Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4](=[O:13])[O:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[OH:38][CH2:39][CH2:40][C:41](=[O:43])[CH3:42]>C1COCC1>[O:43]=[C:41]([CH3:42])[CH2:40][CH2:39][O:38][CH2:2][C:3]1[C:4](=[O:13])[O:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=c1oc2ccccc2cc1CCl
Reactant: CC(=O)CCO
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)CCOCc1cc2ccccc2oc1=O
Temperature: 25 °C

Procedure:
3-(Chloromethyl)-2H-chromen-2-one (19.461 g, 100 mmol) is dissolved into 100 mL of anhydrous THF in a three neck flask equipped with a condenser, stir bar, and argon inlet. To the mixture is added 27.6 g (200 mmol) of anhydrous potassium carbonate and 2.0 g of 18-crown-6. 4-Hydroxy-2-butanone (16.2 g, 200 mmol) is added and the system is refluxed for 16 hours, cooled to room temperature, filtered, and the organic solvents are removed by rotary evaporation. The solid organic residue is purified by column chromatography using 3:1 ethyl acetate:hexanes to yield 3-(3-oxo-butoxymethyl)-chromen-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C@@:7]23[CH2:14][C@H:13]([O:15]C(=O)C)[CH2:12][N:11]2[C:10](=[O:19])[N:9]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:8]3=[O:28])=[CH:4][CH:3]=1.O.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@:7]23[CH2:14][C@H:13]([OH:15])[CH2:12][N:11]2[C:10](=[O:19])[N:9]([C:20]2[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:8]3=[O:28])=[CH:29][CH:30]=1
Reactant: CC(=O)O[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@]2(Cc2ccc(Br)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]2(Cc3ccc(Br)cc3)C[C@H](O)CN12
Reaction time: 4 h
Yield: 47.4 %

Procedure:
To a solution of (5S,7S)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-7-acetoxy-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.10 g) in THF (5 in L), MeOH (0.10 mL), and water (0.10 mL) was added 2N LiOH (0.11 mL). After 4 hours, the mixture was quenched with acetic acid (0.10 mL) and concentrated. Purification by chromatography (Silica gel: 4% methanol/CH2Cl2, Chromatotron) afforded the titled compound (0.0435 g). MS (m/z) 469 (MH+), mp 88.3° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[C:39](Cl)=[O:40]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][C:39]([C:30]2[CH:31]=[CH:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:29]=2)=[O:40])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OC(=O)c2ccc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
A solution of 5.0 g (16.9 mmol) of tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-hydroxy-piperidine-1-carboxylate in 50 ml of methylene chloride was treated with 240 mg (1.96 mmol) of 4-dimethylamino-pyridine and 4.2 ml (29 mmol) of triethylamine and cooled to 0° C. Subsequently, 4.65 g (24.4 mmol) of 2-naphthoyl chloride were added portionwise and the reaction mixture was stirred at room temperature for 18 hours. Thereupon, the reaction mixture was treated with ice-water and extracted with methylene chloride. The combined methylene chloride phases were dried over magnesium sulphate, filtered and the solvent was distilled off in a water-jet vacuum. The crude product was chromatographed on silica gel with methylene chloride as the eluent. The thus-obtained product fractions were recrystallized from ether and n-hexane. There were obtained 7.4 g (97% of theory) of tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-(naphthalen-2-ylcarbonyloxy)-piperidine-1-carboxylate as a colourless solid; MS: 450 (M+H)+.
Reaction SMILES: [C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:11][N:10]([C:12](=[O:31])[C@@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]([CH3:22])([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:32]([OH:34])=O)[CH2:8]2)=[CH:3][CH:2]=1.[NH2:46][C@:47]1([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:49][C@H:48]1[CH:50]=[CH2:51].P([O-])([O-])([O-])=O.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:11][N:10]([C:12](=[O:31])[C@@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]([CH3:21])([CH3:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:32]([NH:46][C@:47]3([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:49][C@H:48]3[CH:50]=[CH2:51])=[O:34])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: C=CCCCCC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](SCCCC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](SCCCC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To an iced slurry of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylnon-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxylic acid (126 mg, 0.198 mmol), (1R,2S)-ethyl 1-amino-2-vinylcyclopropanecarboxylate (36.8 mg, 0.237 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium phosphate (HATU, 113 mg, 0.297 mmol) in dichloromethane (4 mL) was added N,N-diisopropylethylamine (0. 104 mL, 0.594 mmol). The formed light brown solution was stirred at room temperature overnight. Diluted with ethyl acetate, washed it with 5% citric acid, 0.1 M NaOH, and brine, dried over MgSO4, filtered, and concentrated. The resulting brown residue was purified by BIOTAGE® column, eluted with gradient 5˜45% ethyl acetate-hexane to afford the desired product (1R,2S)-ethyl 1-((2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylnon-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate (75 mg, 0.097 mmol, 49.0% yield) as a white film. 1H NMR (500 MHz, MeOD) δ ppm 0.75-0.90 (m, 3 H) 1.24-1.54 (m, 24 H) 1.61 (tt, J=9.00, 4.27 Hz, 1 H) 1.65-1.77 (m, 2 H) 1.86 (d, J=7.32 Hz, 1 H) 1.94-2.11 (m, 2 H) 2.19-2.41 (m, 3 H) 2.41-2.51 (m, 1 H) 2.77 (dd, J=13.12, 7.02 Hz, 1 H) 3.03 (dd, J=12.51, 7.63 Hz, 1 H) 3.94-4.04 (m, 1 H) 4.09-4.24 (m, 3 H) 4.35 (t, J=7.48 Hz, 1 H) 5.07-5.18 (m, 1 H) 5.24-5.36 (m, 1 H) 5.70-5.86 (m, 2 H) 7.30-7.41 (m, 1 H) 7.46 (t, J=7.63 Hz, 2 H) 7.58-7.75 (m, 6 H). LC-MS (retention time: 3.72 min, method C), MS m/z 774 (M-C2 H4).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].I[CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CN(C)C=O.O1CCCC1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Reactant: ICC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CC1CCOCC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of Example 74B (1.0 g, 3.1 mmol) in 4:1 N,N-dimethylformamide/tetrahydrofuran (20 mL) were added potassium tert-butoxide (Aldrich, 0.42 g, 3.7 mmol) and 4-(iodomethyl)tetrahydro-2H-pyran (Maybridge, 0.97 g, 4.3 mmol). The reaction mixture was stirred at 80° C. for 16 hours, cooled to room temperature, quenched with saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-100% ethyl acetate in hexanes) to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.21-1.51 (m, 4H), 1.32 (s, 9H), 2.06-2.35 (m, 1H), 3.20-3.30 (m, 2H), 3.79 (s, 3H), 3.80-3.91 (m, J=9.3, 2.2, 2.0 Hz, 2H), 4.06 (d, J=7.1 Hz, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.30 (s, 1H), 7.45 (dd, J=8.8, 3.1 Hz, 1H), 7.64 (d, J=2.7 Hz, 1H); MS (ESI+) m/z 423 (M+H)+; Anal. Calculated for C21H27ClN2O3S: C, 59.63; H, 6.43; N, 6.62. Found: C, 59.66; H, 6.36; N, 6.56.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:20]([NH-])([CH3:22])[CH3:21].O>CC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:20]([CH3:22])[CH3:21])=[C:7]([OH:12])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: CC(C)[NH-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OC(C)C)c(O)c1
Yield: 25 %

Procedure:
To a solution of 3,4-dihydroxybenzoic acid ethyl ester (2.0 g, 11 mmol) in acetone (450 l) were added potassium carbonate (2.28 g, 16.5 mmol) and isopropylamide (1.03 ml, 11 mmol), and the resultant mixture was stirred at room temperature for 2 days. The reaction mixture was poured into chilled water and extracted with ethyl acetate under acidic conditions. The organic layer was concentrated, and the residue was chromatographed On a silica gel column to give a mixture (617 mg) of 3-hydroxy-4-isopropyloxybenzoic acid ethyl ester and its position isomer, 4-hydroxy-3-isopropyloxybenzoic acid ethyl ester (6:1). There was observed NOE of protons at 1'-position of the isopropyl group and 5-position. The reaction was effected using this mixture (617 mg) in the same manner as in Reference Example 18, and the resultant product was recrystallized from hexane to give the titled compound (370 mg, yield 12%).
Reaction SMILES: C(#N)C.[CH:4]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([F:20])=[C:14](F)[C:15]=3[O:17][CH3:18])[C:10](=[O:21])[C:9]([C:22]([OH:24])=[O:23])=[CH:8]2)[CH2:6][CH2:5]1.Cl.Cl.[CH3:27][CH:28]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29]1>C(N(CC)CC)C>[CH:4]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([F:20])=[C:14]([N:32]4[CH2:31][CH2:30][NH:29][CH:28]([CH3:27])[CH2:33]4)[C:15]=3[O:17][CH3:18])[C:10](=[O:21])[C:9]([C:22]([OH:24])=[O:23])=[CH:8]2)[CH2:6][CH2:5]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC1CNCCN1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
An acetonitrile solution (30 mL) containing 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (3 g), 2-methylpiperazine dihydrochloride (1.93 g), triethylamine (1.43 mL), and boron trifluoride-tetrahydrofuran complex (2.84 g) was stirred at room temperature for one hour. Triethylamine (5.71 mL) was further added to the reaction mixture, followed by stirring at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and methanol (30 mL) was added to the residue. The mixture was refluxed for 5 hours, and the solvent was evaporated under reduced pressure. 80% Hydrated methanol (30 mL) was added to the residue, and the pH of the product was adjusted to 7 by use of 5N aqueous sodium hydroxide solution, followed by stirring at room temperature for 16 hours. The thus-produced crystals were recovered through filtration and dried, to thereby yield 3.55 g of the title compound (yield: 91%).
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:3]=1[NH2:4].[CH3:12][S:13][CH3:14].ClN1C(=O)CCC1=O.[OH-].[Na+]>C(N(CC)CC)C.ClCCl>[F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([CH2:12][S:13][CH3:14])[C:3]=1[NH2:4]
Reactant: Cc1c(F)c(N)cc(F)c1F
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCc1c(N)c(F)c(C)c(F)c1F
Reaction time: 0.5 h

Procedure:
To anhydrous dichloromethane (170 ml) are added 2,4,5-trifluoro-3-methylaniline (16.89 g) and dimethyl sulfide (11 ml). Thereto N-chlorosuccinimide (17.2 g) is added gradually below 5° C. After stirring for 30 minutes, triethylamine (21 ml) is added dropwise and the mixture is refluxed over night. After the mixture is cooled and made alkaline with 5% aqueous sodium hydroxide solution, the resultant is extracted with dichloromethane, and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is purified by silica-gel column-chromatography (dichloromethane: n-hexane =1:1) to give 2,4,5-trifluoro-3-methyl-6-methylthiomethylaniline (8.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].Br[N:11]1C(=O)CC[C:12]1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C-]#N.[Na+]>C(Cl)(Cl)(Cl)Cl.C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:12]#[N:11])=[CH:4][C:3]=1[F:9]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: N#CCc1ccc(Br)c(F)c1

Procedure:
A solution of 1-bromo-2-fluoro-4-methyl-benzene (5.0 g, 26.45 mmol), N-bromosuccinimide (4.94 g, 27.75 mmol) and benzoyl peroxide (100 mg) in carbon tetrachloride (75 mL) was heated under reflux for 3 hrs, allowed to cool, filtered and the residue flashed through a plug of silica gel, eluting with hexanes. The solvent was evaporated to dryness to afford a colorless oil. The crude product (1.73 g, 6.46 mmol) and sodium cyanide (317 mg, 6.46 mmol) was heated to reflux in a mixture of ethanol (17 mL) and water (3 mL) for a period of 4 hrs. After cooling, the solution was evaporated to dryness and the residue purified by column chromatography (0 to 10% EtOAc in hexanes) to afford (4-bromo-3-fluoro-phenyl)-acetonitrile as a pale orange solid. 1H NMR (500 MHz, CDCl3) δ 7.56 (1H, m), 7.12 (1H, d, J=8.9 Hz), 7.02 (1H, d, J=8.9 Hz), 3.73 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(#N)C.ClCCl>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][CH:5]2[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1cccc(C2CCCN2CCN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1cccc(C2CCCN2CCNC(=O)c2ccc(Cl)cc2)c1
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of N-(2-aminoethyl)-2-(3-methoxyphenyl)pyrrolidine (0.58 g) in acetonitrile (15 ml) was added milled potassium carbonate (1.10 g) followed by 4-chlorobenzoyl chloride (0.33 ml) at ambient temperature, under nitrogen. The reaction mixture was stirred for 1.5 hrs, diluted with dichloromethane, and filtered. The filter cake was washed with dichloromethane, and the combined filtrates were concentrated. The residue was purified by flash column chromatography (silica gel, 0-20% methanol/dichloromethane). The appropriate fractions were collected and concentrated to afford 0.80 g (85%) of product. Trituration with ether/petroleum ether gave the analytical sample, mp 96°-98° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.N1C=CC=CC=1.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[F:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH:2]([NH:1][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(N)Cc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)C(Cc1ccc(F)cc1)NS(=O)(=O)c1ccc(C)cc1
Yield: 80.7 %

Procedure:
Methyl 2-amino-3-(4-fluorophenyl)propionate (2.01 g), p-toluenesulfonyl chloride (2.25 g) and 4-dimethylaminopyridine (309 mg) were dissolved in chloroform (30 ml), and pyridine (3.0 ml) was added to heat the mixture under reflux for 4.5 hours. P-Toluenesulfonyl chloride (2.20 g) was additionally added, and the mixture was heated under reflux for 3.5 hours. The reaction mixture was poured into ice and 1N hydrochloric acid (17 ml) to conduct liquid separation. The resultant organic layer was successively washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate 9:1→2:1) to obtain the title compound (2.89 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:8]=1[F:16])C>[Pd].CO>[C:20]([O:19][C:17]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][C:8]=2[F:16])[NH:13][C:4](=[O:3])[CH2:5]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)c1c(F)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(=O)Nc2cccc(F)c21
Reaction time: 1 h

Procedure:
A mixture of 2.06 g of N-(tert-butyloxycarbonyl)-N-(2-fluoro-6-nitrophenyl)glycine ethyl ester (XX, EXAMPLE 22, 2.06 g) and palladium on carbon (10%, 0.19 g) in methanol (150 ml) is shaken under hydrogen on a Parr apparatus at 37 psi for 1 hr. The catalyst is then filtered off and p-toluenesulfonic acid 0.016 g) is added. The solution is stirred at 80° for 1 hr and then at 20°-25° overnight. The solvent is then removed under reduced pressure and the residue is chromatographed on silica gel (200 ml) elating with ethyl acetate/dichloromethane (5/95). The appropriate fractions are pooled and concentrated to give the title compound, mp 155°-156°; MS (m/z) at 266; NMR (CDCl3) 1.48, 6.70, 6.84, 7.12 and 8.61 δ.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Br:16]Br.O>FC(F)(F)C(O)=O.ClCCl>[Br:16][C:7]1[C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[C:9]([S:11][C:12]([F:15])([F:13])[F:14])[CH:8]=1
Reactant: BrBr
Reactant: Nc1ccc(SC(F)(F)F)cc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Nc1c(Br)cc(SC(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
24 g of finely pulverulent 2-nitro-4-trifluoromethylmercaptoaniline were dissolved in 50 ml of tri-fluoroacetic acid, and 18 g of bromine were metered in at 20° C. Stirring was then continued for 3 hours at 20° C. and for a further 30 minutes at 40° C. The mixture poured into water and the product taken up in dichloromethane. After the solvent had been removed, 31 g of 6-bromo-2-nitro-4-trifluoromethylmercaptoaniline were obtained.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.OS(O)(=O)=O.[CH2:27](O)[CH3:28]>>[C:10]1([C:9]2[NH:7][C:1]3[C:6]([C:17]=2[CH2:18][C:19]([O:21][CH2:27][CH3:28])=[O:20])=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCO
Reactant: NNc1ccccc1
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 0 °C
Yield: 73 %

Procedure:
Phenylhydrazine (80 mmol), 3-benzoylpropionic acid (1a) (80 mmol), and 12 ml of concentrated H2SO4 in 100 ml of ethanol were heated at reflux for 24 hours. The cooled reaction mixture was poured onto 500 g of ice, and the resulting mixture was extracted with ether (300 ml×2). Workup gave a red oil, which was purified by column chromatography (silica gel, ethyl acetate/n-hexane=1/5) to afford 15.2 g (73%) of ethyl 2-phenyl-3-indole acetate (8) as a pale yellow solid. mp: 61°-62° C.; IR (KBr) 3370, 1718, 1585, 1458 cm-1 ; 1H NMR (CDCl3, 300 MHz), 8 8.17 (s, 1H), 7.67-7.71 (m, 3H), 7.47 (dd, 2H), 7.40 (dd, 2H), 7.40 (dd, 2H), 7.20 (m, 2H), 4.12 (q, 2H), 3.98 (s, 2H), 1.07 (t, 3H), mass spectrum (15 ev) m/Z 279 (M), 206, 179, 128, 102, 77, 58, 43; exact mass calcd for C18H17NO2 279.1259; found 279.1259.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[Cl:27][C:28]1[N:37]=[C:36](Cl)[C:35]2[C:30](=[CH:31][C:32]([O:41][CH3:42])=[C:33]([O:39][CH3:40])[CH:34]=2)[N:29]=1>CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:36]3[C:35]4[C:30](=[CH:31][C:32]([O:41][CH3:42])=[C:33]([O:39][CH3:40])[CH:34]=4)[N:29]=[C:28]([Cl:27])[N:37]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nc(Cl)nc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
To a stirred solution of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (prepared as described in Example 1A) (80 mg, 0.291 mmol) in anhydrous degassed DMF (2 mL) at rt and under an argon atmosphere, was added potassium tert-butoxide (65 mg, 0.581 mmol). The reaction mixture was stirred at rt for a further 2 h. A solution of 2,4-dichloro-6,7-dimethoxyquinazoline (75 mg, 0.291 mmol) in anhydrous DMF (1 mL) was added and the reaction mixture was stirred at rt for a further 15 h. The reaction mixture was partitioned between a mixture of ethyl acetate (20 mL) and brine solution (20 mL), and the organic layer separated. The aqueous layer was extracted further with ethyl acetate (1×20 mL) and the combined organic layers dried over magnesium sulfate. Concentration under reduced pressure gave the crude product which was purified via silica gel flash chromatography (eluting with a gradient of 25% ethyl acetate in hexanes to 100% ethyl acetate) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(2-chloro-6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (46 mg, 32%) as a solid. 1H NMR (300 MHz, CDCl3) 89.60 (brs, 1H), 9.03 (brs, 1H), 7.61 (m, 1H), 7.57 (m, 1H), 7.39-7.46 (m, 2H), 7.31 (m,1H), 7.01 (m, 1H), 6.48 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 498 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][C:11]([O:15][CH3:16])=[N:12]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4].[Br:18][CH2:19][CH2:20][CH:21](Br)C.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[Br:18][CH2:19][CH2:20][CH2:21][N:12]1[C:11]([O:15][CH3:16])=[N:10][C:9]2[C:13]1=[N:14][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7][C:8]=2[NH2:17]
Reactant: CC(Br)CCBr
Reactant: CCCCOc1nc(N)c2[nH]c(OC)nc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCBr)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of 2-butoxy-8-methoxyadenine (5 g, 14.2 mmol) in dimethylformamide (50 ml) were added 1,3-dibromobutane (7.2 ml) and potassium carbonate (9.2 g), and the mixture was stirred at room temperature for 1.5 hour. Water (200 ml) and ethyl acetate (75 ml) were added thereto, and the mixture was extracted, and further extracted with ethyl acetate (75 ml) twice. The organic layers were combined, dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. To the residue was added diethyl ether (25 ml), and the precipitated crystals were collected by filtration, washed with ether (5 ml), and dried to give the subtitle compound (3.6 g) as a white solid. Yield: 71%