Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1.[CH:22]([C:24]1[CH:39]=[CH:38][C:27]([O:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=2)=[CH:26][CH:25]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:24]3[CH:39]=[CH:38][C:27]([O:28][C:29]4[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=4)=[CH:26][CH:25]=3)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: Clc1cccc(C2CCCNC2)c1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCCC(c4cccc(Cl)c4)C3)cc2)nc1
Yield: 74 %

Procedure:
Using a method similar to Example 345, using 3-(3-chloro-phenyl)-piperidine fumaric acid salt (0.129 g, 0.414 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.100 g, 0.413 mmol) sodium triacetoxyborohydride (0.132 g, 0.623 mmol), and acetic acid (0.035 mL, 0.611 mmol) in 1,2-dichloroethane (8.0 mL) provides, after reverse-phase HPLC, 0.129 g (70%) of the title compound as a white foam: high resolution mass spectrum (electrospray): m/z calc for C24H25ClN3O2 422.1635, found 422.1664; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.6 Hz), 8.30 (dd, 1H, J=2.6, 8.8 Hz), 7.47 (d, 2H, J=8.8 Hz), 7.34-7.27 (m, 2H), 7.26-7.19 (m, 2H), 7.16 (d, 2H, J=8.3 Hz), 7.05 (d, 1H, J=8.3 Hz), 3.70 (s, 2H), 3.07 (d, 2H, J=11.4 Hz), 2.89 (tt, 1H, J=4.0, 11.9 Hz), 2.29-2.16 (m, 2H), 2.00-1.72 (m, 3H), 1.56 (dq, 1H, J=4.0, 12.3 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1.[CH3:19][C:20]1([CH3:28])[O:27][C:25](=[O:26])[CH2:24][C:22](=[O:23])[O:21]1.N1CCCCC1>C(O)(=O)C>[CH3:19][C:20]1([CH3:28])[O:27][C:25](=[O:26])[C:24](=[CH:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:22](=[O:23])[O:21]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)C(=Cc2ccc([N+](=O)[O-])cc2)C(=O)O1
Reaction time: 5 h
Yield: 69.7 %

Procedure:
To 4-nitrobenzaldehyde (15.1 g) were added a toluene (180 mL) solution, Meldrum's acid (14.4 g), piperidine (300 μL) and acetic acid (300 μL) at room temperature, and the mixture was stirred for 5 hr. Insoluble material was collected by filtration, and the obtained solid was washed with ethyl acetate (80 mL). The resulting precipitate was collected by filtration to give the title compound (19.3 g) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22](OC)[O:23]C)[CH:6]=1.Cl.CCOC(C)=O.O>C1COCC1>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[CH:22]=[O:23])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C(OC)OC)c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
[3-(2-Dimethoxymethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester (0.479 g, 1.42 mmol) and hydrogen chloride (4N in 1,4-dioxane; 1.5 mL, 6.0 mmol) were combined in THF (4 mL) and stirred at 70° C. for 1 hour. Some starting material was still seen by analytical LCMS, so additional hydrogen chloride (4N in 1,4-dioxane; 0.5 mL) was added, and the reaction was stirred for another hour at 70° C. After cooling to room temperature, the mixture was worked up with EtOAc and H2O, and the combined organic layers were dried and concentrated to give the title compound.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[CH3:6][N:7]1[C:11](CO)=[CH:10][C:9]([CH3:14])=[N:8]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:5][CH2:1][C:11]1[N:7]([CH3:6])[N:8]=[C:9]([CH3:14])[CH:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(CO)n(C)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(CBr)n(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
CBr4 (4.7 g, 14.2 mmol) was added to a solution of (1,3-dimethyl-1H-pyrazol-5-yl)methanol (1.2 g, 9.5 mmol) and triphenylphosphine (3.7 g, 14.2 mmol) in THF (20 mL) at 0° C. and the resulting mixture was stirred for approximately 2 h at rt. After concentration in vacuo purification by column chromatography eluting with 2% EtOAc in hexane yielded the title compound (1.31 g, 6.93 mmol).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])C.[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:19]3[C:20]([CH3:35])=[C:21]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:22]([CH3:26])=C(C=C)[C:18]=3[O:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:8])[CH3:7].S([O-])([O-])=[O:37].[Na+].[Na+]>O.C1COCC1>[OH:5][CH:1]([C:4]1[C:18]2[O:17][CH2:16][CH:15]([C:12]3[CH:13]=[CH:14][C:9]([CH:6]([CH3:7])[CH3:8])=[CH:10][CH:11]=3)[C:19]=2[C:20]([CH3:35])=[C:21]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:32])([CH3:33])[CH3:31])[C:22]=1[CH3:26])[CH2:3][OH:37]
Reactant: CC(C)(C)O
Reactant: C=Cc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(O)CO)OCC2c1ccc(C(C)C)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of AD-mix β (4.62 g) in a mixed solvent of water (15 mL), tert-butanol (15 mL) and THF (15 mL) was added with ice-cooling N-(3-(4-isopropylphenyl)-4,6-dimethyl-7-vinyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (670 mg, 1.65 mmol) obtained in Example 83 and the reaction mixture was stirred at 80° C. for 3 hours. To the reaction solution were added water and sodium sulfite and the resulting mixture was stirred at room temperature for 30 minutes. The product was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20) to obtain 558 mg (yield: 77%) of the title compound. Melting point: 159-161° C. (hexane-ethyl acetate).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[H][H].F[C:13]1[N:18]=[C:17]([C:19]([NH:21][C:22]2[CH:30]=[C:29]([C:31]3[CH:39]=[CH:38][CH:37]=[C:36]4[C:32]=3[CH:33]=[CH:34][NH:35]4)[CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][NH:26]3)=[O:20])[CH:16]=[CH:15][CH:14]=1>C1COCC1.O>[NH:35]1[C:36]2[C:32](=[C:31]([C:29]3[CH:28]=[C:27]4[C:23]([CH:24]=[N:25][NH:26]4)=[C:22]([NH:21][C:19]([C:17]4[CH:16]=[CH:15][CH:14]=[C:13]([O:9][CH:6]5[CH2:7][CH2:8][O:3][CH2:4][CH2:5]5)[N:18]=4)=[O:20])[CH:30]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:34]1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(F)n1
Reactant: [H][H]
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(OC2CCOCC2)n1
Temperature: 25 °C
Yield: 11 %

Procedure:
Under an atmosphere of nitrogen, sodium hydride (5 mg, 0.14 mmol, 60% suspension in mineral oil) was added to a solution of tetrahydro-2H-pyran-4-ol (13 mg, 0.14 mmol) in THF (2 ml). After hydrogen evolution was complete, 6-Fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (50 mg, 0.14 mmol) was added and the mixture was heated to reflux for 1 h. Another portion of tetrahydro-2H-pyran-4-ol (13 mg, 0.14 mmol) and sodium hydride (5 mg, 0.14 mmol) was added and the mixture was heated to reflux overnight. The mixture was cooled to room temperature, water was added and the mixture was extracted with DCM. The organic extracts were combined, dried over MgSO4, filtered and the solvent was removed in vacuo to give an orange oil. This was purified by mass-directed automated preparative HPLC (Method B) to give the title compound (7 mg) as a white solid.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][C:4]2([O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]3[CH:16]=[CH:17][CH:18]=[C:7]23)[CH2:3][CH2:2]1.C1(C)C=CC=CC=1.[ClH:33]>O1CCOCC1>[ClH:33].[NH:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]3[CH:16]=[CH:17][CH:18]=[C:7]23)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Yield: 76 %

Procedure:
A 5 L 3-neck round bottom flask was fitted with a mechanical stirrer, an addition funnel, a temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged under nitrogen with a clear amber solution of tert-butyl spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate and (50 g, 0.15 mol) and toluene (250 mL). Stirring was commenced and the addition funnel was charged with (73 mL, 0.29 mol) of 4M HCl in 1,4-dioxane which was added dropwise over 10 minutes resulting in a very dark solution. The mixture was continued to stir at ambient temperature for 1 h before the reaction mixture was filtered to remove the residual solids. The filtrate was concentrated under reduced pressure to provide a solid which was triturated with diethyl ether (2×200 mL) and was then dried under vacuum to provide (31 g, 76%) of spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] hydrochloride as an off-white solid. ESI-MS m/z calc. 240.1, found 241.3 (M+1)+. Retention time: 1.21 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 9.45 (s, 2H), 7.76-7.62 (m, 1H), 7.55 (dd, J=2.8, 1.3 Hz, 1H), 7.23-7.08 (m, 3H), 6.31 (t, J=3.2 Hz, 1H), 6.11 (dd, J=3.4, 1.3 Hz, 1H), 3.29-3.13 (m, 4H), 2.25 (td, J=14.4, 5.0 Hz, 2H), 2.09 (d, J=14.1 Hz, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([C:20](O)=[O:21])=[C:17]([C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)[C:16]=2[CH3:33])=[CH:11][CH:10]=1.[CH3:34][N:35]([CH:37]=O)[CH3:36].C(N(CC)CC)C.Cl.[CH3:47][NH:48][O:49][CH3:50]>ClCCl>[CH3:37][N:35]([CH:34]=[N:30][S:29]([C:26]1[CH:25]=[CH:24][C:23]([C:17]2[C:16]([CH3:33])=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:14][CH:13]=3)[S:19][C:18]=2[C:20]([N:48]([O:49][CH3:50])[CH3:47])=[O:21])=[CH:28][CH:27]=1)(=[O:31])=[O:32])[CH3:36]
Reactant: COc1ccc(-c2sc(C(=O)O)c(-c3ccc(S(N)(=O)=O)cc3)c2C)cc1
Reactant: CNOC
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2sc(C(=O)N(C)OC)c(-c3ccc(S(=O)(=O)N=CN(C)C)cc3)c2C)cc1
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
Oxalyl chloride (1.77 g, 1.2 ml, 13.9 mmol) was added drop wise at 0° C. to a solution of 5-(4-methoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (compound 7e, 2.8 g, 6.94 mmol) in a mixture of dichloromethane (75 ml) and DMF (1.01 g, 1.1 ml, 13.89 mmol). The so obtained mixture was allowed to come at room temperature and stirred for 1.5 hr under a nitrogen atmosphere. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was dissolved in dry dichloromethane (75 ml) and to this was added triethylamine (2.8 g, 3.9 ml, 27.76 mmol) followed by the addition of N,O-dimethylhydroxylamine hydrochloride (1.35 g, 13.89 mmol) under stirring. The reaction mixture was then stirred at room temperature for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then washed with water (2×25 ml) and the organic layer so obtained was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude product. The crude product was further purified by column chromatography over silica gel (100-200 mesh) using 80% ethyl acetate in hexane as an eluent to obtain the title compound (2.73 g, 78%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][S:13]([O:16]C)(=[O:15])=[O:14]>C1C=CC=CC=1>[CH3:11][O:12][S:13]([O-:16])(=[O:15])=[O:14].[CH3:11][N+:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2ncccc2c1
Reactant: COS(=O)(=O)OC
Solvent: c1ccccc1
Product: COS(=O)(=O)[O-]
Product: C[n+]1cccc2ccccc21

Procedure:
Pure, commercial grades of quinoline, benzene and dimethylsulfate were stored over Molecular Sieve 4A for two days prior to reaction. Into a three liter, three-necked round bottomed flask fitted with an electrical heater, stirrer, dropping funnel and an efficient reflux condenser equipped with calcium chloride drying tube were placed quinoline 300 ml. (328.8 g., 2.54 moles) in benzene 900 ml. Dimethyl sulfate 240 ml. (319.2 g., 2.53 moles) in benzene 180 ml. was run in rapidly over five minutes while the contents were vigorously stirred. Spontaneous warming and refluxing occurred and the liquid separated into two phases. After the initial reaction had subsided the flask was heated to reflux for two hours and then allowed to cool for two hours. All the time the reagents were vigorously stirred until the cooled mixture became a suspension of small particles. These were filtered as far as removing Cthe solvent, washed with benzene 1000 ml. and refiltered, and were transferred to tared bottles in a vacuum desiccator over sulfuric acid and sodium hydroxide. The desiccator was evacuated at room temperature for about six hours when no further benzene was collected in a liquid nitrogen trap. Total yield of dried material 633.5 g. (98%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](B(O)O)=[CH:25][N:24]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:2]2[CH:3]=[C:4]([N:8]3[C:16]4[CH:11]=[CH:12][C:13]([CH3:17])=[CH:14][C:15]=4[C:21]4[CH2:20][N:19]([CH3:22])[CH2:18][CH2:10][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)=[CH:25][N:24]=1
Reactant: OB(O)c1cncc2ccccc12
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cncc4ccccc34)c2)CCN(C)C1
Temperature: 90 °C

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 4-isoquinolineboronic acid (96.8 mg, 0.56 mmol) and K2CO3 (116 mg, 0.84 mmol) in DME-water (2:1) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was heated at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(isoquinolin-4-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 9.5 (s, 1H), 8.57 (s, 1H), 8.4 (d, 1H), 8.09 (d, 1H), 8.0 (dd, 1H), 7.8-7.95 (m, 2H), 7.7 (d, 1H), 7.6 (m, 2H), 7.37 (s, 1H), 7.21 (d, 1H), 7.07 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.81 (m, 1H), 3.61 (m, 1H), 3.1-3.3 (m, 5H), 2.4 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:35][CH2:36][CH2:37][NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[C:4]2[O:9][CH2:8][C@H:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:6]3[CH:16]=[C:17]([C:32]([OH:34])=[O:33])[C:18](=[O:31])[C:19]([C:20]=1[NH:21]CC1C=CC(OC)=CC=1)=[C:5]23.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:21][C:20]1[C:19]2[C:18](=[O:31])[C:17]([C:32]([OH:34])=[O:33])=[CH:16][N:6]3[C@@H:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:8][O:9][C:4]([C:5]=23)=[C:3]([NH:35][CH2:36][CH2:37][NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:2]=1[F:1]
Reactant: COc1ccc(CNc2c(F)c(NCCNc3ccccn3)c3c4c2c(=O)c(C(=O)O)cn4[C@@H](c2ccccc2)CO3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1c(F)c(NCCNc2ccccn2)c2c3c1c(=O)c(C(=O)O)cn3[C@@H](c1ccccc1)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a solution of (S)-9-fluoro-2,3-dihydro-8-(4-methoxybenzylamino)-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (355 mg, 0.596 mmol) in CH2Cl2 (4 mL) was added TFA (2.0 mL, 26.9 mmol) at 0° C. and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The solution of the residue in DMSO (3 mL) was added water and 2M aq. NaOH was added to adjust pH=7. A precipitate formed and was collected by filtration. The cake was added to EtOH (10 mL), and boiled on water-bath. A precipitate was collected by and then dried to give (S)-8-amino-9-fluoro-2,3-dihydro-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (163 mg, 58%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl-].[NH4+].C(O)C>[Fe].O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(Br)c2ncccc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)c2ncccc2c1
Yield: 47.6 %

Procedure:
To a flask containing 8-bromo-6-nitroquinoline (2.05 g, 8.1 mmol), electrolytic iron (2.26 g, 40.5 mmol) and ammonium chloride (2.25 g, 42.1 mmol) was added ethanol (20 ml) and water (10 ml). The flask was fitted with an efficient reflux condenser and then heated to near reflux (oil bath) for 3 hours. The hot material was then filtered through a plug of celite and rinsed well with hot methanol (100 ml). The solvent was removed. The residue was taken up in ethyl acetate (60 ml) and water (60 ml) and transferred to a separatory funnel, agitated and the organic phase collected. The organic phase was washed with an equal volume of brine. The aqueous phases were back extracted with ethyl acetate (2×50 ml). The combined ethyl acetate extracts were dried over MgSO4, and concentrated in vacuo. The resulting residue was crystallized from hot dichloromethane/hexanes to provide the desired product as a brown powder (860 mg).
Reaction SMILES: ClCC([Si](C)(C)C)[CH2:4][O:5][CH2:6][CH:7]([Si:10]([CH3:13])([CH3:12])[CH3:11])CCl.[Cl:18][C:19]1[N:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH2:25][O:26][CH2:4][O:5][CH2:6][CH2:7][Si:10]([CH3:11])([CH3:12])[CH3:13])[N:24]=1
Reactant: OCc1cccc(Cl)n1
Reactant: C[Si](C)(C)C(CCl)COCC(CCl)[Si](C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCOCc1cccc(Cl)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
3.20 ml of chloromethyl-2-(trimethylsilyl)ethyl ether (18.2 mmol) are added dropwise to a solution containing 2.50 g of (6-chloropyridin-2-yl)methanol (17.4 mmol), 3.30 ml of diisopropylethylamine (19.1 mmol) and 20 ml of dichloromethane cooled to 0° C. maintained under a nitrogen atmosphere. The mixture is stirred for 3 hours at room temperature and then the dichloromethane is evaporated off, the residue is taken up in water, the mixture is extracted with diethyl ether, the organic phase is washed with water and then dried over sodium sulfate. After filtration and evaporation of the solvent, the title product is isolated by chromatography on a silica column (eluent: dichloromethane).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1.[CH2:33](N(CC)CC)C>O1CCOCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:21]2[CH2:22][CH2:23][N:24]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:33])=[O:11])=[CH:5][CH:4]=3)[CH2:25][CH2:26]2)=[CH:18][CH:19]=1
Reactant: CCN(CC)CC
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(CN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)cc1

Procedure:
Using 2.4 g of 4-bromomethylphenylacetic acid, 2.9 g of 1-[(4-chlorophenyl)phenylmethyl]piperazine, 2.8 ml of triethylamine, and 100 ml of dioxane, the reaction procedure of Example 1 was otherwise repeated and recrystallized from benzene-hexane to provide 1.8 g of methyl 4-[[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]methyl]phenylacetate melting at 113° C.-115° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]([O:29][C:30]([N:32]1[CH:36]=[C:35]([C:37]([OH:39])=O)[C:34]([CH3:40])=[N:33]1)=[O:31])([CH3:28])[CH3:27].CCN(C(C)C)C(C)C.[NH:50]1[C:58]2[C:53](=[C:54]([C:59]3[CH:60]=[C:61]([NH2:68])[C:62]4[CH:63]=[N:64][NH:65][C:66]=4[CH:67]=3)[CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51]1>CN(C=O)C.CS(C)=O>[NH:50]1[C:58]2[C:53](=[C:54]([C:59]3[CH:67]=[C:66]4[C:62]([CH:63]=[N:64][NH:65]4)=[C:61]([NH:68][C:37]([C:35]4[C:34]([CH3:40])=[N:33][N:32]([C:30]([O:29][C:26]([CH3:25])([CH3:27])[CH3:28])=[O:31])[CH:36]=4)=[O:39])[CH:60]=3)[CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nn(C(=O)OC(C)(C)C)cc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reaction time: 0.17 h

Procedure:
To a solution of HATU (0.162 g) in anhydrous DMF (4 ml) was added 1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-1H-pyrazole-4-carboxylic acid (0.097 g) and DIPEA (0.149 ml) and the mixture was left to stand for 10 min. 6-(1H-Indol-4-yl)-1H-indazol-4-amine (0.053 gl) dissolved in anhydrous DMF (3 ml) was added and the solution was left to stand at RT for 18 h. The DMF was blown down to dryness under a stream of nitrogen and the residue was dissolved in DMSO:methanol (1 ml, 1:1) and purified by MDAP (method K). The solvent was removed in vacuo to give title compound, 6 mg.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.I[CH:13]([CH3:15])[CH3:14]>C(=O)([O-])[O-].[Ag+2].CCCCCCC>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH:13]([CH3:15])[CH3:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1ccc(Cl)nc1O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCCCCCC
Product: CC(C)Oc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 88.5 %

Procedure:
1.63 g of 6-chloro-3-nitropyridin-2-ol, 66 ml of heptane, 3.175 g of 2-iodopropane and 3.09 g of silver carbonate are introduced. The reaction medium is microwave-heated at 130° C. for 10 minutes and is then evaporated to dryness, bound to silica and purified by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of heptane and ethyl acetate (90/10). 1.79 g of 6-chloro-3-nitro-2-(propan-2-yloxy)pyridine are obtained in the form of a beige solid.