Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:11]=[C:10]3[C:22]([OH:24])=O)[CH:2]=1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][C:22]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[N:12]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[N:11]=2)=[O:24])[CH:27]=1
Reactant: O=C(O)c1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
To a solution of 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (CXXXIII) (0.39 g, 1.21 mmol) and 3-aminopyridine (CXXVII) (0.11 g, 1.21 mmol) in DMF (4.0 mL) was added N,N-diisopropylethylamine (0.42 mL, 1.21 mmol). The solution was cooled to 0° C. before adding HATU (0.46 g, 1.21 mmol). The ice bath was removed, and the reaction warmed to room temperature and stirred for 2 h. The DMF was removed under reduced pressure, and the residue was partitioned between chloroform and water. The organic phase was separated and washed sequentially with water and brine, dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography using a 25 g Thomson normal phase silica gel cartridge (100% CHCl3→2:98 MeOH:CHCl3) to afford N,5-di(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (CXXXIV) (0.36 g, 0.90 mmol, 75% yield) as an off-white solid. 1H NMR (DMSO-d6) δ ppm 10.56 (s, 1H), 9.06 (d, J=2.4 Hz, 1H), 8.94 (d, J=2.3 Hz, 1H), 8.60 (dd, J=4.8, 1.5 Hz, 1H), 8.47 (d, J=1.1 Hz, 1H), 8.34-8.33 (m, 1H), 8.31-8.29 (m, 1H), 8.16-8.14 (m, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.90 (dd, J=8.8, 1.8 Hz, 1H), 7.54-7.52 (m, 1H), 7.43-7.41 (m, 1H), 7.43-7.41 (m, 1H), 6.08-6.06 (m, 1H), 4.01-3.99 (m, 1H), 3.87-3.82 (m, 1H), 2.64-2.57 (m, 1H), 2.11-2.06 (m, 2H), 1.84-1.80 (m, 1H), 1.69-1.65 (m, 2H); ESIMS found for C23H21N5O2 m/z 400 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:56]1[CH2:61][CH2:60][CH:59]([O:62][CH2:63][CH2:64][N:65]2[CH2:70][CH2:69][CH2:68][CH2:67]C2)[CH2:58][CH2:57]1>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:56]1[CH2:57][CH2:58][CH:59]([O:62][CH2:63][CH2:64][N:65]2[CH2:70][CH2:69][CH2:68][CH2:67]2)[CH2:60][CH2:61]1)=[O:5]
Reactant: C1CCN(CCOC2CCNCC2)CC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OCCN2CCCC2)CC1
Reaction time: 2 h
Yield: 89.5 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.20 g, 0.67 mmol) and HBTU (0.381 g, 1.01 mmol) were added to DMF (4 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and then 4-(2-(pyrrolidin-1-yl)ethoxy)piperidine (109) (0.133 g, 0.67 mmol). The reaction was stirred for 2 hours before being evaporated to dryness and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (0.287 g, 89% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.65-1.81 (6H, m), 1.87-1.96 (3H, m), 2.53-2.61 (3H, m), 2.65-2.72 (2H, m), 3.04-3.14 (1H, m), 3.38-3.57 (3H, m), 3.61 (2H, t), 3.97-4.06 (1H, m), 4.28 (2H, s), 7.01 (1H, t), 7.21-7.33 (2H, m), 7.68-7.80 (3H, m), 8.43-8.48 (1H, m), 9.85-9.95 (1H, m); m/z (LC-MS, ESI+), RT=1.88 (M+H 479.5).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:21]1[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=1)#[CH:20].C(N(CC)CC)C>O1CCCC1>[O:1]([C:8]1[N:9]=[CH:10][C:11]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=3)[O:17][N:16]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(Oc2ccccc2)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccccc4)nc3)no2)c(N)n1
Temperature: 50 °C
Reaction time: 1.08 h
Yield: 96.5 %

Procedure:
To a solution of (2-phenoxy-pyridin-5-yl)-acetohydroximoyl chloride (59.1 mg, 225 μmol) described in Manufacturing Example 40-1-4 and 3-ethynyl-pyridin-2,6-diamine (20.0 mg, 150 μmol) described in Manufacturing Example 13-1-3 in tetrahydrofuran (1.3 mL) was added triethylamine (41.8 μL, 300 μmol) at room temperature, which was stirred for 65 minutes at 50° C. The reaction solution was allowed to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (52 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([OH:11])[C:5]2=[C:4]([CH3:12])[CH:3]=1.[N:13]([C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)=[C:14]=[O:15]>C1COCC1.CN(C=O)C>[C@H:16]1([NH:13][C:14]([N:9]2[C:10](=[O:11])[C:5]3[C:6](=[N:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:12])[NH:8]2)=[O:15])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: O=C=N[C@@H]1CCc2ccccc21
Reactant: Cc1cc(Cl)nc2[nH]nc(O)c12
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc2[nH]n(C(=O)N[C@@H]3CCc4ccccc43)c(=O)c12

Procedure:
In analogy to example 1c, 200 mg (1.089 mmol) of 6-chloro-4-methyl-1H-pyrazolo-[3,4-b]pyridin-3-ol were reacted with 208.1 mg (1.2 mmol) of (R)-1-isocyanatoindane in THF/DMF at RT. Yield: 154 mg (41%), M+H+: 343.32.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][NH2:11]>O1CCOCC1>[Cl:8][C:7]1[C:2]([NH:10][NH2:11])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: NN
Reactant: Clc1cnc(Cl)c(Cl)c1
Solvent: C1COCCO1
Product: NNc1ncc(Cl)cc1Cl
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a 500 mL flask, 2,3,5-trichloropyridine (20.00 g, 0.110 mol), 80% hydrazine (34.30 g, 0.550 mol) and dioxane (200 mL) were added sequentially. The reaction mixture was heated to reflux for 20 hours. Then the reaction mixture was cooled down to room temperature overnight and white crystal was precipitated. The white crystal was isolated via filtration and dried to give the product (14.0 g) as a white solid in 72% yield. Melting point: 187-189° C. 1H NMR (300 MHz, DMSO-d6): 8.123 (d, 1H), 7.849 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH:15]([NH:17][NH2:18])=O>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]3[N:10]([CH:15]=[N:17][N:18]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(Br)cc2)nn1
Reactant: NNC=O
Solvent: CCCCO
Product: Brc1ccc(-c2ccc3nncn3n2)cc1

Procedure:
A mixture of 3.76 g. of 3-(p-bromophenyl)-6-chloropyridazine, 1.80 g of formylhydrazine and 50 ml. of butyl alcohol is heated to reflux and allowed to reflux overnight. The reaction mixture is allowed to cool and the precipitated product is washed with water, air dried and recrystallized from methyl alcohol, m.p. 209°-211° C.
Reaction SMILES: [Na+:1].[Na+].C([O:7][C:8]([CH:10]([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[C:11]([NH:13][CH:14]1[C:36](=[O:37])[N:16]2[C:17]([C:33]([O-:35])=[O:34])=[C:18]([CH:21]([S:27][C:28]3[NH:32][N:31]=[N:30][N:29]=3)[CH2:22][S:23]([OH:26])(=[O:25])=[O:24])[CH2:19][S:20][C@H:15]12)=[O:12])=[O:9])(C)(C)C.C([O:47][C:48]([CH:50]([C:78]1[S:79][CH:80]=[CH:81][CH:82]=1)[C:51]([NH:53][CH:54]1[C:76](=[O:77])[N:56]2[C:57]([C:73]([O-:75])=[O:74])=[C:58]([CH:61]([S:67][C:68]3[NH:72][N:71]=[N:70][N:69]=3)[CH2:62][S:63]([OH:66])(=[O:65])=[O:64])[CH2:59][S:60][C@H:55]12)=[O:52])=[O:49])(C)(C)C.FC(F)(F)C(O)=O.COC1C=CC=C(OC)C=1>>[Na+:1].[Na+:1].[Na+:1].[C:8]([CH:10]([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[C:11]([NH:13][CH:14]1[C:36](=[O:37])[N:16]2[C:17]([C:33]([O-:35])=[O:34])=[C:18]([CH:21]([S:27][C:28]3[NH:29][N:30]=[N:31][N:32]=3)[CH2:22][S:23]([OH:26])(=[O:25])=[O:24])[CH2:19][S:20][C@H:15]12)=[O:12])([OH:9])=[O:7].[C:48]([CH:50]([C:78]1[S:79][CH:80]=[CH:81][CH:82]=1)[C:51]([NH:53][CH:54]1[C:76](=[O:77])[N:56]2[C:57]([C:73]([O-:75])=[O:74])=[C:58]([CH:61]([S:67][C:68]3[NH:69][N:70]=[N:71][N:72]=3)[CH2:62][S:63]([OH:66])(=[O:65])=[O:64])[CH2:59][S:60][C@H:55]12)=[O:52])([OH:49])=[O:47].[C:8]([CH:10]([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[C:11]([NH:13][CH:14]1[C:36](=[O:37])[N:16]2[C:17]([C:33]([O-:35])=[O:34])=[C:18]([CH:21]([S:27][C:28]3[NH:29][N:30]=[N:31][N:32]=3)[CH2:22][S:23]([OH:26])(=[O:25])=[O:24])[CH2:19][S:20][C@H:15]12)=[O:12])([OH:9])=[O:7]
Reactant: CC(C)(C)OC(=O)C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C(CS(=O)(=O)O)Sc3nnn[nH]3)CS[C@H]12)c1cccs1
Agent: COc1cccc(OC)c1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C([O-])C1=C(C(CS(=O)(=O)O)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)C(C(=O)O)c3cccs3)C(=O)N12

Procedure:
7-(α-t-Butoxycarbonyl-2-thienylacetamido)-3-(1-sulfomethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid disodium salt (1.0 g.) is stirred in a mixture of 10 ml. of trifluoroacetic acid and 10 ml. of m-dimethoxybenzene at 25° for one hour. The mixture is evaporated to dryness and the residue is triturated with ether. The precipitated product is collected by filtration and dissolved in methanol. A sodium methoxide solution is added until pH 7.0, the mixture is diluted with ether and the product is dissolved in water and lyophilized to give 7-(α-carboxy-2-thienylacetamido)-3-(1-sulfomethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid trisodium salt.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:11][CH2:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([NH:8][C:9]([C:10]1[NH:11][C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]2[C:14]=1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18]2)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 36.1 g. of 1-benzyl-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one in 300 ml. of dimethylformamide is treated under an atmosphere of argon at room temperature with 0.11 mol. of sodium hydride (4.8 g of a 55% dispersion in mineral oil). The mixture is first heated to 60° C. over a period of about 30 minutes, and then stirred for 1 hour at this temperature for an additional 1 hour at 70° C. After cooling, 10 ml. of water are added dropwise and the mixture is poured into 3 liters of ice-water. After the addition of 100 g. of sodium chloride, the separated product is extracted with methylene chloride. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The resulting oily residue is chromatographed on 1000 g. of silica gel with methylene chloride/ethyl acetate (4:1) as the eluant. The homogeneous fractions are combined, evaporated and triturated with a small amount of ether, and there is obtained 5-chloro-3-phenylisoindole-1-carboxylic acid benzylamide in the form of fibrous, greenish crystals; melting point 202°-204° C. (decomposition). Recrystallization from chloroform does not increase the melting point.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:18][CH3:19])[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:7]=1.C=O.[BH3-][C:23]#N.[Na+].C(O)(=O)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:18]([CH3:23])[CH3:19])[CH:5]=[C:6]([S:8][C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: CNc1cc(Br)cc(Sc2ccc([N+](=O)[O-])cc2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(C)c1cc(Br)cc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
0.34 g (0.001 mol) of [3-bromo-5-(4-nitrophenylsulphanyl)-phenyl]-methylamine was dissolved in 10 ml of acetonitrile, treated with 1.52 ml (0.020 mol) of formaldehyde, 0.74 g (0.010 mol) of NaBH3CN and 1.76 ml of acetic acid and stirred at room temperature for 1 hr. Thereafter, the solvent was removed, the residue was partitioned in ethyl acetate/water and the organic phase was washed with sat. sodium chloride solution, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:19. There was obtained 0.35 g (99%) of [3-bromo-5-(4-nitro-phenylsulphanyl)-phenyl]-dimethylamine as yellow crystals; m.p.: 102-104° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([O:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:7][CH:8]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([O:16][CH:17]([CH3:18])[CH3:19])[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1)=[O:30]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(Cc1cccc(CO)c1)OC(C)C
Product: CC(C)OC(Cc1cccc(COC(=O)Nc2ccc(Cl)cc2Cl)c1)C(=O)O

Procedure:
Using ethyl 3-[3-(hydroxymethyl)phenyl]-2-isopropoxypropanoate and 2,4-dichlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[C:22]([C:24]2[C:29]([I:30])=[C:28]([N:31]([CH3:35])[C:32](=[O:34])[CH3:33])[C:27]([I:36])=[C:26]([N:37]([CH3:41])[C:38](=[O:40])[CH3:39])[C:25]=2[I:42])[CH:21]=[C:20]([N+:43]([O-])=O)[C:5]=1[C:6]([C:8]1([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[NH2:11])[OH:9])=[O:7])([O-])=O.[H][H]>[Pd]>[NH2:43][C:20]1[CH:21]=[C:22]([C:24]2[C:25]([I:42])=[C:26]([N:37]([CH3:41])[C:38](=[O:40])[CH3:39])[C:27]([I:36])=[C:28]([N:31]([CH3:35])[C:32](=[O:34])[CH3:33])[C:29]=2[I:30])[CH:23]=[C:4]([NH2:1])[C:5]=1[C:6]([C:8]1([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[NH2:11])[OH:9])=[O:7]
Reactant: [H][H]
Reactant: CC(=O)N(C)c1c(I)c(-c2cc([N+](=O)[O-])c(C(=O)C3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3N)c([N+](=O)[O-])c2)c(I)c(N(C)C(C)=O)c1I
Agent: [Pd]
Product: CC(=O)N(C)c1c(I)c(-c2cc(N)c(C(=O)C3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3N)c(N)c2)c(I)c(N(C)C(C)=O)c1I

Procedure:
2,6-dinitro-4-[3′,5′-bis(N-methylacetamido)-2′,4′,6′-triiodophenyl]-benzoyl-D-glucosamine (15) is catalytically reduced by hydrogen in the presence of palladium on charcoal to yield 2,6-diamino-4-[3′,5′-bis(N-methylacetamido)-2′,4′,6′-triiodophenyl]-benzoyl-D-glucosamine (16).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=3)[O:22][C:21]([CH3:31])([CH3:30])[CH:20]=2)=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([NH:29][S:8]([CH3:7])(=[O:10])=[O:9])=[CH:26][CH:27]=3)[O:22][C:21]([CH3:31])([CH3:30])[CH:20]=2)=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)C=C(c2ccc(F)cc2)c2ccc(N)cc2O1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1(C)C=C(c2ccc(F)cc2)c2ccc(NS(C)(=O)=O)cc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under ice-cooling, pyridine (90 μL) and methanesulfonyl chloride (60 μL) were added dropwise to a solution of [4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen-7-yl]amine (a compound of Reference Example 5(5), 100 mg) in chloroform (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel, Solvent: chloroform/methanol=100/0 to 90/10) to give the titled compound (123 mg) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12]1>>[NH2:1][C:2]1[CH:9]=[C:8]([NH:16][CH:13]2[CH2:14][CH2:15][O:11][CH2:12]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: NC1CCOC1
Reactant: N#Cc1cnc(N)cc1F
Product: N#Cc1cnc(N)cc1NC1CCOC1

Procedure:
From intermediate 21 and racemic tetrahydrofuran-3-amine, reacted in an analogous manner to the preparation of intermediate 49. (UPLC-MS 3) tR 0.32 min; ESI-MS 205.1 [M+H]+.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[Cl:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.ClCCl>O1CCOCC1>[Cl:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH2:15][CH2:14]1
Reactant: ClCCCN1CCNCC1
Reactant: O=C1CCCC(=O)O1
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)CCCC(=O)N1CCN(CCCCl)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
1.5 g of glutaric anhydride and then 2.13 g of N-(chloropropyl)piperazine in solution in 5 cm3 of dioxane and 1 cm3 of dichloromethane are added to 15 cm3 of dioxane in a round-bottomed flask kept under an argon atmosphere. After stirring for 2 hours at 20° C., the solvent is evaporated under reduced pressure (2.7 kPa) at 20° C., to give 3.75 g of 5-[4-(3-chloropropyl)piperazin-1-yl]-5-oxopentanoic acid in the form of a yellow oil which is used as it is.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[CH2:24][C@H:13]23)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: Nc1cc(C(=O)O)ccc1F
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1cc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)ccc1F
Yield: 68 %

Procedure:
The title compound is prepared from 3-amino-4-fluoro-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 68% of theory; LC (method 4): tR=1.91 min; Mass spectrum (ESI+): m/z=311 [M+H]+.
Reaction SMILES: C([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:48])([F:47])[C:32]([F:46])([F:45])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)CCCCCCC.[CH2:49]([O:56]C1C=NC(C2C=CC(O)=CC=2)=NC=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>CN(C)C=O>[CH2:49]([O:56][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:47])([F:48])[C:32]([F:45])([F:46])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:38])[F:39])([F:29])[F:28])=[CH:19][CH:20]=2)=[N:13][CH:14]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Solvent: CN(C)C=O
Product: CCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-chloropropane (5.5 g, 15.0 mmol, Example 24) with 5-heptyloxy-2-(4-hydroxyphenyl)pyrimidine (3 g, 10.5 mmol) in dimethylformamide and stirring at 120° C. overnight to provide product boiling at 195-210° C. at 0.3 torr (yield of 5.6 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[OH-].[Na+].CN([CH:29]=[O:30])C>>[F:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:29]=[O:30])=[CH:12][NH:13]2)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2cc3cc[nH]c3cc2F)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3c(C=O)c[nH]c3cc2F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
Phosphorous oxychloride (185.0 mg, 1.20 mmol) was added to DMF (2 mL) at 0° C. and the reaction mixture was stirred for 15 minutes. To this solution was added 6-fluoro-5-(4-methoxy-phenyl)-1H-indole (147.0 mg, 0.61 mmol) in DMF (2 mL) and the reaction mixture was stirred at 95° C. for 20 minutes. The reaction mixture was cooled to room temperature, treated with 1 N aqueous NaOH (3 mL) and heated to 100° C. for 1 minute. The reaction mixture was cooled to room temperature and filtered. The collected solids were air dried to give the title compound (106 mg, 65% yield). MS (ES+) 270.2 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[N:17]4)[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:31]([C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][CH:34]=1)[CH3:32]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[N:17]4)[N:12]([CH:31]([C:33]3[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])=[CH:35][CH:34]=3)[CH3:32])[N:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Clc1cc(Cl)cc(-c2cc(-c3ccc4nccnc4c3)n[nH]2)c1
Reactant: CC(Br)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccc(C(=O)OC(C)(C)C)cc1)n1nc(-c2cc(Cl)cc(Cl)c2)cc1-c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the intermediate from step E (330 mg, 0.97 mmol) in 8 mL of anhydrous DMF was added Cs2CO3 (473 mg, 1.45 mmol) followed by tert-butyl 4-(1-bromoethyl)benzoate (331 mg, 1.16 mmol). The reaction was stirred at room temperature overnight and then diluted with water. The aqueous layer was then extracted with EtOAc (3×) and the combined organic layers were then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting oil was purified by flash chromatography (20% EtOAc/Hexanes) to give the product as a yellow oil. 1H NMR (CDCl3, 500 MHz): 1.60 (s, 9H), 2.02 (d, J=7.1 Hz, 3H), 5.67 (q, J=7.1 Hz, 1H), 6.78 (s, 1H), 7.26 (d, J=8.2 Hz, 2H), 7.34 (t, J=1.8 Hz, 1H), 7.68 (dd, J=8.7, 1.9 Hz, 1H), 7.83 (d, J=1.8, 2H), 7.95 (d, J=8.2 Hz, 2H), 8.10 (d, J=1.9, 1H), 8.18 (d, J=8.7, 1H), 8.94 (s, 2H). LC-MS: 4.74, 4.89 min. (M+H)=546.46.