Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:17])[CH:13]=2)[CH:8]=1)=[O:6].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][N:20]=[C:19]2[O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:5]([O:4][CH3:3])=[O:6])[CH:16]=[CH:15]2
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(Oc3ncnc4cc(OC)c(OC)cc34)ccc2c1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To a stirred mixture of NaH (200 mg, 60% in mineral oil, 5.0 mmol, Aldrich) in 10 mL of DMF at RT was added 6-hydroxy-naphthalene-2-carboxylic acid methyl ester (Step a, 675 mg, 3.34 mmol). After 20 min, 4-chloro-6,7-dimethoxy-quinazoline (750 mg, 3.34 mmol, Oakwood) was added and the reaction was heated to 60° C. for 20 min. The reaction was cooled to RT, quenched with saturated aqueous NH4Cl solution (30 mL) and extracted with CHCl3 (30 mL). The organic solution was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (30% EtOAc/hexane) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 390.9 (M+1). Mass Calc'd for C22H18N2O5: 390.12.
Reaction SMILES: [H-].[Na+].[N:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[N:6]=[CH:5][CH:4]=1.C[C:18]#[C:19][C:20]([O-:22])=[O:21].[CH2:23](COC)OC>>[C:20]([CH:19]=[CH:18][N:15]1[C:16]2[N:3]=[CH:4][CH:5]=[N:6][C:7]=2[S:8][C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2)([O:22][CH3:23])=[O:21]
Reactant: COCCOC
Reactant: c1ccc2c(c1)Nc1nccnc1S2
Reactant: CC#CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C=CN1c2ccccc2Sc2nccnc21
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.1 g, 4.2 mmoles) in dimethoxyethane (10 ml) was added 1,4-diazaphenothiazine (200 mg, 1 mmole). After stirring for 30 minutes a deep red solution of the anion was obtained and this was treated with methylpropiolate (85 μl, 1.0 mmole). Stirring was maintained for 30 minutes. The mixture was evaporated to dryness and the residue was purified by chromatography. Elution with 40% EtOAc/hexane gave the desired product as on orange solid, m.p. 165°-169°. NMR analysis showed the product to be a mixture of trans and cis isomers in a ratio of 4 to 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[N:12]O)[CH2:6][CH2:5]2.Cl.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH2:12])[CH2:6][CH2:5]2
Reactant: ON=C1CCc2cc(Br)ccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC1CCc2cc(Br)ccc2C1
Temperature: 25 °C

Procedure:
A solution of BH3-THF complex (1M) (35.9 mL, 35.9 mmol) was added drop-wise to a stirred solution of 6-bromo-3,4-dihydro-1H-naphthalen-2-one oxime (Step A) (3.450 g, 14.37 mmol) in THF (125 ml) at 0° C. The mixture was warmed to RT and to reflux for 24 h. The reaction was cooled to RT and 1 N aqueous HCl was added carefully until the mixture was acidic and the system was stirred until no further gas was evolved. The solution was made basic by the addition of NaOH and the aqueous layer was extracted with EtOAc. The combined organics were dried over MgSO4 and concentrated in vacuo to afford the crude title compound, which was purified by flash column chromatography to yield the title compound. MS (APCI pos) 228 (M+H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.[CH:26]([I:29])([CH3:28])[CH3:27].C(N(CC)CC)C>CN(C)C=O>[IH:29].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]4[CH2:16][CH2:17][N:18]([CH:26]([CH3:28])[CH3:27])[CH2:19][CH2:20]4)[C:12]=3[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Reactant: CC(C)I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Product: I
Temperature: 80 °C
Yield: 44.3 %

Procedure:
A mixture of 3.5 g (0.01 mol) of 1-cyclopropyl-6,8-difluoro- 7-(piperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3.4 g (0.02 mol) of isopropyl iodide and 2.1 (0.02 mol) of triethylamine in 50 ml of dimethylformamide is heated to 80° C. in the course of 6 hours. After the solvent has been evaporated off, the residue is stirred with 30 ml of water and is then filtered off under suction, washed with water and recrystallised from methanol. 2.3 g of 1-cyclopropyl-6,8-difluoro-7-(4-isopropylpiperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydriodide having a decomposition temperature of 306°-308° C. are obtained.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:13](=[O:17])[N:14]([CH2:15][CH3:16])[C:7]=12)(=O)C.[OH-].[Na+].[NH4+:27].[Cl-]>CCO>[CH2:15]([N:14]1[C:7]2[C:8](=[N:9][CH:10]=[CH:11][C:6]=2[CH2:5][OH:4])[N:12]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:13]3[N:12]([CH3:18])[C:8]4=[N:9][CH:10]=[CH:11][CH:6]=[C:7]4[N:27]=3)=[CH:20][CH:19]=2)[C:13]1=[O:17])[CH3:16]
Reactant: [NH4+]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(COC(C)=O)c21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccc(CO)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of [1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methyl acetate (150 mg) and EtOH (3 mL) was added 1N NaOH (2 mL) at 0° C. The mixture was stirred at 0° C. for 30 min, treated with saturated NH4Cl solution, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DMA (4 mL) and KOtBu (52 mg) was added at room temperature. The mixture was stirred for 2 min, and then 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (97 mg) was added. The mixture was stirred at 150° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, AcOEt/MeOH=20/1) and crystallized from AcOEt/hexane to give the title compound (46 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:46]=[C:47]([F:49])[CH:48]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([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)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:10]=[C:9]2[NH:34][C:35](=[O:45])[C:36]1[CH:41]=[C:40]([CH:42]=[O:43])[CH:39]=[CH:38][C:37]=1[F:44].CC(=CC)C.Cl([O-])=[O:56].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:46]=[C:47]([F:49])[CH:48]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:10]=[C:9]2[NH:34][C:35](=[O:45])[C:36]1[CH:41]=[C:40]([CH:39]=[CH:38][C:37]=1[F:44])[C:42]([OH:56])=[O:43]
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1ccc(F)c(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(Cc4cc(F)cc(F)c4)cc23)c1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc(F)c(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(Cc4cc(F)cc(F)c4)cc23)c1
Yield: 117.6 %

Procedure:
N-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-2-fluoro-5-formyl-benzamide (88 mg, 0.135 mmol) in tert-butanol (1.8 mL) at room temperature was treated first with 2-methyl-2-butene (0.079 mL, 1.082 mmol) and then with sodium chlorite (37 mg, 0.405 mmol) and sodium dihydrogenphosphate in water (0.8 mL) drop-wise. The reaction was stirred over-night, EtOAc was then added (30 mL) and washed with water (25 mL). The aqueous layer was extracted twice with EtOAc (2×10 mL). The combined organic layers were washed with brine, evaporated to dryness to leave 106 mg of title compound which was employed in the following step with no need of further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.CN(C)C=O.[H-].[Na+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CO.O1CCCC1>[CH2:34]([O:15][C:10]1[CH:11]=[C:12]2[C:7]3=[C:8]([C:16](=[O:26])[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][N:6]3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]2=3)[CH:9]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(OCc4ccccc4)cc1c32
Temperature: 25 °C
Reaction time: 12 h
Yield: 146.7 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (2.0 g) obtained in Example 2 was suspended in a mixed solvent of anhydrous dimethylformamide (64 ml) and anhydrous tetrahydrofuran (120 ml), and sodium hydride(60%, 260 mg) was added to the suspension in an ice bath. Benzylbromide (400 mg) was added dropwise and the mixture was stirred at room temperature for 12 hours. A small amount of methanol was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 1N aqueous solution of sodium hydroxide and saturated aqueous solution of sodium chloride in succession, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride containing 3% methanol) to produce the title compound (1.7 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([NH:13][C:14](=[O:24])[NH:15][CH2:16][CH2:17][O:18]C(=O)C(C)=C)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5].[OH-].[Na+].C([O-])(O)=O.[Na+].O>CCO.CCOC(C)=O>[Cl:1][C:2]1[CH:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([NH:13][C:14]([NH:15][CH2:16][CH2:17][OH:18])=[O:24])[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5]
Reactant: C=C(C)C(=O)OCCNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)NCCO)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C

Procedure:
Compound 259 (0.05 g, 0.095 mmol) was dissolved in EtOH (2.5 mL). 2 N NaOH (0.25 mL) was added and the solution was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and saturated aqueous NaHCO3 (2 mL) was added. H2O and EtOAc were added and the phases were separated. The water phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:13])([F:12])[F:11])=[C:6]([CH:9]=1)[CH2:7]Cl.[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH2:7][C:6]4[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[C:10]([F:13])([F:12])[F:11])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: Fc1ccc(C(F)(F)F)c(CCl)c1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(Cc3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 5-fluoro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (40% yield). 1H NMR (300 MHz, CDCl3) δ 7.95-8.01, 7.57-7.68, 7.04, 6.95, 3.79, 3.71, 3.56, 2.64, 1.51, 0.68-0.82, 0.43-0.51, 0.06-0.13. MS (ES+) m/z 452 (M+1).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][C:11]([CH3:43])([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:32]=[C:31]3[C:26]([C:27]([C:34](=[O:42])[NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:28][C:29]([CH3:33])=[N:30]3)=[CH:25][CH:24]=2)=[CH:19][N:18]=1)[C:12](O)=[O:13].Br.[N:45]1[NH:46][N:47]=[N:48][C:49]=1[CH2:50][NH2:51].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[N:45]1[NH:46][N:47]=[N:48][C:49]=1[CH2:50][NH:51][C:12](=[O:13])[C:11]([CH3:10])([CH3:43])[CH2:15][O:16][C:17]1[N:18]=[CH:19][C:20]([C:23]2[CH:32]=[C:31]3[C:26]([C:27]([C:34]([NH:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:42])=[CH:28][C:29]([CH3:33])=[N:30]3)=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: NCc1nn[nH]n1
Reactant: Cc1cc(C(=O)Nc2ccccc2)c2ccc(-c3ccc(OCC(C)(C)C(=O)O)nc3)cc2n1
Agent: Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)Nc2ccccc2)c2ccc(-c3ccc(OCC(C)(C)C(=O)NCc4nn[nH]n4)nc3)cc2n1
Reaction time: 8 h
Yield: 65 %

Procedure:
N-Ethyl-N,N-diisopropylamine (50.0 μL, 0.300 mmol) was added at room temperature to a solution of 2,2-dimethyl-3-(5-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)pyridin-2-yloxy)propanoic acid B-17 (45.5 mg, 0.10 mmol), (2H-tetrazol-5-yl)methanamine hydrobromide (27.7 mg, 0.154 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (64.0 mg, 0.123 mmol) in anhydrous N,N-dimethylformamide (5.0 mL) under an atmosphere of nitrogen. The reaction mixture was stirred overnight, then partitioned between methylene chloride (30 mL) and an aqueous solution of pH 7 phosphate buffer (30 mL). The aqueous layer was extracted with methylene chloride (3×30 mL); the combined extracts were successively washed with water (30 mL), brine (30 mL), then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give 7-(6-(3-((2H-tetrazol-5-yl)methylamino)-2,2-dimethyl-3-oxopropoxy)pyridin-3-yl)-2-methyl-N-phenylquinoline-4-carboxamide B-24 (34.9 mg, Yield=65%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.35 (s, 6H), 2.77 (s, 3H), 3.71-3.74 (m, 2H), 4.75 (d, J=5.5 Hz, 2H), 6.86 (d, J=8.5 Hz, 1H), 7.23-7.30 (m, 2H), 7.45 (t, J=6.5 Hz, 3H), 7.87 (d, J=8.0 Hz, 2H), 7.87 (d, J=8.5 Hz, 1H), 8.24 (d, J=8.5 Hz, 1H), 8.47 (s, 1H), 8.45 (d, J=9.5 Hz, 1H), 8.59 (s, 1H); MS (ESI) [M+1]+ 537.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1>CN(C=O)C>[ClH:14].[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][N:30]5[CH:34]=[CH:33][N:32]=[CH:31]5)=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][N:16]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCn1ccnc1
Reactant: O=C1Cc2ccc(F)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4cc(F)ccc43)ncnc2cc1OCCn1ccnc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
A solution of 6-fluorooxindole (407 mg, 2.7 mmol), (Synthesis 1993, 51), in DMF (6 ml) was added dropwise to sodium hydride (108 mg, 2.7 mmol, prewashed with hexane) in DMF (6 ml). The mixture was stirred for 30 minutes at ambient temperature and 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (274 mg, 0.9 mmol), (prepared as described for the starting material in Example 22), was added as a solid. The mixture was heated at 65° C. for 30 minutes, allowed to cool and was partitioned between saturated aqueous ammonium chloride solution and methylene chloride. The organic layer was separated, dried (MgSO4), and the solvent removed by evaporation. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum. The solid was dissolved in methylene chloride/methanol and 5M ethereal hydrogen chloride (4 ml) was added. The mixture was concentrated by evaporation to 5 ml total volume and the resulting solid was collected by filtration, washed with ether and dried under vacuum to give 4-(6-fluorooxindol-3-yl)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline hydrochloride (175 mg, 40%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].CC1C=CC(S(O[CH2:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[CH2:39][CH2:38]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 77.1 %

Procedure:
A solution of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (161 mg, 0.5 mmol), (prepared as described in Example 49), 4-(4-methylphenylsulphonyloxymethyl)-1-tert-butoxycarbonylpiperidine (222 mg, 0.6 mmol), (prepared as described for the starting material in Example 10), and potassium carbonate (188 mg, 1 mol) in DMF (1.6 ml) was heated at 100° C. for 2 hours. After cooling, water was added. The precipitate was collected by filtration, washed with water, and dried under vacuum over phosphorus pentoxide at 60° C. The solid was triturated with petroleum ether, collected by filtration, washed with a mixture of ether/petroleum ether (1/1) and dried under vacuum to give 6-methoxy-4(2-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)quinazoline (200 mg, 77%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]([CH3:29])[C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:30]([O:32]C)=[O:31])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]([CH3:29])[C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:30]([OH:32])=[O:31])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N(C)[C@@H](C)c3ccccc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H](c1ccccc1)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.2 %

Procedure:
To a solution of (S)-methyl 2-(1H-indazol-5-yl)-3-(methyl(1-phenylethyl)amino)quinoxaline-6-carboxylate (100 mg, 0.23 mmol) in methanol (20 mL) was added NaOH (37 mg, 0.93 mmol) and water (1 mL) with stirring for 1 day at room temperature. The resulting mixture was concentrated under vacuum, diluted with water (20 mL), and adjusted to pH 5 with HCl (3N). The product was precipitated from solution via the addition of water and collected by filtration to give (S)-2-(1H-indazol-5-yl)-3-(methyl(1-phenylethyl)amino)quinoxaline-6-carboxylic acid as a yellow solid (48.9 mg, 51%).
Reaction SMILES: CO.C(N)CCC.[S:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2C(=O)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[S:9]1>C1(C)C=CC=CC=1>[S:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:9]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCC1CCSS1
Solvent: CCCCN
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(NCCCCCC1CCSS1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
2 ml of methanol and 2 ml of butylamine were added to 3 ml of a solution of 1.6 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindoline-1,3-dione (prepared as described in Example 58) in toluene, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then left to stand at room temperature for 2 days, after which the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extraction solution was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and 5 ml of anhydrous tetrahydrofuran, 0.33 ml of triethylamine and 0.28 ml of benxoyl chloride were added to the residue. The mixture was then stirred at room temperature for 6 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1:8, 1:4 and 1:2 by volume mixtures of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using 2:3 and 1:1 by volume mixtures of acetonitrile and water was eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 56 mg of the title compound as a yellow amorphous substance, melting at 58 to 59° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH:36]([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH2:40]([O:39][C:37]([CH:36]([O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)[CH3:42])=[O:38])[CH3:41]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)C(C)OC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method D, 0.5 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.15 ml of ethyl 2-bromopropionate are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.40 (1:1 EtOAc-heptane); Rt=5.93/6.0.