Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[H-].[Na+].[CH3:16]I.[OH-].[Na+].Cl>CN(C)C=O.O.CO>[CH3:16][O:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)O)c(C(=O)O)c1
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a solution of 4-hydroxyphthalic acid (0.25 g, 1.37 mmol) in anhydrous N,N-dimethylformamide (3 ml) under nitrogen was added sodium hydride (0.22 g, 5.48 mmol). The solution was stirred for 5 minutes and then methyl iodide (0.68 ml) was added and continued stirring for 3 hours. Several drops of water were added to quench the reaction and the mixture was concentrated in vacuo. The crude material was partitioned between ethyl acetate (40 ml) and water (10 ml). The layers were separated and the organic layer washed with brine (2×10 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo. The resulting oil was dissolved in methanol (8 ml) and 1N sodium hydroxide (4 ml) was added. The reaction was stirred at ambient temperature for 24 h., after which LC-MS indicated only partial hydrolysis. The material was reconstituted in methanol (5 ml) and treated with of sodium hydroxide (0.12 g, 3.0 mmol) dissolved in water (1 ml). The reaction mixture was stirred for 48 h., at which time a precipitate had formed. The mixture was acidified with 6N hydrochloric acid until pH=1, causing the solution to become homogeneous. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate (30 ml) and 0.5N hydrochloric acid (10 ml). The layers were separated and the organic layer concentrated in vacuo to give 100 mg (51%) of 4-methoxy-phthalic acid as a solid.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:25][CH3:26])=[C:21]([OH:24])[CH:22]=2)[N:17]=[CH:16][N:15]=1.O[C@H:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:30]([C:41]([O:43][CH3:44])=[O:42])[CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:25][CH3:26])=[C:21]([O:24][C@@H:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C@H:30]([C:41]([O:43][CH3:44])=[O:42])[CH2:29]3)[CH:22]=2)[N:17]=[CH:16][N:15]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Reactant: COc1cc2ncnc(Cl)c2cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](Oc2cc3c(Cl)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Yield: 79 %

Procedure:
A solution of DEAD (0.329 ml, 2.08 mmol) in DCM (2 ml) was added to as stirred suspension of 4-chloro-7-methoxyquinazolin-6-ol (283 mg, 1.74 mmol prepared as described in Example 16 of WO03/082831),1-tert-butyl 2-methyl (2S,4S)-4-hydroxypiperidine-1,2-dicarboxylate (11) (450 mg, 2.08 mmol) and triphenylphosphine (547 mg, 2.098 mmol) in DCM (10 ml), such that the internal temperature remained <30° C. The reaction mixture was stirred overnight and evaporated to dryness. The residues were purified by column chromatography on SiO2 eluting with increasingly polar mixtures of DCM/methanol (100/0-95/5). The fractions containing the desired product were combined and evaporated to give 1-tert-butyl 2-methyl (2S,4R)-4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1,2-dicarboxylate (12) as a gum (478 mg, 79%): 1H NMR Spectrum: (DMSO-d6) δ1.39-1.46 (10H, m), 1.73-1.84 (1H, m), 1.92-2.03 (1H, m), 2.10-2.18 (1H, m), 2.60-2.69 (1H, m), 3.15-3.40 (3H, m), 3.74-3.85 (1H, m), 4.01 (3H, s), 4.61-4.73 (1H, m), 5.06 (1H, s), 7.43 (1H, s), 7.47 (1H, s), 8.89 (1H, s), 8.97 (1H, s); Mass Spectrum: (M+H)+ 452.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[Cl:28].Cl>O1CCCC1.O>[Cl:28][C:22]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=1[C:20]1[O:19][N:18]=[CH:17][C:16]=1[CH2:3][CH2:2][C:1]([OH:9])=[O:8]
Reactant: ClCc1cnoc1-c1cc(Cl)ccc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1cnoc1-c1cc(Cl)ccc1Cl
Reaction time: 0.17 h
Yield: 57.6 %

Procedure:
To a solution of diethyl malonate (2.89 g) in tetrahydrofuran (40 ml) was gradually added sodium hydride (60%, oil, 655 mg) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(2,5-dichlorophenyl)isoxazole (2.15 g) in tetrahydrofuran (40 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (40 ml) and acetic acid (60 ml) and heated under reflux for 8 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated, dried and recrystallized from ethyl acetate to give a colorless prism (1.35 g, yield 58%) of 3-[5-(2,5-dichlorophenyl)-4-isoxazolyl]propionic acid. melting point: 103–104° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O>>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:13]1[S:12][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccs1
Reactant: COc1ccc(C=O)cc1Br
Product: COc1ccc(C=O)cc1-c1cccs1
Yield: 96 %

Procedure:
Ex-41A: 4-Methoxy-3-(thiophen-2-yl)-benzaldehyde was prepared from 3-bromo-4-methoxybenzaldehyde and thiophene-2-boronic acid in a similar manner as described in Ex-3A. Orange oil, 96% yield. 1H-NMR (CDCl3) δ 9.94 (s, 1H), 8.16 (d, J=1.8 Hz, 1H), 7.80 (dd, J=2.4, 8.4 Hz, 1H), 7.57 (dd, J=1.8, 3.6 Hz, 1H), 7.38 (d, J=5.1 Hz, 1H), 7.12 (dd, J=3.6, 5.1 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 4.02 (s, 3H). HRMS m/z: calc. 218.0402, found 218.0406.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].N1C=CC=CC=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=1)(=[O:26])=[O:25]
Reactant: Nc1ccc(F)cc1F
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(S(=O)(=O)Nc2ccc(F)cc2F)c1
Reaction time: 12 h

Procedure:
To 2,4-difluoro-phenylamine(42, 0.44 mL, 4.4 mmol) in methylene chloride (10.0 mL), under an atmosphere of nitrogen, were added pyridine (1.00 mL, 12.4 mmol) and 3-methoxy-benzenesulfonyl chloride (1.00 g, 4.84 mmol). After 12 hours, the reaction was poured into cold 1 M HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give light yellow solid (91, 0.90 g, 69%). MS(ESI) [M+H+]+=300.
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH:4]([CH3:14])[CH:5]([CH:11]1[CH2:13][CH2:12]1)[C:6]([O:8]CC)=[O:7].[OH-].[Na+].O.C([O-])(=O)CC([O-])=O>C(O)C>[Cl:1][C:2]([Cl:15])=[CH:3][CH:4]([CH3:14])[CH:5]([CH:11]1[CH2:12][CH2:13]1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(C(C)C=C(Cl)Cl)C1CC1
Agent: O=C([O-])CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C=C(Cl)Cl)C(C(=O)O)C1CC1
Yield: 90.5 %

Procedure:
A 500 ml flask was equipped with a magnetic stirrer and a reflux condenser with a nitrogen inlet. The flask was charged with 57.0 g (0.227 mol) of ethyl 5,5-dichloro-3-methyl-2-cyclopropyl-4-pentenoate, 27.24 g (0.681 mol) of sodium hydroxide, 97 ml of water, and 97 ml of ethanol. The reaction mixture was refluxed for four days. After cooling to room temperature, most of the ethanol was removed on the rotary evaporator, the residue diluted with water and extracted twice with ether. The aqueous layer was acidified with concentrated hydrochloric acid, and extracted three times with ether. The combined ether extracts were washed twice with water, dried (MgSO4), and the solvent removed to leave 45.82 g (90% yield) of a honey colored oil.
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([Cl:19])[C:13]=3[CH:12]=[C:11]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=O)=O)C=CC=CC=1.CO.[OH-].[Na+]>C1COCC1>[Cl:19][C:18]1[C:13]2[CH:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:10][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc2c(Cl)ncnc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Clc1ncnc2[nH]c(-c3ccccc3)cc12
Reaction time: 0.25 h
Yield: 76 %

Procedure:
The product from Method D was dissolved in 10 mL of THF and to this solution was added 5.0 mL of methanol and 1.0 g of NaOH. The reaction mixture was stirred for 15 min., concentrated in vacuo and partitioned between a saturated aqueous solution of ammonium chloride (NH4Cl) and ethyl acetate. The resulting aqueous layer was extracted twice with ethyl acetate. The ethylacetate layers were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica-gel chromatography (1:5 ethyl- acetate/hexane) to obtain 0.59 g (76%) of the title compound as a pale yellow solid, mp 145° C. (dec). LRMS: 230, 232 (M+2).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.C1C=CC(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)=CC=1.[CH2:30]1[CH2:40][CH2:39][N:38]2[C:33](=[N:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31]1>C1COCC1.CCOC(C)=O>[OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[N:27]([CH2:30][C:40]1[CH:39]=[N:38][CH:37]=[C:36]2[C:35]=1[N:34]=[CH:33][CH:32]=[CH:31]2)=[N+:28]=[N-:29]
Reactant: C1CCC2=NCCCN2CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: OCc1cncc2cccnc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1cncc2cccnc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.93 g (5.8 mmol) 8-hydroxymethyl-1,6-napthyridine in 20 mL THF was added 1.5 mL (7 mmol) DPPA and 1.2 mL (6.7 mmol) DBU. The reaction mixture was allowed to stir at room temperature 18 hours, then another 0.3 mL DPPA and 0.25 mL DBU were added and the reaction mixture heated to 50° C. for 8 hours then cooled to room temperature then another 0.3 mL DPPA and 0.25 mL DBU were added and the reaction mixture was allowed to stir 18 more hours at room temperature. The resulting solution was then diluted with 200 mL EtOAc, washed with saturated NaHCO3 solution, and brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (40×120 mm silica gel, linear gradient 2-15% MeOH:CH2Cl2) yielded 8-hydroxymethyl-1,6-napthyridine and 8-azidomethyl-1,6-napthyridine. 1H NMR (CDCl3, 400 MHz) δ9.30 (s, 1H); 9.16 (dd, 1H, J=4.3 and 1.8 Hz); 8.78 (s, 1H); 8.35 (dd, 1H, J=8.3 and 1.74 Hz); 7.61 (dd, 1H, J=8.3 and 4.3 Hz); 5.00 (s, 2H).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:32])=[CH:28][C:29]=5[F:31])[N:24]([CH3:33])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN.O>ClCCl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:32])=[CH:28][C:29]=5[F:31])[N:24]([CH3:33])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)cc(F)c34)nc12)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)cc(F)c34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.6 %

Procedure:
2-(6-Chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (84 mg, 0.137 mmol) was suspended in dichloromethane (2 ml) and cooled in an ice bath. Trifluoroacetic acid (0.9 ml) was slowly added and the reaction was stirred at room temperature for 3 h then evaporated. The residue was dissolved in dichloromethane (1.4 ml) and ethylenediamine (0.55 ml, 8.25 mmol) was added. The reaction was stirred for 8 h. Water was added giving a cloudy mixture, which was extracted with ethyl acetate eight times. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. Drying agent was filtered off and rinsed with 10% methanol/dichloromethane, and evaporated to a residue. This was combined with solid which had appeared in the aqueous layer. The combined material was purified by silica gel chromatography (methanol/dichloromethane) to give 32 mg (48%) of 2-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide. (M+H)+=481; mp=267-268° C. 1H NMR (300 MHz, DMSO-d6) δ: 9.00 (s, 1H), 8.54 (d, J=7.2 Hz, 1H), 8.49 (d, J=10.6 Hz, 1H), 7.86-7.90 (m, 1H), 7.18 (d, J=10.2 Hz, 1H), 4.42-4.69 (m, 3H), 4.18 (s, 3H), 4.07-4.17 (m, 1H), 3.95-4.05 (m, 1H), 3.76-3.87 (m, 1H), 1.32-1.41 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][CH:7]([OH:19])[CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[C:4]([O:5][CH2:6][CH:7]([OH:19])[CH2:8][N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: OC(COc1cccc(Br)c1)CN1CCc2ccccc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: OC(COc1cccc(-c2ccccc2)c1)CN1CCc2ccccc2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
To a solution of 1-(3-bromophenoxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (300 mg, 0.828 mmol) in dioxane (4 ml) and H2O (1 mL) was added phenylboronic acid (151.5 mg, 1.24 mmol), Pd(dppf)Cl2 (30.3 mg, 0.041 mmol) and K2CO3 (343.4 mg, 2.484 mmol) at 6° C. The reaction mixture was stirred for 16 h at 80° C. It was concentrated to remove the solvents and the residue was dissolved in ethyl acetate, washed with water. The separated organic layer was concentrated and the crude product purified by HPLC separation to give the title compound (89 mg, 30.0%) as a white solid. 1HNMR (CH3OD, 400 MHz) δ: 8.47 (br, 1H), 7.60-7.62 (m, 2H), 7.40-7.46 (m, 2H), 7.33-7.38 (m, 2H), 7.17-7.28 (m, 6H), 6.97-6.99 (m, 1H), 4.46-4.50 (m, 1H), 4.35 (s, 2H), 4.12 (d, J=2.6, 2H), 3.47-3.50 (m, 2H), 3.26-3.37 (m, 2H), 3.16 (s, 2H). LCMS (m/z): 360.2 [M+H]+
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10].C(OCC)C>Cl.CC(O)=O.CO>[NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOCC
Product: N=C(NCCC[C@H](N)C(=O)O)N[N+](=O)[O-]
Yield: 159.2 %

Procedure:
45.4 Grams (0.1 mole) of BOC-Arg(NO2)-CHA was dissolved in 300 ml (0.6 mole) of 2N-HCl/AcOH with a small amount of MeOH, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, 300 ml of dried diethyl ether was added to the reaction mixture so as to precipitate the crystals. There was obtained 34.9 g (89.4%) of H-Arg(NO2)-CHA.HCl.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:13])=[O:12])=[CH:6][CH:5]=1)=[O:3].[Br:14]Br>O1CCOCC1.C(OCC)C>[Br:14][CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[CH3:13])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1
Reactant: BrBr
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=O)Nc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.5 %

Procedure:
To a suspension of 4-acetamidoacetophenone (Lancaster, 5.32 g, 0.03 mol) in 1,4-dioxane/diethyl ether (100 mL, 1:2, v/v) was added bromine (1.53 mL, 0.03 mol) via a syringe. The reaction mixture was stirred at room temperature for 4 hours until the color of the mixture was changed from brown to white. The solid was collected by filtration, washed with diethyl ether, and dried under high vacuum to give the title compound as a white solid (4.8 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([OH:12])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:49]1[CH2:54][CH2:53][O:52][CH2:51][CH:50]1[C:55]1[C:63]2[S:62][C:61]([NH2:64])=[N:60][C:59]=2[C:58]([O:65][CH3:66])=[CH:57][CH:56]=1>C1COCC1.C(Cl)(Cl)Cl>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([NH:64][C:61]2[S:62][C:63]3[C:55]([CH:50]4[CH2:51][O:52][CH2:53][CH2:54][O:49]4)=[CH:56][CH:57]=[C:58]([O:65][CH3:66])[C:59]=3[N:60]=2)=[O:12])[CH2:2][CH2:3]1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)c1ccnc(COCC2CC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(COCC4CC4)c3)nc12

Procedure:
From 2-cyclopropylmethoxymethyl-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+6.7° (c=1.04, CHCl3), ES-MS m/e (%): 456 (M+H+, 100).
Reaction SMILES: B.[Na].[C:3]([C:6]1[S:10][C:9]2[C:11]3[C:16]([CH2:17][CH2:18][C:8]=2[CH:7]=1)=[C:15]([CH3:19])[CH:14]=[C:13]([CH3:20])[CH:12]=3)(=O)[CH3:4].[Cl-].[NH4+].C([OH:25])C>>[OH:25][CH2:4][CH2:3][C:6]1[S:10][C:9]2[C:11]3[C:16]([CH2:17][CH2:18][C:8]=2[CH:7]=1)=[C:15]([CH3:19])[CH:14]=[C:13]([CH3:20])[CH:12]=3
Reactant: CCO
Reactant: CC(=O)c1cc2c(s1)-c1cc(C)cc(C)c1CC2
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cc(C)c2c(c1)-c1sc(CCO)cc1CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.18 g of sodium boron hydride was added under nitrogen replacement and ice cooling to a 10 mL ethanol solution of 0.50 g of the compound obtained in Example 1, and the system was stirred for 2 hours at room temperature. After the reaction, reduced-pressure solvent distillation was performed, a saturated ammonium chloride aqueous solution was added under ice cooling, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine, dried with magnesium sulfate, and then subjected to reduced-pressure solvent distillation, and the residue was refined by silica gel column chromatography (25% ethyl acetate/hexane) to obtain 0.50 g of 2-(2-hydroxyethyl)-4,5-dihydro-6,8-dimethylnaphtho[1,2-b]thiophene (Table 9-1) in the form of a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[C:7]([NH:9][C:10]1[CH:31]=[CH:30][C:13]2[N:14]([CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=[N:16][C:12]=2[CH:11]=1)=[O:8])([O-])=O.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:32]=[CH:33][CH:34]=1)[C:7]([NH:9][C:10]1[CH:31]=[CH:30][C:13]2[N:14]([CH:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=[N:16][C:12]=2[CH:11]=1)=[O:8]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3cccc([N+](=O)[O-])c3)ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3cccc(N)c3)ccc21
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-{5-[(3-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (190 mg, 415 μmol) in a mixture of ethanol and water (4:1, 10 mL) was added palladium on carbon (38 mg, 10% w/w Pd) and ammonium formate (130 mg, 2.06 mmol). The suspension was heated to reflux for 2 hours, cooled to room temperature and filtered through a pad of Celite®. The filtrate was then evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=3.85 min, MH+ 429].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][C:20](=O)[C:13]3=[CH:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27](=[O:48])[CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19]/[C:20](=[CH:28]\[C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:48])/[C:13]3=[CH:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCn2c1cc1cc(OCc3ccccc3)ccc12
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C1\CCn2c1cc1cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (20.0 g, 72.1 mmol) and tert-Butyl(triphenylphosphoranylidene)acetate (136 g, 361 mmol) in THF (700 mL) was heated at reflux for 4 days. Additional and tert-Butyl(triphenylphosphoranylidene)acetate (27.1 g, 72.1 mmol) was added and stiffing at reflux was continued for an additional 24 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. Recrystallization from hot IPA gave (E)-tert-butyl 2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate as a white solid. Exact mass calculated for C24H25NO3: 375.2, found: LCMS m/z=376.2, (M+H+); 1H NMR (400 MHz, CDCl3) δ ppm 1.53 (s, 9 H), 3.75 (td, J1=6.4, J2=2.4 Hz, 2 H), 4.20 (t, J=6.4 Hz, 2 H), 5.11 (s, 2 H), 6.23 (t, J=2.4 Hz, 1 H), 6.58 (s, 1 H), 6.98 (dd, J1=8.9, J2=2.3 Hz, 1 H), 7.13 (d, J=2.3 Hz, 1 H), 7.21 (d, J=8.9 Hz, 1 H), 7.33 (m, 1 H), 7.39 (m, 2 H), 7.48 (m, 2 H).
Reaction SMILES: [CH2:1]([OH:10])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[CH2:11]([NH:15][C:16]#[N:17])[CH2:12][CH2:13][CH3:14]>>[CH2:11]([NH:15][C:16]1[O:10][CH:1]=[C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:17]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCNC#N
Reactant: O=C(CO)c1ccccc1
Product: CCCCNc1nc(-c2ccccc2)co1
Yield: 47 %

Procedure:
The procedure as described in Example 1 was followed using phenacyl alcohol and butylcyanamide. A colourless oil was obtained after distillation of the product. Wt. = 5.0 g., 47% Yield. b.p. 134° C/0.1 mm., which crystallised on standing. The analytical sample which separated as needles from petrol (40°-60° C) had m.p. 52°-53° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39].[Cl-].[Na+]>CN(C)C=O.O>[C:38]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1NC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of 528 mg (1.25 mmol) of 4-(6-amino-7-ethylamino-4-quinazolinyl)-N-benzyl-1-piperazinethiocarboxamide obtained in Example 461 in 15 ml of dimethylformamide were added 0.57 ml (4.09 mmol) of triethylamine and 0.31 ml (3.29 mmol) of acetic anhydride, followed by overnight stirring at room temperature in an atmosphere of argon. The reaction mixture was poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel chromatography to give the desired compound as colorless crystals.