Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH2:28][N:29]5[CH2:30][CH2:31][CH2:32][CH2:33]5)=[CH:34][CH:35]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(OCCN5CCCC5)cc4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (0.10 mL, 0.48 mmol) in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.025 g, 15%). MP=170-173° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49-8.45 (m, 1H), 8.25-8.20 (m, 2H), 8.10-8.06 (m, 2H), 7.65-7.61 (m, 1H), 7.51-7.46 (m, 2H), 7.00 (t, J=6.9 Hz, 1H), 6.97-6.93 (m, 2H), 6.70 (s, 1H), 4.11 (t, J=6.1 Hz, 2H), 3.10 (s, 3H), 2.91 (t, J=6.0 Hz, 2H), 2.67-2.60 (m, 4H), 1.86-1.87 (m, 4H). MS=478 (MH)+.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[C:4](Cl)(=[O:14])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:11])=[O:10])=[CH:7][CH:6]=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:11])=[O:10])=[CH:7][CH:6]=1)=[O:14])[CH3:2]
Reactant: CCO
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(C(=O)Cl)cc1

Procedure:
p-Ethoxycarbonylbenzoyl chloride is prepared according to the method of M. J. Dewar and J. P. Schroeder, J. Org. Chem., 30, 2297 (1965), by the gradual addition of a small amount of ethyl alcohol to a boiling solution of terephthaloyl chloride in benzene. After removal of the solvent the residue is distilled under reduced pressure to give the acyl chloride which boils at 102°-105° C. at 0.4 mm.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:18])[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH:9]([CH3:18])[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C[C@@H](CCN1CCOCC1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)CCN1CCOCC1
Temperature: 25 °C

Procedure:
The product of example 22 (c) (0.41 g, 1.59 mmol) was dissolved in CH2Cl2 (10 mL) and cooled in an ice bath while stirring under argon. A solution of trifluoroacetic acid (5 mL) in CH2Cl2 (5 mL) was added and the mixture allowed to warm to room temperature for 1 h. The solvents were evaporated to give the title compound as an oil. ES (+) MS m/e=159 (MH+)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[N:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:20][O:21][N:22]=[C:23]1[C:27]2([CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]2)[CH2:26][NH:25][CH2:24]1>C(#N)C>[C:34]([O:33][C:31]([N:29]1[CH2:30][C:27]2([C:23](=[N:22][O:21][CH3:20])[CH2:24][N:25]([C:11]3[N:12]=[C:13]4[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:15])[CH2:26]2)[CH2:28]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Solvent: CC#N
Product: CON=C1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC12CN(C(=O)OC(C)(C)C)C2
Temperature: 47.5 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid and 840 mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate were added to 10 ml of acetonitrile and the resulting mixture was stirred for 3 hours at 45-50° C. Then the precipitated solid was filtered and dried to give 650 mg of the titled compound (yield: 93.9%).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[NH:5][C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:2].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[N:5]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=O
Product: CCOC(=O)c1c(C=O)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1

Procedure:
React 3-formyl-2-carboethoxy-4,6-dichloroindole with p-toluenesulfonyl chloride as describe in Preparation 1.1 to give the title compound.
Reaction SMILES: [CH:1]([N:5]1[CH:10]=[C:9]([C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)[C:8](OC)=[C:7]([C:19]#[N:20])[C:6]1=[O:21])([CH2:3][CH3:4])[CH3:2].O.[NH2:23][NH2:24]>C(O)C>[NH2:20][C:19]1[C:7]2[C:6](=[O:21])[N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH:10]=[C:9]([C:11]3[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=3)[C:8]=2[NH:24][N:23]=1
Reactant: NN
Reactant: CCC(C)n1cc(-c2ccn(C)n2)c(OC)c(C#N)c1=O
Solvent: O
Solvent: CCO
Product: CCC(C)n1cc(-c2ccn(C)n2)c2[nH]nc(N)c2c1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a mixture of 1-(sec-butyl)-4-methoxy-5-(1-methyl-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step C (140 mg) and ethanol (5 mL) was added hydrazine monohydrate (122 mg), and the mixture was stirred at 90° C. for 1 hr, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane), and recrystallized from ethyl acetate/diisopropyl ether to give the title compound (82 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[C:5]([C:24]([O:26]CC)=[O:25])[CH:4]=[N:3]1.[Li+].[OH-].Cl>C1COCC1.C(O)C>[CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[C:5]([C:24]([OH:26])=[O:25])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)NCCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)O)cnn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of ethyl 1-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethylcarbamoyl)-1H-pyrazole-4-carboxylate (407 mg, 1.06 mmol) in THF (3.00 mL) and Ethanol (1.5 mL) was added LiOH (1M aqueous solution, 2.13 mL, 2.13 mmol) at 0-5° C. The reaction mixture was stirred at RT for 2 h and poured into HCl (1 M, 2.15 mL). The resulting thick suspension was filtered and the filtrate was extracted with dichloromethane (3×50 mL). The organic layers were combined, dried over MgSO4 and concentrated in vacuo to give 341 mg (90.4%) off-white solid as crude product which was used without any further purification.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=O)[CH:13]2[CH2:14][CH2:15][CH2:16][CH:12]2[C:11](=[O:17])[O:10]1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[C:9](=[O:10])[C@@H:13]2[CH2:14][CH2:15][CH2:16][C@@H:12]2[C:11]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C1OC(=O)C2CCCC12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1[C@H]2CCC[C@H]2C(=O)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of benzylamine (6.4 mL) and tetrahydro-1H-cyclopenta[c]furan-1,3(3aH)-dione (8 gm) in tetrahydrofuran (28 mL) was heated under reflux for 18 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and filtered through a pad of celite. Evaporation under reduced pressure gave crude (3aR,6aS)-2-benzyltetrahydrocyclopenta[c]pyrrole-1,3(2H,3 aH)-dione.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:9]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])#[CH:10]>ClCCl>[C:9]([C:11]1[CH:12]=[C:13]([NH:14][C:5]([CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])[CH:15]=[CH:16][CH:17]=1)#[CH:10]
Reactant: C#Cc1cccc(N)c1
Reactant: O=C1CCCC(=O)O1
Solvent: ClCCl
Product: C#Cc1cccc(NC(=O)CCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.3 %

Procedure:
Glutaric anhydride (215 mg, 1.9 mmol) was dissolved in anhydrous dichloromethane (7 ml) and followed by the addition of 3-ethynylaniline (200 mg, 1.7 mmol). The mixture was allowed to stir at room temperature for 6 hours before the solvent was evaporated under reduced pressure to provide the product as a white solid (363 mg, 99%);
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[N:15]=[C:14]3[C:22](O)=[O:23])[CH:8]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH:59]([N:62]1[CH2:67][CH2:66][CH:65]([NH2:68])[CH2:64][CH2:63]1)([CH3:61])[CH3:60]>CN(C=O)C>[CH:59]([N:62]1[CH2:67][CH2:66][CH:65]([NH:68][C:22]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[O:23])[CH2:64][CH2:63]1)([CH3:61])[CH3:60]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(O)c1nc2cccnc2n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NC(=O)c2nc3cccnc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
150.0 mg (0.41 mmol) 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazo[4,5-b] pyridine-2-carboxylic acid were dissolved in 4 mL DMF. Sequentially 142 μl DIPEA and 151.8 mg (0.41 mmol) HATU were added and the mixture was stirred for 20 min at room temperature. 74.3 mg (0.41 mmol) 1-Isopropyl-piperidine-4-ylamine-hydrochloride and another 71 μl DIPEA were added and the resulting mixture was stirred 3 h at room temperature. Concentration under reduced pressure and final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide as a light brown amorphous solid. The title compound was obtained as its hydroformiate.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[OH-].[Na+].S(OC)(O[CH3:17])(=O)=O>C(O)C.O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:17])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(C)=O)cc1

Procedure:
In 200 ml of ethanol was dissolved 30.0 g of 4-hydroxyacetophenone, and a solution of 11.3 g (1.28 eq.) of sodium hydroxide in 60 ml of water and 33.9 g (1.22 eq.) of dimethyl sulfate were added dropwise consecutively. After the reaction mixture was refluxed for 30 minutes', a solution of 2.8 g (0.32 eq.) of sodium hydroxide dissolved in 10 ml of water was added, followed by heating under for 3 hours' reflux. After the solvent was distilled off, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried. Then, the solvent was distilled off. The resulting crystals were collected by filtration with hexane.
Reaction SMILES: [CH2:1]([N:8]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=1)[CH2:9][C@H:10]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Si:40]([O:47][C:48]1[CH:55]=[CH:54][C:51]([CH:52]=[O:53])=[CH:50][CH:49]=1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>O1CCCC1.CCCCCC>[CH2:1]([N:8]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:52]([C:51]2[CH:50]=[CH:49][C:48]([O:47][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])=[CH:55][CH:54]=2)[OH:53])=[CH:30][CH:29]=1)[CH2:9][C@H:10]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCc1ccc(Br)cc1)Cc1ccccc1)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C(O)c2ccc(CCN(Cc3ccccc3)C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)cc2)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
To a solution of (2R)-N-benzyl-N-[2-(4-bromophenyl)-ethyl]-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethanamine (2.1 g) in tetrahydrofuran (25 ml) was added a solution of butyllithium in hexane (1.59M, 2.83 ml) dropwise at −70° C. under nitrogen and the mixture was stirred at −70° C. for 30 minutes. To the reaction mixture was added 4-[[tert-butyl(dimethyl)silyl]oxy]benzaldehyde (977 mg) at −70° C., and the mixture was stirred at −70° C. for 1 hour. The mixture was allowed to warm to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium biscarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=10/1) to give [4-[2-[N-benzyl-N-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)-ethyl]amino]ethyl]phenyl][4-[[tert-butyl(dimethyl)silyl]-oxy]phenyl]methanol (1.1 g).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36]C5CCCCO5)[CH:33]=[CH:32][C:31]=4[F:43])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:31]=4[F:43])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(OC4CCCCO4)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(O)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 50 °C
Reaction time: 20 h
Yield: 81.2 %

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-cyclopropyl-3-(3-(((6-(2-fluoro-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-5-neopentylpyridin-3-yl)oxy)methyl)phenyl)propanoate (984 mg) in methanol (8.35 mL) was added pyridinium p-toluenesulfonate (126 mg) at room temperature, and the mixture was stirred at 50° C. for 20 hr. The reaction mixture was cooled, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (685 mg) as a colorless gummy substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:28])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][Br:28])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2cccc(C(=O)OC(C)(C)C)c2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
To a solution of tert-Butyl-3-(4-tolyl)benzoate (60 g, 0.22 mol) in CCl4 (800 mL) were added NBS (47.8 g, 0.268 mol) and benzoylperoxide (10 g) and the reaction mixture was refluxed overnight. Cooled to RT and filtered. The filtrate was concentrated to give 4-(3-tert-butoxy carbonyl phenyl)benzyl bromide (65 g, 84%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[OH:4].O=[C:16]([CH3:30])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:29][O:28][C:26]([CH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH:16]([NH:1][CH2:2][CH:3]([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][CH:6]=2)[OH:4])[CH3:30])=[CH:24][CH:23]=1)=[O:27]
Reactant: NCC(O)c1cccc2ccccc12
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc3ccccc23)cc1
Yield: 30.1 %

Procedure:
Following a procedure similar to that described in Example 6, but using 3 g of 2-amino-1-(1-naphthyl)ethanol (prepared as described in Preparation 10), 3.87 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 50 ml of absolute methanol and 3 g of sodium cyanoborohydride, 1.9 g of the title compound were obtained having an Rf=0.35 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=O)[C:14]([Cl:20])=[C:15]([Cl:19])[C:16]([OH:18])=[O:17])=[C:5]1[CH3:22])[CH:2]=[CH2:3].[CH2:23]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CC1NC2C(C=1)=CC=CC=2>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2([C:31]3[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:30]=3)[O:18][C:16](=[O:17])[C:15]([Cl:19])=[C:14]2[Cl:20])=[C:5]1[CH3:22])[CH:2]=[CH2:3]
Reactant: C=CCn1c(C)c(C(=O)C(Cl)=C(Cl)C(=O)O)c2ccccc21
Reactant: CCCCCCn1ccc2ccccc21
Agent: Cc1cc2ccccc2[nH]1
Product: C=CCn1c(C)c(C2(c3cn(CCCCCC)c4ccccc34)OC(=O)C(Cl)=C2Cl)c2ccccc21

Procedure:
Following a procedure similar to that described above in part B of this example except that 4-(1-allyl-2-methyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid is used in place of 4-(1-ethyl-2-methyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid and 1-n-hexylindole is substituted for 2-methylindole, there is obtained 5-(1-allyl-2-methyl-3-indolyl)-5-(1-n-hexyl-3-indolyl)-3,4-dichloro-2(5H)-furanone (Formula V: R=CH2 =CHCH2 ; R1 =CH3 ; R2 =CH3 (CH2)4CH2 ; R3 =Y=Y1 =H).
Reaction SMILES: N.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17](C1NC=CN=1)(C1NC=CN=1)=[S:18]>C(Cl)Cl.CCCCCC>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([N:13]=[C:17]=[S:18])[CH:14]=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1cccc(OCc2ccccc2)c1
Agent: N
Solvent: CCCCCC
Solvent: ClCCl
Product: S=C=Nc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
The final product, Compound 1 is obtained by treatment of Z with thiocarbonyl di-imidazole followed by ammonia. 3-Benzyloxyaniline (5 g, 25 mmol) is added dropwise over a one minute period to 4.94 g (27.6 mmol) thiocabonyl di-imidazole in methylene chloride (150 ml). The resulting mixture is stirred at room temperature overnight. An additional 400 mg thiocarbonyl di-imidazole (TCDI) is added and the reaction is continued for 2 hours more. The reaction is diluted with hexane and filtered through silica. Concentration provides 5.1 g of the desired 3-benzyloxyphenyl isothiocyanate.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:31][CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>>[CH3:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Reactant: CC1CCCN1
Product: CC1CCCN1CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1

Procedure:
The product from Example 23D and 2-methyl-pyrrolidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, d4-methanol) δ 7.83 (m, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.57 (m, 2H), 7.52 (d, J=8.4 Hz, 2H), 6.80 (s, 1H), 3.2-3.9 (m, 7H), 2.35 (m, 1H), 2.10 (m, 2H), 1.76 (m, 1H), 1.48 (d, J=7.2 Hz, 3H); MS (DCI) m/z 419 (M+H)+;
Reaction SMILES: Br.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH2:4][C:3]1=[O:11].[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:35][CH3:36])=[C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:23]=2)[N:18]=[CH:17][N:16]=1>C1COCC1.CN(C=O)C>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:35][CH3:36])=[C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[CH:23]=3)[N:18]=[CH:17][N:16]=2)[C:3]1=[O:11]
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Reactant: O=C1Cc2cccnc2N1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2ncnc(C3C(=O)Nc4ncccc43)c2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.9 %

Procedure:
7-Azaoxindole hydrobromide (269 mg, 1.25 mmol), (Tet.Let. 1987, 28, 4027), was added to a suspension of sodium hydride (100 mg, 2.5 mmol, prewashed with hexane) in a mixture of THF (3 ml) and DMF (3 ml). After stirring for 40 minutes at ambient temperature, 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (169 mg, 0.5 mmol) was added. After heating for 1 hour at 75° C., the volatiles were removed by evaporation. The residue was partitioned between ethyl acetate and water. The aqueous layer was separated and adjusted to pH8 with 2M hydrochloric acid. After extraction with methylene chloride, the organic layer was dried (MgSO4), filtered and the volatiles removed by evaporation. The residue was dissolved in methylene chloride/methanol and 3M hydrogen chloride in ether (0.5 ml) was added. After dilution with ether, the solid was collected by filtration and dried under vacuum to give 4-(7-azaoxindol-3-yl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline (150 mg, 59%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:27][CH:28]=2)=[CH:20][CH:19]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:27][CH:28]=3)=[CH:35][CH:36]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: ClCc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a mixture of ethyl 3-[3-ethoxy-1H-pyrazol-4-yl]propionate (318 mg), 4-(4-chloromethylphenoxymethyl)-2-phenyloxazole (450 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 60.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration, and ethyl 3-[3-ethoxy-1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (616 mg, yield: 86%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 80–81° C.