Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC([C:34]1[CH:39]=[CH:38][C:37]([O:40]CC2OC2)=[CH:36][CH:35]=1)(C1C=C[C:26]([O:29][CH2:30][CH:31]2OC2)=[CH:25]C=1)C.C(C(C)=[O:50])C(C)C>>[C:37]1([CH:38]=[CH:39][CH:34]=[C:35]([OH:50])[CH:36]=1)[OH:40].[CH3:25][CH2:26][O:29][CH2:30][CH3:31]
Reactant: CC(=O)CC(C)C
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOCC
Product: Oc1cccc(O)c1
Temperature: 117 °C

Procedure:
A resorcinol-formaldehyde resin/diglycidyl ether of bisphenol A addition product was prepared in a lab reactor by a procedure comparable to that employed in Example 1. The reactor was charged with about 31.1 g. of a commercial resorcinol-formaldehyde resin, Penacolite B-19-S, (INDSPEC Chemical Corporation, Pittsburgh, Pa., U.S.A.), 125 ml methyl isobutyl ketone and 0.5 g. triphenylphosphine. Then, 90.4 g diglycidyl ether of bisphenol A (Dow epoxy resin DER-331) was added dropwise in about 0.5 hours. The stirred solution was refluxed for about one hour at about 117° C. and devolatilized at reduced pressure to give a dark amber resorcinol ether compound (RE2) having a 72° C. softening point, and having a 0.9 wt. % residual oxirane oxygen.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][CH:10]=1.O.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>ClC1C=CC=CC=1>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:18])=[CH:10][CH:11]=2)=[O:16])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: Clc1ccccc1
Product: COc1ccc(C(=O)c2ccc(C)cc2)cc1
Yield: 7 %

Procedure:
In like manner to Example 8, anisole and para-toluic acid were reacted together (4 hour reflux) in chlorobenzene in the presence of ytterbium (III) trifluoromethanesulfonate hydrate, to give crude 4-methoxy-4′-methylbenzophenone (0.15 g, 7% yield).
Reaction SMILES: [OH:1][C:2]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]([O:35]CCCC)=[O:34])[CH2:29][CH2:28]1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3].[OH-].[Na+].Cl>CO.O.C(OCC)(=O)C>[OH:1][C@:2]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3].[OH:1][C@@:2]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3]
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@](C)(O)[C@H]3CC[C@H](C(=O)O)CC3)s2)c1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@](C)(O)[C@H]3CC[C@H](C(=O)O)CC3)s2)c1
Temperature: 100 °C

Procedure:
To a solution of butyl trans-4-{1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylate (600 mg, 1.066 mmol) in methanol (10.7 mL) was added sodium hydroxide (1.0 M in H2O, 2.13 mL, 2.13 mmol) and the reaction was heated overnight at 100° C. The reaction was then cooled to room temperature, acidified with HCl (1.0 M in H2O) to a pH of ˜3 and then diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. The residue was purified and at the same time the enantiomers separated by supercritical fluid chromatography (Chiral OJ column, 35%:75% methanol/CO2 5.0 min run time) to yield trans-4-{(1R)-1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid and trans-4-{(1S)-1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid. Characterization data for the faster eluting enantiomer (Rt=3.22 min): MS ESI calc'd. for C24H26F3N4O3S [M+H]+ 507. found 507. 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.83 (d, J=4.9, 1H), 7.99-7.92 (m, 2H), 7.45 (s, 1H), 7.27 (d, J=4.9, 1H), 7.14 (s, 1H), 5.82 (s, 1H), 2.31 (s, 3H), 2.10-1.95 (m, 1H), 1.95-1.73 (m, 2H), 1.72-1.58 (m, 1H), 1.58-1.50 (m, 1H), 1.47 (s, 3H), 1.32-1.11 (m, 4H), 1.10-0.94 (m, 1H). rhSyk=+++. The slower eluting enantiomer Rt=4.04 min. rhSyk=+++
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[C:10](=[O:28])[N:11]([CH:21]3[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]3)[C:12]3[N:13]([N:18]=[CH:19][N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1.[N+](=CC(OCC)=[O:41])=[N-].[C:45]1([CH3:51])[CH:50]=CC=C[CH:46]=1>C([O-])(=O)C.[Rh+]>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[C:10](=[O:28])[N:11]([C@H:21]3[CH2:22][CH2:23][C@H:24]([O:27][CH2:46][C:45]([OH:41])([CH3:51])[CH3:50])[CH2:25][CH2:26]3)[C:12]3[N:13]([N:18]=[CH:19][N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccccc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n(C2CCC(O)CC2)c2ncnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+]
Agent: CC(=O)[O-]
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Reaction time: 1 h

Procedure:
To a mixture of 2′-fluoro-4′-{[4-(4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.95 g), rhodium(I) acetate (0.007 g) and toluene (20 mL) was added dropwise ethyl diazoacetate (0.96 mL) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography. The obtained residue was dissolved in tetrahydrofuran (15 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 5.8 mL) was added at room temperature. The reaction mixture was stirred for 1 hr, 1 N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 23%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[Cl-].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][Zn+])=[CH:22][N:21]=1>C1COCC1.O.C(OCC)(=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>[Cl:19][C:20]1[N:21]=[CH:22][C:23]([CH2:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][CH3:13])=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1cc(Br)c2ccccc2c1OC
Reactant: Clc1ccc(C[Zn+])cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cc2ccc(Cl)nc2)c2ccccc2c1OC
Temperature: 90 °C

Procedure:
To a solution of methyl 4-bromo-1-methoxy-2-naphthoate (see Example 2, 0.500 g, 1.69 mmol) in 5 mL of THF under an atmosphere of nitrogen was added (2-chloro-5-pyridyl)methylzinc chloride (0.5 M in THF, 10.2 mL, 5.08 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.050 g, 0.043 mmol). The reaction was heated at 90° C. for 2 hours, then cooled to room temperature and diluted with water and ethyl acetate. The mixture was filtered through celite and the organic solution was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes to provide methyl 4-[(6-chloropyridin-3-yl)methyl]-1-methoxy-2-naphthoate that gave a mass ion (ES+) of 342.0 for [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[O:18][C:16](=O)[C:15](=[C:19]=[O:20])[CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O.[NH2:22][NH2:23]>C(O)C>[OH2:2].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[O:18][C:16](=[N:22][NH2:23])[C:15](=[C:19]=[O:20])[CH2:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C2CC(=C=O)C(=O)O2)cc(OC)c1OC
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1cc(C2CC(=C=O)C(=NN)O2)cc(OC)c1OC

Procedure:
11.2 g (0.04 mol) of 4-(3,4,5-trimethoxyphenyl)-carbonyl-γ-butyrolactone and 2 ml (0.04 mol) of hydrazine hydrate are stirred in 60 ml of ethanol at room temperature for 1 hour and the precipitate is filtered off with suction.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:22])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH2:15]C1C=CC=CC=1)[CH:2]=[CH2:3].[CH:23](O)(C)C>>[CH2:1]([O:4][C:5](=[O:22])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH:14]([CH3:15])[CH3:23])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: CC(C)O
Product: C=CCOC(=O)NC1CC(=O)OC1OC(C)C
Yield: 81 %

Procedure:
Prepared as described for compound 40 using isopropanol to afford 3.80 grams (81% yield) of the title compound as a colorless oil. 1H-NMR (500 MHz, CDCl3) δ 1.10-1.35 (m, 6H), 2.32-2.60 (m, 1H), 2.82 (dd, 0.5H), 3.02 (dd, 0.5H), 3.82-4.11 (m, 1H), 4.48-4.66 (m, 3H), 5.20-5.36 (m, 2H), 5.54 (dd, 1H), 5.82-6.05 (m, 1H). LC-MS (ES+): m/e=244.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:8][S:9]([O:12]C)(=[O:11])=[O:10].[CH3:14]N(C)C=O>CO>[S:9]([OH:12])(=[O:11])(=[O:10])[CH3:8].[NH2:1][C:2]1[N:3]([CH3:14])[NH:4][CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccnn1
Reactant: CN(C)C=O
Reactant: COS(C)(=O)=O
Solvent: CO
Product: CN1NC=CN=C1N
Product: CS(=O)(=O)O
Reaction time: 0.5 h

Procedure:
A mixture of the 3-amino-1,2,4-triazine [6] (500 mg), methyl methanesulphonate (0.5 cm3), dimethylformamide (0.5 cm3) and methanol (10 cm3) was stirred at 60° for 30 mins. and the resulting deep yellow solution allowed to stand at room temperature for 24 hrs. The deep yellow plates that were deposited were filtered off washed with acetone-ether (1:1) and dried.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li].[C:13](=[O:15])=[O:14].CCOCC>O1CCCC1.CCCCCC>[C:1]1([C:7]2[S:8][C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cccs2)cc1
Reactant: O=C=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(O)c1ccc(-c2ccccc2)s1
Reaction time: 1 h

Procedure:
A solution of 2-phenylthiophene (16.0 g, 0.1 mole) in 100 ml anhydrous tetrahydrofuran (THF) is treated dropwise with a solution of n-bityl lithium (0.11 mole) in hexane (2 M solution). Thereafter the mixture is stirred for 1 hr. The resulting black solution is poured onto 50 g of solid CO2 covered with ether. When all the CO2 is evaporated, the mixture is treated with 200 ml of water, acidified with 10% HCl and extracted with ether. The extract is washed with 5% NaOH. The latter washings are cooled and rendered acidic with 20% HCl. The resulting precipitate is collected and recrystallized from 1000 ml CCl4 to give 5-phenyl 2-thiophenecarboxylic acid, mp 180° C, γmaxCHCl3 1665 cm -1, as yellow green crystals.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.Cl[CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C)C=O.O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: ClCCCN1CCOCC1
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(=O)c1cnc2c(OCCCN3CCOCC3)cccc2c1Nc1ccccc1C
Reaction time: 2.5 h
Yield: 58.1 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) and potassium t-butoxide (5.0 g, 40 mmol) were stirred in dry dimethylformamide (100 ml) at 100° , then 4-(3-chloropropyl)morpholine hydrochloride (5 0 g, 14 mmol) was added. Heating was continued for 2.5 hours, then the mixture was diluted with water and extracted with ether. The combined extracts were dried and evaporated to an oily residue. Chromatography (silica gel, 3% methanolic ammonia in chloroform) and crystallisation from petroleum ether gave 3-butyryl-4-(2-methylphenylamino)-8-(3-morpholinopropoxy)quinoline (2.6 g, 58 %), m.p. 111°-113°.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[Br-].Br[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.O>CN(C)C=O.C(OCC)(=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Oc1ccccc1I
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Ic1ccccc1OC1CCCC1
Temperature: 120 °C
Yield: 95.3 %

Procedure:
A mixture of 2-iodophenol (8.0 g, 36.4 mmol), milled potassium carbonate (5.5 g, 39.9 mmol, 1.1 eq) and 1-bromocyclopentane bromide (3.9 ml, 36.4 mmol) in 25 ml of N,N-dimethylformamide was heated at 120° C. for 1.1 hrs and cooled. The mixture was poured into water and extracted twice with ether. The ether layer was dried over magnesium sulfate, filtered, and concentrated to give an oil. The crude product was dissolved in ethyl acetate and filtered through a short pad of silica gel. The filtrate was redried over magnesium sulfate, filtered and concentrated under vacuum to give 10 g (95%) of product as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[C:22]3[N:21]=[N:20][NH:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[C:22]3[N:21]=[N:20][NH:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CCNS(=O)(=O)c2cccc3[nH]nnc23)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCNS(=O)(=O)c2cccc3[nH]nnc23)cc1
Yield: 71.5 %

Procedure:
N-(4-Nitrophenethyl)benzotriazole-4-sulphonamide (10 g, 29 mM) was suspended in ethanol (250 ml) and hydrogenated at 50 psi over 10 percent palladium on carbon catalyst (1 g) until hydrogen uptake ceased. The mixture was filtered through anhydrous sodium sulphate and the filtrate was concentrated under reduced pressure to leave the product as a pale yellow solid (6.53 g, 71 percent), m.p. 178° to 179° (uncorr.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([S:18]([N:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]1=2.Br[CH2:37][C:38]([NH2:40])=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:21]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:18]([C:15]2[CH:16]=[CH:17][C:9]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[O:1][CH2:37][C:38]([NH2:40])=[O:39])[CH2:13][CH2:12][O:11][C:10]=3[CH:14]=2)(=[O:19])=[O:20])=[CH:33][CH:32]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2O)cc1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2OCC(N)=O)cc1
Temperature: 80 °C
Yield: 49 %

Procedure:
To a solution of 4-(2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (550 mg, 1.080 mmol), 2-bromoacetamide (704 mg, 5.108 mmol, Aldrich) in DMF (10 mL) was added potassium carbonate (528 mg, 3.83 mmol). The reaction mixture was heated at 80° C. for 12 h. After completion, the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water (50 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 0-60% ethyl acetate in hexane) to get 2-(2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)phenoxy)acetamide (300 mg, 49.0%). MS (ESI, positive ion) m/z; 567.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:21][N:20](S(CC5CCCC5)(=O)=O)[CH2:19]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.N1CC(NC2C(F)=CN=C(C3C4C(=NC=C(Cl)C=4)N(S(C4C=CC(C)=CC=4)(=O)=O)C=3)N=2)C1.[N:65]([Si](C)(C)C)=[C:66]=[O:67]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:19][N:20]([C:66]([NH2:65])=[O:67])[CH2:21]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(CC1CCCC1)N1CC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: C[Si](C)(C)N=C=O
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CNC4)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Product: NC(=O)N1CC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 79 %

Procedure:
According to the procedure for compound 469 using 61 mg (0.11 mmol) of 6c and isocyanatotrimethylsilane (15.14 μL, 0.11 mmol) afforded 87 mg (79% yield) of 512, as a white solid:
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH2:12][C:11]([CH2:17][NH2:18])=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH3:5].[C:19](Cl)(=[O:23])[CH2:20][CH2:21][CH3:22]>>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH2:12][C:11]([CH2:17][NH:18][C:19](=[O:23])[CH2:20][CH2:21][CH3:22])=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc2c(c1)C=C(CN)CO2
Reactant: CCCC(=O)Cl
Product: CCCCCOc1ccc2c(c1)C=C(CNC(=O)CCC)CO2

Procedure:
0.37 g (1.5 mmol) of the amine obtained in Step F of Example 55 is condensed with butanoyl chloride according to the same procedure as in Example 54. Purification on a silica column (eluant:ethyl acetate/petroleum ether 50/50) allows isolation of the title amide in the form of a yellowish solid.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:33][C:34]1[CH:38]=[C:37]([CH2:39][C:40](O)=[O:41])[O:36][N:35]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])[O:11][C:10](=[O:12])[C:9]([C:40](=[O:41])[CH2:39][C:37]3[O:36][N:35]=[C:34]([CH3:33])[CH:38]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c(OC)c1
Reactant: Cc1cc(CC(=O)O)on1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(C(=O)Cc3cc(C)no3)C(=O)O2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
To a solution of 6-cyclopentyl-6-[2-(2,4-dimethoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione (52 mg, 0.15 mmol) from Step 2 below, triethylamine (0.075 mL, 0.68 mmol) and (3-Methyl-isoxazol-5-yl)-acetic acid (0.027 g, 0.196 mmol) in CH2Cl2 (1.5 mL) were added DMAP (1 mg), and EDC (37 mg, 0.196 mmol). The reaction was stirred at room temperature for 18 hours, and then diluted with CH2Cl2. The organic was washed with water, and the layers were separated. The organic layer was dried under vacuum, and then purified by preparatory HPLC to give the desired compound (26.2 mg, 37% yield).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.Cl[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29].CCOCC.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:7][C:4]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)=[CH:12][CH:13]=2)=[C:2]([NH:1][C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29])[O:6][N:5]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1noc(N)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 1 h

Procedure:
To tert-butyl 4-[4-(5-amino-3-methylisoxazol-4-yl)phenyl]piperazine-1-carboxylate (900 mg, 2.51 mmol) and DMAP (1.02 g, 8.3 mmol) in CH2Cl2 (25 mL) at 0° C. under dry nitrogen was added 2,2,2-trichloroethyl chloroformate (1.02 g, 8.3 mmol) dropwise and the reaction was warned to rt and stirred for 1 hour. Additional aliquots of DMAP (1.02 g, 8.3 mmol) and 2,2,2-trichloroethyl chloroformate (1.02 g, 8.3 mmol) were added and the reaction mixture was stirred for 2½ hours. Et2O was added and the reaction was poured into aqueous 10% HCl, extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 3/7) to afford tert-butyl 4-[4-(3-methyl-5-{[(2,2,2-trichloroethoxy)carbonyl]amino}isoxazol-4-yl)phenyl]piperazine-1-carboxylate.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([F:8])=[C:5]([F:7])[F:6].[K].[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(Cl)(Cl)Cl>CN(C)C=O.O>[F:8][C:4](=[C:5]([F:7])[F:6])[CH2:3][CH2:2][N:14]1[C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]2[C:10]1=[O:20]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: FC(F)=C(F)CCBr
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCC(F)=C(F)F
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 10.0 grams (0.053 mole) of 4-bromo-1,1,2-trifluoro-1-butene in 50 ml of dimethylformamide was added 10.4 grams (0.056) of the commercially available potassium salt of phthalimide. The reaction mixture was warmed to 50° C. where it stirred for four hours. The reaction mixture was allowed to cool and 50 ml of chloroform was added. The mixture was poured into 200 ml of water. The aqueous layer was separated and extracted with two 50 ml portions of chloroform. The combined organic layers were washed with two 50 ml portions of aqueous 5% sodium hydroxide and one 50 ml portion of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 4.8 grams of N-(3,4,4-trifluoro-3-butenyl)phthalimide as an oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[CH3:9].[OH-].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)[O:14]C1.O>C(O)COCCO>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:14])[CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Reactant: Cc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Cc1c(O)cccc1Cl

Procedure:
16.1 g (0.1 mol) of 2,6-dichlorotoluene, 19.8 g (0.3 mol) of potassium hydroxide (85%) and 0.3 g of dibenzo-18-crown-6 are heated in 30 ml of diethylene glycol at a bath temperature of 190° C. with reflux for 16 hours. The water released during the reaction is distilled off. After cooling, the reaction mixture is stirred with 100 ml of water until a solution is obtained and extracted three times with 50 ml of dichloromethane. The aqueous phase is admixed with 35 ml of 30% hydrochloric acid and extracted three times with 70 ml of dichloromethane. The organic phases are dried and concentrated under reduced pressure. 3-Chloro-2-methylphenol is obtained as a solid (11.5 g, content by HPLC: 97%, 78% of theory).