Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH3:11])[CH:2]=C.C[OH:13]>C(Cl)Cl>[CH2:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH:2]=[O:13])[CH3:11]
Reactant: C=CCc1ccccc1CC
Reactant: CO
Solvent: ClCCl
Product: CCc1ccccc1CC=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 54.05 g of the crude 1-allyl-2-ethylbenzene in 500 mL of 1:1 CH2Cl2 --CH3OH was cooled to -78° C. A stream of O3 was bubbled through the solution for 3 h, until all of the starting material had disappeared. Then a stream of air was bubbled through the solution until the blue color had faded. A total of 25 mL of methyl sulfide was added and the solution was stirred at room temperature for 1 h. The solution was concentrated and dried under vacuum to afford (2-ethylphenyl) acetaldehyde as a colorless oil which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][CH3:17])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].[CH3:20][C:21]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=O.COC(=O)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1C>>[CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][N:16]([CH3:17])[C:23]([C:22]2[C:21]([CH3:20])=[N:29][C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[CH:27][CH:26]=2)=[O:25])=[CH:12][CH:13]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNC)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)O
Agent: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(C)C(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-[4-(2-methylamino-ethyl)-phenoxy]-propionic acid ethyl ester (example 88A]) was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-methyl-2-[4-(2-{methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-ethyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [FH:1].[CH2:2]=O.[CH:4]([OH:13])([C:9]([F:12])([F:11])[F:10])[C:5]([F:8])([F:7])[F:6]>S(=O)(=O)(O)O>[CH2:2]([F:1])[O:13][CH:4]([C:9]([F:12])([F:11])[F:10])[C:5]([F:8])([F:7])[F:6]
Reactant: C=O
Reactant: F
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: O=S(=O)(O)O
Product: FCOC(C(F)(F)F)C(F)(F)F
Temperature: 65 °C
Yield: 87.5 %

Procedure:
A 500 ml reactor was charged with 50 ml of 98% sulfuric acid, 100 g (5 mol) of hydrogen fluoride, and 30 g (1 mol) of paraformaldehyde. This reaction mixture was heated to 65° C. Then, 134 g (0.8 mol) of HFIP was added dropwise, over 2 hr. Vapors generated by the reaction were collected using water. With this, 140 g of crude SEVOFLURANE was obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:15][C@H:14]2[C@H:5]([C@H:6]3[C@H:11]([CH2:12][CH2:13]2)[CH2:10][C@:9]2([CH3:20])[C:16](=[O:19])[CH2:17][CH2:18][C@H:8]2[CH2:7]3)[CH2:4][CH2:3]1.[I-].[CH3:22][S+](C)C.CC(C)([O-])C.[K+].O>CS(C)=O>[CH3:20][C@@:9]12[C@:16]3([CH2:22][O:19]3)[CH2:17][CH2:18][C@H:8]1[CH2:7][C@@H:6]1[C@H:11]([CH2:12][CH2:13][C@@H:14]3[C@H:5]1[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:15]3)[CH2:10]2
Reactant: C[S+](C)C
Reactant: C[C@]12C[C@H]3CC[C@H]4C[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]1CCC2=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@]12C[C@H]3CC[C@H]4C[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]1CC[C@@]21CO1
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To a solution of compound 14 (60 mg, 0.23 mmol) in DMSO (3 mL) was added trimethylsulfonium iodide (204 mg, 1.0 mmol) and potassium tert-butoxide (112 mg, 1.0 mmol) at room temperature. After 3 h, water (20 mL) was added and the product extracted into EtOAc (50 mL×3). The combined extracts were dried, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 30% EtOAc in hexanes) to give compound 15 (48 mg, 72%) as a white solid: 160-162° C.; [α]D20 16.5 (c 0.20, CHCl3); 1H NMR (CDCl3) δ 3.64-3.50 (m, 1H), 2.91 (d, J=4.9 Hz, 1H), 2.62 (d, J=4.9 Hz, 1H), 0.87 (s, 3H); 13C NMR (CDCl3) δ 71.7, 70.6, 53.6, 47.1, 42.0, 40.3, 40.2, 38.9, 38.4, 36.3, 35.7, 31.8, 29.8, 29.6, 28.9 (2×C), 25.8, 25.5, 14.4; IR νmax 3387, 1733 cm−1. Anal. Calcd for (C19H30O2): C, 78.57; H, 10.41. Found: C, 78.36; H, 10.50.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:13]([N:15]1[CH:19]=[C:18]([NH:20][C:21](=[O:32])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])[CH:17]=[N:16]1)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:13]([N:15]1[CH:19]=[C:18]([NH:20][C:21](=[O:32])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:25][C:24]=2[O:30][CH3:31])[CH:17]=[N:16]1)[CH3:14]
Reactant: Fc1ccc2nccc(Cl)c2c1
Reactant: CCn1cc(NC(=O)Cc2ccc(O)cc2OC)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1cc(NC(=O)Cc2ccc(Oc3ccnc4ccc(F)cc34)cc2OC)cn1
Temperature: 120 °C
Yield: 61.6 %

Procedure:
A mixture of 4-chloro-6-fluoroquinoline (0.11 g), N-(1-ethylpyrazol-4-yl)-2-(4-hydroxy-2-methoxyphenyl)acetamide (0.168 g), caesium carbonate (0.433 g) and DMF (3 ml) was stirred and heated to 120° C. for 2.5 hours. The solvent was evaporated and the residue was purified by column chromatography on silica using a solvent gradient of 100:0 to 93:7 of ethyl acetate and methanol as eluent. There was thus obtained the title compound (0.157 g); 1H NMR: (DMSOd6) 1.33 (t, 3H), 3.6 (s, 2H), 3.77 (s, 3H), 4.07 (q, 2H), 6.71 (d, 1H), 6.83 (m, 1H), 6.99 (d, 1H), 7.35 (d, 1H), 7.42 (s, 1H), 7.75 (m, 1H), 7.88 (s, 1H), 7.98 (m, 1H), 8.12 (m, 1H), 8.7 (d, 1H), 10.04 (s, 1H); Mass Spectrum: M+H+ 421.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([CH3:17])=[C:13]([CH3:16])[N+:14]=2[O-])=[CH:6][CH:5]=1.C[O:19][C:20]1C=CC(C2OC(C)=C(C)N=2)=C[CH:21]=1.C([O:37]C)(C)(C)C>[Zn]>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([CH3:17])=[C:13]([C:16]([O:19][CH2:20][CH3:21])=[O:37])[N:14]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(-c2oc(C)c(C)[n+]2[O-])cc1
Reactant: COC(C)(C)C
Reactant: COc1ccc(-c2nc(C)c(C)o2)cc1
Agent: Cl
Agent: [Zn]
Product: CCOC(=O)c1nc(-c2ccc(OC)cc2)oc1C
Yield: 61 %

Procedure:
2-(4-Methoxyphenyl)-4-carbethoxy-5-methyloxazole was prepared in 61% yield by zinc dust reduction of the compound of part (a) in accordance with the procedure of Example 89, part (b), and obtained as a crystalline material, m.p. 74°-76° C. (from methyl t-butyl ether).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19](C=O)=[C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:41]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([OH:41])=[C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(NC(=O)OCc4ccccc4)c(C=O)c3O2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(NC(=O)OCc4ccccc4)c(O)c3O2)cc1
Reaction time: 8 h
Yield: 41.4 %

Procedure:
A solution of {(2R)-7-{[(benzyloxy)carbonyl]amino}-8-formyl-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (4.45 g, 8.95 mmole) in methylene chloride (50 mL) was added dropwise to a solution of m-chloroperoxybenzoic acid (6.45 g, 22.4 mmole) in methylene chloride (120 mL). The reaction was stirred under nitrogen overnight. After dilution to 300 mL in volume, it was washed with saturated sodium bicarbonate (2×200 mL), brine (100 mL), dried over magnesium sulfate, filtered and evaporated to dryness. A H1 NMR spectra was taken of the crude product and it was determined to be the formate ester. Cleavage was effected by stirring in methanol over basic alumina overnight. After filtration and evaporation, the product was purified by column chromatography on silica gel with hexane to remove the impurities, and the product eluted with methylene chloride to give the (R)-enantiomer of the title compound as a yellow oil (1.80 g, 40%). 1H (CDCl3) doublet 7.8 δ (2H); multiplet 7.2-7.4 δ (7H); broad singlet 7.0 δ (1H); doublet 6.4 δ (1H); singlet 5.2 δ (2H); multiplet 4.4 δ (1H); multiplet 4.2 δ (3H); multiplet 4.0 δ (1H); singlet 2.4 δ (3H).
Reaction SMILES: N1CCCCC1.[CH:7]1([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:18][C:19]=3[N:20]3[CH2:26][C:25]([C:27](=[O:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][C:23]4[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:22]=4[C:21]=23)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:48](=O)[CH:49]([CH3:51])[CH3:50]>CCO>[CH:7]1([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])=[CH:18][C:19]=3[N:20]3[CH2:26][C:25]([C:27](=[O:34])/[C:28](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:48]/[CH:49]([CH3:51])[CH3:50])=[CH:24][C:23]4[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:22]=4[C:21]=23)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)C=O
Reactant: CCOC(=O)CC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)/C(=C\C(C)C)C(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
Piperidine (17 μL, 0.18 mmol) was added to a stirring solution of tert-butyl 13-cyclohexyl-6-(3-ethoxy-3-oxopropanoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (1.0 g, 1.79 mmol) and isobutyraldehyde (16.4 mL, 179 mmol) in EtOH (9 mL) at room temperature. After 3 hrs of stirring an additional amount of piperidine (38 μL, 0.40 mmol) was added and the reaction was allowed to stir overnight at room temperature. The mixture was concentrated and was purified on silica gel (BIOTAGE®, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the titled compound (950 mg, 1.55 mmol, 87% yield) consistent by LCMS and NMR as a yellow foamy sticky solid.
Reaction SMILES: CC(C)(C)[C@H](NC(C1N=C(C2C=CC=CC=2)N2CCNCC=12)=O)C(NC)=O.[CH3:28][NH:29][C:30](=[O:37])[C@H:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH2:32].[Br:38][C:39]1[N:43]2[CH2:44][CH2:45][N:46]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:47][C:42]2=[C:41]([C:55](O)=[O:56])[N:40]=1>>[Br:38][C:39]1[N:43]2[CH2:44][CH2:45][N:46]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:47][C:42]2=[C:41]([C:55](=[O:56])[NH:32][C@@H:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:30]([NH:29][CH3:28])=[O:37])[N:40]=1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nc(C(=O)O)c2C1
Agent: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCC2)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C

Procedure:
Additional compounds 22-29 were synthesized by the same procedure as described above (Examples 1 and 2) for Compound 2 except that in Example 1, alternative amines were used in place of L-tert-Leucine methylamide in the reaction with intermediate Intermediate 1I to form intermediate Intermediate 1J. For example, Compound 22 was synthesized in the same manner as Compound 2 except that (S)-2-amino-3,3-dimethylbutan-1-ol was used in place of L-tert-Leucine methylamide. Compound 23 was synthesized in the same manner as Compound 2 except that (R)-2-amino-3,3-dimethylbutan-1-ol was used in place of L-tert-Leucine methylamide. These resulting intermediates were deprotected with TFA, as described in Example 2, to form additional Compounds 22-29.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:13]C1C=CC(C(OC)=O)=CC=1>>[CH3:13][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C)cc1
Reactant: COc1ccc(C(C)(C)N)cc1
Product: Cc1ccc(C(C)(C)N)cc1
Yield: 34 %

Procedure:
Following a procedure similar to that described in Preparation 10a, but using methyl 4-methylbenzoate as a starting material, in a relative amount similar to that used in that Preparation, the title compound was obtained in a yield of 34%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:14])=[CH:11][CH:10]=1
Reactant: Brc1ccccn1
Reactant: O=Cc1ccc(Br)cc1
Product: OC(c1ccc(Br)cc1)c1ccccn1

Procedure:
Using the same protocol as described in example 22, step 1, 2-bromopyridine (477 μL, 5.0 mmol) was added to 4-bromobenzaldehyde (1.018 g, 5.5 mmol). The crude residue obtained was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:13](=[O:18])[NH:14][NH:15][C:16]=2[CH3:17])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:25](OC(=O)C)(=[O:27])[CH3:26].C(O)(=O)C>CN(C)C=O.O>[C:25]([N:15]1[C:16]([CH3:17])=[C:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=2)[C:13](=[O:18])[NH:14]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1[nH][nH]c(=O)c1Cc1ccc(OC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)n1[nH]c(=O)c(Cc2ccc(OC(C)C)cc2)c1C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
1,2-Dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one (1.00 g) was suspended in N,N-dimethyl-formamide (5 mL) at room temperature. In addition, potassium carbonate (0.319 g) was added to the suspension, and the mixture was stirred for 30 minutes. Acetic anhydride (0.412 g) was added to the mixture in a dropwise manner at room temperature. The mixture was stirred at room temperature overnight and at 50° C. for 2 hours. In addition, the mixed solution of glacial acetic acid (0.139 g) and water (5.0 g) was added to the reaction mixture under stirring at room temperature. After confirming the precipitation of the crystals, water (25 g) was added to the mixture. The obtained crystals were collected by filtration, washed with water and dried under reduced pressure to give a white solid of 1-acetyl-1,2-dihydro-4-[(4-isopropoxy-phenyl)methyl]-5-methyl-3H-pyrazol-3-one (0.90 g).
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:9]([OH:11])=O)[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:52]([O:59][C:60]([N:62]1[CH2:66][CH:65]([C:67]2[C:75]3[C:70](=[CH:71][C:72]([F:76])=[CH:73][CH:74]=3)[NH:69][CH:68]=2)[CH:64]2[NH:77][CH2:78][CH2:79][CH:63]12)=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN1C(=O)CCC1.CCOC(C)=O>[CH2:52]([O:59][C:60]([N:62]1[CH2:66][CH:65]([C:67]2[C:75]3[C:70](=[CH:71][C:72]([F:76])=[CH:73][CH:74]=3)[NH:69][CH:68]=2)[CH:64]2[N:77]([C:9](=[O:11])[CH:2]([NH:1][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]3)[CH2:78][CH2:79][CH:63]12)=[O:61])[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: O=C(OCc1ccccc1)N1CC(c2c[nH]c3cc(F)ccc23)C2NCCC21
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: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)OCc1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution containing Boc-Chg-OH (600 mg, 2.3 mmol) in anhydrous NMP (6 mL) was cooled to 0° C. HATU (865 mg, 2.3 mmol) and DIPEA (0.67 g, 5.2 mmol) were added followed by the addition of crude 42 (900 mg, 2.4 mmol) in anhydrous NMP (6 mL). The reaction mixture was slowly warmed to ambient temperature. After 16 h, the reaction mixture was diluted with EtOAc and washed successively with 1M HCl, aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.5 g of crude 48 as a light brown-colored foam which was used without further purification. 1H NMR (300 MHz, CDCl3), mixture of rotamers: δ8.38 (s, 0.5H), 8.31 (s, 0.5H), 8.19 (dd, J=5.4, 8.7 Hz, 0.5H), 8.12 (dd, J=5.4, 8.7 Hz, 0.5H), 7.44-7.35 (m, 5H), 7.00-6.88 (m, 2H), 6.78 (s, 0.5H), 6.61 (s, 0.5H), 5.38-5.28 (m, 1H), 5.22-5.12 (m, 2H), 4.65 (d, J=4.8 Hz, 0.5H), 4.58 (d, J=5.1 Hz, 0.5H), 4.39-4.31 (m, 2H), 4.23 (d, J=11.7 Hz, 0.5H), 4.16-4.02 (m, 2H), 3.92 (d, J=5.4 Hz, 1H), 3.54-3.43 (m, 2H), 2.47-2.37 (m, 0.5H), 2.29-2.23 (m, 0.5H), 1.93-1.70 (m, 7H), 1.43 (s, 9H), 1.19-1.12 (m, 2H) ppm. Mass spectrum, m/z [619.5] (M+H)+.
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].C(O)C.S([O-])(O)(=O)=O.[K+]>O>[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: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNc1ccc(C(=O)O)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 72.5 °C
Reaction time: 0.75 h

Procedure:
2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one (1.0 kg) and 4-Hydrazino benzoic acid (0.699 kg), Ethanol (9.0 lit), Water (1.0 lit) was stirred at 25-35° C. in round bottom flask. Followed by addition of Potassium hydrogen sulphate (0.15 kg) into the reaction mass and heated the reaction mass at 70-75° C. for two hrs. Cooled the reaction mass at 25-30° C. and stirred for 45 minutes. Filtered off the solid and washed with ethanol. Obtained solid and water (1.0 lit) stirred at 25-30° C. for 15 minutes and then heated at 50-55° C. for 1 hr. The solid was filtered at 50-55° C. and washed with water. Charge this wet cake in DMF (5.0 lit) and stirred at 25-30° C. In this solution 30% H2O2 was added at 25-30° C. within 1 hr. Followed by addition of water at 25-30° C. and stirred for 30 minutes. Filtered off the solid and washed it with water. The obtained solid was added in pre heated water and stirred at 45-50° C. Gradually increased the temperature up to 65-75° C. & stir it for 60 min. cooled the reaction mass at 45-50° C. and stirred it for 40 minutes. The precipitated Deferasirox filtered off and washed with water. Dry the solid at 65-75° C. in vacuum tray drier.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[CH:18]=[C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:21][C:16]=3[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:27][CH:28]([F:30])[F:29])[O:9]2)[CH:5]=[CH:6][CH:7]=1.[Br-].[CH2:32]([O:34][C:35](=[O:39])[CH2:36][CH2:37][Zn+])[CH3:33].O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[F:29][CH:28]([F:30])[O:27][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][C:17]=1[CH:8]([C:4]1[CH:3]=[C:2]([CH2:37][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:39])[CH:7]=[CH:6][CH:5]=1)[O:9]2
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(c1cccc(Br)c1)Oc1cccc(OC(F)F)c1-2
Reactant: CCOC(=O)CC[Zn+]
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCc1cccc(C2Oc3cccc(OC(F)F)c3-c3ccc(NS(C)(=O)=O)cc32)c1

Procedure:
A solution of Example 103 (0.05 g, 0.10 mmol), tetrakis(triphenylphosphine) palladium(O) (0.01, 0.01 mmol), and 3-ethoxy-3-oxopropylzincbromide (0.6 ml of 0.5M solution in THF) in THF (2 mL) was shaken in a sealed tube at 80° C. for 15 hours, treated with water (2 mL), and extracted with ethyl acetate. The extract was the concentrated and the residue was purified by high throughput HPLC with aqueous 0.1% TFA and CH3CN to provide the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.17 (d, J=9 Hz, 1H), 6.52-7.74 (m, 10H), 6.31 (s, 1H), 4.18 (q, J=7 Hz, 2H), 3.02 (s, 3H), 1.25 (t, J=7 Hz, 3H); MS (ESI(−)Q1MS m/z 516 (M−H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:5][C@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[N:8]=1)[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C1C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH:20][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:7]1[NH:8][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC1=N[C@@H]2Cc3ccccc3[C@@H]2O1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Yield: 72.8 %

Procedure:
A solution of (±) cis-2-ethoxy-3a,8b-dihydro-4H-indeno[2,1-d]oxazole (1.0 g, 0.005 mol) in dry toluene (20 ml) was treated with 3,4-dichloroaniline (0.81 g, 0.005 mol) and a catalytic amount of p-toluenesulfonic acid (5 ml of an anhydrous 0.1M solution of p-toluenesulfonic acid in benzene). The mixture was heated under nitrogen at 60° C. for 3 h. The reaction was worked up as described in Preparation 5. Purification on a silica gel column using 1% ethanol in chloroform as eluant afforded the title compound as a solid (1.33 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[N:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:45]([C:42]3[CH:43]=[CH:44][N:39]=[CH:40][CH:41]=3)(=[O:47])=[O:46])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Reactant: O=S(=O)(Cl)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccncc3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
Diisopropylethylamine (0.3 mL, 1.7 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 100 mg, 0.24 mmol) in CH2Cl2 (6 mL). The solution was stirred at room temperature for 30 min and then a solution of pyridine-4-sulfonyl chloride (which may be prepared as described above; 213 mg, 1.2 mmol) in CH2Cl2 (1 mL) was added. The mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel to give {6-fluoro-4-[1-(pyridine-4-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (45 mg, 42%) as an orange liquid. MS cald. for C23H24FN2O4S [(M+H)+]: 443, obsd. 443.4.