Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][CH2:5][CH:6]([OH:31])[CH2:7][NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:18][C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[N:20]=2)=[CH:13][CH:12]=1.[N:37]([O-])=O.[Na+]>C(O)(=O)C.O>[NH:36]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:3]([O:4][CH2:5][C@@H:6]([OH:31])[CH2:7][NH:8][CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([S:17][CH2:18][C:19]4[O:23][N:22]=[C:21]([C:24]5[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=5)[N:20]=4)=[CH:13][CH:12]=3)[C:2]=2[N:1]=[N:37]1
Reactant: Cc1ccc(-c2noc(CSc3ccc(CCNCC(O)COc4cccc(N)c4N)cc3)n2)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-c2noc(CSc3ccc(CCNC[C@H](O)COc4cccc5[nH]nnc45)cc3)n2)cc1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a solution of 1-(2,3-diaminophenoxy)-3-[[2-[4-[[[3-(4-methylphenyl)-1,2,4-oxadiazol-5-yl]methyl]thio]phenyl]ethyl]amino]-2-propanol (0.077 g, 0.172 mmol.) in acetic acid (1.2 mL) at 5° C. was added a solution of sodium nitrite (0.013 g, 0.189 mmol) in water (0.5 mL). The mixture was stirred for 30 minutes and evaporated to dryness. The residue was purified by flash chromatography (silica gel; CH2Cl2/MeOH (3/1) to afford 0.079 g of the pure title compound. MP=110° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]2[CH2:19][CH:18]=[CH:17][CH2:16][O:15]2)[CH2:11][O:10]C1(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:12]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH2:11][OH:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CC=CCO2)COC1(C)C
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To the a solution of (S)-4-(3,6-dihydro-2H-pyran-2-ylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester (1.15 g, 3.8 mmol) in tetrahydrofuran (2 mL) was added methanol (15 mL) and p-toluene sulfonic acid monohydrate (40 mg). The mixture was stirred at room temperature overnight. Solvents were evaporated and the residue was extracted with ethyl acetate and sodium bicarbonate solution. The organic layer was washed with saturated sodium chloride solution and dried over sodium sulfate. After the evaporation of solvent, an oil was obtained (1.03 g). This oil (1.0 g) was dissolved in ethanol (25 mL) and 5% palladium on carbon (200 mg) was added. The mixture was hydrogenated at 50 psi for 45 min. The resulting mixture was filtered and solvents were evaporated to afford [(S)-2-hydroxy-1-(tetrahydro-pyran-2-ylmethyl)-ethyl]-carbamic acid t-butyl ester (948 mg) as an oil. 1H NMR (300 MHz, CDCl3) δ ppm 1.45 (s, 9H), 1.47-1.74 (m, 6H), 1.74-1.94 (m, 2H), 3.30-3.51 (m, 2H), 3.62 (br. s., 2H), 3.69-3.85 (m, 2H), 3.98 (d, J=10.9 Hz, 1H), 5.25 (br. s., 1H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:16][C:12]1([CH3:17])[CH2:13][CH2:14][CH2:15][N:10]([C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([N:29]3[CH2:28][CH2:27][N:26]([C:23]4[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=4)[CH2:31][CH2:30]3)[N:7]=2)=[O:9])[CH2:11]1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CC1(C)CCCN(C(=O)c2cccc(Br)n2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1ccc(N2CCN(c3cccc(C(=O)N4CCCC(C)(C)C4)n3)CC2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
(6-bromopyridin-2-yl)(3,3-dimethylpiperidin-1-yl)methanone (40 mg, 0.135 mmol), 1-(4-methoxyphenyl)piperazine (29 mg, 0.149 mmol), Pd2(dba)3 (2.5 mg, 0.00273 mmol), xantphos (4.7 mg, 0.00812 mmol), and sodium-tert-butoxide (19.0 mg, 0.198 mmol) were suspended in toluene (2 ml), and then stirred at 100° C. under nitrogen stream for 2 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (50% EtOAc/Hexanes), to obtain 47 mg of pale yellow solid (85%). MS (ESI): 409 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([CH3:17])[CH2:10][CH:11](O)[CH2:12][C:13](=[O:15])[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([CH3:17])[CH2:10][CH:11]=[CH:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)CC(O)CC(C)Sc1ccccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=CCC(C)Sc1ccccc1F
Yield: 73.1 %

Procedure:
1.00 Gram of 6-(2-fluorophenylthio)-4-hydroxy- 2-heptanone was dissolved in 100 ml of toluene, and 0.02 g of p-toluene sulfonic acid was added thereto. The resulting mixture was refluxed for 2 hours with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 0.84 g of 6-(2-fluorophenylthio)-3-hepten-2-one. (trans : cis =5.1 : 1) (purity: 80.6%). The yield was 73.1%.
Reaction SMILES: [O-:1][P:2]([O:5][P:6]([O:9][P:10]([O-:13])([O-:12])=[O:11])([O-:8])=[O:7])([O-:4])=[O:3].[Na+].[Na+].[Na+].[Na+].[Na+].O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Zn+2:31].O.O.O.[CH2:35]([N:37]([CH2:41][CH3:42])[C:38](=[S:40])[S-:39])[CH3:36].[Na+]>>[CH2:35]([N:37]([CH2:41][CH3:42])[C:38](=[S:39])[S-:40])[CH3:36].[Zn+:31].[O-:13][P:10]([O:9][P:6]([O:5][P:2]([O-:4])([O-:3])=[O:1])([O-:8])=[O:7])(=[O:11])[O-:12]
Reactant: [Zn+2]
Agent: CCN(CC)C(=S)[S-]
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: [Zn+]

Procedure:
18 g/100 ml of sodium tripolyphosphate was slowly poured into a 57.8 g/300 ml aqueous solution of zinc sulfate heptahydrate while stirring to prepare a suspension of a zinc tripolyphosphate crystalline precipitate. 45.3 g/200 ml of sodium N,N-diethyldithiocarbamate trihydrate was then slowly poured into the suspension, while stirring, to give a crystalline precipitate of zinc mono-(N,N-diethyldithiocarbamate)-triphosphate (hereunder, “G”).
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH3:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[N:12]=[CH:11][C:10]=1[C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[C:31]([CH3:33])[CH:32]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CN(C)C=O.O>[CH3:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][N:15]=2)[N:12]=[CH:11][C:10]=1[C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([CH:34]2[CH2:35][CH2:36][N:37]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[CH2:38][CH2:39]2)=[C:31]([CH3:33])[CH:32]=1)=[O:25]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCNCC1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCN(S(=O)(=O)C(C)C)CC1
Temperature: 25 °C

Procedure:
Isopropylsulfonyl chloride (72 μl) was added to a suspension of 5-methyl-N-[5-methyl-6-(piperidin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (222 mg) described in Reference Example 171 and potassium carbonate (138 mg) in N,N-dimethylformamide (1.7 ml) and stirred at room temperature for an hour. Then, isopropylsulfonyl chloride (36 μl) was added and stirred at room temperature for two hours. Triethylamine (350 μl) and water were added and the precipitated solid was washed with ethanol and water. The resulting solid was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (103 mg) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:14])[C@@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:5].NC[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C.C(=O)(O)[O-].[Na+].[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40](Cl)(=[O:42])=[O:41]>ClCCl.O>[OH:14][C@@H:3]([CH2:2][NH:1][S:40]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=1)(=[O:42])=[O:41])[C@@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH3:5]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN
Agent: C[C@H](NC(=O)OC(C)(C)C)[C@H](O)CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Temperature: 0 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
To a solution of 3.06 g (15.0 mmol) of tert-butyl (1S,2S)-3-amino-2-hydroxy-1-methylpropylcarbamate & tert-butyl (1S,2R)-3-amino-2-hydroxy-1-methylpropylcarbamate in 100 mL of dichloromethane was added 3.78 g (45.0 mmol) of sodium bicarbonate and 50 mL of water. The reaction mixture was cooled to 0° C. and 16.5 mL (16.5 mmol) of a 1.0 M solution of 2-pyridinesulfonyl chloride in dichloromethane was added gradually over 20 min. The reaction mixture was stirred at room temperature for 16 h. The layers were then separated and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under vacuum to afford the crude product. This product was purified via silica gel chromatography eluting with ethyl acetate:hexane (8:2) to afford 2.0 g (34%) of tert-butyl (1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate & tert-butyl (1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate as a pale yellow oil. 1H-NMR (300 MHz, CDCl3): δ 8.72 (m, 1H), 8.07–7.92 (m, 2H), 7.51 (m, 1H), 6.25, 6.08 (2br s, 1H), 4.83-4.64 (m, 2H), 3.74–3.47 (m, 3H), 3.27–3.19 (m, 1H), 1.23, 1.22 (2s, 9H), 1.12 (m, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:12](OCC)=[O:13])[CH:11]=[C:6]2[C:5]([CH3:17])=[N:4]1)[CH3:2].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:29]>O>[ClH:29].[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=[C:6]2[C:5]([CH3:17])=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1cnc2c(c1)c(C)nn2CC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1nc(C)c2cc(CO)cnc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
49 g. of 1-Ethyl-3-methyl-1H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid, ethyl ester (0.21 mol.) are dissolved in 250 ml. of anhydrous tetrahydrofuran. Nitrogen is passed through the flask and, while stirring and cooling with tap water, 6 g. of lithium aluminum hydride (0.16 mol.) are added in small portions keeping the reaction temperature at 20°. Stirring is continued for an additional three hours at room temperature. Then 3 N-hydrochloric acid (380 ml.) is added, while cooling the flask with ice water, and the cloudy solution is evaporated in vacuo. The residue is dissolved in 95 ml. of hot water and the solution is allowed to stand over the week-end. The crystallized product (8 g. m.p. 207°-208°) is discarded. The aqueous mother liquor is extracted with three 100 ml. portions of chloroform. The combined chloroform extracts are dried with sodium sulfate and evaporated in vacuo. The resulting oily-crystalline mass is sucked off, washed with acetonitrile and dried at 70°, yield: 10 g. (21%) of 1-ethyl-3-methyl-1H-pyrazolo-[3,4-b]pyridine-5-methanol, hydrochloride (1:1); m.p. 169°-170°. A sample recrystallized from acetonitrile melts at 170°-171°.
Reaction SMILES: N[C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6](/[CH:14]=[C:15]1/[C:16](=[O:24])[N:17]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH2:18][CH2:19]/1)=[C:7]2[C:11]([OH:13])=[O:12].C(N(CC)CC)C.O.Cl>CN(C)C=O>[CH:21]1([CH2:20][N:17]2[CH2:18][CH2:19]/[C:15](=[CH:14]\[C:6]3[CH2:5][S:4][CH:3]4[N:8]([C:9](=[O:10])[CH2:2]4)[C:7]=3[C:11]([OH:13])=[O:12])/[C:16]2=[O:24])[CH2:23][CH2:22]1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)C1=C(/C=C2\CCN(CC3CC3)C2=O)CSC2CC(=O)N12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere to a stirred suspension of 25.6 g (E)-(6R,7R)-7-Amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (73.3 mmol) in 120 ml dimethylformamide was added 20 ml triethylamine (143 mmol) at 10° C. After 15 min, the solution was cooled to 0° C. and 28.5 g (Z)-(2-aminothiazol-4-yl)-acetoxyiminoacetic acid diethoxy thiophosphonyl ester (74.8 mmol) was added in portions over 5 min. Stirring was continued at 0° C. with exclusion of light for 5 h. The reaction was followed by HPLC. The brown reaction mixture was poured at once into 550 ml water of 10° C. Over 30 min, 50 ml HCl 1N was added. The pH dropped from 4.6 to 3.2 and the product precipitated from the reaction mixture. Stirring was continued for 1 h at 0° C. The suspension was filtered. The product was washed with ice-cold water, re-suspended in water, stirred for 20 min at room temperature, filtered and again washed with water. (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-acetoxyimino-acetylamino)]-3-[(E)-1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was obtained as a beige, wet solid. The product was used immediately and without drying for the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:45]=[CH:44][C:9]([CH2:10][C@H:11]([NH:32][C:33](=[O:43])[O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)[C@H:12]([OH:31])[CH2:13][N:14]([S:19]([C:22]2[CH:30]=[CH:29][C:25]3[O:26][CH2:27][O:28][C:24]=3[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:8][CH:7]=1.Cl[C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][N:48]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([S:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:13][C@@H:12]([OH:31])[C@@H:11]([NH:32][C:33](=[O:43])[O:34][C@@H:35]3[C@H:42]4[C@H:38]([O:39][CH2:40][CH2:41]4)[O:37][CH2:36]3)[CH2:10][C:9]3[CH:44]=[CH:45][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:47]4[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][N:48]=4)=[CH:7][CH:8]=3)(=[O:21])=[O:20])=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCN)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCNc2ccc(C#N)cn2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution of 35 mg (0.054 mmol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-[4-(3-aminopropoxy)benzyl]3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxypropylcarbamate, 22 mg (0.16 mmol) of 2-chloro-5-cyanopyridine, and 38 μL (0.22 mmol) of N,N-diisopropylethylamine in 0.5 mL of anhydrous DMF was heated to 80° C. with stirring. After 6 hours the solution was cooled to RT and concentrated to dryness in vacuo. The residue was purified by flash chromatography (SiO2, 95:5 CH2Cl2/MeOH) to afford 33 mg (80%) of the desired compound as a white foam. 1H NMR (CDCl3): 8.30 (s, 1H), 7.50 (d, 1H), 7.29 (d, 1H), 7.13 (s, 1H), 7.09 (d, 2H), 6.84 (d, 1H), 6.78 (d, 2H), 6.37 (d, 1H), 6.04 (s, 2H), 5.62 (d, 1H), 5.44 (br s, 1H), 4.96 (m, 2H), 4.00 (t, 2H), 3.91 (m, 1H), 3.80 (m, 3H), 3.71-3.49 (m, 5H), 3.18-2.65 (m, 7H), 2.08 (m, 2H), 1.80 (m, 1H), 1.61 (m, 1H), 1.50 (m, 1H), 0.90 (d, 3H), 0.81 (d, 3H). MS(ESI): 752(M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[I:11]Cl>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6]
Reactant: ClI
Reactant: O=C(O)c1cccc(O)c1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(I)c(O)c1
Temperature: 45 °C
Reaction time: 15 h

Procedure:
30.0 g (217 mmol) of 3-hydroxybenzoic acid was dissolved in 200 ml of acetic acid. 53.0 g (326 mmol) of iodine monochloride was added to the solution at room temperature. After stirring at 45° C. for 15 hours, the solvent was evaporated under reduced pressure. The residue was washed with 500 ml of 1% aqueous sodium thiosulfate solution twice and then with 500 ml of water twice, and dried to solid at 80° C. under reduced pressure to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:23]O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:25]=1.C(O)C.O>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:15]([NH2:23])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:25]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2ccc(Cl)cc2[nH]1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: NC1c2ccccc2-c2c(-c3nc4ccc(Cl)cc4[nH]3)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
Stir, at room temperature, a mixture of 345 mg of 4-(6-chloro-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z, E) in a mixture of 2 ml of acetic acid, 2 ml of ethanol and 2 ml of water in the presence of 65 mg of powdered zinc. After 1 hour and 3 hours, add, each time, a further 65 mg of powdered zinc and maintain the stirring for approximately 4 hours. Add Celite, filter over sintered glass and wash the precipitate with 200 ml of a mixture of methanol and dichloromethane (20/80 by volume). The filtrate is evaporated to dryness under vacuum, add twice 50 ml of toluene and re-evaporate, each time, to dryness under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of dichloromethane-7N solution of ammonia in methanol (90/10 by volume). In this way, we obtain 275 mg of 4-(6-chloro-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)-amine in the form of a beige foam with the following characteristics:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:28](=S)[NH:29][N:30]=1)C1C=CC=CC=1.C(Cl)Cl.B(Cl)(Cl)Cl.C(=O)([O-])[OH:46].[Na+]>CO>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[C:28](=[O:46])[NH:29][N:30]=1
Reactant: CC(C)c1cc(-c2n[nH]c(=S)n2N2CCCCC2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=C([O-])O
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1cc(-c2n[nH]c(=O)n2N2CCCCC2)c(O)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
5-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-4-piperidin-1-yl-2,4-dihydro-[1,2,4]triazol-3-thione (F67-05: 92 mg, 0.18 mmol), methylene chloride (2 mL) and a methylene chloride solution of boron trichloride (1 mol/L, 1 mL) were placed in a test tube and stirred at room temperature for 1 hour. After completing the reaction, methanol and sodium hydrogencarbonate were added to the reaction mixture and solids were separated by filtration. The mother liquor thus obtained was concentrated under reduced pressure and the residue was purified by HPLC fractionation to obtain the title compound (OH-a24 trifluoroacetate, 9.5 mg, 16.6%).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([S:21]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.8 %

Procedure:
A solution of triethylamine (0.27 mL, 1.94 mmol) and morpholine (0.085 mL, 0.97 mmol) in dry dichloromethane (2 mL) was added to a stirred suspension of 6-chloropyridine-3-sulfonyl chloride (0.204 g, 0.96 mmol; described in: Naegeli, C. et al. Helv. Chim. Acta. 1938, 21, 1746-1750) in dry dichloromethane (1 mL). The resulting clear solution was stirred at room temperature for 20 min. The solvent was evaporated and the residue was purified on a silica gel column using dichloromethane/methanol, (97:3), as the eluent to give 0.176 g (70% yield) of the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 8.75 (dd, J=3, 1 Hz, 1H), 8.18 (dd, J=8, 3 Hz, 1H), 7.82 (dd, J=8, 1 Hz, 1H), 3.63 (m, 4H), 2.96 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[S:25][CH:26]=[CH:27][N:28]=4)=[O:22])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:29]([OH:31])=[O:30].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH3:51][O:52][CH2:53][CH2:54]N>CN(C)C=O.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23][C:24]4[S:25][CH:26]=[CH:27][N:28]=4)=[O:22])=[CH:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:29]([O:31][CH2:54][CH2:53][O:52][CH3:51])=[O:30]
Reactant: COCCN
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nccs4)cc3)c2cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4nccs4)cc3)ccnc2cc1OC
Yield: 24.5 %

Procedure:
After dissolving 7-methoxy-4-(4-(((1,3-thiazol-2-ylamino) carbonyl)amino) phenoxy)-6-quinolinecarboxylic acid (87.3 mg, 0.20 mmol) in dimethylformamide (1 ml), there were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.30 mmol), 1-hydroxy-1H-benzotriazolemonohydrate (41 mg, 0.30 mmol), triethylamine (0.084 ml, 0.60 mmol) and 2-methoxyethylamine (0.052 ml, 0.60 mmol) while stirring on ice, and the mixture was stirred at room temperature for 5 hours. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, ethyl acetate and then hexane was added to precipitate crystals, which were filtered out and dried under reduced pressure to obtain the title compound (24.4 mg, 0.049 mmol 24.7%) as white crystals.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC(OC)=CC=3)C=2N=1)(C)(C)C.[C:29]([C:33]1[N:34]=[C:35](Cl)[C:36]2[N:41]=[N:40][N:39]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[C:37]=2[N:38]=1)([CH3:32])([CH3:31])[CH3:30].Cl.[F:53][C:54]1([F:59])[CH2:58][CH2:57][NH:56][CH2:55]1>>[C:29]([C:33]1[N:34]=[C:35]([N:56]2[CH2:57][CH2:58][C:54]([F:59])([F:53])[CH2:55]2)[C:36]2[N:41]=[N:40][N:39]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[C:37]=2[N:38]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: FC1(F)CCNC1
Reactant: COc1ccc(Cn2nnc3c(Cl)nc(C(C)(C)C)nc32)cc1
Agent: COc1ccc(Cn2nnc3c(N4CCOCC4)nc(C(C)(C)C)nc32)cc1
Agent: Cl
Product: COc1ccc(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of 4-(5-tert-butyl-3-(4-methoxy benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)morpholine (example 58, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo [4,5-d]pyrimidine and 3,3-difluoropyrrolidine hydrochloride and isolated as white solid (271 mg, 83%). MS (m/e): 403.4 (MH+).