Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:12]1([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24]3[N:29]=[CH:28][C:27](Br)=[CH:26][N:25]=3)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.[NH:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]1=[O:37]>[Cu](I)I.O>[CH:12]1([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24]3[N:29]=[CH:28][C:27]([N:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]4=[O:37])=[CH:26][N:25]=3)[CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Brc1cnc(OC2CCN(C3CCCC3)CC2)nc1
Reactant: O=c1cccc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccccn1-c1cnc(OC2CCN(C3CCCC3)CC2)nc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 16.2 %

Procedure:
Potassium carbonate (40 mg) and copper iodide (40 mg) were added to a DMF solution (5 ml) of 2-(1-cyclopentylpiperidin-4-yloxy)-5-bromopyrimidine (130 mg) and 1H-pyridin-2-one (19 mg), and stirred at 150° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to it and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, chloroform:methanol=9:1) to obtain the entitled compound (11 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:21]([NH:22][CH3:23])=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:12]1.N1C=CC=CC=1.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]1[CH2:14][C@H:13]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:21]3[N:22]([CH3:23])[C:34]2=[O:40])[CH2:12]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNc1nccnc1N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1c(=O)n([C@H]2C[C@@H](Nc3nc4ccccc4s3)C2)c2nccnc21
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
To a round bottomed flask was added N2-(cis-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-N3-methylpyrazine-2,3-diamine (0.1100 g, 0.337 mmol) and pyridine (0.082 mL, Sigma-Aldrich Chemical Company, Inc.) in DCM (1.1 mL) to stir at −40° C. for 30 mins. Triphosgene (0.120 g, 0.404 mmol, Sigma-Aldrich Chemical Company, Inc.) was added to stir for 30 mins. The temperature was brought to 0° C. and allowed to stir for 5 h. The reaction mixture was diluted with saturated sodium bicarbonate and extracted with CH2Cl2. The organic extract was washed with water, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (25 g), eluting with a gradient of 40% to 100% EtOAc in hexane, to provide the title compound (0.0352 g, 0.100 mmol, 29.6% yield). LCMS showed product peak at 1.51 min (m+1=353.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.72-2.85 (m, 1 H) 2.94-3.08 (m, 1 H) 3.34 (s, 2 H) 4.14-4.28 (m, 1 H) 4.62-4.76 (m, 1 H) 6.98-7.07 (m, 1 H) 7.19-7.26 (m, 1 H) 7.40 (d, J=7.43 Hz, 1 H) 7.64-7.71 (m, 1 H) 7.98 (s, 1 H) 8.52 (d, J=6.65 Hz, 1 H)
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18])[CH3:13].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[O:14][CH2:12][CH3:13])[CH2:2]1)[CH2:8]2
Reactant: CCOc1ccccc1C(=O)O
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: CCOc1ccccc1C(=O)NC1C2CC3CC1CN(C3)C2

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 2-ethoxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.53 (t, J=7 Hz, 3H), 1.94 (s, 1H), 2.02 (d, 2H), 2.11 (d, 1H), 2.20 (d, J=14 Hz, 2H), 2.32 (s, 2H), 3.48 (s, 2H), 3.59 (s, 4H), 4.28 (q, J=7 Hz, 2H), 4.47 (s, 1H), 7.06-7.10 (m, 1H), 7.17 (d, J=8 Hz, 1H), 7.48-7.53 (m, 1H), 7.96 (dd, J=8, 2 Hz, 1H); MS (APCI/NH3) m/z 301 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:13](=[O:14])[NH:12][N:11]=[N:10]2)=[CH:4][C:3]=1[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CS(O[CH2:27][CH2:28][CH2:29][F:30])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:27][CH2:28][CH2:29][F:30])[N:11]=[N:10]2)=[CH:4][C:3]=1[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CS(=O)(=O)OCCCF
Reactant: CCOC(=O)C=Cc1cc(-n2nn[nH]c2=O)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cc(-n2nnn(CCCF)c2=O)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 24.6 %

Procedure:
To a stirred mixture of 2.62 g (0.00830 mole) of ethyl 3-[2-chloro-4-fluoro-5-(1,4-dihydro-5-oxo-5H-tetrazol-1-yl)phenyl]propenoate in 20 mL of N,N-dimethylformamide was added 1.46 g (0.00939 mole) of 3-fluoropropyl methanesulfonate and 1.30 g (0.00939 mole) of potassium carbonate. The reaction mixture was heated at 50°-60° C. and was stirred at that temperature for approximately 18 hours. The mixture was cooled and was poured into ice water. This mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure to yield 0.76 g of ethyl 3-[2-chloro-4-fluoro-5-[4-(3-fluoropropyl)-1,4-dihydro-5-oxo-5H-tetrazol-1-yl]phenyl]propenoate as an oil, compound 4 of Table 1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[CH2:9][S:10][C@@H:11]2[CH:22]([NH:23][C:24](=[O:31])[CH2:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)[C:21](=[O:32])[N:12]2[C:13]=1[C:14]([O:16]C(C)(C)C)=[O:15]>FC(F)(F)C(O)=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[CH2:9][S:10][C@@H:11]2[CH:22]([NH:23][C:24](=[O:31])[CH2:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)[C:21](=[O:32])[N:12]2[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)C1=C(CC2CCCCO2)CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(CC3CCCCO3)CS[C@H]12
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
The cephem ester (XX) (28 mg) was dissolved in trifluoroacetic acid (0.8 ml) and allowed to stand at room temperature for 30 min. The reaction mixture was evaporated azeotropically from dry benzene to give the acid (XXII) as a glass (25 mg) νmax (CHCl3) 1775, 1730-1750, 1675 cm-1The minimum inhibitory concentrations (MIC) of this compound against five typical Gram-positive bacteria are tabulated below:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:19][C:18]2[C:17]([NH:20][NH2:21])=[N:16][C:15](=[O:22])[N:14]([CH2:23][CH2:24][CH3:25])[C:13]=2[N:12]=1)[CH2:2][CH3:3].[C:26](OCC)(OCC)(OCC)[CH3:27]>>[CH3:26][C:27]1[N:16]2[C:17]([C:18]3[NH:19][C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:1][CH2:2][CH3:3])=[N:12][C:13]=3[N:14]([CH2:23][CH2:24][CH3:25])[C:15]2=[O:22])=[N:20][N:21]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CCCOc1ccccc1-c1nc2c([nH]1)c(NN)nc(=O)n2CCC
Product: CCCOc1ccccc1-c1nc2c([nH]1)c1nnc(C)n1c(=O)n2CCC
Yield: 77 %

Procedure:
A mixture of 8-(2-propoxyphenyl)-3-propyl-6-hydrazino-3,7-dihydropurin-2-one (1.0 g, 2.9 mmol, see Preparation 9) and triethyl orthoacetate (10 mL) was heated under reflux for 2 h. The resulting mixture was cooled and the precipitate collected by filtration and washed with water and ethanol, then dried under vacuum to yield the title compound (0.82 g, 77%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39](O)=[O:40])=[N:36][CH:37]=1>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:37][N:36]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Reactant: O=C(O)Cc1ccc(F)cn1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(F)cn3)c2)c2cnccc21

Procedure:
Prepared according to Method Z (Preparation 8) using (5-Amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 28) and (5-fluoropyridin-2-yl)acetic acid (Preparation 82).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([CH3:31])[CH:18]=1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:39]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=N1.C1(N)C(N)=CC=CC=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[NH2:39][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[NH:41][C:13](=[O:15])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:28])(=[O:29])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([CH3:31])[CH:18]=1
Reactant: Cc1cc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)ccc1C1CC(=O)NS1(=O)=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(C[C@H](NC(=O)OCc2ccccc2)C(=O)Nc2ccccc2N)ccc1C1CC(=O)NS1(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
A solution of (2S)-2-[(benzyloxy)carbonyl]amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-methylphenyl]propanoic acid (200 mg, 0.448 mmol) in N,N-dimethylformamide (2.0 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.218 g, 0.493 mmol). After stirring for 10 minutes at 0° C., a solution of 1,2-benzenediamine (72.7 mg, 0.672 mmol) and N,N-diisopropylethylamine (0.39 mL, 2.24 mmol) in DMF (1.0 mL) was cannulated into the reaction flask. The solution was stirred at 25° C. for 2 h. The solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and 1.0 M hydrochloric acid solution. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by preparative LCMS to yield the desired product (196 mg, 82%). 1H NMR (400 MHz, CD3OD): δ 7.47 (d, 0.5H), 7.39–7.22 (m, 9H), 7.12 (d, 0.5H), 7.07 (s, 1H), 6.82 (d, 0.5H), 6.71 (d, 0.5H), 5.50 (t, 1H), 5.10 (s, 2H), 4.47 (m, 1H), 3.3 (m, 2H), 3.07 (m, 2H), 2.48 (s, 1.5H), 2.38 (s, 1.5H); MF=C27H28N4O6S; LCMS found for C27H29N4O6S (M+H)+: m/z=537.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[C:32]1([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:41]4[CH2:42][CH2:43][N:38]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:39][CH2:40]4)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N2CCN(c3ccccc3)CC2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 38.9 mg (0.24 mmol) 1-phenylpiperazine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 16 mg (22.5%) product as an orange powder. MS (ESI) m/z 593.3 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1.[C:10]1([CH3:20])[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH:18]=O.C1(C)C=CC=CC=1>O>[CH3:20][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH:18]=[N:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1
Reactant: Cc1cc(C)c(C=O)c(C)c1
Reactant: NCc1ccc(Cl)nc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)c(C=NCc2ccc(Cl)nc2)c(C)c1
Yield: 99.1 %

Procedure:
A mixture of 5-aminomethyl-2-chloropyridine (14.25 g), mesitaldehyde (14.8 g) and toluene (100 ml) was heated under reflux for 3 hours. The water which was formed during the reaction was trapped by Dean and Stark constant water separator. The toluene was distilled off from the mixture under reduced pressure, so as to obtain N-(2,4,6-trimethylbenzylidene)-2-chloro-5-pyridylmethylamine (27 g). m.p. 47°-48° C.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]([C:14]2[C:15]3[CH:16]=[N:17][N:18]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:19]=3[CH:20]=[C:21](Br)[CH:22]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:34]1.C([O-])(=O)C.[K+].OO.O.[OH-].[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].C1COCC1>[CH3:1][NH:2][S:3]([C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]([C:14]2[C:15]3[CH:16]=[N:17][N:18]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:19]=3[CH:20]=[C:21]([OH:34])[CH:22]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc(CNC(=O)c2cc(Br)cc3c2cnn3-c2ccc(F)cc2)cc1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(CNC(=O)c2cc(O)cc3c2cnn3-c2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid 4-methylsulfamoyl-benzylamide (0.1 g, 0.2 mmol), bis(pinacolato)diboron (0.1 g, 0.4 mmol), PdCl2(dppf) (0.04 g, 0.05 mmol), potassium acetate (0.05 g, 0.5 mmol) was charged in a sealed tube with anhydrous THF (7 mL). The solution was warmed at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and quenched with water (15 mL) and diluted with CH2Cl2 (20 mL). The organic layer was separated and washed with brine (10 mL) and dried over sodium sulfate. The solvent was removed in vacuo. The residue was dissolved in THF (10 mL), and a solution of 30% H2O2 in water (0.15 mL, 0.5 mmol) and NaOH (0.01 g, 0.3 mmol) were added. The mixture was stirred at 10° C. for 3 hours and then quenched with water (10 mL) and diluted with CH2Cl2 (20 mL). The organic layer was washed with brine (10 mL) and dried over sodium sulfate. The solvent was removed in vacuo. The residue was purified by reversed-phase HPLC, eluting with a gradient of 5-100% CH3CN in water. The desired fractions were combined and diluted with saturated aqueous NaHCO3 (20 mL) and ethyl acetate (20 mL). The organic layer was separated, dried over sodium sulfate and concentrated to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][N:56]1[C:60]([C:61](Cl)=[O:62])=[CH:59][N:58]=[CH:57]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:61]([C:60]2[N:56]([CH3:55])[CH:57]=[N:58][CH:59]=2)=[O:62])[CH2:49][CH2:48]1
Reactant: Cn1cncc1C(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 31 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-methyl-1H-imidazole-5-carbonyl chloride as starting materials in 31% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.97 (s, 1H), 9.41 (s, 1H), 9.38 (s, 1H), 8.97 (s, 1H), 8.91 (s, 1H), 8.22 (m, 3H), 7.85 (s, 1H), 7.65 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 4.00 (m, 2H), 3.83 (s, 3H), 2.98 (m, 6H), 2.32 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C29H31ClN9O2 (M+H)+: m/z=572.2.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.O>[OH:17]/[N:16]=[C:11]1\[CH2:10][CH2:9][CH2:8][C:7]2[C:12]\1=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)/C(=N/O)CCC2
Yield: 21.1 %

Procedure:
A mixture of 5 g of 7-nitro-3,4-dihydronaphthalen-1(2H)-one, 2.18 g of hydroxylamine hydrochloride, 4.29 g of sodium acetate in 90 ml of ethanol and 90 ml of water is refluxed for one hour. The reaction medium is brought back to ambient temperature and an aqueous 10% sodium bicarbonate solution is added until a pH of 7 is reached. The mixture is extracted with ethyl acetate and the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of heptane and of ethyl acetate (80/20 to 50/50). 1.14 g of (1E)-N-hydroxy-7-nitro-3,4-dihydronaphthalen-1(2H)-imine are obtained in the form of a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]([CH3:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[N+](C1C=CC([O:27][C:28]([N:30]2[CH:34]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=3)[CH2:33][O:32][C:31]2=[O:43])=O)=CC=1)([O-])=O>C1COCC1>[CH3:17][C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:28]([N:30]2[CH:34]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=3)[CH2:33][O:32][C:31]2=[O:43])=[O:27])[CH2:10][CH2:9]1
Reactant: CC1(c2ccccc2)CCN(CCCN)CC1
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC1(c2ccccc2)CCN(CCCNC(=O)N2C(=O)OCC2c2ccc(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of 1-(3-amino-propyl)-4-methyl-4-phenyl-piperidine (60 mg, 0.258 mmol) in 10 mL of THF, 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester (60 mg, 0.165 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by MeOH:EtOAc=1:19 (Rf=0.45, MeOH:EtOAc=1:3 to obtain 4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid (3-[4-methyl-4-phenyl-piperidin-1-yl)-propyl}-amide (56 mg, 74%). The compound was dissolved in CH2Cl2 (3 mL) and was treated with 1N HCl in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a pale yellow solid. M.P. 176-178°C.; [α]D=+76.9, (c=0.23, MeOH); Anal. Calcd. For C25H30N3O3F2Cl.0.60 CH2Cl2: C, 56.32; H, 5.94; N, 7.70. Found: C, 56.30; H, 5.80; N, 7.35.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([NH:11][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.[H][H]>CO.[Pt]=O>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([O:14][CH:15]([CH3:16])[CH3:17])=[O:13])=[CH:10][C:4]=1[NH2:1]
Reactant: CC(C)OC(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: CC(C)OC(=O)Nc1ccc(N)c(N)c1
Yield: 66.3 %

Procedure:
A mixture of a solution of 2-nitro-4-isopropoxycarbonylaminoaniline (17.9 g, 0.075 mole) in methanol (450 ml) and platinum oxide (1.0 g) was shaken in an atmosphere of hydrogen at atmospheric pressure and laboratory temperature for several hours, during which time 5.04 liters of hydrogen were absorbed. The mixture was filtered, and the methanol removed in vacuo and the dark solid residue recrystallised from benzene to give 1,2-diamino-4-isopropoxycarbonylaminobenzene (10.4 g), m.p. 108°-110° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:36]([NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[Br:28])=[O:37])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C=Nc1ccccc1Br
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)Nc1ccccc1Br

Procedure:
Prepared according to the procedure described in Example 41, Step 5, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 2-bromophenyl isocyanate.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][C:17](=O)[C:16]([CH3:27])=[C:15]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:35]>O>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][C:17](=[S:35])[C:16]([CH3:27])=[C:15]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1c(-c2ccccc2)n(-c2ccccc2Cl)c(-c2ccccc2)cc1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: Cc1c(-c2ccccc2)n(-c2ccccc2Cl)c(-c2ccccc2)cc1=S
Yield: 81 %

Procedure:
To 40 ml of pyridine were added 1.3 g (0.0035 mole) of 1-(2-chlorophenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone and 0.9 g (0.0042 mole) of phosphorus pentasulfide, followed by refluxing the resultant mixture for 3 hours. After cooling, the reaction mixture was poured into water and the resulting crystals were collected by filtration. The crystals were dissolved in 100 ml of chloroform, and washed first with 30 ml of 2N hydrochloric acid and then with 30 ml of a saturated aqueous solution of sodium hydrogencarbonate. After washing the chloroform solution further with water, it was dried over anhydrous sodium sulfate. After removal of sodium sulfate, the solvent was distilled off to obtain crystals. The crystals were recrystallized from a 1:1 mixture of acetone and hexane, thereby obtaining 1.1 g of 1-(2-chlorophenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinethione having a melting point of 271°-275° C.