Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([NH:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>[C].[Pd]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([NH:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Nc2cccc(O)c2)cc1
Agent: [Pd]
Product: Nc1ccc(Nc2cccc(O)c2)cc1

Procedure:
20 Grams of 3-(4-nitroanilino)phenol was reduced under ordinary pressure in alcohol by the use of a palladium-carbon catalyst. After removing the catalyst by filtration, the alcohol was distilled off under reduced pressure and the residual solids were washed with benzene. The yield was 14 g, and melting point was 146°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][N:17]1C(=O)C3C(=CC=CC=3)C1=O)=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH2:17])=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)Cc1nc2ccc(Cl)cc2c(-c2ccccc2)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)Cc1nc2ccc(Cl)cc2c(-c2ccccc2)c1CN
Yield: 73 %

Procedure:
To a solution of 2-[(6-chloro-2-isobutyl-4-phenylquinolin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (0.54 g, 1.18 mmol) in ethanol (50 ml), being-heated under reflux, was added hydrazine monohydrate (3 ml, 62 mmol), and the mixture was heated under reflux for 2 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (50 ml)-water (100 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 ml) and then saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography, and crystallized from n-hexane to give the title compound (0.28 g, yield 73%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]([CH3:12])[C:10]=2[CH:11]=1.[CH:27]1(C=O)C[CH2:28]1>>[CH2:27]([N:15]([C:3]1[C:2]([CH3:1])=[CH:11][C:10]2[C:9]([CH3:12])=[CH:8][CH2:7][C:6]([CH3:14])([CH3:13])[C:5]=2[CH:4]=1)[C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)[CH3:28]
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Reactant: O=CC1CC1
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Yield: 46.4 %

Procedure:
Following General Procedure D, ethyl 4-(3,5,8,8-tetramethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 39, 0.085 g, 0.24 mmol) was reacted with cyclopropane carboxaldehyde (180 μL, 2.4 mmol) to give 0.042 g (43%) of the title compound as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[O:17]1[C:21]2[CH:22]=[C:23]([S:26](Cl)(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=2[CH2:19][CH2:18]1>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:26]([C:23]1[CH:24]=[CH:25][C:20]2[CH2:19][CH2:18][O:17][C:21]=2[CH:22]=1)(=[O:27])=[O:28])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCC2
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc2c(c1)OCC2

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 109 mg of 2,3-dihydro-benzofuran-6-sulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 2.80 (t, 2H, J=8.8 Hz), 4.42 (t, 2H, J=9.2 Hz), 6.57 (d, 1H, J=8.4 Hz), 7.35 (m, 3H), 7.43 (m, 3H), 7.48 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.6 (m, 1H), 7.74 (d, 1H, J=8.8 Hz), 9.48 (s, 1H). MS: m/z 414.9 (M++1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@@H:3]([OH:33])[CH2:4][C@@H:5]([NH:20][C:21]([C@@H:23]([NH:28][C:29](=[O:32])[O:30][CH3:31])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:41][O:42][C:43]([NH:45][C@@H:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:47](O)=[O:48])=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:41][O:42][C:43](=[O:44])[NH:45][C@@H:46]([C:50]([CH3:52])([CH3:51])[CH3:53])[C:47](=[O:48])[NH:1][C@@H:2]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C@@H:3]([OH:33])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[NH:20][C:21](=[O:22])[C@H:23]([C:24]([CH3:27])([CH3:26])[CH3:25])[NH:28][C:29](=[O:32])[O:30][CH3:31]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccc(C)cn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.7 %

Procedure:
A solution containing the product from Example 92J (0.049 g, 0.090 mmol) in THF (1 mL) was treated with the product from Example 1F (0.018 g, 0.095 mmol), DEPBT (0.040 g, 0.133 mmol), and N,N-diisopropylethylamine (0.080 mL, 0.459 mmol), stirred at 25° C. for 3 days, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The reaction was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and 10% Na2CO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.047 g, 73% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79(s, 9H), 0.82(s, 9H), 1.58-1.43(m, 2H), 2.32(s, 3H), 2.79-2.68(m, 3H), 3.49(s, 3H), 3.55(s, 3H), 3.67-3.59(m, 1H), 3.843.80(d, J=9.93 Hz, 1H), 3.92-3.89(d, J=9.93 Hz, 1H), 4.19-4.01(m, 2H), 4.87-4.85(d, J=5.88 Hz, 1H), 6.63-6.60(d, J=9.19 Hz, 1H), 6.81-6.77(d, J=9.56 Hz, 1H), 7.19-7.12(m, 5H), 7.56-7.53(d, J=8.82 Hz, 1H), 7.68-7.64(m, 1H), 7.81-7.76(m, 3H), 7.86-7.83(d, J=8.09 Hz, 2H), 8.47(bs, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:26][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:27]([N:29]([CH2:46][CH3:47])[CH2:30]/[CH:31]=[CH:32]\[Sn](CCCC)(CCCC)CCCC)[CH3:28].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.CS(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:27]([N:29]([CH2:46][CH3:47])[CH2:30]/[CH:31]=[CH:32]\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:26][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH3:28]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2Br)ccc2c1OCC1CC21
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Temperature: 100 °C
Yield: 75.3 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-(2-bromobenzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermeidate 154, 0.612 g), N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)amine (Intermediate 11, 1.13 g), tri-tert-butylphosphonium tetrafluoroborate (0.041 g), tris-(dibenzylideneacetone)dipalladium (0.064 g) in dioxane (12 mL) and DMSO (0.4 mL) was degassed and purged with nitrogen then heated at 100° C. for 1.5 hours. After cooling, the mixture was diluted with brine and extracted with ethyl acetate. The organic layer was washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-15% to give methyl (1aRS,7bSR)-5-[2-((Z)-3-diethylamino-prop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.495 g) as a solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)([O-:17])=[O:16]
Reactant: NC1CCOCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NC1CCOCC1
Temperature: 135 °C

Procedure:
A solution of tetrahydropyran-4-ylamine (0.75 g, 7.44 mmol) in DMF (2 mL) was added to a mixture of 1-fluoro-2-nitrobenzene (1.00 g, 7.09 mmol) and potassium carbonate (2.94 g, 21.3 mmol) in DMF (10 mL). The reaction mixture was heated for 1 h at 135° C. under microwave irradiation and then volatiles were removed in vacuo. The resulting residue was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc (×2) and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo affording (2-Nitrophenyl)(tetrahydropyran-4-yl)amine as a yellow solid (1.58 g, quantitative). 1H NMR (CDCl3, 400 MHz): δ 8.18 (1H, d, J=8.65 Hz), 8.09 (1H, s), 7.42 (1H, t, J=7.81 Hz), 6.87 (1H, d, J=8.70 Hz), 6.64 (1H, t, J=7.72), 4.06-3.98 (2H, m), 3.79-3.68 (1H, m), 3.57 (2H, t, J=11.32 Hz), 2.14-2.01 (2H, m), 1.74-1.61 (2H, m).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH2:30][CH2:29]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][S:36]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)(=[O:38])=[O:37])[CH2:30][CH2:29]1)=[O:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(C)(C)OC(=O)C(CS(=O)(=O)Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(CS(=O)(=O)N1CCc2ccccc2C1)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 64 h
Yield: 83 %

Procedure:
1,2,3,4-Tetrahydroisoquinoline (0.17 ml) was dissolved in dichloromethane (40 ml) at room temperature under nitrogen. Triethylamine (0.19 ml) was added, followed by 4-(1-tert-butoxycarbonyl-2-chlorosulfonyl-ethyl)-piperidine-1-carboxylic acid benzyl ester (500 mg) as a solution in dichloromethane (1.5 ml). The reaction was left to stir for 64 h then diluted with dichloromethane (60 ml), washed with 10% citric acid solution (2×50 ml), water (2×50 ml), saturated sodium bicarbonate solution (2×50 ml) and brine (50 ml). The organic layer was then dried (MgSO4), filtered and the solvent removed under reduced pressure to give the title compound (506 mg, 83%) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13]CC)=O)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.Cl.[CH2:17]([NH2:19])[CH3:18].C(N(CC)C(C)C)(C)C.C(OCC)(=O)C.O>CN1C(=O)CCC1>[Br:8][C:6]1[N:7]=[C:2]2[N:19]([CH2:17][CH3:18])[C:11](=[O:13])[CH2:10][NH:9][C:3]2=[N:4][CH:5]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Reactant: CCN
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1C(=O)CNc2ncc(Br)nc21
Temperature: 105 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
A mixture of ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example 6.B) (1 equiv), ethylamine hydrochloride (3.1 equiv), N,N-diisopropylethylamine (4 equiv) in N-methyl pyrrolidinone was heated at 105° C. under nitrogen for 14 h. Standard ethyl acetate/water work up gave the crude product in 77% yield. This material was used without further purification. Crude ethyl 2-(5-bromo-3-(ethylamino)pyrazin-2-ylamino)acetate and acetic acid were combined in methanol. The reaction mixture was refluxed at 60-62° C. under nitrogen for 16 h. The reaction was concentrated under reduced pressure and the resultant residue was diluted with methanol and concentrated. The resultant residue was dissolved in ethyl acetate, treated with sodium carbonate and stirred for 10 min until pH˜7. The mixture was filtered and washed with ethyl acetate. The filtrate was concentrated and purification by a silica gel plug purification using (0-40% ethyl acetate in hexanes) gave the product as a tan solid. Additionally the filter-cake was suspended in water to remove potassium carbonate. The remaining solid product was collected by filtration. The process afforded product in a combined yield of 75%.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:12]=3)[CH:9]=2)[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:3]=1.[N+:29]([C:32]1[CH:33]=[C:34]([CH:50]=[CH:51][CH:52]=1)[CH2:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1)([O-:31])=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>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].COCCOC.O>[CH3:21][S:18]([NH:17][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[C:10]3[C:2]([C:39]4[CH:38]=[N:37][N:36]([CH2:35][C:34]5[CH:50]=[CH:51][CH:52]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=5)[CH:40]=4)=[CH:3][N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:5]3=[N:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=1)(=[O:20])=[O:19]
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cc(-c3cccc(NS(C)(=O)=O)c3)cnc21
Reactant: CC1(C)OB(c2cnn(Cc3cccc([N+](=O)[O-])c3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(-c2cnn(Cc3cccc([N+](=O)[O-])c3)c2)c2cc(-c3cccc(NS(C)(=O)=O)c3)cnc21
Yield: 68 %

Procedure:
Using similar reaction conditions as described in step-i of example 1, tert-butyl 3-iodo-5-(3-(methylsulfonamido)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate-32) (300 mg, 0.5 mmol) was coupled with 1-(3-nitrobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 10) (211 mg, 0.6 mmol) in sodium carbonate (189 mg, 1.7 mmol), PdCl2(dppf) (20 mg, 0.02 mmol) and DME/water (3/3 ml) to afford 200 mg (59% yield) of the pure product after column purification using 30% ethyl acetate in hexane as eluent.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:13]([CH2:23][O:24][C:25]2[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:26]=2[F:34])[O:12][CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[F:34][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:25]=1[O:24][CH2:23][C@H:13]1[O:12][CH2:11][C@@H:10]([CH2:9][OH:8])[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](COc2c(F)cccc2[N+](=O)[O-])OC[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](COc2c(F)cccc2[N+](=O)[O-])OC[C@H]1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of the product from step 2 (2.4 g, 4.8 mmol) in anhydrous THF (50 mL) under a nitrogen atmosphere was added a solution of tetra-n-butyl ammonium fluoride (1.0 M in THF, 9.6 mL) and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with saturated solution of ammonium chloride (50 mL), brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified on a 40 g SiO2 column using a gradient elution of 20-50% EtOAc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to provide the product (1.6 g) as a yellow oil. LC MS: RT=3.66 min, M+H=387 (6 min gradient).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH2:21][CH:22]([CH3:42])[CH:23]([C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[F:41])[S:24]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1.F.C(=O)(O)[O-].[Na+].CCCCCC>C(Cl)Cl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([CH:23]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[F:41])[CH:22]([CH3:42])[CH2:21][CH2:20][CH2:19][OH:18])(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: CC(CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(CCCO)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.6 %

Procedure:
The 2-[5-(t-butyldiphenylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]-2-methylpentyl]-1,4-difluorobenzene (Isomer 38-B) (450 mg, 0.717 mmol) obtained in Example 38 was dissolved in methylene chloride (10 ml). Under ice cooling, hydrogen fluoride-pyridine (0.41 ml) was added dropwise. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 14 hours. To the reaction mixture was added a saturated aqueous solution (20 ml) of sodium bicarbonate, followed by extraction with diethyl ether. The organic layer was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to yield a colorless oil. The resulting colorless oil was solidified with hexane, whereby the title compound (194 mg, 70%) was obtained as a white powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[C:20]2=[C:21]3[N:16]([C:17](=[CH2:22])[CH2:18][CH2:19]2)[CH:15]=[C:14]([C:23]([OH:25])=[O:24])[C:13](=[O:26])[C:12]3=[CH:11][C:10]=1[F:27]>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[C:20]3=[C:21]4[N:16]([C:17](=[CH2:22])[CH2:18][CH2:19]3)[CH:15]=[C:14]([C:23]([OH:25])=[O:24])[C:13](=[O:26])[C:12]4=[CH:11][C:10]=2[F:27])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: C=C1CCc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CS(C)=O
Product: C=C1CCc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 16.5 %

Procedure:
400 mg of N-methylpiperazine and 6 ml of dimethyl sulfoxide were added to 400 mg of 8,9-difluoro-5-methylene-6,7-dihydro-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylic acid and the resulting mixture was heated for 2.5 hours at 100°-110° C. (bath temperature). The solvent was distilled off in vacuo and water was added to the residue. The mixture was extracted with chloroform and the extract was dried. The solvent was distilled off and the residue was purified by silica gel column chromatography and then recrystallized from ethanol to give 85 mg of 8-(4-methyl-1-piperazinyl)-9-fluoro-5-methylene-6,7-dihydro-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylic acid as microcrystals with 282°-285° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[CH:15]=2)[C:10](I)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(O)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>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[CH:15]=2)[C:10]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[Cl:26])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)n1nc(I)c2ccc(Oc3ccccc3F)cc21
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: C1COCCO1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)n1nc(-c2ccccc2Cl)c2ccc(Oc3ccccc3F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
To a solution of (Ph3P)4Pd (36 mg, 0.03 mmol) in dioxane ( 4 mL) under Argon was added 6-(2-Fluoro-phenoxy)-3-iodo-indazole-1-carboxylic acid tert-butyl ester (140 mg, 0.3 mmol) and the solution was stirred for 10 min, then 2-chlorophenyl boronic acid (96.4 mg, 0.6 mmol) in ethanol (1.2 mL) was added. After 10 min potassium carbonate (132 mg, 0.9 mmol) in water (0.4 mL) was added and the mixture was stirred at 85° C. under Argon for 18 h. The mixture was cooled to room temperature, filtered through Celite, partitioned between water and EtOAc, the separated organic phase was dried over Na2SO4 filtered, concentrated and the residue was purified by flash chromatography eluting with Hex:EtOAc 9:1 to yield 90 mg of 3-(2-Chloro-phenyl)-6-(2-fluoro-phenoxy)-indazole-1-carboxylic acid tert-butyl ester: MS: 345 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:9][C@H:10]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[N:38][CH:39]=[N:40][CH:41]=2)=[CH:32][CH:31]=1)[C@H:11]([CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:12]([OH:14])=[O:13])=O.O1CCCC1>CO>[OH:9][C@H:10]([CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[N:40][CH:39]=[N:38][CH:37]=2)=[CH:34][CH:35]=1)[C@H:11]([CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:12]([OH:14])=[O:13]
Reactant: O=CO[C@H](CCc1ccc(-c2cncnc2)cc1)[C@H](CCn1nnc2ccccc2c1=O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@@H](CCn1nnc2ccccc2c1=O)[C@H](O)CCc1ccc(-c2cncnc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (0.081 g) was added to a solution of the compound obtained from step n above (0.25 g) in methanol (5 mL) and tetrahydrofuran (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. Solvents were evaporated and the residue was taken into water and ethyl acetate. The organic layer was washed with water and brine solution and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 60% ethyl acetate in hexane as eluant to afford the title compound (0.030 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[CH:15]=[C:14]([CH2:25][CH3:26])[N:13]=[C:12]1[O:27][CH3:28])=[O:10])C1C=CC=CC=1.Cl[C:30]([O:32][CH3:33])=[O:31]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:33]([O:32][C:30]([C:15]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[N:11]([C:9]([O:8][CH3:1])=[O:10])[C:12]([O:27][CH3:28])=[N:13][C:14]=1[CH2:25][CH3:26])=[O:31])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCC1=CC(c2ccc(F)c(F)c2)N(C(=O)OCc2ccccc2)C(OC)=N1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)OC)C(OC)=N1
Yield: 135 %

Procedure:
To a well stirred solution of (benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-diflurophenyl)pyrimidine (0.6 g, 1.5 mmol) and 4-(N,N-dimethylamino)pyridine (0.32 g, 2.66 mmol) in CH2Cl2 (6 mL) was added methyl chloroformate (0.2 mL, 2.66 mmol) at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with 3:1 Petroleum ether/EtOAC as the eluting system to obtain 0.45 g (78% yield) of (−)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[methoxy-carbonyl]pyrimidine as a colorless oil.