Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[C:10]([C:11]=1[N+:12]([O-:14])=[O:13])=[CH:9][C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=2.C(N(CC)CC)C.[CH2:27]([N:29]([CH2:33][CH3:34])[C:30](Cl)=[O:31])[CH3:28]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:27]([N:29]([CH2:33][CH3:34])[C:30]([O:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[C:10]([C:11]=1[N+:12]([O-:14])=[O:13])=[CH:9][C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=2)=[O:31])[CH3:28]
Reactant: CCN(CC)C(=O)Cl
Reactant: COc1cc2c(C)nc(O)c([N+](=O)[O-])c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)Oc1nc(C)c2cc(OC)c(OC)cc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a slurry of 3-hydroxy-6,7-dimethoxy-1-methyl-4-nitroisoquinoline (1.90 g, 7.19 mmol) in methylene chloride (100 mL) were added triethylamine (1.5 mL, 10.78 mmol), 4-dimethylaminopyridine (176 mg, 1.44 mmol) followed by diethylcarbamoyl chloride (0.81 mL, 8.62 mmol) in 5 mL of methylene chloride), added over a 10 minute period. The addition of each of the last three reagents was repeated twice two hours apart and then the mixture was stirred at room temperature overnight. The clear dark red-brown solution was washed with water (3×150 mL), saturated sodium bicarbonate solution and again with water. The organic phase was dried (Na2SO4), filtered and evaporated to dryness in vacuo. The tan residue was recrystallized from methylene chloride/ether to yield the title compound (2.04 g, 92.1%), mp 220°-221° C. (d). IR (KBr): 1738, 1520, 1260 cm-1. NMR (CDCl3): δ 1.24 and 1.28 [two t, J=7 Hz, total 6H, N(CH2CH3)2 ], 2.90 (s, 3H, 1-CH3), 3.20-3.80 (m, 4H, N(CH2CH3)2), 4.03 (s, 6H, 5,6-OCH3), 7.24 (s, 1H, 5- or 8-H), 7.28 (s, 1H, 5- or 8-H); MS (DCI): 364 (MH)+
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7]([NH:9][C:10](=[O:14])OCC)=[S:8])=[CH:4][CH:3]=[N:2]1.[OH-].[Na+]>>[S:8]=[C:7]1[NH:9][C:10](=[O:14])[N:1]2[N:2]=[CH:3][CH:4]=[C:5]2[NH:6]1
Reactant: CCOC(=O)NC(=S)Nc1ccn[nH]1
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c(=S)[nH]c2ccnn12
Temperature: 25 °C
Yield: 91.1 %

Procedure:
Ethyl 1H-pyrazol-5-ylcarbamothioylcarbamate (4.64 g, 21.68 mmol) from 1a was added to 2N NaOH solution (51 mL). The reaction mixture was stirred at room temperature for 2½ hours and then acidified with 2NH2SO4. The resulting precipitate was collected by vacuum filtration, washed with water followed by diethyl ether, and then air dried to give 3.32 g (82%) of 2-thioxo-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one as a pale yellow solid.
Reaction SMILES: N1C=CN=C1.[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.[Cl-].[Na+].O>[C:17]([Si:21]([O:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([CH3:6])(=[O:8])=[O:9])=[CH:11][CH:12]=1)([CH3:24])[CH3:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(S(C)(=O)=O)cc1
Yield: 96 %

Procedure:
9.9 g (145.18 mmol) of imidazole was added to and dissolved in an N,N-dimethylformamide solution (150 mL) of 10 g (58.07 mmol) of 4-methylsulfonylphenol, and then 10.5 g (69.7 mmol) of tert-butyldimethylchlorosilane was added thereto and stirred. After the reaction, brine was added thereto and extracted with ethyl acetate. The organic layer was washed three times with brine, and dried over anhydrous magnesium sulfate. Purifying by silica gel column chromatography (hexane/ethyl acetate=5/1→3/1) gave 15.97 g (55.75 mmol) of tert-butyl-(4-methanesulfonylphenoxy)dimethylsilane (XII-6) (yield 96%). Its physical properties are shown below.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.CC(C)N=C=NC(C)C.O>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:12][C:7]2[CH:6]=[C:5]([C:4]([OH:3])=[O:13])[CH:10]=[CH:9][C:8]=2[N:11]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c1
Reaction time: 2 h

Procedure:
A mixture of 3,4-diamino-benzoic acid ethyl ester (5.0 g, 27.8 mmol) and 1,3-dichloro-2-isothiocyanato-benzene (5.66 g, 27.8 mmol) in 40 mL DMF was stirred for 2 h. DIC (4.40 mL, 28.2 mmol) was added and the mixture stirred overnight. After 30 min stirring at 80° C. water was added and the mixture was concentrated i.vac. The residue was taken up in ethanol and 1 M aq. NaOH. The mixture stirred overnight at reflux. Ethanol was evaporated and the aq. phase diluted with water. The precipitate was filtered and washed with water. The filtrate was acidified with formic acid and cooled. The mixture was filtered and washed with water.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]([CH3:12])[CH3:11].C(O)(C)C.C(=O)=O.C([Li])CCC.[B:25](OC)([O:28][CH3:29])[O:26][CH3:27]>O1CCCC1>[CH3:11][N:10]([CH3:12])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:25]([O:28][CH3:29])[O:26][CH3:27]
Reactant: COB(OC)OC
Reactant: CN(C)CCc1ccccc1Br
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COB(OC)c1ccccc1CCN(C)C
Temperature: -70 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
19.0 g (83.2 mmol) of the [2-(2-bromophenyl)ethyl]dimethylamine prepared according to example 10 (2nd stage) were dissolved in 300 ml tetrahydrofuran and the solution was cooled to −70° C. in a cooling bath (isopropanol/dry ice). 60 ml (95.7 mmol) butyllithium solution (1.6 M in hexane) were added dropwise under nitrogen such that the temperature did not rise above −60° C. After the mixture had been stirred at −70° C. for two hours, 28 ml (250 mmol) trimethyl borate were also added dropwise such that the temperature did not rise above −60° C. The mixture was warmed to 25° C. in the course of 15 hours and the solution was concentrated on a rotary evaporator (500-10 mbar) without heat being supplied. The residue was taken up in 200 ml n-hexane, the mixture was stirred for one hour and filtered over an inert gas frit under nitrogen and the filtrated was concentrated on a rotary evaporator (500-10 mbar) without heat being supplied. 14.1 g dimethyl 2-(2-dimethylaminoethyl)benzeneboronate (76.5% of theory) were obtained in this manner.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][NH:17]3)=[C:13]([NH:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(OCC)(=O)C.CO.[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][NH:17]3)=[C:13]([NH:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(Nc2nc(Nc3cccc([N+](=O)[O-])c3)nc3[nH]cnc23)cc1
Agent: O=[Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Nc2nc(Nc3cccc(N)c3)nc3[nH]cnc23)cc1
Yield: 39.3 %

Procedure:
214 mg of the product of Example 24 are treated with 95 mg of platinum oxide (PtO2) in a mixture of 2.6 ml of ethyl acetate and 2.6 ml of methanol in the presence of hydrogen, H2. 78 mg of the expected product are thus obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:3]=12.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(OCCO)C>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[O:12][C:3]=23)[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(Br)c1
Reactant: N#Cc1cnc2c(oc3ccccc32)c1Cl
Solvent: CCOCCO
Product: N#Cc1cnc2c(oc3ccccc32)c1Nc1cccc(Br)c1
Yield: 63.4 %

Procedure:
A solution of 300 mg (1.30 mmol) of 4-chlorobenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile and 0.160 mL (1.43 mmol) of 3-bromoaniline in 8 mL of 2-ethoxyethanol is heated at reflux temperature for 24 hours. The reaction mixture is partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is washed with saturated sodium bicarbonate, followed by brine, then dried over sodium sulfate, filtered through a pad of diatomaceous earth and concentrated in vacuo. The resultant solid is collected by filtration to give 300 mg (42%) of a beige solid, mp 242–245° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH:5]1[CH2:10][OH:11].[N+](C1C=CC([O:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)=O)=CC=1)([O-])=O.C([O-])(O)=O.[Na+]>C1COCC1>[F:36][C:33]1[CH:32]=[CH:31][C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([O:11][CH2:10][CH:5]3[CH2:6][O:7][CH2:8][CH2:9][N:4]3[CH3:3])=[O:21])[CH2:29][CH2:28]2)=[CH:35][CH:34]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2)CC1
Reactant: CN1CCOCC1CO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCOCC1COC(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 0 °C
Yield: 243.2 %

Procedure:
NaH (60% in oil, prewashed with hexane; 0.91 g, 22.9 mmol) was suspended in anhydrous THF (25 mL) under nitrogen and cooled to 0° C. with stirring. A solution of (4-methyl-morpholin-3-yl)-methanol (1.00 g, 2.62 mmol) in THF (25 mL) was added dropwise. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 3.16 g, 9.15 mmol) was added and the reaction mixture was stirred overnight at room temperature. A saturated aqueous solution of NaHCO3 (10 mL) was added and the solvents were removed in vacuo. The residue was partitioned between water and EtOAc and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with sat aq NaHCO3 (3×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash normal column chromatography (Apollo silica, 40-63 μm, 60 A) eluting with 1% MeOH in DCM to give (4-methylmorpholin-3-yl)methyl 4-(4-fluorophenyl)piperazine-1-carboxylate (2.15 g, 83%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:17][O:18][C:19](Cl)=[O:20]>C1COCC1>[CH3:17][O:18][C:19](=[O:20])[C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[N:5][C:4]=1[Cl:8]
Reactant: COC(=O)Cl
Reactant: Clc1cc(Br)ccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1c(Br)ccnc1Cl
Temperature: -80 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-2-chloro-pyridine (4.5 mL, 41 mmol) in anhydrous THF (60 mL) was added dropwise to a stirred solution of lithium diisopropylamide (1.8 M in THF, 25 mL, 45 mmol) in anhydrous THF (60 mL) at −85° C. After stirring for 30 min at −80° C., the reaction mixture was added dropwise via cannula to a stirred solution of methylchloroformate (31 mL, 400 mmol) in anhydrous THF at −80° C. After stirring for 50 min at −80° C., the reaction was quenched by the addition of concentrated aqueous NaHCO3 (90 mL), and subsequently diluted with EA (250 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EA 4:1) to give the title compound. MS (m/z): 252.0.1 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH3:25]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:18][CH2:17][C:16]4[C:21](=[CH:22][CH:23]=[CH:24][C:15]=4[F:14])[CH:20]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(F)cccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cccc(F)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C([O:13][C:14](=O)[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)[CH:19]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[CH3:30][C:26]1[CH:25]=[C:24]([C:20]2[CH:19]=[C:18]([C:16]3[CH2:15][C:14](=[O:13])[NH:8][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=4[N:7]=3)[CH:23]=[CH:22][CH:21]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Nc1ccccc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2cccc(C3=Nc4ccccc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from commercially available 1,2-phenylendiamine (108 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) in xylene (20 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as an off-white solid (230 mg, 70%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][C:4]1[CH:3]=[C:2]([O:1][CH2:13][CH2:14][CH2:15][Cl:16])[CH:7]=[CH:6][C:5]=1[C:8](=[O:10])[CH3:9]
Reactant: ClCCCBr
Reactant: CC(=O)c1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCCCl)cc1C
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of 4′-hydroxy-2′-methyl-acetophenone (10.5 g) and 1-bromo-3-chloropropane (7.6 mL) in acetone (70 mL) was treated with potassium carbonate (14.5 g). The mixture was stirred at 50° C. for approximately 18 hours. The reaction mixture was cooled to ambient temperature and partitioned between dichloromethane (200 mL) and water (200 mL). The aqueous layer was washed twice with fresh portions of dichloromethane (200 mL) and brine was used to break any emulsions. The organic fractions were combined, dried over sodium sulfate, and evaporated. The residue was re-dissolved in dichloromethane (100 mL) and washed with 0.5 M sodium hydroxide (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered and evaporated to give the title compound which was used without further purification.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][NH:10][C:11](=[O:31])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:20]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[OH:1][C:2]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][NH:10][C:11](=[O:31])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH:20]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2cccc(C(O)C(F)(F)F)c2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2cccc(C(=O)C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a stirred solution of N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-[3-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenoxy]-nicotinamide (0.520 grams, 1.13 mmole), NMO (0.192 grams, 1.7 mmole) and 4 Å molecular sieves (0.5 g) in methylene chloride (15 ml) was added TPAP (0.020 grams, 0.06 mmole) and stirred at room temperature for 1 hour. The mixture was filtered through celite, washed with methylene chloride. The filtrate was diluted with 150 ml methylene chloride, washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to give an oil which was purified by chromatography on silica eluting with 2.5% methanol methylene chloride to give a foam (0.506 g). 1H NMR (CDCl3) d 1.54 (6H, s), 4.69 (2H, d), 7.50-7.15 (9H, m), 8.16 (1H, m), 8.64 (1H, m); MS: m/e 458 (M+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:20]C1C=C2C(C=CN2)=CC=1>>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Reactant: Fc1ccc2cc[nH]c2c1
Product: Fc1ccc2c(C3=CCC4(CC3)OCCO4)c[nH]c2c1
Yield: 96.3 %

Procedure:
This compound was prepared in the manner described for intermediate 1a by replacing indole with 6-fluoroindole (5.14 g, 38 mmol) ) to afford 10 g (96.3%) of the title compound as a white solid: mp 196-197° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)C>[C].[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 78.8 %

Procedure:
A mixture of tert-butyl (2E)-3-[4-(benzyloxy)phenyl]acrylate (13.3 g, 42.8 mmol), 10% palladium carbon (1.3 g), ethanol (100 mL) and ethyl acetate (30 mL) was stirred under a hydrogen atmosphere at room temperature for 19 hrs. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (7.5 g, yield 79%) as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:7][PH:8](=[O:10])[O-:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11](N(CC)CC)[CH3:12].C(OC(Cl)=O)C>O1CCCC1>[CH:1]1([CH2:7][PH:8](=[O:9])[O:10][CH2:11][CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=[PH]([O-])CC1CCCCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCO[PH](=O)CC1CCCCC1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
19.3 g of cyclohexylmethylphosphinate are is dissolved in 60 ml of absolute tetrahydrofuran under an inert atmosphere. The solution is cooled to 0° C. and a suspension forms which is treated with 12.14 g of triethylamine. An exothermic reaction occurs. The suspension is re-cooled to 0° C. before dropwise addition of 13.02 g of ethylchloroformate. A further exothermic reaction with gas-evolution is observed together with the formation of a white precipitate. The resulting suspension is warmed to 20° and stirred for 20 hours. The solid is removed by filtration and the filtrate is evaporated to dryness. The residue is dissolved in dichloromethane and washed with water. Drying and removal of the solvent affords a pale yellow oil. Distillation under high vacuum affords ethyl cyclohexylmethylphosphinate, b.p. 120°-130° C/2×10-1 mbar. 1H-NMR (CDCl3): δ (ppm)=7.17 (1H, d, t, 5=527 MZ, P-H), 4.13 (2H, m, CH2OP), 1.95-1.58 (7H, m, 3×CH2 +CH), 1.38-0.95 (6H, m, 3×CH2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20]>CN1CCCC1=O.C(O)(=O)CC>[CH:16]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([C:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Solvent: CN1CCCC1=O
Solvent: CCC(=O)O
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 ml of N-methylpyrrolidone and 5 ml of propionic acid is heated to 120° C. The mixture is maintained at this temperature and stirred for 1 hour. After completion of the reaction, the mixture is cooled and poured onto crushed ice. The resulting crystals are aspirated and washed with water. After drying, 0.99 g of raw deferasirox is obtained, i.e. 91% of the theory, with an HPLC content of 92.9% and a melting temperature of 250 to 261° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.Cl.[NH2:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][C@H:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C@H:14]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([NH:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][C@H:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C@H:14]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CN1CC[C@H](Oc2ccc(N)cc2)[C@H](c2ccccc2)C1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(O[C@H]2CCN(C)C[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.4 ml of acetyl chloride in 75 ml of chloroform is added dropwise under nitrogen over a 15-minute period to a solution of 5.05 g of the free base of cis-4-(4-aminophenoxy)-1-methyl-3-phenylpiperidine of Example 8 in 150 ml of dry chloroform containing 2.74 ml of triethylamine. The pot temperature reaches a maximum of 28° C. The reaction is complete in 30 minutes. The chloroform solution is washed with 10% aqueous NaOH solution, then with saturated aqueous NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuo to a foam which solidifies upon trituration with hexane. The hexane mixture is briefly heated to boiling, then cooled to room temperature and allowed to stand for 30 minutes before filtering. A crude solid results, mp s 172°, 173°-175° C. Recrystallization from toluene affords cis-4-(4-acetamidophenoxy)-1-methyl-3-phenylpiperidine, mp 174.5°-176.5° C.
Reaction SMILES: [CH2:1]([C:4]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CO.[Br:14]Br.C[O-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:4]1([CH2:1][CH2:2][CH2:3][Br:14])[CH2:5][CH2:6]1
Reactant: C=CCC1(CC(=O)OC)CC1
Reactant: BrBr
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC1(CCCBr)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon and at 0° C., 3.4 ml (3.4 mmol) of borane/THF complex solution (1 M in THF) were added dropwise to 1542 mg (10 mmol) of methyl [1-(prop-2-en-1-yl)cyclopropyl]acetate in 10 ml of anhydrous THF. After 30 min at 0° C., the reaction was stirred at RT for a further 30 min, and 22 μl (0.54 mmol) of methanol were then added. At −5° C., 0.62 ml (12 mmol) of bromine and 2971 mg (16.5 mmol) of sodium methoxide solution (30% in methanol) were then successively added dropwise to the reaction mixture. Once the reaction had reached room temperature, 10 ml of saturated sodium bicarbonate solution were added, the organic phase was separated off and the aqueous phase was extracted three more times with tert-butyl methyl ether. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave 683 mg (2.9 mmol, 29% of theory) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:11]([CH:21]([CH3:23])[CH3:22])=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=2)[C:15]([NH2:17])=O)=[CH:4][N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:11]([CH:21]([CH3:23])[CH3:22])=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=2)[C:15]([NH2:17])=[S:33])=[CH:4][N:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(N)=O
Solvent: C1CCOC1
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(N)=S
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
A mixture of 5-(2,4-Diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzamide (0.25 g, 0.79 mmol, prepared according to the procedure of Example 52) and Lawesson's reagent (0.96 g, 2.37 mmol) in anhydrous THF (20 ml) was stirred at room temperature for 16 hrs and concentrated in vacuo. Flash chromatography on silica (5% CH3OH in methylene chloride with 1% NH4OH) gave 5-(2,4-Diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-thiobenzamide (0.201 g, 76% ) as a yellow solid.