Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][C:13]2[C:12]3[C:7](=[C:8](Br)[CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[CH2:4][CH2:3]1.C(#N)C.[CH3:25][CH2:26][CH2:27]CCCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][CH:2]1[CH2:14][C:13]2[C:12]3[C:7](=[C:8]([CH2:27][CH:26]=[CH2:25])[CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]=2[CH2:4][CH2:3]1
Reactant: CCCCCCC
Reactant: CCOC(=O)Cn1c2c(c3cccc(Br)c31)CC(N)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=CCc1cccc2c3c(n(CC(=O)OCC)c12)CCC(N)C3
Temperature: 25 °C

Procedure:
To a stirred and degassed solution of an appropriately protected ethyl (3-amino-8-bromo-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 2c (0.2 mmol) and Pd(PPh3)4 (0.02 mmol, 0.1 eq.) in dry DMF (1.5 ml) is added under inert atmosphere the appropriate tetraC1-5-alkyltin or allyltrialkyltin, respectively (0.22 mmol, 1.1 eq.). The reaction mixture is allowed to stir overnight at 110° C. After cooling to rt, acetonitrile (1 ml) and heptane (1 ml) are added. The acetonitrile-DMF phase is washed three times with heptane. Water is then added and the resulting aq. phase is extracted twice with AcOEt. The combined org. phases are washed with brine and dried over Na2SO4. Evaporation of the solvent in vaccuo yields the protected ethyl (3-amino-8-C1-5-alkyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative or ethyl (3-amino-8-allyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](I)=[C:9]([NH2:12])[N:8]=[C:7]([Cl:13])[N:6]=1)=[O:4].[CH:14]([Sn](CCCC)(CCCC)CCCC)=[CH2:15]>ClCCCl.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>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:14]=[CH2:15])=[C:9]([NH2:12])[N:8]=[C:7]([Cl:13])[N:6]=1)=[O:4]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(Cl)nc(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=Cc1c(N)nc(Cl)nc1C(=O)OC
Yield: 65.8 %

Procedure:
6-Amino-2-chloro-5-iodopyrimidine-4-carboxylic acid methyl ester (10 g, 32 mmol) was dissolved in 1,2-dichloroethane (100 mL), treated with vinyltributylstannane (11.6 mL, 12.6 g, 40 mmol) and sparged with a nitrogen stream for 10 min. Bis(triphenylphosphine)palladium(II) dichloride (1.1 g, 1.6 mmol, 5 mole %) was added and the mixture was heated at reflux under a nitrogen atmosphere for 3 h. The mixture was cooled, stirred with 10% aqueous KHF2 for 30 min, and filtered through diatomaceous earth to remove solids. The filter cake was washed with more 1,2-dichloroethane and ethyl acetate. The combined filtrates were washed with water, washed with saturated NaHCO3, washed with brine, dried, and evaporated. The crude material was chromatographed on silica (5-20% ethyl acetate/dichloromethane containing 2% acetic acid) to give the title compound (4.5 g, 70% yield). This material contained approximately 5% PPh3, but was used without further purification. MS: m/z=213. 1H NMR(CDCl3) δ 6.77(dd, 1H), 6.4(br, 2H), 5.70(d, 1H), 5.61(d, 1H).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)=O.[Na].[C:13]([NH:21][OH:22])([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:14]>>[C:13]([N+:21]([O-:22])=[CH:1][C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:14]
Reactant: CC(C)(C)CC(C)(C)NO
Reactant: O=Cc1ccc(S(=O)(=O)O)o1
Agent: [Na]
Product: CC(C)(C)CC(C)(C)[N+]([O-])=Cc1ccc(S(=O)(=O)O)o1
Yield: 98 %

Procedure:
Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-tert-octylhydroxylamine, the title compound was prepared in 98% yield as the sodium salt, m.p. 216.9° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.Br[C:36]1[CH:37]=[CH:38][C:39]([OH:50])=[C:40]([C:42]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:43])[CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.ClCCl>[OH:50][C:39]1[CH:38]=[CH:37][C:36]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[C:12]3=[N:13][CH:14]=2)=[CH:41][C:40]=1[C:42]([N:44]1[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1)=[O:43]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C(c1cc(Br)ccc1O)N1CCOCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(O)c(C(=O)N4CCOCC4)c3)cc12
Yield: 30 %

Procedure:
A mixture of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.21 mmol), (5-bromo-2-hydroxy-phenyl)-morpholin-4-yl-methanone (66 mg (0.23 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (9 mg, 11 μmol) in acetonitrile (2 mL) and aqueous solution of sodium carbonate (2M, 2 mL) was irradiated in a Personal Chemistry Optimizer at 135° C. for 20 min. The crude reaction mixture was distributed between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The aqueous phase was then extracted with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was then purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford {2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-morpholin-4-yl-methanone (35 mg, 30% yield) as a colorless solid. 1H-NMR (500 MHz, d6-DMSO) δ8.86 (d, 1H), 8.27 (d, 1H), 7.64 (dd, 1H), 7.62 (dd, 1H), 7.54 (d, 1H), 7.49 (ddd, 1H), 7.24 (d,br, 1H), 7.11 (ddd, 1H), 7.00 (d, 1H), 5.84 (s, 2H), 3.84 (s, 3H), 3.69 (t, 2H), 3.7-3.2 (m, 8H), 0.86 (t, 2H), −0.08 (s, 9H). MS: m/z 583 [MNa+], 561 [MH+], 443 [MH+-(Me3Si(CH2)2O)]
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].CS([C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][N:26]=1)(=O)=O.O>C1COCC1>[CH3:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([O:14][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)=[N:26][CH:27]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc(Oc3ccccc3)cc2)nc1
Yield: 88 %

Procedure:
To 4.75 g of 4-phenoxyphenol dissolved in a 20 ml THF/20 ml DMSO mixture was added 2.9 g of t-BuOK and then 6.0 g of 2,5-bis(methylsulfonyl)pyridine, and the resulting mixture heated at 58° C. for 11/2 hrs. The reaction mixture was cooled overnight and then poured into 200 ml of water and stirred. A pink-white solid precipitated which was recovered and then dried on a porous plate. Recrystallization and ethanol/CH2Cl2 gave purified 5-(methylsulfonyl)-2-(4-phenoxyphenoxy)pyridine, (88% yield), as slightly pink shiny plates, m.p. 136.5°-138° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[Br:30]Br.C(#N)C>C(Cl)(Cl)Cl>[Br:30][C:29]1[C:9]2[C:10](=[N:11][C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[NH:27][N:28]=1
Reactant: BrBr
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2nc3[nH]nc(Br)c3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.3 %

Procedure:
To a suspension of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (1.00 g, 2.6 mmol, obtained in example 1) in CHCl3 (10 mL), a solution of Br2 (0.69 g, 4.3 mmol) in CHCl3 (3 mL) was added under argon atmosphere. Acetonitrile (4 mL) was added and the mixture was stirred at room temperature for 2 days. The residue was concentrated, dissolved in CHCl3 and washed with 1 N NaOH. A precipitate was formed, which was filtered and dissolved with MeOH. The solution was concentrated and washed with 1 N NaOH. It was extracted with EtOAc, dried over Na2SO4 and concentrated. This was treated with diethyl ether, the solvent was decanted and the product obtained was dried to afford 1.16 g of the title compound (yield: 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:13]1[N:14]=[C:15]([Cl:22])[C:16]2[CH:21]=[CH:20][NH:19][C:17]=2[N:18]=1.[OH-].[Na+]>CC(C)=O>[Cl:22][C:15]1[C:16]2[CH:21]=[CH:20][N:19]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[C:17]=2[N:18]=[CH:13][N:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.9 %

Procedure:
4-Methylbenzene-1-sulfonyl chloride (3.7 g, 19.32 mmol, 1.20 equiv.) was added to a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine 1 (3 g, 16.1 mmol, 1.00 equiv.) in acetone (20 mL). At about 0° C., an aqueous sodium hydroxide solution (2 mol/L, 12 mL) was added dropwise to the solution. The solution was then stirred at ambient temperature for about 3 hours. The solids were collected by filtration and washed with acetone/water to give the title product as a white solid (5.2 g; yield=95%). LC-MS: m/z=342 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCOC(C)=O>C1COCC1>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:2][C:3]2[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cc(CCl)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCN(Cc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Yield: 99.9 %

Procedure:
Stir the mixture of 1-(chloromethyl)-3-nitro-5-(trifluoromethyl)benzene (640 mg, 2.68 mmol) and N-methylpiperazine (536 mg, 5.36 mmol) in THF (8 mL) for 2 hrs at 60° C. TLC (EtOAc:PE=1:1) shows the reaction is complete. Concentrate the reaction mixture under reduced pressure to obtain the crude product (812 mg, 100%). MS: (M+1): 303.1.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]3[O:11][C@@H:12]([CH2:15][OH:16])[CH2:13][O:14][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:16][CH2:15][CH:12]2[CH2:13][O:14][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([CH3:1])[O:3][C:4]=4[C:10]=3[O:11]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2ccc3c(c2o1)O[C@@H](CO)CO3
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nc(C)oc4c3O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [(8S)-2-methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methanol (1.80 g, 8.14 mmole) in methylene chloride (100 mL) was added p-toluenesulfonyl chloride (3.90 g, 20.4 mmole). The mixture was cooled in an ice bath and a solution of diisopropylethylamine (3.55 mL, 20.4 mmole) in methylene chloride (20 mL) was then added dropwise, followed by 4-dimethylaminopyridine (0.65 g, 5.30 mmole). The solution was allowed to warm to room temperature and was stirred under nitrogen overnight. The reaction was diluted to 500 mL in volume with methylene chloride, then washed with aqueous 2 N HCl (200 mL), with saturated aqueous sodium bicarbonate (200 mL), and with brine (150 mL), dried over magnesium sulfate, filtered and evaporated in vacuum to a yellow oil. The crude oil was column chromatographed on silica gel using methylene chloride to remove impurities and 3% methanol/methylene chloride to elute the (R)-enantiomer of the title compound, which becomes a white solid under vacuum (2.56 g, 84%), m.p. 123° C. MS (ESI) m/z 376 (M+H)+.
Reaction SMILES: [NH3:1].[C:2]1([C:9]([O:11][CH3:12])=[O:10])([C:5](OC)=[O:6])[CH2:4][CH2:3]1>CO>[NH2:1][C:5]([C:2]1([C:9]([O:11][CH3:12])=[O:10])[CH2:4][CH2:3]1)=[O:6]
Reactant: COC(=O)C1(C(=O)OC)CC1
Reactant: N
Solvent: CO
Product: COC(=O)C1(C(N)=O)CC1
Temperature: 8 °C
Reaction time: 10 h

Procedure:
Ammonia (20 l/h) is passed at 20° C. into a solution of 1,106 g (7 mol) of dimethyl cyclopropanedicarboxylate in 700 ml of methanol, with stirring. After approximately 10 hours, addition of NH3 is stopped, and the reaction mixture is cooled to 8° C. The solid formed is filtered off with suction, then washed using 200 g of cold methanol. After drying the product, 926.2 g (92.5%) of methyl 1-aminocarbonylcyclopropanecarboxylate are obtained (m.p.: 157° C.).
Reaction SMILES: Cl[CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1.O.[S-2:13].[Na+].[Na+].O>C(O)C>[N:3]1([CH2:2][S:13][CH2:2][N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[N:4]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1
Reactant: ClCn1nnc2ccccc21
Reactant: [S-2]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc2c(c1)nnn2CSCn1nnc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.5 %

Procedure:
1-(Chloromethyl)benzotriazole (20.4 g), prepared above, and sodium sulfide monohydrate (14.4 g) in anhydrous ethanol (75 ml) were stirred overnight (20 hours) at room temperature. Water (240 ml) was added to the reaction mixture. The precipitate was filtered, washed with water to remove inorganic salts and dried. Crystallization from ethanol gave 15.6 g (88%) of desired product (Compound 1); m.p. 179°-181° C. (lit. 182°-184° C.). Thin Layer Chromotography in (CHCl3 /Ethyl acetate) showed only one spot.
Reaction SMILES: [CH2:1]([N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[P:40]([OH:43])([OH:42])[OH:41].P(Cl)(Cl)Cl>O>[CH2:1]([N:19]([CH:20]([P:40]([OH:43])(=[O:41])[OH:42])[P:40]([OH:43])(=[O:42])[OH:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN(C=O)CCCCCCCCCCCCCCCCCC
Reactant: OP(O)O
Solvent: O
Solvent: ClP(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(P(=O)(O)O)P(=O)(O)O
Yield: 65 %

Procedure:
137 parts of about 90% dioctadecylformamide and 20.5 parts of phosphorous acid were slowly reacted with 34.3 parts of phosphorus trichloride at 70°C and the mixture was maintained for 3 hours at this temperature. At this time, it was hydrolyzed with 500 parts of water. The product was filtered by suction, and the residue was dissolved in alcohol, precipitated again with acetone, isolated and dried in vacuo at 50°C over P2O5. N,N-dioctadecylaminomethanediphosphonic acid was obtained in a yield of 65%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[O:8][C:9]([NH:11][C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:18][C:13]2[C:12]([NH:11][C:9]([O:8][CH:7]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[O:10])=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1ccccc1NC(=O)OC(c1ccncc1)C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1NC(=O)c1ccc(Br)cc1)OC(c1ccncc1)C1CCNCC1
Reaction time: 20 h
Yield: 42.7 %

Procedure:
A solution of N1-[1-(4-pyridyl)piperidin-4-ylmethoxycarbonyl)-1,2-benzenediamine (300 mg, 0.920 mmol) and pyridine (0.74 mL) in chloroform (5 mL) was treated with 4-bromobenzoyl chloride (405 mg, 1.84 mmol). After 20 h, the mixture was concentrated and the residue partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate and the combined organics were washed with 1 N aqueous sodium hydroxide, water, saturated sodium chloride solution. The solution was dried (potassium carbonate), filtered, and concentrated in vacuo. Recrystallization (methanol/chloroform and hexanes) yielded 200 mg (43%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[CH2:21][CH2:20]1.[Li+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][CH2:25][N:22]2[CH2:23][CH2:24][O:19][CH2:20][CH2:21]2)=[CH:29][CH:30]=1)(=[O:35])=[O:36]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: O=S([O-])c1ccc(CCCN2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(CCCN4CCOCC4)cc3)c(C)o2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
A mixture of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (2.0 g, 7.55 mmol, 1.00 equiv), lithium 4-(3-morpholinopropyl)benzenesulfinate (4.0 g, 14.55 mmol, 1.93 equiv) and potassium carbonate (1.35 g, 9.78 mmol, 1.30 equiv) in N,N-dimethylformamide (50 mL) was stirred overnight at 70° C. The product was precipitated by the addition of 150 mL ice and water after the reaction was cooled to room temperature. The solid was collected by filtration, washed with 2×15 mL of water and dried in a vacuum oven to give 2.8 g (74%) of methyl 4-(5-methyl-4-((4-(3-morpholinopropyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate as a white solid. LC-MS: (ES, m/z): 499 [M+H]+, 115.
Reaction SMILES: [C:1]([O:5]C(=O)NC1(C2C=CC(C3C(=O)C4C=CC5NC(=O)NC=5C=4OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[NH2:40][C:41]1[C:50]([OH:51])=[C:49]2[C:44]([C:45](=[O:59])[C:46]([I:58])=[C:47]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48]2)=[CH:43][CH:42]=1>>[I:58][C:46]1[C:45](=[O:59])[C:44]2[CH:43]=[CH:42][C:41]3[NH:40][C:1](=[O:5])[O:51][C:50]=3[C:49]=2[O:48][C:47]=1[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]c(=O)[nH]c54)c3=O)cc2)CCC1
Reactant: Nc1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1O
Product: O=c1[nH]c2ccc3c(=O)c(I)c(-c4ccccc4)oc3c2o1
Yield: 100 %

Procedure:
Following the procedure used to {1-[4-(2,6-dioxo-8-phenyl-1,2,3,6-tetrahydro-chromeno[7,8-d]imidazol-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-amino-8-hydroxy-3-iodo-2-phenyl-chromen-4-one was reacted to give the title compound as a yellow solid (105 mg, 100%). LCMS (Method G): RT=3.27, [M+H]+=406.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[OH-].[K+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>CS(C)=O.O>[Br:1][C:2]1[C:9]([O:10][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc(C=O)c(Br)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C=O)c(Br)c1Oc1ccc([N+](=O)[O-])cc1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
2-Bromo-3-hydroxy-4-methoxy-benzaldehyde (15.0 g, 64.9 mmoles) is dissolved in DMSO (100 mL). Potassium hydroxide (4.01 g, 71.4 mmoles) and 1-Fluoro-4-nitro-benzene (13.74 g, 97.4 mmoles) are added to the solution. The reaction mixture is stirred at 130° C. for 3 hours. As the crude is poured in water (500 mL), precipitation occurs. The solid is filtered, washed with water and dried under vacuum overnight. The pale-brown solid obtained (23.4 g) is used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C(C)(C)C)cc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 95.7 %

Procedure:
A reactor was charged with acetic acid (8.7 L), followed by N-(4-tert-butylphenyl) acetamide (Preparation 110, 6.0 kg, 31.4 mol), The mixture was stirred for ten minutes, followed by the addition of acetic anhydride (6.47 kg, 63.4 mol) slowly at room temperature. The reaction was stirred for fifteen minutes. A solution of fuming nitric acid (3.56 kg, 56.5 mol) in acetic acid (2.1 L) was added slowly at 20-25° C., and stirred at that temperature for another 2 hours. The reaction mixture was added to ice water (42 L) at 10-15° C. and the mixture stirred for one hour. The resulting solids were collected by filtration, washed with water (17 L) and dried at 65-70° C. to provide 7.1 kg of the title compound.
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=[O:15]>CO>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:1])=[O:15]
Reactant: O=C(O)Cc1ccccc1F
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trimethylsilyl chloride (4.12 mL) was added to a solution of 2-fluorophenylacetic acid (2 g) in methanol (40 mL) in a nitrogen atmosphere, and the reaction solution was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.978 g of the title compound. The physical properties of the compound are as follows.