Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11](Br)[CH:12]=[CH2:13]>O1CCCC1>[C:3]1([CH2:2][CH2:1][CH2:13][CH:12]=[CH2:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Br[Mg]CCc1ccccc1
Reactant: C=CCBr
Solvent: C1CCOC1
Product: C=CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of phenethyl magnesium bromide (prepared from 25 l g, 0.135 mol of phenethyl bromide and excess magnesium turnings) in anhydrous tetrahydrofuran (50 ml) was added to a stirred solution of allyl bromide (16.34 g, 0.135 mol) in anhydrous tetrahydrofuran (150 ml) at room temperature and under an atmosphere of dry nitrogen. The mixture was stirred at room temperature for 3 hours and the solvent was then evaporated off under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with a saturated aqueous solution of ammonium chloride and the solvent was evaporated off under reduced pressure to give an oil which was distilled to give 5-phenylpent-1-ene as a colourless oil (b.p. 40° C., 0.5 mm, Hg).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]2[N:11]=[C:12]([CH3:39])[C:13]([C:14]3[S:15][C:16]([C:28]4[N:32]=[CH:31][N:30](C5CCCCO5)[N:29]=4)=[C:17]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[F:27])[N:18]=3)=[C:7]2[CH:6]=1.[CH3:40][S:41]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:43])=[O:42].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl>C1COCC1.CO.CCOC(C)=O>[F:27][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:19]=1[C:17]1[N:18]=[C:14]([C:13]2[C:12]([CH3:39])=[N:11][N:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:47]4[CH2:48][CH2:49][N:44]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:45][CH2:46]4)=[CH:6][C:7]=23)[S:15][C:16]=1[C:28]1[N:32]=[CH:31][NH:30][N:29]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1cccc(F)c1-c1nc(-c2c(C)nn3ccc(OCCCl)cc23)sc1-c1ncn(C2CCCCO2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(F)c1-c1nc(-c2c(C)nn3ccc(OCCN4CCN(S(C)(=O)=O)CC4)cc23)sc1-c1nc[nH]n1

Procedure:
According to the similar manner described in Example 88-B (ii) and (iii), the title compound (162 mg, 70%) has been obtained as a colorless solid using 5-(2-chloroethoxy)-3-{4-(2-fluoro-6-methoxyphenyl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}-2-methylpyrazolo[1,5-a]pyridine (215 mg, 0.378 mmol) obtained in Example 86-B3 (i), 1-methanesulfonylpiperazine (124 mg, 0.756 mmol), potassium carbonate (104 mg, 0.756 mmol) and sodium iodide (113 mg, 0.756 mmol) by standard alkylation reaction followed by deprotection of THP group using 2 N hydrochloric acid (2 mL) in THF (6 mL) and MeOH (2 mL) by standard manner. The pure title compound has been obtained by crystallization from THF (2 mL) and EtOAc (4 mL).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[H-].[Na+].Cl[S:22]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>CN(C=O)C.CCOC(C)=O>[C:14]([O:13][C:12]([N:11]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:2]=1[CH3:1])[S:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=1)(=[O:24])=[O:23])=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: Cc1c(NC(=O)OC(C)(C)C)nc2ccccn12
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3ccccn3c2C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a solution of compound 1-E (0.174 g, 0.703 mmol) in DMF (5 mL), cooled to 0° C., was added 60% NaH (0.028 g, 0.703 mmol) and the reaction mixture was stirred at 0° C. for 20 min. Methyl 4-(chlorosulfonyl)benzoate (0.247 g, 1.06 mmol) was added in one-portion and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with EtOAc, washed with H2O (2×), brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford a crude solid. The crude material was purified by flash column chromatography (SiO2) eluting with a heptanes-EtOAc gradient to afford compound 1-F as a white solid (0.188 g, 60%). 1H-NMR (CDCl3): δ 8.22-8.35 (dd, 2H), 7.90-7.92 (d, 1H), 7.61-7.64 (d, 1H), 7.22-7.24 (m, 1H), 6.90-6.93 (m, 1H), 3.98 (s, 3H), 2.55 (s, 3H), 1.32 (s, 9H); MS: m/z 446.1 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]=[CH:13][CH2:12][N:11](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[C@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>C(#N)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]=[CH:13][CH2:12][NH:11][C@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CC=CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C[C@@H]1CN(C(=O)OC(C)(C)C)C/C=C\CN1
Agent: C[C@@H]1CN(C(=O)OC(C)(C)C)C/C=C\CN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CC=CCN1
Temperature: 25 °C

Procedure:
60 mg of the compound obtained in Step 4 was dissolved in 5 mL of acetonitrile, and 100 mg of potassium carbonate and 0.03 mL of thiophenol were added thereto with stirring at room temperature. After stirring at room temperature for 6 hours, the reaction solution was diluted with water, followed by extraction with dichloromethane (50 mL×2). Then, the extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:10) to obtain 25 mg of the compound of interest as a colorless oil (76%).
Reaction SMILES: [CH2:1]1C[C@H]2N(C[C@@H]3[C@@H]4CCCCN4C[C@H]2C3)CC1.C[Li].[C:20]([N:24]1[C:28](=[O:29])[C:27](=[CH:30][CH3:31])[NH:26][C:25]1=[S:32])([CH3:23])([CH3:22])[CH3:21].Cl>C1COCC1.[NH4+].[Cl-].CCOC(C)=O>[C:20]([N:24]1[C:28](=[O:29])[CH:27]([CH:30]([CH3:1])[CH3:31])[NH:26][C:25]1=[S:32])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC=C1NC(=S)N(C(C)(C)C)C1=O
Reactant: C1CCN2C[C@H]3C[C@H](CN4CCCC[C@@H]34)[C@H]2C1
Agent: Cl
Agent: [Cl-]
Agent: [Li]C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C1NC(=S)N(C(C)(C)C)C1=O
Reaction time: 1 h

Procedure:
Sparteine (0.94 g, 0.0040 mol) was dissolved in 2 mL of THF in a flask equipped with a magnetic stirrer, septum, and nitrogen pressure. The flask was immersed in a −40° bath, and a 1.6 M ethereal solution of methyllithium (2.5 mL, 0.0040 mol) was added by syringe. Then a solution of 3-t-butyl-5-ethylidenethiohydantoin (0.20 g, 0.0010 mol) in 2 mL of THF was added dropwise by syringe over 20 min. After 1 hr, HPLC analysis showed no starting material. The reaction mixture was diluted with 5 mL of saturated aqueous NH4Cl, then 4 mL of 1 M HCl, and then 10 mL of EtOAc. The layers were separated, and the organic layer was washed with 2×30 mL of 1 M HCl. The solvent was removed at aspirator pressure, and the residue was reconcentrated×3 from small amounts of dichloromethane. An HPLC trace at 270 nm revealed a purity of only 71% for the major product, although there was no major impurity. NMR (CDCl3) δ 8.5 (bs, 1H), 3.8 (m, 1H), 0.9-2.8 (m, 16H). It is notable that the methyls of the isopropyl group are magnetically nonequivalent.
Reaction SMILES: [NH2:1][C:2]1[NH:21][C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[F:53][C:54]([F:66])([F:65])[O:55][C:56]1[CH:64]=[CH:63][CH:62]=[CH:61][C:57]=1[C:58](O)=[O:59]>C1COCC1>[CH3:19][C:8]1([CH3:20])[C:7]2[CH:6]=[C:5]3[NH:21][C:2]([NH:1][C:58](=[O:59])[C:57]4[CH:61]=[CH:62][CH:63]=[CH:64][C:56]=4[O:55][C:54]([F:53])([F:65])[F:66])=[N:3][C:4]3=[CH:12][C:11]=2[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]1=[O:18]
Reactant: O=C(O)c1ccccc1OC(F)(F)F
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NC(=O)c4ccccc4OC(F)(F)F)nc3cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.3 %

Procedure:
To a solution of D5 (849 mg), TBTU (987 mg; 3.07 mmol) and DIPEA (1 ml) in THF (25 ml) is added drop-wise a solution of 2-trifluoromethoxy-benzoic acid (737 mg; 3.58 mmol) in THF (5 ml) at 0° C. over a period of 15 min. The reaction mixture is warmed to RT and stirred for 20 h. After completion of the reaction the solution is filtered over Alox B and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with cyclohexane/EtOAc yield the desired compound (736 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:22](=[O:32])[C:23](=[N:30][OH:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19](=[O:33])[N:10]2[C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:22](=[O:32])[C:23](=[N:30][OH:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19](=[O:33])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Reaction time: 0.17 h
Yield: 40.3 %

Procedure:
A solution of t-butyl 3-acetoxymethyl-7β-[2-hydroxyimino-2-phenylacetamido]-ceph-3-em-4-carboxylate (syn-isomer) (1.45 g.) in trifluoroacetic acid (25 ml.) was allowed to stand at room temperature for 10 minutes. The trifluoroacetic acid was evaporated under reduced pressure, the residue dissolved in ether (50 ml.) and extracted with saturated aqueous sodium bicarbonate. The combined aqueous extracts were acidified (2 N hydrochloric acid) and extracted with ethyl acetate. The combined extracts were washed with water, dried and evaporated. The residue was redissolved in ethyl acetate (5 ml.) and added dropwise with stirring to petroleum (b.p. 40°-60° C.; 500 ml.). The precipitated solid was filtered and dried, giving 3-acetoxymethyl-7β-[2-hydroxyimino-2-phenylacetamido]-ceph-3-em-4-carboxylic acid (syn-isomer) (0.515 g; 42%), [α]D +56° (c 0.5, DMSO), λmax. (EtOH) 253 nm (ε 16,600), νmax. (Nujol) 3380 (NH and OH), 1778 (β-lactam), 1720 (CO2H and acetate), 1666 and 1540 cm.-1 (CONH) τ (DMSO-d6) values include 0.32 (doublet, J 9 Hz; NH) 2.15-2.7 (multiplet; aromatic protons), 7.8 (singlet; CH3CO).
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18](C)[C@@H:8]([C@:9]3([OH:21])[CH2:10][CH2:11][C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([OH:22])[CH:4]=[CH:5]2.C(OC(=O)C)(=O)C.N>C1(C)C=CC=CC=1>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][NH:18][C@@H:8]([C@:9]3([OH:21])[CH2:10][CH2:11][C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([OH:22])[CH:4]=[CH:5]2
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Agent: N
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3)[C@H]1O5
Temperature: 97.5 °C

Procedure:
A mixture of 4,5α-Epoxy-3,14-dihydroxy-17-methyl morphinan-6-one (32.0 kg), toluene (225 L) and acetic acetic anhydride (32 L) were heated to 95-100° C. and maintained for 8.0 hrs. After reaction completion, the solvent was distilled at 60-65° C. under vacuum and acetic anhydride traces were stripped out with toluene and the residue degassed. Chlorobenzene (290 L), lithium carbonate (23.5 kg), sodium iodide (20.8 kg), DM water (3.2 L) and ethylchloroformate (280 L) were added to the degassed mass and heated to 95-105° C., the reaction was maintained at 95-105° C. for 12.0 hrs. After reaction completion, the solids were filtered and filtrate was concentrated at 70° C. under vacuum and the residue degassed. To the degassed mass acetic acid (96 L) and 15% aqueous sulphuric acid (480 L) was added and the solution was heated to 100-110° C. and maintained at 100-110° C. for 24 hrs. After reaction completion, the reaction mass was cooled to 0-5° C. and pH of the solution was adjusted to ˜4.0 with aqueous ammonia. The aquesous solution was washed with MDC and the aqueous layer was separated. The separated aqueous layer was treated with activated charcoal and filtered. The pH of the filtrate was adjusted to 9-9.5 with aqueous ammonia at below 20° C., the solution was further cooled to 0-5° C. and the product formed was filtered and dried. Yield: 20.3 kg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[Br-:21]>[Al+3].[Cl-].[Cl-].[Cl-]>[Br:21][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:20]
Reactant: O=C(CCc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Reactant: [Br-]
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(F)cc1)C(Br)Cc1ccc([N+](=O)[O-])cc1
Yield: 95.3 %

Procedure:
A procedure similar to step 3 of Example 1 was used. 1-(4-fluoro-phenyl)-3-(4-nitro-phenyl)-propan-1-one prepared in the step 1 and bromide were used as starting materials, and anhydrous AlCl3 was used as catalyst, the obtained product was a pale yellow crystal in a yield of 95.3%, mp: 126-128 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.47 (1H, dd, J=14.28, 7.28 Hz), 3.74 (1H, dd, J=14.28, 7.28 Hz), 5.25 (1H, t, J=7.28 Hz, CHBr), 7.15 (2H, t, 3JFH=3JHH=8.40 Hz, ArH), 7.46 (2H, d, J=8.40 Hz, ArH), 8.03 (2H, dd, 3JHH=8.72, 4JFH=5.36 Hz, ArH), 8.17 (2H, d, J=8.40 Hz, ArH); ESI-MS (negative ion): 352.2 (M−1, 54), 350.2 (M-3, 52), 256.2 (100).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][CH:38]([NH2:47])[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:47][CH:38]([CH3:37])[CH2:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: CC(N)CCc1ccccc1
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NC(C)CCc4ccccc4)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 1-methyl-3-phenylpropylamine, m.p. 152-154° C. MS [(+)ESI, m/z]: 566 [M+H]+ Anal. Calcd for C36H37N3O2: C, 80.39; H, 6.57; N, 7.40. Found: C, 80.27; H, 6.70; N, 7.27.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C@H:2]12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=1>>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([N:1]2[CH2:5][CH2:4][C@@H:3]3[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C@H:2]23)=[CH:21][CH:22]=1
Reactant: Clc1ccc(I)cn1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCN[C@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@H]2CCN(c3ccc(Cl)nc3)[C@H]2C1
Yield: 89.1 %

Procedure:
tert-Butyl cis-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (550 mg, 2.60 mmol), prepared as described in (U.S. Pat. No. 5,071,999) and 2-chloro-5-iodopyridine (660 mg, 2.76 mmol), prepared as described in (Tetrahedron Lett. (1993), 34, 7493-7496), were processed as described in Example 1E to provide the title compound as a tan foam (750 mg, 89% yield). MS (DCI/NH3) m/z 324, 326 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C:22]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:23]([NH:25][CH3:26])=[O:24]>>[CH2:27]([C:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:23](=[O:24])[NH:25][CH3:26])[CH2:29][CH3:30])[CH3:28]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CCC(CC)(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=411.1 [M+H]+.
Reaction SMILES: CC(OP(C1C=CC(N)=CC=1)(=O)OC(C)C)C.[CH3:18][CH:19]([O:21][P:22]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-])=O)[CH:29]=1)(=[O:27])[O:23][CH:24]([CH3:26])[CH3:25])[CH3:20]>>[CH3:26][CH:24]([O:23][P:22]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=1)(=[O:27])[O:21][CH:19]([CH3:18])[CH3:20])[CH3:25]
Reactant: CC(C)OP(=O)(OC(C)C)c1cccc([N+](=O)[O-])c1
Agent: CC(C)OP(=O)(OC(C)C)c1ccc(N)cc1
Product: CC(C)OP(=O)(OC(C)C)c1cccc(N)c1
Yield: 45 %

Procedure:
Prepared according to the procedure described for dipropan-2-yl(4-aminophenyl)phosphonate using dipropan-2-yl(3-nitrophenyl)phosphonate. Yield: 45%. 1H-NMR (DMSO-d6, 400 MHz): δ=1.15 (d, J=6.4 Hz, 6H), 1.24 (d, J=6.4 Hz, 6H), 4.45-4.50 (m, 2H), 5.35 (s, br, 2H), 6.70-6.77 (m, 2H), 6.58 (d, J=8.0 Hz, 1H), 7.10-7.25 (m, 1H). MS: m/z 257.97 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].[CH3:16][O:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][NH:23][C:24]2[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][N:27]=[C:26](Br)[CH:25]=2)=[CH:20][CH:19]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C.C1(C)C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][NH:23][C:24]2[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][N:27]=[C:26]([NH:1][C:2]3[N:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=3)[CH:25]=2)=[CH:34][CH:35]=1
Reactant: COc1ccc(CNc2cc(Br)ncc2[N+](=O)[O-])cc1
Reactant: N#Cc1cnc(N)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Nc3cnc(C#N)cn3)ncc2[N+](=O)[O-])cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
A mixture of palladium (II) acetate (38 mg, 0.17 mmol) and (±)-2,2″-bis(diphenylphosphino)-1,1″-binaphthalene (318 mg, 0.51 mmol) a mixture of toluene and DMF (1:1, 10 mL) was degassed under a stream of nitrogen gas with stirring for 30 minutes. After addition of 2-amino-5-cyanopyrazine (245 mg, 2.04 mmol), sodium tert-butoxide (196 mg, 2.04 mmol) and N-(4-methoxybenzyl)-2-bromo-5-nitropyridin-4-amine (575 mg, 1.70 mmol), the mixture was degassed for a further 5 minutes and then heated at 140° C. for 30 minutes in a microwave reactor. Upon cooling, the mixture was diluted with methanol and isolated by SPE using 3×2.5 g MP-TsOH cartridges, washing with methanol and then eluting with 2 M ammonia in methanol. The basic fractions were concentrated in vacuo to give the title compound (470 mg, 1.25 mmol, 73%) which was used without further purification. LCMS (2) Rt=2.18 min; m/z (ESI−) 376 (M−H); (ESI+) 378 (MH+).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[F:32])[CH:27]=[O:28].O>C(OCC)C>[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[F:32])[CH:27]([C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:28]
Reactant: COCOc1cccnc1Br
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: COCOc1cccnc1C(O)c1ccc(F)c(Br)c1
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of 2-bromo-3-methoxymethoxypyridine (11.8 g) in diethyl ether (250 mL) was added, at -78° C., a 1.6M n-butyl lithium hexane solution (36.0 mL). The mixture was stirred for one hour at the same temperature, to which was further added a solution of 3-bromo-4-fluorobenzaldehyde (10.0 g) in diethyl ether (50 mL), and the mixture was stirred for one hour at the same temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract was washed with a saturated aqueous saline solution, which was then dried (sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromo-4-fluoro-α-hydroxybenzyl)-3-methoxymethoxypyridine (14.0 g) (compound A-5). Physical properties and spectrum data of the product are shown in Table 1 and Table 2.
Reaction SMILES: [F:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:1][C:2]1[C:3]([C:13]([F:16])([F:14])[F:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25])[CH2:8][CH2:7]2
Reactant: O=C1NCCc2ccc(C(F)(F)F)c(F)c21
Reactant: FC(F)(F)c1ccncc1Br
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2c(ccc(C(F)(F)F)c2F)CCN1c1cnccc1C(F)(F)F
Yield: 15.4 %

Procedure:
8-Fluoro-7-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one (I-77d: 100 mg, 0.4288 mmol) was reacted with 3-bromo-4-(trifluoromethyl)-pyridine (120 mg, 0.5575 mmol), 1,4-dioxane (5 mL), copper iodide (8.1 mg, 0.0428 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (6.1 mg, 0.0428 mmol) and potassium phosphate (273 mg, 1.2866 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), followed by preparative HPLC afforded 25 mg of the product (15.4% yield).
Reaction SMILES: [CH3:1][P:2]([CH3:34])(=[O:33])[O:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[CH:17]=[CH:16][C:15]=2[NH:25]C(OC(C)(C)C)=O)=[O:12])=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][P:2]([CH3:34])(=[O:33])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[CH:17]=[CH:16][C:15]=2[NH2:25])=[O:12])=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(COP(C)(C)=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CP(C)(=O)OCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1

Procedure:
[4-({[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl dimethylphosphinate (1.1 g, 2.198 mmol) was taken up in DCM (20 mL)/TFA (8 mL). After 2 hours at room temperature the solvent was removed in vacuo. Saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated in EtOAc to give [4-({[2-amino-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl dimethylphosphinate as a beige solid. 1H-NMR (600 mHz, DMSO-d6) δ 9.72 (s, 1H), 7.98 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.44 (d, J=1.8 Hz, 1H), 7.32 (dd, J=4.8 and 1.2 Hz, 1H), 7.27 (dd, J=8.4 and 2.4 Hz, 1H), 7.21 (dd, J=3.6 and 1.2 Hz, 1H), 7.01 (dd, J=4.8 and 3.6 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 5.13 (s, 2H), 5.01 (d, J=8.4 Hz, 2H), 1.45 (d, J=14.4 Hz, 6H). MS: cal'd 401 (MH+), exp 401 (MH+).