Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.C(O)(=O)C.[Br:15]Br>O>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[Br:15]
Reactant: BrBr
Reactant: Nc1ccncc1C(=O)O
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(Br)cncc1C(=O)O
Temperature: 75 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
A sealed tube was charged with 4-aminonicotinic acid 45 (8.00 g, 57.9 mmol), acetic acid (75 mL) and water (75 mL). The reaction was heated at 75° C. and stirred vigorously until homogeneous. After cooling to 50° C., bromine (10.0 mL, 195 mmol) was added and stirring continued for 16 h. Upon cooling to 0° C., the resulting orange precipitate was collected by filtration, rinsed with H2O, and dried under vacuum to give 46 (10.5 g, 84% yield).
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH2:13][C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30]Cl)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CCOCC>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH:13]([C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)[C:14]#[N:15])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CCc1cccc2ccccc12
Reactant: ClCCN1CCC(Cc2ccccc2)CC1
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N#CC(CCN1CCC(Cc2ccccc2)CC1)c1cccc2ccccc12

Procedure:
2 g of sodium amide are added in small portions to a solution of naphth-1-ylacetonitrile in 150 ml of anhydrous ether and the mixture is refluxed for 5 hours. 11.8 g of 2-(4-benzylpiperidino)chloroethane are then added and the mixture is refluxed again for 3.5 hours. 200 ml of water are added and the organic phase is decanted and extracted with 300 ml of 10% hydrochloric acid. The aqueous phase is washed with ether, neutralized with 30% sodium hydroxide and extracted with ether. The organic phase is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate and the solvent is then evaporated off to give 16.4 g of the expected product.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:17]([OH:19])=O)=[CH:11][NH:12][C:13]2=[O:16])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:32][CH2:33][C@@H:34]([OH:51])[CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([O:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([Cl:50])[CH:44]=2)[CH2:38][CH2:37]1.O>CN(C)C=O>[Cl:50][C:45]1[CH:44]=[C:43]([CH:48]=[CH:47][C:46]=1[Cl:49])[O:42][CH:39]1[CH2:38][CH2:37][N:36]([CH2:35][C@H:34]([OH:51])[CH2:33][NH:32][C:17]([C:10]2[C:9]3[C:14](=[CH:15][C:6]([S:3]([NH:2][CH3:1])(=[O:4])=[O:5])=[CH:7][CH:8]=3)[C:13](=[O:16])[NH:12][CH:11]=2)=[O:19])[CH2:41][CH2:40]1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: CNS(=O)(=O)c1ccc2c(C(=O)O)c[nH]c(=O)c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc2c(C(=O)NC[C@@H](O)CN3CCC(Oc4ccc(Cl)c(Cl)c4)CC3)c[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.9 %

Procedure:
7-[(Methylamino)sulfonyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (0.1 g) in dimethyl formamide (7 ml) was treated with N,N-carbonyldiimidazole (0.06 g) and the mixture was heated at 55° C. for 45 min. (2R)-1-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.11 g) in dimethyl formamide (1 ml) was added and the mixture was stirred at ambient temperature for 18 h. 1 Drop of water was added and the solvent was evaporated. Purification using revere phase HPLC (Symmetry C8 column) and acetonitrile/aqueous ammonium acetate as eluent yielded the title compound as a white solid (0.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][C@@H:25]([CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:26][OH:27])=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.[Si:35](OC[C@@H](NC(=O)OC1C=CC([N+]([O-])=O)=CC=1)CC1CCCCC1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].ClC1C=C([C@]([C@@H]2CCCNC2)(O)CCCCOC)C=CC=1>>[Si:35]([O:27][CH2:26][C@@H:25]([NH:24][C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@@H:16]([C@@:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH2:17]1)=[O:23])[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@H](CO)CC2CCCCC2)C1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](CC1CCCCC1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Product: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CC2CCCCC2)C1

Procedure:
(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-hydroxypropan-2-yl)piperidine-1-carboxamide (I-158A) was prepared by applying analogous procedures to those described in Example 32 Step 1 to (S)-4-nitrophenyl 1-(tert-butyldimethylsilyloxy)-3-cyclohexylpropan-2-ylcarbamate and (S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol to afford (R)-N-((S)-1-(tert-butyldimethylsilyloxy)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide followed by removal of the t-butyldimethylsilyl group with aqueous acid.
Reaction SMILES: [C:1]1([C@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][Cl:33]>CN(C=O)C>[C:1]1([C@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:31][CH2:32][Cl:33])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCBr
Reactant: Oc1cccc2c1c1cccc3c1n2[C@H](c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCOc1cccc2c1c1cccc3c1n2[C@H](c1ccccc1)CO3
Temperature: 85 °C
Yield: 54.1 %

Procedure:
To a mixture of (1R)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (3.67 g, 12.19 mmol) in DMF (90 mL) is added potassium carbonate (8.4 g, 60.9 mmol) and 1-bromo-2-chloroethane (5.0 mL, 60.9 mmol). The mixture is heated to 85° C. for 24 h. The temperature is then increased to 95° C. and heated for 4 h. Mechanical stirring is employed and the reaction heated an additional 1.5 h. The mixture is then partitioned between water and Et2O. The layers are separated and the organic layer washed with water (100 mL). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography with silica gel using hexane/CH2Cl2 (60/40) gave 2.4 g (54%) of the title compound.
Reaction SMILES: FC1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([O:17]C)=O)[C:8]2=[O:22])=CC=1.C1(CN2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)CC1.[F:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][C:53]=1[F:54])[CH2:49][NH2:50]>>[CH:5]1([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15]([NH:50][CH2:49][C:48]3[CH:51]=[CH:52][C:53]([F:54])=[C:46]([F:45])[CH:47]=3)=[O:17])[C:8]2=[O:22])[CH2:23][CH2:24]1
Reactant: NCc1ccc(F)c(F)c1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: COC(=O)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Product: O=C(NCc1ccc(F)c(F)c1)c1ccnc(N2CCN(CC3CC3)C2=O)c1
Yield: 49 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)isonicotinate to react with 3,4-difluorobenzylamine, 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-N-(3,4-difluorobenzyl)isonicotinamide was obtained as a colorless solid in 49% yield: mp 134-136° C.; 1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.36 (d, J=5.1 Hz, 1H), 7.41-7.39 (m, 1H), 7.17-7.00 (m, 4H), 4.54 (d, J=6.0 Hz, 2H), 4.07 (t, J=8.1 Hz, 2H), 3.60 (t, J=8.1 Hz, 2H), 3.14 (d, J=7.2 Hz, 2H), 1.00-0.87 (m, 1H), 0.58-0.52 (m, 2H), 0.24-0.19 (m, 2H); MS (ES+) m/z 387.3 (M+1).
Reaction SMILES: [CH:1]#[C:2][CH3:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[N:17]([C@@H:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH3:19])[C:16](=[O:27])[C:15]3[CH:28]=[C:29](I)[CH:30]=[CH:31][C:14]=3[NH:13][C:12]2=[O:33])=[CH:7][CH:6]=1.C(N(CC)CC)C>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[N:17]([C@@H:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH3:19])[C:16](=[O:27])[C:15]3[CH:28]=[C:29]([C:1]#[C:2][CH3:3])[CH:30]=[CH:31][C:14]=3[NH:13][C:12]2=[O:33])=[CH:7][CH:6]=1
Reactant: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(I)ccc2NC(=O)[C@@H]1c1ccc(Cl)cc1
Reactant: C#CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC#Cc1ccc2c(c1)C(=O)N([C@H](C)c1ccc(Cl)cc1)[C@@H](c1ccc(Cl)cc1)C(=O)N2
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
Propyne (2 mL) was condensed in a sealed tube at −78° C. Then, (3S)-3-(4-Chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-7-iodo-1,4-benzodiazepine-2,5-dione (200 mg, 0.362 mmol), copper iodide (15 mg, 0.0788 mmol), dichlorobis(triphenylphosphine)palladium (II) (39 mg, 0.0556 mmol), triethylamine (2 mL), and acetonitrile (4 mL) were added. The sealed tube was closed and the reaction mixture was allowed warm up to room temperature. After 12 h, the reaction mixture was cooled to −78° C. and the sealed tube was opened and allowed to warm up to room temperature under vigorous stirring. Then, solvents were evaporated in vacuo and the residue was purified by column chromatgraphy on silica (EtOAc/Hexanes, 1:1) to give the title compound as colorless solid (150 mg, 89%): 1H NMR (400 MHz, CDCl3) δ 1.73 (d, J=7.1 Hz, 3H), 2.06 (s, 3H), 5.24 (s, 1H), 6.49 (q, J=7.1 Hz, 1H), 6.62–6.65 (m, 3H), 6.93 (d, J=8.4 Hz, 2H), 7.20 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.79 (d, J=2.0 Hz, 1H), 8.57 (br s, 1H). Mass spectrum (LCMS, ESI pos.): Calcd for C26H20Cl2N2O2: 463; found: 464 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: Brc1cccc2[nH]ncc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ncc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of NaH (0.78 g) in anhydrous THF (17.5 ml) at −5° C. was added 4-bromo-1H-indazole (3.5 g) in anhydrous THF (35 ml). Benzenesulfonyl chloride (2.5 ml) in anhydrous THF (17.5 ml) was added dropwise over 10 mins. The reaction was stirred for 1 h at 0° C. then quenched with water. The layers were separated and the aqueous was re-extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered and then evaporated to yield a solid residue that was triturated with methanol to give title compound, 5.18 g.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([C:14]2[CH:67]=[CH:66][C:17](OCC3C=CC(C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)COCC[Si](C)(C)C)C=CC=6)C5)=NC=4C(OCC)=O)=CC=3)=[CH:16][CH:15]=2)[C:3]=1[C:68]#[N:69].NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[OH:92][CH2:93][C:94]1[S:98][C:97]([N:99]2[CH2:108][CH2:107][C:106]3[C:101](=[C:102]([C:109](=[O:128])/[N:110]=[C:111]4/[S:112][C:113]5[CH:127]=[CH:126][CH:125]=[CH:124][C:114]=5[N:115]/4[CH2:116][O:117][CH2:118][CH2:119][Si:120]([CH3:123])([CH3:122])[CH3:121])[CH:103]=[CH:104][CH:105]=3)[CH2:100]2)=[N:96][C:95]=1[C:129]([O:131][CH3:132])=[O:130].NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC=C(O)C=2)C=1C#N>>[NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([C:14]2[CH:15]=[C:16]([CH:17]=[CH:66][CH:67]=2)[O:92][CH2:93][C:94]2[S:98][C:97]([N:99]3[CH2:108][CH2:107][C:106]4[C:101](=[C:102]([C:109](=[O:128])/[N:110]=[C:111]5/[S:112][C:113]6[CH:127]=[CH:126][CH:125]=[CH:124][C:114]=6[N:115]/5[CH2:116][O:117][CH2:118][CH2:119][Si:120]([CH3:123])([CH3:122])[CH3:121])[CH:103]=[CH:104][CH:105]=4)[CH2:100]3)=[N:96][C:95]=2[C:129]([O:131][CH3:132])=[O:130])[C:3]=1[C:68]#[N:69]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1CO
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: CC(C)(C)OC(=O)n1nc(-c2cccc(O)c2)c(C#N)c1N
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1COc1cccc(-c2nn(C(=O)OC(C)(C)C)c(N)c2C#N)c1

Procedure:
The title compound (46A) was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34D and compound 31F with compound 45D and compound 36A, respectively, in step 1 of Example 35: LCMS (ESI(+)): m/z 892 (M+NH4—H2O).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([C:20]#[N:21])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1>C1COCC1>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:20]([C:18]2[N:19]=[C:14]3[CH:13]=[CH:12][N:11]([S:1]([C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=4)(=[O:2])=[O:3])[C:15]3=[N:16][CH:17]=2)=[NH:21])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C#N)cnc32)cc1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=N)c2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (0.500 g, 1.68 mmol) in anhydrous THF (3.35 mL) was added molecular sieves (4A, beads, 8-12 mesh, 0.643 g). The mixture was stirred at rt for about 40 min. A solution of (4-methoxyphenyl)magnesium bromide (0.5 M in THF, 4.12 mL, 2.01 mmol,) was added dropwise over about 3 min. The mixture was stirred at rt for about 2 h. The mixture was concentrated in vacuo to give (4-methoxyphenyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanimine which was assumed to be quantitative and used immediately in the next step: LC/MS (Table 2, Method b) Rt=2.25 min; MS m/z: 407 (M+H)+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CCN(CC)CC>C(Cl)Cl>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1nc(Cl)nc(N2CCOCC2)n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
To a solution of cyanuric chloride (2.5 g, 13.5 mmol) in CH2Cl2 (150 mL) was added dropwise morpholine (1.14 g, 13.5 mmol) at −78° C., followed by addition of Et3N (3.0 mL, 21.5 mmol). The resulting reaction mixture was stirred at −78° C. for 20 min, and then diluted with CH2Cl2. The organic phase was washed with water and brine, and dried over MgSO4. The solvent was removed in vacuum to give the title compound as white crystalline solid (3.027 g, 95% yield). MS (ESI) m/z 235.1.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:7]([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:8][CH2:9][CH2:10][O:11][C:12]([C:14]1[CH:26]=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([C:27]([O:29][CH2:30][CH2:31][CH2:32][N:33]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])=[O:28])=[CH:21][CH:22]=3)[C:17](=[O:42])[C:16]=2[CH:15]=1)=[O:13])[CH2:4][CH2:5][CH3:6].S(=O)(=O)(O)O.[N-:52]=[N+]=[N-].[Na+]>FC(F)(F)C(O)=O>[ClH:1].[ClH:1].[CH2:38]([N:33]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:32][CH2:31][CH2:30][O:29][C:27]([C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[C:16]([C:17](=[O:42])[NH:52][C:18]=2[CH:19]=1)=[CH:15][C:14]([C:12]([O:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:43][CH2:44][CH2:45][CH3:46])=[O:13])=[CH:26][CH:25]=3)=[O:28])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCN(CCCC)CCCOC(=O)c1ccc2c(c1)C(=O)c1cc(C(=O)OCCCN(CCCC)CCCC)ccc1-2
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCCCN(CCCC)CCCOC(=O)c1ccc2c(c1)[nH]c(=O)c1cc(C(=O)OCCCN(CCCC)CCCC)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20.4 g (0.03 mole) of bis[3-(dibutylamino)propyl]9-oxo-fluorene-2,7-dicarboxylate dihydrochloride and 13 ml of concentrated sulfuric acid contained in 150 ml of trifluoroacetic acid, which has been cooled to 0° C., is slowly added 2.6 g (0.04 mole) of sodium azide with stirring. Stirring is continued for 30 minutes whereupon most of the trifluoroacetic acid is removed in vacuo. Cracked ice is added and the residue is made alkaline with a 50% sodium hydroxide solution. The reaction mixture is extracted with methylene chloride, the extracts are combined, dried over magnesium sulfate, filtered and the filtrate treated with a slight excess of ethereal hydrogen chloride. The solution is concentrated to approximately 300 ml in vacuo, and approximately 500 ml of warm butanone is added. The mixture is permitted to cool slowly whereupon the desired bis[3-(dibutylamino)propyl]5,6-dihydro-6-oxophenanthridine-3,8-dicarboxylate crystallizes as the dihydrochloride salt. The product when recrystallized from a methylene chloride-ethyl acetate mixture has a m.p. 204.5°-6.5° C., and a N.E. of 349.4.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C:11]1[C:12]2[C:17]([C:18]3[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][C:23]=3[CH:24]=1)=[CH:16][C:15]([CH3:29])=[CH:14][CH:13]=2.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[C:30]([NH:10][C:11]1[C:12]2[C:17]([C:18]3[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][C:23]=3[CH:24]=1)=[CH:16][C:15]([CH3:29])=[CH:14][CH:13]=2)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: COc1ccc2cc(N)c3ccc(C)cc3c2c1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2cc(NC(C)=O)c3ccc(C)cc3c2c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
105.7 ml (0.750M) of N-ethyl-N,N-diisopropyl-amine are added to a solution of 100.2 g (0.375M) of 9-amino-3,4-dimethoxy-6-methyl-phenanthrene in 1000 ml methylene chloride. To the resulting mixture is added dropwise over 30 minutes a solution of 34.5 ml (0.450M) of acetyl chloride in 250 ml methylene chloride. During the addition, the temperature of the reaction mixture is maintained at 20° by cooling with ice. The reaction mixture is stirred for 2 hours at room temperature and extracted with methylene chloride. The organic phases are washed with ice cooled 2N hydrochloric acid, water and 2N sodium bicarbonate, dried over sodium sulfate and evaporated, to give the title compound. M.pt. 190°-192° after crystallization from acetone/ether.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.Cl>ClCCl>[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:4]2[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: OC1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCCC(O)C1
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A mixture of 3-hydroxypiperidine (0.6 g, 5.93 mmol), 4-fluorobenzoic acid (0.83 g, 5.93 mmol), HOBT (0.8 g, 5.93 mmol), EDCI.HCl (1.7 g, 8.9 mmol) and dry triethylamine (1.66 mL, 11.86 mmol) in dry dichloromethane (30 mL) was kept under stiffing overnight at ambient temperature, under nitrogen atmosphere. HCl 1N (30 mL) was then added and the phases separated. The organic layer was washed with HCl 1N (30 mL), with NaOH 1N (30 mL×2 times), then with water (30 mL). Evaporation of the organic solvent afforded (4-fluoro-phenyl)-(3-hydroxy-piperidin-1-yl)-methanone as a white oil (0.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:18][CH2:19][CH2:20][N:21]2[C:29](=[O:30])[NH:28][C:27]3[C:22]2=[N:23][C:24]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[N:25][C:26]=3[NH2:31])[C:13](=[O:17])[CH2:14][S:15][CH3:16])[CH:6]=1.CO.C1C=C(Cl)C=C(C(OO)=[O:48])C=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:18][CH2:19][CH2:20][N:21]2[C:29](=[O:30])[NH:28][C:27]3[C:22]2=[N:23][C:24]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[N:25][C:26]=3[NH2:31])[C:13](=[O:17])[CH2:14][S:15]([CH3:16])=[O:48])[CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)CSC)c2n1
Solvent: CO
Solvent: ClCCl
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)CS(C)=O)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from example 12 (150 mg) was dissolved in DCM (10 ml) and methanol (2 ml) and mCPBA (0.1 g) added. The mixture was stirred at rt for 3 h then purified by RPHPLC, which afforded the title compound. Yield 50 mg.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([Li])CCC.CN(C)[CH:22]=[O:23]>O1CCCC1.[Cl-].[Na+].O>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:10]=[C:2]([CH:22]=[O:23])[C:3]2[CH:4]=[CH:5][NH:6][C:7]=2[CH:8]=1
Reactant: FC(F)(F)c1cc(Br)c2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(C(F)(F)F)cc2[nH]ccc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-bromo-6-(trifluoromethyl)-1H-indole (5.23 g, 19.81 mmol) in tetrahydrofuran (20 ml) was cooled to −78 ° C. and treated slowly with n-butyllithium (1.6 M solution in hexanes, 39.6 ml, 63.4 mmol). The solution was stirred for 15 min at −78 ° C., and then treated with dimethylformamide (7.67 ml, 99 mmol), and stirred for 30 minutes more, allowing the reaction to warm to ambient temperature. The resulting solution was poured into brine and extracted with ethyl acetate. The pooled organics were dried over sodium sulfate and concentrated to give an amber oil. Column chromatography (ethyl acetate/hexanes gradient elution) afforded 1.17 g, (32%). 1H-NMR (CDCl3, 500 MHz) δ ppm 10.28 (s, 1H), 8.72 (br s, 1H), 7.93 (s, 1H), 7.88 (s, 1H), 7.58 (s, 1H), 7.42 (s, 1H). Mass spec.: 214.14 (MH)+.
Reaction SMILES: N=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[N:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:20][C:21]=3[CH3:22])=[CH:11][CH:10]=2)[S:3]1.[OH:29]S(O)(=O)=O.O1CCOCC1>O>[CH3:22][C:21]1[O:20][C:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:18][C:17]=1[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:29])[NH:6][C:5]2=[O:7])=[CH:10][CH:11]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CC2SC(=N)NC2=O)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 58.8 %

Procedure:
A mixture of 2-imino-5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-thiazolidinone (11.4 g), 1N.H2SO4 (100 ml) and dioxane (100 ml) was stirred at 80° C. for 5 hours, and poured in water. The aqueous mixture was extracted with chloroform. The chloroform layer was washed with water, dried (MgSO4) and concentrated. The oily residue was chromatographed on a column of silica gel (200 g), and from the fractions eluted with chlorform-methanol (100:1, V/V), there was obtained 5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-2,4-thiazolidinedione (6.7 g, 58.8%). Recrystallization from ethyl acetate-hexane afforded colorless plates. m.p. 162°-163° C. Elemental analysis for C21H18N2O4S, Calcd.: C, 63.95; H, 4.60; N, 7.10. Found: C, 63.84; H, 4.63; N, 6.90. This product showed the IR and NMR spectra in accordance with those of the compound obtained in Example 6.