Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:36])[CH2:14][N:15]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][CH:25]([C:28]([O:30]C)=O)[CH2:24][CH2:23]5)=[C:18]([C:32]([F:35])([F:34])[F:33])[CH:17]=4)[C:5]=3[C:4]=2[CH:3]=1.O.[OH-].[Li+].Cl.[CH3:41][N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C1COCC1.O.C(Cl)Cl.O.CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:36])[CH2:14][N:15]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:23][CH2:24][CH:25]([C:28]([NH:48][CH:45]6[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]6)=[O:30])[CH2:26][CH2:27]5)=[C:18]([C:32]([F:33])([F:34])[F:35])[CH:17]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: COC(=O)C1CCN(c2ccc(N3CC(=O)Nc4cnc5ccc(Br)cc5c43)cc2C(F)(F)F)CC1
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)C2CCN(c3ccc(N4CC(=O)Nc5cnc6ccc(Br)cc6c54)cc3C(F)(F)F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a solution of compound 8.4 methyl 1-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (55 mg, 0.10 mmol, 1 equiv.) in THF/H2O (1.0 mL/1.5 mL) was added lithium hydroxide monohydrate (13 mg, 0.30 mmol, 1 equiv.). The resulting mixture was stirred overnight at room temperature. Upon completion, the reaction was diluted with CH2Cl2 (5 mL) and water (5 mL). The aqueous layer was adjusted with 1 N HCl to about pH3 and extracted with CH2Cl2 (5 mL×3). The combined organic layer was washed with brine (20 mL) and dried over Na2SO4. After removal of solvent under vacuum, the resulting residue was used for the next step without further purification. To a solution of the above acid in DMF (2 mL) was added 1-methylpiperidin-4-amine (25 μL, 0.20 mmol, 2 equiv.), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (95 mg, 0.25 mmol, 2.5 equiv.) and DIEA (52 μL, 0.30 mmol, 3 equiv.). The reaction mixture was stirred at room temperature for overnight. After removal of the solvent, the residue was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL). The organic phase was dried over Na2SO4. Removal of solvent under vacuum afforded crude product 8.5 1-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)-N-(1-methylpiperidin-4-yl)piperidine-4-carboxamide 46 mg. It was used for next step without further purification. LC-MS (M+H): 645.22
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]Br.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH:9]=1
Reactant: c1ccc(-c2nccc3ccccc23)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Brc1cnc(-c2ccccc2)c2ccccc12
Yield: 41.2 %

Procedure:
20.5 g of 1-phenylisoquinoline are dissolved in 100 ml of carbon tetrachloride, and 16 g of bromine are added at room temperature. The temperature is raised slowly and the mixture is kept under reflux for 1 hour. 7.9 g of pyridine in 10 ml of carbon tetrachloride are added dropwise to the boiling reaction mixture in the course of 2 hours, and the mixture is then heated at reflux temperature for a further 18 hours. The reaction solution is decanted off from the resinous precipitate and is concentrated, and the residue is crystallized from diisopropyl ether. 11.7 g of 4-bromo-1-phenylisoquinoline of melting point 123°-125° C. are obtained. 0.7 g of 4-bromo-1-phenylisoquinoline, 0.45 g of copper cyanide and 10 ml of dimethylformamide are heated at 160° C. for 6 hours. The reaction solution is decanted off, diluted with methylene chloride and washed with water. 0.75 g of crude product are isolated from the methylene chloride phase, and 0.2 g of 4-cyano-1-phenylisoquinoline of melting point 138°-140° is obtained from this crude product by column chromatography over silica gel using a 98:2 mixture of chloroform and ethyl acetate. 0.2 g of 4-cyano-1-phenylisoquinoline is heated with 10 ml of 20% strength sodium hydroxide solution at 100° C. for 4 hours. The solution is cooled and acidified with acetic acid. The precipitate is filtered off and dried. 0.18 g of 1-phenylisoquinoline-4-carboxylic acid of melting point 215°-217° is isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-])=O.[Na+].[NH:16](C(OC(C)(C)C)=O)[C@H:17]([C:23]([O:25]C(C)(C)C)=[O:24])[CH2:18][CH2:19][C:20](=O)[OH:21].Cl.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O.C(#N)C.CN(C=O)C.O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:12][C:20](=[O:21])[CH2:19][CH2:18][C@@H:17]([C:23]([OH:25])=[O:24])[NH2:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)[O-])ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N[C@@H](CCC(=O)Nc1cc(S(=O)(=O)O)ccc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 mL of methanol and 3 mL of water were added to sodium 4-chloro-3-nitrobenzensulfonate (1 mmol). 2% Pt—S/C in catalyst quantity was added thereto and stirred under hydrogen atmosphere overnight at room temperature. After filtering out the catalyst, the mixture was sufficiently dried. Then, 303 mg (1 mmol) of Boc-Glu-OtBu hydrochloride, 163 mg (1.2 mmol) of HOAt, 456 mg (1.2 mmol) of HATU, 2 mL of DMF and 0.35 mL of DIEA were added thereto and stirred at room temperature overnight. The reaction solution was diluted with water-acetonitrile and purified in accordance with the purification process A to obtain a protected form of a title compound. The obtained protected form was dissolved in 3 mL of a trifluoroacetic acid and stirred at room temperature for 2 hours. After removing a solvent, purification was conducted in accordance with the purification process A to obtain a title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1.[Li+].[OH-].C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(Oc2ccccn2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A mixture of 44b (430 mg, 1.87 mmol), LiOH (180 mg, 7.5 mmol), THF (3 mL), MeOH (3 mL), and H2O (3 mL) was stirred at room temperature for 4 h. Then the reaction mixture was acidified with 15% citric acid (10 mL). The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give 44c (350 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].[CH3:34]OC(=O)C1C=CC=NC=1N>>[CH3:34][O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([NH:15][C:13](=[O:14])[CH2:12][CH2:11][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:33])[N:8]2[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[N:17][CH:18]=1
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Reactant: COC(=O)c1cccnc1N
Product: COC(=O)c1ccc(NC(=O)CCC2c3c(F)cccc3C(=O)N2Cc2ccc(F)cc2)nc1

Procedure:
The product from Example 11, Part D (331 mg, 1 mmol) and 2-aminonicotinic acid methyl ester (316 mg, 2.1 mmol) were converted to the title compound in a manner analogous to the method described in Example 7, Part E without crystallization (269 mg, 58%). 1H NMR (300 MHz, CDCl3) δ 8.83 (d, J=2 Hz, 1H), 8.27 (dd, J=8 Hz, 2 Hz, 1H), 8.16 (d, J=9 Hz, 1H), 7.87 (br s, 1H), 7.69 (d, J=7 Hz, 1H), 7.46 (m, 1H), 7.31 (m, 2H), 7.20 (t, J=9 Hz, 1H), 7.02 (t, J=9 Hz, 2H), 5.25 (d, J=15 Hz, 1H), 4.70 (m, 1H), 4.25 (d, J=15 Hz, 1H), 3.92 (s, 3H), 2.52 (m, 2H), 1.98 (m, 2H). MS: m/z (MH+) 466.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:34])[CH2:32][OH:33])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@@H:24]([CH:31]([CH3:34])[CH2:32][O:33][C:41](=[O:43])[CH3:42])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:35])[C@H:20]4[O:36][C:37](=[O:39])[CH3:38])=[O:17])[CH2:15][C@@:7]3([OH:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)CO)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC(C)[C@H]1CC[C@@H](C)[C@@]2(O)[C@@H]1C=C(C)[C@@H](OC(C)=O)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
To ((1S,2R,4aS,5S,8R,8aR)-2-(acetyloxy)-8a-hydroxy-5-[2-hydroxy-1-methylethyl]-3,8-dimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 140, 63.8 mg, 0.11 mmol) in dichloromethane (1.1 ml) was added acetic anhydride (22 mg, 2.0 □l, 0.22 mmol) and 4-dimethylaminopyridine (14.3 mg, 0.12 mmol) and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (20 ml) and washed with aqueous citric acid solution, dried (MgSO4) and concentrated in vacuo to give a gum. The crude product was purified by chromatography on silica eluting with hexane:ethyl acetate (60:40). The pure fractions were combined and concentrated in vacuo, to give the title product as a white solid (42 mg, 61%).
Reaction SMILES: [OH:1][C@H:2]([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[Cl-].[NH4+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:16]([O:8][CH2:7][C@@H:2]([OH:1])[C:3]([O:5][CH3:6])=[O:4])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: COC(=O)[C@H](O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
The compound of Example 68-1 (308 mg, 2.57 mmol) was dissolved in methylene chloride (10 ml), and thereto were added triethylamine (704 mg, 6.95 mmol), 4-dimethylaminopyridine (33 mg, 0.27 mmol), and t-butyldimethylsilyl chloride (524 mg, 3.48 mmol). The mixture was stirred at room temperature for 2 hours, and thereto was added a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (356 mg, 57%).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]([NH2:7])=[O:6])[CH3:4].[O:8]=[CH:9][CH2:10][CH2:11][C:12](OCC(C)C)=O>>[O:6]=[C:5]1[C@@H:3]([CH3:4])[N:2]2[C:9](=[O:8])[CH2:10][CH2:11][C@H:12]2[NH:7]1
Reactant: CC(C)COC(=O)CCC=O
Reactant: CC(N)C(N)=O
Agent: Cl
Product: C[C@@H]1C(=O)N[C@@H]2CCC(=O)N12

Procedure:
DL-Alaninamide hydrochloride (6.9 g, 0.055 mol) and isobutyl 4-oxobutanoate (7.3 g, 0.046 mol) were reacted together according the procedure of Example 2 to give the title compound, 1.7 g (24%), m.p. 84°-86°. NMR (DMSO-d6): deltaH =8.55 (bs, 1H, NH); 5.20 (t, J=5 Hz, NCHNH); 3.92 (q, J=6.5 Hz, 1H, CHCH3); 2.82-1.50 (c.a., 4H, CH2CH2); 1.17 (d, J=6.5 Hz, 3H, CHCH3). MS (E.I., 70 eV, 1.5 mA) m/z=154 (M+), 111 (M-CHNO)+, 98 (M-C3H4O)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]([CH2:11][C:12]1[CH:13]=[C:14]([NH:22]C(=O)OC(C)(C)C)[CH:15]=[CH:16][C:17]=1[Si:18]([CH3:21])([CH3:20])[CH3:19])[CH3:10].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:10][N:9]([CH2:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[Si:18]([CH3:20])([CH3:19])[CH3:21])[NH2:22])[CH3:8]
Reactant: CN(C)Cc1cc(NC(=O)OC(C)(C)C)ccc1[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1cc(N)ccc1[Si](C)(C)C
Reaction time: 2 h

Procedure:
At 0° C., 5 ml TFA was slowly added into a solution of tert-butyl 3-((dimethylamino)methyl)-4-(trimethylsilyl)phenylcarbamate (compound 29) in CH2Cl2. The reaction mixture was stirred at 0° for 2 hours. After adjusted with saturated NaHCO3 solution to pH 8, the reaction mixture was extracted by ethyl acetate. The organic layer was dried and evaporated to give a crude product, which was purified using column chromatography to give the product. (0.9 g, 32%)
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[F:42][C:43]([F:53])([F:52])[CH2:44][N:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1.Cl>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:51][CH:48]5[CH2:49][CH2:50][N:45]([CH2:44][C:43]([F:53])([F:42])[F:52])[CH2:46][CH2:47]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCN(CC(F)(F)F)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(CC(F)(F)F)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.20 mL (1.1 mmole) of ethyldiisopropyl amine and 0.068 g (0.26 mmole) of 1-(2,2,2-trifluoro-ethyl)-piperidin-4-ylamine; hydrochloride in 4.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate solution, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexane-ethylacetate (gradient, 80:20-0:100) gave 0.11 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-[1-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]-benzamide (I-77) as a white solid.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:24]([Cl:25])=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][N:22]3[CH2:26][CH2:27][F:28])=[CH:17][C:16]=2[F:33])[CH2:10]1)=O)(C)(C)C.N>CO.Cl>[NH2:8][C@H:9]1[C@@H:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:24]([Cl:25])=[C:23]3[C:18]([C:19](=[O:32])[C:20]([C:29]([OH:31])=[O:30])=[CH:21][N:22]3[CH2:26][CH2:27][F:28])=[CH:17][C:16]=2[F:33])[CH2:10]1
Reactant: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(CCF)c3c2Cl)C[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Agent: N
Solvent: CO
Product: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(CCF)c3c2Cl)C[C@H]1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
A mixture of 7-(cis-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-8-chloro-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.13 g) in methanol (1.5 ml) and concentrated hydrochloric acid (1.5 ml) was stirred at room temperature for 30 minutes. The reacting mixture was neutralized with concentrated aqueous ammonia and then cooled. The resulting precipitate was collected by filtration and washed with water, methanol and ether successively to give the title compound (0.05 g) as pale yellow powder, mp 234°-236° C. (decompd.).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1([F:23])[CH2:10][CH:9]1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[OH:12].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:24]([O:12][CH:11]([CH:9]1[CH2:10][C:8]1([F:23])[F:7])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=1)(=[O:26])[CH3:25]
Reactant: OC(c1ccc(C(F)(F)F)cc1)C1CC1(F)F
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OC(c1ccc(C(F)(F)F)cc1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.23 ml (2.86 mmol) of pyridine was added dropwise to 2.40 g (9.52 mmol) of the compound from Example 190A and 1.94 g (19.0 mmol) of acetic anhydride, and the mixture was stirred at RT overnight. The reaction mixture was then added to ethyl acetate and saturated aqueous sodium bicarbonate solution. The phases were separated, and the organic phase was concentrated, and the crude product was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 6/1). 2.66 g (95% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[CH3:2].[H-].[Na+].[Cl:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1>CN(C=O)C>[Cl:22][C:23]1[N:28]=[C:27]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]3[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH2:13][CH2:12]2)[CH:26]=[CH:25][N:24]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3ccnc(Cl)n3)CC2)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.2 equiv; intermediate A1) in dry DMF (1.5 mL) under Ar was added sodium hydride (6.6 mg, 0.15 mmol, 1.2 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 2,4-dichloro-pyrimidine (18.6 mg, 0.125 mmol, 1.0 equiv; commercially available) was added and the mixture heated by microwave irradiation to 140° C. for 1 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 10.9 mg (23%) of the title compound. MS (ISP): 377.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl[CH:20]([CH3:24])[C:21](Cl)=[O:22].O>CN(C)C=O.C(OCC)(=O)C>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:12][CH:20]([CH3:24])[C:21](=[O:22])[NH:1][C:2]=2[CH:7]=1)=[O:9]
Reactant: COC(=O)c1ccc(O)c(N)c1
Reactant: CC(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)NC(=O)C(C)O2
Temperature: 50 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of 2-amino-4-methoxycarbonylphenol [Acta Chimica Academiae Scientiarum Hungaricae, 99(1), 49-50 (1979)] (5.0 g) in dimethylformamide (30 ml) were added potassium carbonate (8.3 g) and 2-chloropropionyl chloride (4.0 g) and the mixture was stirred at 50° C. for 2 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The extraction was concentrated and hexane was added thereto to give precipitates, which were taken by filtration and dried to give 6-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (4.7 g).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:6]1(=[O:20])=[O:19])[CH2:2][CH2:3][CH3:4].[F:21][CH:22]([F:31])[O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>CC#N>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([O:23][CH:22]([F:21])[F:31])=[CH:25][CH:26]=2)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:6]1(=[O:20])=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccc(Cl)cc2)S1(=O)=O
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc(OC(F)F)cc2)=C(c2ccc(Cl)cc2)S1(=O)=O
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 44.5 %

Procedure:
2-Butyl-4-chloro-5-(4-chlorophenyl)isothiazol-3(2H)-one 1,1-dioxide (0.20 g, 0.60 mmol) and 4-(difluoromethoxy)-aniline (0.190 g, 1.20 mmol) were mixed in MeCN (2.5 mL). The mixture was heated in a microwave reactor at 130° C. for 15 mins, then additional 60 mins and then at 140° C. for 15 mins, then additional 30 mins. The mixture was evaporated and the residue was purified by column chromatography (ISOLUTE SI 20 g/70 mL), eluting with heptane, then DCM:heptane (25:75, then 50:50), to give the title compound (0.122 g, 45%); 1H NMR (400 MHz, CDCl3): δ 7.28 (s, 1H), 7.12 (d, 2H), 7.04 (d, 2H), 6.81 (d, 2H), 6.70 (d, 2H), 6.37 (t, 1H), 3.76 (t, 2H), 1.87-1.80 (m, 2H), 1.50-1.40 (m, 2H), 0.97 (t, 3H); 13C NMR (100 MHz, CDCl3): δ 158.9, 148.0, 135.6, 133.1, 131.3, 130.3, 128.4, 123.7, 123.1, 120.1, 115.5 (t), 110.1, 40.3, 30.1, 20.0, 13.4; Mass Spectrum: M−H+ 455.
Reaction SMILES: [Na+].[Na+].[Na+].C([NH:6][C@H:7]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][C:28]([OH:37])([P:33]([O-:36])(=[O:35])[OH:34])[P:29]([O-:32])(=[O:31])[O-:30])=[O:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:19][CH2:20][Cl:21])[CH2:16][CH2:17][Cl:18])=[CH:11][CH:10]=1)=O.Cl>CO>[ClH:18].[Cl:18][CH2:17][CH2:16][N:15]([CH2:19][CH2:20][Cl:21])[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C@@H:7]([C:22]([NH:24][CH2:25][CH2:26][CH2:27][C:28]([OH:37])([P:29]([OH:32])(=[O:30])[OH:31])[P:33]([OH:35])(=[O:34])[OH:36])=[O:23])[NH2:6])=[CH:14][CH:13]=1
Reactant: O=CN[C@@H](Cc1ccc(N(CCCl)CCCl)cc1)C(=O)NCCCC(O)(P(=O)([O-])[O-])P(=O)([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N[C@@H](Cc1ccc(N(CCCl)CCCl)cc1)C(=O)NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Yield: 171.9 %

Procedure:
A solution of N-{N'-formyl-4-[bis(2-chloroethyl)amino]-(L)phenylalanyl}-4-amino-1-hydroxybutane-1,1-diphosphonic acid trisodium salt (32 mg) in methanol saturated with hydrochloric acid (1 ml) is heated to 40°-50° C. for 4 hours, then the solution is concentrated to reduced volume and the precipitated sodium chloride is filtered. The filtrate is evaporated to dryness and the residue is triturated with acetone and filtered. After recrystallization from ethanol/ethyl ether, N-{4-[bis(2-chloroethyl)amino]-(L)-phenylalanyl}-4-amino-1-hydroxybutane-1,1-diphosphonic acid monohydrochloride (25 mg) is obtained, m.p. >260° C.; [α]D =+7.8 (c=2, methanol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:15][C:16]([OH:18])=O)[CH2:11][C:12](O)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:19]C(N)=O>CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][C:16](=[O:18])[NH:19][C:12](=[O:13])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(N)=O
Reactant: O=C(O)CC(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: O=C1CC(c2ccc([N+](=O)[O-])cc2)CC(=O)N1
Temperature: 150 °C
Yield: 22.5 %

Procedure:
A mixture of 250 mg (0.987 mmol) of 3-(4-nitro-phenyl)-pentanedioic acid (as prepared in the previous step) and 119 mg (1.98 mmol) of urea was heated to 150° C. for 40 min (until all solid melted and gas evolution stopped). The mixture was cooled to RT, taken up in EtOAc (70 mL), washed with saturated aqueous NaHCO3 (2×40 mL), dried (MgSO4), and concentrated in vacuo to afford 52.0 mg (22%) of the title compound as a brown solid: 1H-NMR (CDCl3; 400 MHz): δ 8.28 (d, 2H, J=8.8 Hz), 7.44 (d, 2H, J=8.8 Hz), 3.64-3.54 (m, 1H), 3.04-2.96 (m, 2H), 2.86-2.76 (m, 2H).