methyl ester hydrochloride using the procedure described in Method 3. The resulting methyl ester was deesterified via hydrolysis using LiOH in THF/water to provide the title compound as a solid, mp=160.5-162.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[CH2:11][C:12]([O:14][CH3:15])=[O:13].CC([O-])(C)C.[K+]>C1COCC1>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])([O-:3])=[O:2]
Reactant: COC(=O)CCl
Reactant: O=[N+]([O-])c1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
3-Nitropyridine (5.00 g, 40.3 mmol) and methyl chloroacetate (7.30 g, 67.3 mmol) were dissolved in THF (50 mL) and added drop-wise to a slurry of KOtBu (18.1 g, 161 mmol) in THF (50 mL) at 0° C. The reaction mixture was stirred at RT for 1 h, cooled to 0° C. and quenched with sat aq NH4Cl (100 mL). The THF was removed in vacuo and the reaction mixture was diluted with DCM (75 mL). The aq fraction was extracted with DCM (3×40 mL) and the combined organic fractions were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound as a dark brown oil (3.94 g, 50%). LCMS (ES+): 196.9 [MH]+.
Reaction SMILES: [C:1]([C:3]([O:5][CH3:6])=[O:4])#[N:2].[NH2:7][C:8]1[C:12]([C:13]#[N:14])=[C:11]([N:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21]C(OC(C)(C)C)=O)[CH2:16]2)[N:10]([CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[Cl:37])[C:9]=1[C:38](OCC)=[O:39]>Cl.CO>[NH2:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][N:15]([C:11]2[N:10]([CH2:29][C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[Cl:37])[C:9]3[C:38](=[O:39])[NH:2][C:1]([C:3]([O:5][CH3:6])=[O:4])=[N:7][C:8]=3[C:12]=2[C:13]#[N:14])[CH2:16]1
Reactant: CCOC(=O)c1c(N)c(C#N)c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n1Cc1cc(F)ccc1Cl
Reactant: COC(=O)C#N
Agent: Cl
Solvent: CO
Product: COC(=O)c1nc2c(C#N)c(N3CCC[C@@H](N)C3)n(Cc3cc(F)ccc3Cl)c2c(=O)[nH]1
Temperature: 90 °C

Procedure:
Methyl cyanoformate (170 μl) was added to a solution of ethyl 3-amino-5-{(3R)-3-[(tertbutoxycarbonyl)amino]piperidin-1-yl}-1-(2-chloro-5-fluorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (104 mg) in hydrochloric acid-methanol reagent 10 (4 ml), and the resulting mixture was stirred with heating at 90° C. in a sealed tube for 15 hours. The reaction solution was concentrated under reduced pressure and chloroform was added to the residue. The solid precipitated was removed by filtration and the filtrate was concentrated under reduced pressure. To the resulting residue was added diethyl ether, and the solid precipitated was collected by filtration to obtain a crude product of the title compound (107 mg).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:2][CH2:3][CH3:4].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][N:19]=2)[N:14]=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22].C(N(CC)CC)C.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][NH:9][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][N:19]=2)[N:14]=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: CCCCOCCCN
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCOCCCNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 25 °C
Yield: 79.2 %

Procedure:
Under a nitrogen atmosphere, 3-butoxypropylamine (4.0 mL, 26 mmol) was added dropwise over a period of 10 minutes to a solution of 4-chloro-3-nitro[1,5]naphthyridine (4.6 g, 22 mmol) and triethylamine (4.6 mL, 33 mmol) in dichloromethane (150 mL). The reaction mixture was maintained at ambient temperature overnight. Water (100 mL) was added and the phases were separated. The aqueous phase was extracted with dichloromethane (100 mL). The organic fractions were combined, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide a yellow oil. The oil was purified by flash chromatography (silica gel eluting with 1:1 ethyl acetate:hexanes) to provide 5.3 g of N4-(3-butoxypropyl)-3-nitro[1,5]naphthyridin-4-amine as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 10.08 (broad s, 1H), 9.38 (broad s, 1H), 8.78 (m, 1H), 8.22 (dd, J=8.4,1.6 Hz, 1H), 7.64 (dd, J=8.4,4.1 Hz, 1H), 4.57 (broad s, 2H), 3.63 (t, J=5.8 Hz, 2H), 3.46 (t, J=6.7 Hz, 2H), 2.10-2.03 (m, 2H), 1.65-1.55 (m, 2H), 1.44-1.32 (m, 2H), 0.92 (t, J=7.3 Hz, 3H); MS (EI): m/e 304.1535 (304.1535 calc'd for C15H20N4O3).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][N:15]2[C:38](=[O:49])[CH:39]([NH:44][C:45]([O:47][CH3:48])=[O:46])[C:40]([CH3:43])([CH3:42])[CH3:41])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])C.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:48][O:47][C:45]([NH:44][CH:39]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:38]([N:15]1[CH2:16][CH:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:21]=2)[CH2:18][CH:14]1[C:12]([NH:11][C:6]1([C:4]([OH:5])=[O:3])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:13])=[O:49])=[O:46]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)C(NC(=O)OC)C(C)(C)C)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)C(NC(=O)OC)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 1-{[1-(2-methoxycarbonylamino-3,3-dimethyl-butyryl)-4-(7-methoxy-2-phenyl-quinolin-4-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropane-carboxylic acid ethyl ester (410 mg, 0. 52 mmol) in THF (20 mL), methanol (11.5 mL) and water (3.8 mL) mixture, lithium hydroxide monohydrate (328 mg, 7.82 mmol) was added. The reaction mixture was stirred at rt for overnight. Then it was acidified with 1N HCl solution and concentrated. The residue was extracted with EtOAc twice and the organic layers were combined. Then it was dried (MgSO4) and concentrated to give an off-white solid. (230 mg, 69% yield). 1H NMR (400 MHz, CD3OD) δ 1.02 (s, 9H), 1.43 (dd, J=9.54, 5.14 Hz, 1H), 1.68 (dd, J=8.07, 5.14 Hz, 1H), 2.17 (m, 1H), 2.57 (m, 1H), 2.75 (m, 1H), 3.34 (s, 3H), 4.03 (s, 3H), 4.06 (m, 1H), 4.18 (s, 1H), 4.60–4.70 (m, 2H), 4.88 (m, 1H), 5.08 (dd, J=10.39, 1.59 Hz, 1H), 5.25 (dd, J=17.36, 1.71 Hz, 1H), 5.77–5.87 (m, 2H) 7.38 (dd, J=9.29, 2.20 Hz, 1H), 7.50 (m, 1H), 7.62 (m, 1H), 7.69–7.78 (m, 3H), 8.03–8.07 (m, 2H), 8.36 (d, J=9.20 Hz, 1H). LC-MS (retention time: 2.177 min.), MS m/z 645 (MH+).
Reaction SMILES: Cl[CH:2]([Cl:4])C.[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:9](Cl)=[O:10].[O:16]1CCCOO1>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4].O>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:9]([O:16][CH2:2][Cl:4])=[O:10]
Reactant: CC(Cl)Cl
Reactant: C1COOOC1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: O
Product: O=C(OCCl)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 10 ml of dichloroethane were added 1 g of zirconium tetrachloride and 1 g of 3,5-dichlorobenzoyl chloride, and the mixture was stirred at room temperature for 15 minutes. The mixture was cooled to 0° C., 0.16 g of trioxane was added, and the mixture was stirred for 1 hour, and further stirred at room temperature for 2 hours. Water was added slowly at 0° C., the resultant solution was extracted with chloroform three times, and the organic layers were combined, washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel chromatography to obtain 1 g of chloromethyl 3,5-dichlorobenzoate.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)[OH:16])[CH:9]=[CH:8]2.[H][H].[CH3:43]I>O.CN(C=O)C.C1COCC1>[CH3:43][O:16][CH:15]([C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:11]=1)[C:17]1[N:18]=[CH:19][NH:20][CH:21]=1
Reactant: CI
Reactant: COc1ccc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc(C(OC)c3c[nH]cn3)ccc2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% oil dispersion, 1.77 g) was added to a mixture of THF (200 ml) and DMF(100 ml). To the mixture was added (6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)methanol (20.0 g). The mixture was heated at 50 until the evolution of hydrogen ceased. The mixture was cooled to 0° C., and to the mixture was added methyl iodide (2.6 ml). The mixture was stirred for 15 min. Water was added to the reaction mixture to quench the reaction. THF was distilled off under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous solution of sodium chloride, dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to give the titled compound (18.6 g) as a colorless powder.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17](=[O:26])[C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=3)[CH2:14][CH2:13][N:12]2[C:27](=[O:36])[CH2:28][NH:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:7]=[CH:8][C:9]=1[Cl:10].CCN(C(C)C)C(C)C.[C:46](O)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[C:46]([N:33]1[CH2:32][CH2:31][CH:30]([NH:29][CH2:28][C:27]([N:12]2[CH2:13][CH2:14][N:15]([C:17](=[O:26])[C:18]3[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=3)[CH2:16][CH:11]2[C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)=[O:36])[CH2:35][CH2:34]1)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CNC3CCNCC3)C(c3ccc(Cl)c(Cl)c3)C2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CNC3CCN(C(=O)c4ccccc4)CC3)C(c3ccc(Cl)c(Cl)c3)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of compound obtained from Example 9 (0.23 g, 0.4 10 mmol) in CH2Cl2 (5 mL) was added Hunig's base (0.13 g, 1.0 mmol). This was followed by the addition of benzoic acid (49 mg, 0.4 mmol), HOBT (54 mg, 0.4 mmol), Et3N (40 mg, 0.4 mmol) and DEC (77 mg, 0.4 mmol) at 0° C. The solution was gradually warmed to RT and stirred overnight. After reaction was complete, the solution was diluted with CH2Cl2 (50 mL) and washed with saturated NaHCO3 solution (30 mL, 2×) and brine (20 mL, 3×). The organic layer was dried over MgSO4, filtered and concentrated to give crude material as an oil. The product was purified by chromatography on flash grade silica gel (50 g), eluting with 5% [NH4OH/MeOH (1:9)]/CH2Cl2 to give the title compound as a white solid (0.18 g), m.p. 94°-96° C.; FAB MS [M+1]+ 35 Cl 607.3.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20](O)=[O:21])=[CH:17][CH:18]=3)[C:13]([CH3:23])=[CH:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][C:25]1[C:34]2[O:33][C:32]([C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:31][C:30](=[O:40])[C:29]=2[CH:28]=[CH:27][CH:26]=1>>[O:40]=[C:30]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:24][C:20]([C:16]3[CH:15]=[C:14]4[C:19](=[CH:18][CH:17]=3)[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]=[C:13]4[CH3:23])=[O:21])[C:34]=2[O:33][C:32]([C:35]2[NH:39][N:38]=[N:37][N:36]=2)=[CH:31]1.[CH3:20][OH:21]
Reactant: Nc1cccc2c(=O)cc(-c3nnn[nH]3)oc12
Reactant: Cc1cn(CCCCc2ccccc2)c2ccc(C(=O)O)cc12
Product: CO
Product: Cc1cn(CCCCc2ccccc2)c2ccc(C(=O)Nc3cccc4c(=O)cc(-c5nnn[nH]5)oc34)cc12
Yield: 54 %

Procedure:
Following the process described in example 1 (point K), starting from 1-(4-phenylbutyl)-3-methylindole-5-carboxylic acid and 8-amino-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran, the title compound was prepared as a yellow solid with melting point 186°-187° C., which was purified by crystallization in methanol (54% yield).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)([OH:3])=[O:2].[NH2:14][C:15]1[C:16](=[O:29])[N:17]([CH2:26][CH2:27][CH3:28])[C:18](=[O:25])[N:19]([CH2:22][CH2:23][CH3:24])[C:20]=1[NH2:21]>CO.C(O)(=O)C>[NH2:21][C:20]1[N:19]([CH2:22][CH2:23][CH3:24])[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH3:28])[C:16](=[O:29])[C:15]=1[N:14]=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:7][CH:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Solvent: CC(=O)O
Solvent: CO
Product: CCCn1c(N)c(N=Cc2ccc(OCC(=O)O)cc2)c(=O)n(CCC)c1=O

Procedure:
A representative synthesis of benzylidene adduct is given. Compound A (1.51 g, 8.37 mmol) was dissolved in a mixture of methanol (35 ml) and acetic acid (5 ml) in a 50 ml boiling flask on a steam bath. To this was added a methanolic solution (60 ml) of freshly synthesized 5,6-diamino-1,3-dipropyluracil. After heating 15 minutes, the volume was reduced by evaporation until crystallization occurred. Ether (40 ml) was added and the nearly white solid was collected. Yield 2.80 g (86%), mp 179°-180° C. Analysis (C19H24N4O5): calc. 58.60% C, 6.21% H, 14.39% N; found 58.72% C, 6.16% H, 14.43% N.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[S:8][CH2:7]1.Cl.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:18]1.[Na+].[I-].[C:34](#N)C>>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]4([CH2:15][CH2:14][CH2:13][CH2:12][CH2:34]4)[S:8][CH2:7]3)[CH2:30][CH2:31]2)=[N:18]1
Reactant: CC#N
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C1N(CCCCBr)CSC12CCCC2
Agent: Cl
Agent: [I-]
Agent: [Na+]
Product: O=C1N(CCCCN2CCN(c3nsc4ccccc34)CC2)CSC12CCCCC2
Temperature: 70 °C

Procedure:
A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]nonan-4-one (4.00 g), 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (3.67 g), K2 CO3 (7.00 g) and NaI (300 mg) in acetonitrile (220 ml) was heated at 70° C. for 20 hours and the product was processed in substantially the same manner as in Example 10 to afford 3.01 g of crystalline solid, m.p. 209° C.