Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:31]=[C:18]3[N:19]=[C:20]([CH3:30])[C:21]([CH:24]([OH:29])[C:25]([O:27][CH3:28])=[O:26])=[C:22]([Cl:23])[N:17]3[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:31]=[C:18]3[N:19]=[C:20]([CH3:30])[C:21]([CH:24]([O:29][C:2]([CH3:7])([CH3:3])[CH3:1])[C:25]([O:27][CH3:28])=[O:26])=[C:22]([Cl:23])[N:17]3[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)c1c(C)nc2cc(-c3cccc(OCc4ccccc4)c3)nn2c1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2cc(-c3cccc(OCc4ccccc4)c3)nn2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a suspension of methyl 2-(2-(3-(benzyloxy)phenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate. (80 mg, 0.18 mmol) in tert-butyl acetate (5 mL) at room temperature was added CH2Cl2 (10 mL) followed by perchloric acid (27 mg, 0.26 mmol). The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic phase was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (80 mg, 92%). Used as is in the next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13]2)[CH:3]=1.C[S-:24].[Na+].Cl>CN(C)C=O.O>[CH2:13]1[C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[CH2:16][CH2:17][CH2:18][N:12]1[C:4]1[CH:3]=[C:2]([SH:24])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: C[S-]
Reactant: Clc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Sc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (2 g, 6.47 mmol) and sodium thiomethoxide (2.4 g, 34 mmol) in dry N,N-dimethylformamide (20 mL) was heated with stirring overnight under reflux. The reaction mixture was cooled to 50° C. and the volatile components were evaporated under reduced pressure to give a residue which was dissolved in 30 mL of chilled water and carefully acidified with 20% hydrochloride aid to pH 4-5 under argon. The resultant solution was extracted with chilled dichloromethane (30 mL×3). The dichloromethane fractions were combined and washed with chilled brine (30 mL×2) and then concentrated under reduced pressure at room temperature to give the crude product. It was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:18](=[O:21])([O-])O.[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][C:36]1[CH:37]=[C:38]([NH2:42])[CH:39]=[N:40][CH:41]=1>ClCCl>[Cl:17][C:13]1[N:12]=[C:11]([NH:10][C@H:8]([C:4]2[CH:3]=[C:2]([NH:1][C:18]([NH:42][C:38]3[CH:39]=[N:40][CH:41]=[C:36]([CH3:35])[CH:37]=3)=[O:21])[CH:7]=[CH:6][CH:5]=2)[CH3:9])[CH:16]=[N:15][CH:14]=1
Reactant: Cc1cncc(N)c1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1cccc(N)c1
Reactant: O=C([O-])O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cncc(NC(=O)Nc2cccc([C@H](C)Nc3cncc(Cl)n3)c2)c1
Reaction time: 3 h
Yield: 42 %

Procedure:
To a vigourously stirred mixture of N-[(1S)-1-(3-aminophenyl)ethyl]-6-chloropyrazin-2-amine (49 mg, 0.2 mmol) and saturated aqueous sodium hydrogen carbonate (1.2 mL) in dichloromethane (1.2 mL) was added triphosgene (20 mg, 0.067 mmol) in one portion and the mixture was stirred for 3 hours. After this time 5-methylpyridin-3-amine (60 mg, 0.55 mmol) was added and the mixture was stirred for 17 hours. The mixture was then diluted with dichloromethane (20 mL) and was washed with brine (20 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and extracted with dilute aqueous hydrochloric acid (0.5M, 3×15 mL). The combined acidic extracts were basified to pH 5 with solid potassium hydroxide and were then extracted with dichloromethane (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated under reduced pressure to give an orange oil which was purified by passage through a column of Sephadex with methanol as eluant. N-(3-{(1S)-1-[(6-Chloropyrazin-2-yl)amino]ethyl}phenyl)-N′-(5-methylpyridin-3-yl)urea (32 mg, 42%) was obtained as a colourless foam.
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[C:3]#[CH:4].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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>[F:6][C:7]1[C:8]([C:4]#[C:3][C@H:2]([OH:5])[CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: C#C[C@@H](C)O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H](C)O)c21

Procedure:
Using Method C above, (R)-but-3-yn-2-ol (37 mg, 0.53 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and Cul (2 mg) in a mixture of DMF (3mL) and Et3N (3 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-butynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after a silica gel column with a 0-70% EtOAc in hexanes gradient and trituration with petroleum ether. (Yield 21 mg, 48%).
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[CH:20]([C:22]1[C:23]([NH:33][C:34](=[O:58])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[N:45]=[C:46]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[O:47][C:48]=3[CH3:49])=[C:38]([O:56][CH3:57])[CH:37]=2)=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=1)=O.O>CN(C)C=O>[CH3:57][O:56][C:38]1[CH:37]=[C:36]([CH2:35][C:34]([NH:33][C:23]2[C:22](/[CH:20]=[CH:1]/[P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:26][N:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=2)=[O:58])[CH:41]=[CH:40][C:39]=1[O:42][CH2:43][C:44]1[N:45]=[C:46]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[O:47][C:48]=1[CH3:49]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(CC(=O)Nc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 21 %

Procedure:
To a solution of tetraethyl methylenediphosphonate (357 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 54 mg), and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added a solution of N-(4-formyl-1-phenyl-1H-pyrazol-3-yl)-2-{3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}acetamide (590 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1 to 1:0, v/v) to give diethyl (E)-2-{3-[({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}acetyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless amorphous form (159 mg, yield 21%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:4]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][NH:31][C:32](=[O:34])[CH3:33].[H-].[Na+]>O1CCCC1>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][N:31]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:4]=1)[C:32](=[O:34])[CH3:33]
Reactant: CCCCCCCCCCCCCCOc1cccc(CBr)c1
Reactant: CC(=O)NCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cccc(CN(Cc2ccccn2)C(C)=O)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
The title compound is prepared by the procedure of Example 27 using 2.25 g of product from Example 25, 0.881 g of product from Example 12, 0.282 g of 50% sodium hydride and 30 ml of tetrahydrofuran. The reaction is stirred at 0° C. for 1 hour, room temperature for 18 hours and at reflux temperature for 6 hours. The residue is purified by column chromatography (silica gel: 90% ethyl acetate/hexane) to give 1.57 g of product as pale yellow crystals. Spectral data shows the product as 2 rotomers.
Reaction SMILES: [Na][Na].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[S:20](Cl)([OH:23])(=[O:22])=O.[CH:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([S:20]([O:3][C:4]2[CH:5]=[CH:6][C:7]([S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][S:10]([C:7]4[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=4)(=[O:12])=[O:11])=[CH:15][CH:14]=3)(=[O:12])=[O:11])=[CH:8][CH:9]=2)(=[O:23])=[O:22])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccccc1
Reactant: O=S(=O)(O)Cl
Reactant: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na][Na]
Product: O=S(=O)(Oc1ccc(S(=O)(=O)c2ccc(OS(=O)(=O)c3ccccc3)cc2)cc1)c1ccccc1

Procedure:
Alternatively, the sulfonyl halide may be reacted with bisphenolate in the first stage in a molar ratio of more than 1:1 to 2:1 under the reaction conditions described. For example, if one mole of disodium-bis-(4-hydroxyphenyl)-sulfone is reacted with 2 moles of benzene sulfochloride, there is obtained bis-(4-phenylsulfonyloxyphenyl)-sulfone, which may then be condensed, in the subsequent polycondensation stage, again with one mole of disodium-bis-(4-hydroxyphenyl)-sulfone to form the polyether. This condensation is preferably carried out in a solvent which has already been used for the synthesis of the alkali metal salt. At a lower excess of sulfonyl halide, e.g. a ratio of from 1.5:1, there are obtained in the first stage mixtures of bis-(4-phenylsulfonyloxyphenol)-sulfone and the sodium salt of 4-(4-phenylsulfonyloxyphenyl-sullfone)-phenol, which may then be condensed with appropriately smaller quantities of disodium-bis-(4-hydroxyphenyl)-sulfone to form the polyethers.
Reaction SMILES: CO.[C:3](=[O:6])(O)[O-].[Na+].[N:8]1[C:15](Cl)=[N:14][C:12](Cl)=[N:11][C:9]=1[Cl:10].[C:17](=O)=[O:18]>O>[Cl:10][C:9]1[N:11]=[C:12]([O:18][CH3:17])[N:14]=[C:15]([O:6][CH3:3])[N:8]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(Cl)nc(OC)n1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 45.0 grams of methanol and 5.0 grams of water was added 16.8 grams (0.2 mole) of sodium bicarbonate and 18.5 grams (0.1 mole) of cyanuric chloride. The addition caused the reaction mixture temperature to rise to 35° C. and the liberation of carbon dioxide gas. After the gas evolution slowed, the reaction mixture was heated to reflux where it stirred for 30 minutes. The reaction mixture was cooled, diluted with water, and the resultant solid was collected by filtration. The solid was washed repeatedly with water and dried to yield 13.0 grams of 2-chloro-4,6-dimethoxy-1,3,5-triazine, m.p. 74°-76° C. Recrystallization of the solid from heptane raised the melting point to 75°-76° C.
Reaction SMILES: ClC1C=CC(C2[C:9]([CH:14]=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=CC=1.[NH:16]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17]1.N1(C(OC(C)(C)C)=O)CCNC[CH2:30]1>>[CH3:30][C:12]1([CH3:13])[CH2:11][CH:10]([N:16]2[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:17]2)[CH2:9][CH2:14][O:15]1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C2CCOC(C)(C)C2)C1

Procedure:
The title compound was prepared by substituting 2,2-dimethyldihydro-2H-pyran-4(3H)-one for 4′-chlorobiphenyl-2-carboxaldehyde and (S)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([O:10][CH3:14])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)cc(C=O)c1O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C)cc(F)cc1C=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5-Fluoro-2-hydroxy-3-methylbenzaldehyde (1.24 g, 8.01 mmol) was dissolved in N,N-dimethylformamide (20 mL) and to the solution was added methyl iodide (0.8 mL, 12.71 mmol) and potassium carbonate (3.1 g, 22.52 mmol). The mixture was stirred at 100° C. for one hour, cooled to room temperature and then diluted with water (40 mL). After extraction twice with ethyl acetate (40 mL) the combined organic layer was washed with brine and then dried over Na2SO4. The solvent was removed and the solid residue was treated with methanol. After filtration and drying desired compound was obtained 1.2 g (99%). 1H NMR (400 MHz, CDCl3): δ10.12 (s, 1H), 7.23 (dd, 1H), 6.85 (dd, 1H), 3.75 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[C:11]2[C:6](=[C:7]([Cl:26])[C:8]([O:24]C)=[C:9]([O:22]C)[CH:10]=2)[CH2:5]1)[CH:2]=[CH2:3].B(Br)(Br)[Br:28]>C(Cl)Cl.C(OCC)(=O)C.CO>[BrH:28].[CH2:1]([N:4]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:11]2[C:6](=[C:7]([Cl:26])[C:8]([OH:24])=[C:9]([OH:22])[CH:10]=2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: BrB(Br)Br
Reactant: C=CCN1Cc2c(cc(OC)c(OC)c2Cl)C(c2ccc(OC)cc2)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Br
Product: C=CCN1Cc2c(cc(O)c(O)c2Cl)C(c2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
The N-allyl trimethoxy base (VII) (2.4 g, 0.0064 m) was dissolved in 50 ml of methylene chloride and mixed with a solution of 6.0 ml (0.64 m) of boron tribromide in 40 ml of methylene chloride at -15°. After stirring for 2 hours at room temperature, the mixture was cooled and quenched with methanol several times, the last time with 4 drops of 48% hydrogen bromide added. Final evaporation gave a foam which was dissolved in ethyl acetate-methanol. The mixture was heated at reflux briefly then cooled to give 1.5 g (52%) of 2-allyl-8-chloro-6,7-dihydroxy-4-(p-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrobromide, m.p. 252°-254° (d.).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[C:32]([O:34]C)=[O:33])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.Cl.O1CCOCC1>C(O)CCC>[F:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]5[CH2:31][CH2:30][CH2:29][C@H:28]5[C:32]([OH:34])=[O:33])=[O:26])=[CH:21][CH:20]=4)=[CH:17][CH:18]=3)=[N:6][C:5]=2[CH:7]=1
Reactant: Fc1ccc2sc(Cl)nc2c1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)ccc4s3)cc2)cc1
Temperature: 90 °C

Procedure:
2-Chloro-5-fluoro-1,3-benzothiazole (29 mg, 0.16 mmol) and methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclopentanecarboxylate (50 mg, 0.16 mmol) were combined in 1-butanol. The solution was treated with 4 M HCl in dioxane (4 μL, 0.016 mmol) and heated at 90° C. for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was suspended in methanol, and the resulting solid was collected by filtration and dried in vacuo. The title compound was obtained as a pale yellow solid (55 mg, 77%); LC-MS m/z 475.3 (MH+), retention time 3.97 minutes.
Reaction SMILES: [H-].[Na+].[Br:3][CH:4]1[CH:8]=[N:7][N:6]=[CH:5]1.[CH3:9][O:10][C:11](=[O:15])[CH:12](Cl)[CH3:13]>CN(C=O)C>[CH3:9][O:10][C:11](=[O:15])[CH:12]([N:6]1[CH:5]=[C:4]([Br:3])[CH:8]=[N:7]1)[CH3:13]
Reactant: COC(=O)C(C)Cl
Reactant: BrC1C=NN=C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)n1cc(Br)cn1
Reaction time: 0.17 h
Yield: 77 %

Procedure:
Sodium hydride (0.12 g, 4.9 mmol) was added to a solution of 4-bromo-4H-pyrazole (0.60 g, 4.1 mmol) in DMF (10 mL). After stirring for 10 minutes, a solution of 2-chloro-propionic acid methyl ester in DMF (4 mL) was added. After stirring for 4 hours, the reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of ethyl acetate and hexanes to afford 2-(4-bromo-pyrazol-1-yl)-propionic acid methyl ester (733 mg, 77%).
Reaction SMILES: CC(N)(C)C[C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[O:20]1[CH2:22][C@H:21]1[CH2:23][O:24][C:25]1[C:37]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1>CCO>[OH:20][C@@H:21]([CH2:22][N:30]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[CH:16][CH:17]=1)[CH2:29][CH:37]([CH3:25])[CH3:36])[CH2:23][O:24][C:25]1[C:37]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(N)Cc1ccc(Oc2ccc(O)cc2)cc1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Solvent: CCO
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(Oc2ccc(O)cc2)cc1
Temperature: 60 °C

Procedure:
4-(4-(2-Methyl-2-aminopropyl)phenoxy)phenol (0.40 g, 1.55 mmol) was combined with (S)-4-(oxiranylmethoxy)-9H-carbazole (0.250 g, 1.0 mmol) in EtOH (50 mL) and the mixture heated at 60° C. for 20 hours. The mixture was then concentrated in vacuo and the resulting residue chromatographed over silica (1–10% MeOH/CHCl3) which allowed for isolation of the product as the free base. The free base was then dissolved in minimal EtOAc and treated with diethyl ether (25 mL) saturated with HCl. Filtration and drying netted 0.410 g (76%) of product as the HCl salt. MS (FD+): 497. m.p. 80–85° C. (dec). Anal. Calcd for C31H32N2O4.1.3HCl: C, 68.31; H, 6.16; N, 5.14. Found: C, 68.30; H, 6.75; N, 4.62.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH2:21])=O)=[CH:15][CH:14]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:22])[C:19]#[N:21])=[CH:23][CH:24]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3c2)cc1)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C#N)Oc1ccc(Oc2cnc3cc(Cl)ccc3c2)cc1

Procedure:
2-[4-(7-Chloroquinolin-3-yloxy)phenoxy]propionamide (see Example 23) (1.2 g) was added slowly with stirring to phosphorus oxychloride (10 ml) at 20° C. The mixture was heated briefly to the boiling point then poured on to water and neutralized carefully with aqueous sodium bicarbonate solution. Extraction with ethyl acetate gave, after drying and evaporation, the crude product as a pale yellow oil. Purification by chromatography on silica gel gave 2-[4-(7-chloroquinolin-3-yloxy)phenoxy]propionitrile, characterised by its proton magnetic resonance spectrum (Table 3).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([OH:13])(=[O:12])[CH:10]=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=[CH2:20]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]2[C:5]3[C:3](=[C:2]([I:1])[CH:8]=[CH:7][CH:6]=3)[NH:4][CH:10]([C:9]([OH:13])=[O:12])[CH2:20]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: Nc1ccccc1I
Reactant: O=CC(=O)O
Reactant: C=Cc1ccc(OC)c(OC)c1
Product: COc1ccc(C2CC(C(=O)O)Nc3c(I)cccc32)cc1OC

Procedure:
Compound 70 was prepared from 2-iodoaniline, glyoxylic acid and 3,4-dimethoxystyrene by the automated process.
Reaction SMILES: N1C=CC=CC=1.[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[CH2:24][CH2:25][CH3:26].[C:27](OC(=O)C)(=[O:29])[CH3:28].CO>ClCCl>[C:27]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:23])([C:15]([F:16])([F:17])[F:18])[C:19]([F:20])([F:21])[F:22])=[CH:10][C:9]=1[CH2:24][CH2:25][CH3:26])(=[O:29])[CH3:28]
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1OC(C)=O
Reaction time: 8 h
Yield: 87 %

Procedure:
Pyridine (14.7 mL) was added to 2-(4-hydroxy-3-propylphenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (13.76 g, 45.5 mmol) in dichloromethane (200 mL) at room temperature, and then acetic anhydride (17.3 mL) was added. After stirring overnight, methanol (300 mL) was added. After stirring at room temperature for one hour, the reaction solution was concentrated under reduced pressure. Water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 13.67 g of the title compound (yield: 87%) as a red brown oil.