Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:33])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:23]=1[Cl:32])[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.CO.[OH-].[Li+].O>C(O)(=O)C>[Cl:32][C:23]1[CH:24]=[C:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:26]=[CH:27][C:22]=1[CH2:21][C:9]1[C:10]([O:17][CH:18]([F:19])[F:20])=[N:11][C:12]2[C:7]([C:8]=1[CH3:33])=[C:6]([O:5][CH2:4][C:3]([OH:34])=[O:2])[CH:15]=[CH:14][C:13]=2[F:16]
Reactant: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(S(C)(=O)=O)cc3Cl)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Cc1c(Cc2ccc(S(C)(=O)=O)cc2Cl)c(OC(F)F)nc2c(F)ccc(OCC(=O)O)c12

Procedure:
A solution of [3-(2-chloro-4-methanesulfonylbenzyl)-2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.22 g), methanol (8.0 mL), 5.0 M aqueous lithium hydroxide solution (0.4 mL) and water (0.8 mL) was stirred at room temperature for 2 hours. The pH of the solution was adjusted to 4 by the addition of glacial acetic acid and the solvent removed under reduced pressure. The residue was diluted with water (4.0 mL) and the solid collected by filtration, washed with water and methanol and dried to afford to title compound as a white solid, 0.17 g.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[OH:17].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([NH:10][C:11](=[O:16])[C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:4][C:3]=1[O:17][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][O:18]1
Reactant: C1=COCCC1
Reactant: CC(C)(C)C(=O)Nc1cc(O)c(F)c(F)c1F
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(OC2CCCCO2)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
1.19 g (4.82 mmol) of the above 2,3,4-trifluoro-5-pivaloylaminophenol was dissolved in 50 mL of dichloromethane, 0.88 mL (9.6 mmol) of 3,4-dihydro-2 H-pyran and 22 mg (0.095 mmol) of dl-camphorsulfonic acid were added and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 100 mL of a 10% aqueous solution of potassium carbonate and the mixture was extracted once with chloroform. The organic layer was washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was triturated with n-hexane to give 1.25 g of 2,3,4-trifluoro-5-pivaloylamino-O-tetrahydropyranylphenol (yield: 78%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1B(O)O.I[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[C:34]3[N:35]=[C:36]([NH2:38])[S:37][C:33]=3[CH:32]=[CH:31][CH:30]=2)[CH:23]=1>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[C:34]3[N:35]=[C:36]([NH2:38])[S:37][C:33]=3[CH:32]=[CH:31][CH:30]=2)[CH:23]=1
Reactant: Nc1nc2c(Oc3cc(I)ncn3)cccc2s1
Reactant: CC1CCCN1Cc1cc(C(F)(F)F)ccc1B(O)O
Product: CC1CCCN1Cc1cc(C(F)(F)F)ccc1-c1cc(Oc2cccc3sc(N)nc23)ncn1

Procedure:
2-((2-Methylpyrrolidin-1-yl)-methyl)-4-(trifluoromethyl)phenylboronic acid, Example 19(b), (72 mg, 0.25 mmol) and 4-(6-iodopyrimidin-4-yloxy)benzo[d]thiazol-2-amine (93 mg, 0.25 mmol, prepared as described in WO04014871) was reacted under conditions of Example 19(f) to give the title compound. MS (ESI, pos. ion.) m/z: 486 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[SH:16][C:17]1[S:21][C:20]([S:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(C(C)=O)C>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:16][C:17]2[S:21][C:20]([S:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:19][N:18]=2)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CSc1nnc(S)s1
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(CSc2nnc(SCC(=O)OCC)s2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a mixture of 0.42 g of 4-acetyl-3-hydroxy-2-propylbenzyl chloride, 0.54 g of ethyl [(5-mercapto-1,3,4-thiadiazol-2-yl)thio]acetate, 0.30 g of anhydrous potassium carbonate and 5 ml of methyl ethyl ketone were added catalytic amounts of potassium iodide and tetra-n-butylammonium bromide followed by stirring at 60° C. for 3 hours. The reaction mixture was diluted with toluene and insoluble matters were filtered off. The filtrate was washed with an aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate. The solvent was then distilled off. The residue was subjected to silica gel column chromatography. Elution with a mixture of hexane-ethyl acetate (5:1) gave 0.75 g of oily ethyl [[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]1,3,4-thiadiazol-2-yl]thio]acetate. Nuclear magnetic resonance spectrum (in CDCl3,
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:29]=[CH:30][C:31]([C:34](O)=[O:35])=[N:32][CH:33]=1)#[N:27].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl>CN(C=O)C.CCOC(C)=O.O>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:34]([C:31]3[CH:30]=[CH:29][C:28]([C:26]#[N:27])=[CH:33][N:32]=3)=[O:35])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)COC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)(C(F)F)COC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
[(R)-5-(5-Amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (35 g, 97.4 mmol), 5-cyano-pyridine-2-carboxylic acid (15.87 g, 107.14 mmol) and HOBt hydrate (22.35 g, 146.1 mmol) were dissolved in 185 ml DMF and stirred with ice cooling. When the temperature had reached 0-5° C. EDC (22.33 ml, 126.62 mmol) was added dropwise. The mixture was stirred for 2 h. The ice bath was taken away and stirring was continued for 2 h. The mixture was taken up in EtOAc and water. The phases were separated and the organic phase was washed with 5% aqueous NaHCO3 and brine. The organic phase was dried with MgSO4.H2O and evaporated to provide a beige solid. Crystallisation from EtOAc/hexane gave the title compound as colorless crystals. Yield 44.47 g.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.P([O-])([O-])([O-])=O.N.C1CCCCC1>C(OC(C)C)(C)C.O>[CH:35]([C:5]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:2]([CH3:1])=[N:3][N:4]=1)([CH3:36])[CH3:37]
Reactant: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCCCC1
Solvent: O
Solvent: CC(C)OC(C)C
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
Crystalline form 1 of maraviroc phosphate (5 gm) was dissolved in diisopropyl ether (60 ml) and water (40 ml). The pH of the reaction mass was adjusted to 8.0 to 8.5 with ammonia solution (3 ml) and stirred for 15 minutes. The separated organic layer was dried with sodium sulfate and treated with carbon. The diisopropyl ether was distilled off under vacuum at below 45° C. to obtain residual mass. To the residual mass was added cyclohexane (50 ml) and stirred for 20 minutes at room temperature, filtered. The solid obtained was dried to obtain 3.4 gm of maraviroc amorphous form.
Reaction SMILES: C([NH:8][CH:9]1[CH2:12][CH:11]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])[CH2:10]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]1[CH2:12][CH:11]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])[CH2:10]1
Reactant: CON(C)C(=O)C1CC(NCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CON(C)C(=O)C1CC(N)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 95 %

Procedure:
A mixture of 3-(benzylamino)-N-methoxy-N-methylcyclobutanecarboxamide (349 mg, 2.2 mmol) and wet palladium hydroxide on activated carbon (50 wt %, 200 mg) in methanol (30 mL) was stirred under hydrogen (30 psi) at room temperature for 13 hours then the reaction mixture was filtered through CELITE™ H and washed with methanol. The filtrate was concentrated in vacuo to give 3-amino-N-methoxy-N-methylcyclobutanecarboxamide (332 mg, 2.09 mmol, yield 95%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[CH3:15][C:16]([CH3:18])=O.N1CCCC1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:15][C:16]1([CH3:18])[CH2:2][C:1](=[O:3])[C:4]2[C:13](=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=2)[O:14]1
Reactant: CC(C)=O
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: COC(=O)c1ccc2c(c1)C(=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-acetyl-4-hydroxybenzoate (200 mg, 1.03 mmol), acetone (151 μL, 2.06 mmol) and pyrrolidine (25.6 μL, 0.31 mmol) were mixed in toluene (515 μL) and stirred at room temperature for 1 hour. It was then heated to 100° C. for 5 hours, allowed to cool to room temperature, diluted with EtOAc (50.0 mL) and poured into ice. The two layers were separated. The organic layer was washed with 2 N aqueous HCl (10.0 mL), 2 N aqueous NaOH (10.0 mL), water (10.0 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude mixture was purified by silica gel chromatography eluting with 0-30% EtOAc/hexanes to give the desired product as a pale-yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)=[CH:3][CH:2]=1.[CH3:16]I.[OH-].[Na+]>O.C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11]([S:14][CH3:16])=[N:12][CH:13]=2)=[CH:3][CH:2]=1
Reactant: CI
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ncc(Cc2ccncc2)c(=O)[nH]1

Procedure:
A solution of 5-(4-pyridylmethyl)-2-thiouracil (11.0 g), methyl iodide (7.2 g) and sodium hydroxide (2.1 g) in water (50 ml) and ethanol (100 ml) was stirred at 60° for 30 minutes, allowed to cool and filtered to give 5-(4-pyridylmethyl)-2-methylthio-4-pyrimidone m.p. 179°-182° (ethanol).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:10](=[O:11])[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:3]1.[Br:23]Br>CN(C=O)C>[Br:23][C:3]1[N:2]([CH3:1])[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:14])([F:16])[F:15])[C:10](=[O:11])[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cn1cc(-c2ccccc2)c2c(=O)n(CC(F)(F)F)cnc21
Reactant: BrBr
Solvent: CN(C)C=O
Product: Cn1c(Br)c(-c2ccccc2)c2c(=O)n(CC(F)(F)F)cnc21
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a stirring solution of 7-methyl-5-phenyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (825 mg, 2.68 mmol) in anhydrous DMF (6 ml) at 0° C. was added bromine (0.152 ml, 2.95 mmol) and the mixture stirred for 30 min. The mixture was partitioned between ethyl acetate (50 ml) and an aqueous mixture (water, saturated sodium hydrogen carbonate solution and 20% w/w sodium thiosulfate solution, 3:1:4; 100 ml). The aqueous phase was separated and extracted using ethyl acetate (3×25 ml). The combined ethyl acetate fractions were washed with brine/water (1:1, 4×25 ml), dried (anhydrous sodium sulfate), filtered and reduced in vacuo. The resulting residue was purified by silica gel chromatography (gradient 0-40% ethyl acetate in cyclohexane) to afford the title compound (0.97 g, 94%). LCMS RT=1.40 min, M+H+=385.9/388.0.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][CH:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:21]([O:23][C:24]([C@@H:26]([NH:35][C@H:36]([C:38](O)=[O:39])[CH3:37])[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C@@H:26]([NH:35][C@H:36]([C:38]([N:11]1[N:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[S:13][C@H:12]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:39])[CH3:37])[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH3:22]
Reactant: CSc1ccc(C2=NNC(C(=O)OC(C)(C)C)S2)cc1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccc(SC)cc2)S[C@H]1C(=O)OC(C)(C)C

Procedure:
Prepared from the product of step e) and N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine by similar processes to those of Example 1, steps b and c as a yellow oil.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13][CH:7]2[CH2:6][CH:5]=[CH:4][CH2:3]1.C(=O)(O)[O-].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCOCC>O.C1COCC1>[C:22]([NH:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@H:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13][C@H:7]2[CH2:6][CH:5]=[CH:4][CH2:3]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC1CC=CCC2CCC(C(=O)O)N2C1=O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@H]1CC=CC[C@@H]2CC[C@@H](C(=O)O)N2C1=O)c1ccccc1
Reaction time: 18 h

Procedure:
A solution of 6-amino-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid, 9, (5.6 g, 25 mmol) in 70 mL of H2O/THF solution is then treated with sodium bicarbonate (2.3 g, 27.4 mmol) and benzoyl chloride (3 ml, 25.84 mmol). The reaction is stirred for 18 hours and then ether (100 mL) is added. The organics are washed two times with 1 N HCl, once with water, and dried over MgSO4, filtered, and concentrated in vacuo to a residue which is purified over silica to afford the desired compound which is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[OH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:21])([F:22])[F:23])[CH:13]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: N#Cc1ccc(O)cc1C(F)(F)F
Product: N#Cc1ccc(Oc2ccc(C=O)cc2F)cc1C(F)(F)F

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 4-hydroxy-2-(trifluoromethyl)-benzonitrile.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>C(OCC)(=O)C>[C:4]1(=[O:6])[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCCCCC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCCN1C(=O)c2ccccc2C1=O
Yield: 50.8 %

Procedure:
A mixture of phthalic anhydride (5.3 g.) and 7-aminoheptanoic acid (5.8 g.) was heated at 185°-190° C. for 40 minutes and then cooled. The cooled partially solidified product was dissolved in ethyl acetate and the solution washed several times with dilute HCl. The organic layer was dried (MgSO4), filtered and evaporated to dryness and the residue recrystallized from acetic acid to give 7-phthalimidoheptanoic acid (5 g.), m.p. 112°-115° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[CH3:22][C:23]1([CH2:27][S:28](Cl)(=[O:30])=[O:29])[CH2:26][O:25][CH2:24]1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:28]([CH2:27][C:23]2([CH3:22])[CH2:26][O:25][CH2:24]2)(=[O:30])=[O:29])=[C:3]2[O:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Reactant: CC1(CS(=O)(=O)Cl)COC1
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)CC2(C)COC2)c2n(c1=O)CCO2
Yield: 9.1 %

Procedure:
Using the same reaction conditions and procedure as described for the preparation of Example 7A, 8-Amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 0.2 g, 0.499 mmol) was reacted with (3-methyloxetan-3-yl)methanesulfonyl chloride (0.13 g, 0.748 mmol) in dry pyridine (3 mL) to afford the crude product. Purification by preparative HPLC afforded 25 mg of the product (9% yield).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:20]([OH:21])[C@@H:19]([CH3:22])[C:17](=[O:18])[C:16]([CH3:24])([CH3:23])[C@@H:15]([OH:25])[CH2:14][C:12](=[O:13])[O:11][C@H:10](/[C:26](/[CH3:35])=[CH:27]/[C:28]2[N:32]=[C:31]([CH2:33][OH:34])[S:30][CH:29]=2)[CH2:9][C@@H:7]2[O:8][C@:6]2([CH3:36])[CH2:5][CH2:4][CH2:3]1.C[C@@H]1[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O[C@H](/C(/C)=C/C2N=C(C)SC=2)C[C@@H]2O[C@@]2(CO)CCC1.CC(C)=O>C1(C)C=CC=CC=1>[OH:25][CH:15]1[C:16]([CH3:24])([CH3:23])[C:17](=[O:18])[CH:19]([CH3:22])[CH:20]([OH:21])[CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]2([CH3:36])[CH:7]([O:8]2)[CH2:9][CH:10]([C:26]([CH3:35])=[CH:27][C:28]2[N:32]=[C:31]([CH2:33][OH:34])[S:30][CH:29]=2)[O:11][C:12](=[O:13])[CH2:14]1
Reactant: C/C(=C\c1csc(CO)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@@]2(CO)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=Cc1csc(CO)n1)C1CC2OC2(C)CCCC(C)C(O)C(C)C(=O)C(C)(C)C(O)CC(=O)O1

Procedure:
The latter mixture of epothilone F and 26-hydroxyepothilone B was refined further by column chromatography using a 700 ml gradient of toluene to 35% acetone in toluene. A total of twenty 35 ml fractions were collected. TLC analysis showed that fractions 14 and 15 contained pure epothilone F, while fractions 18 through 20 contained pure 26-hydroxyepothilone B. The total yield of epothilone F, calculated from the amount of epothilone F recovered (126.4 mg) to the amount of starting substrate, epothilone B (610 mg), was 20.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:11][C:10]=1[CH2:21][CH2:22]O)=[O:8].CCOC(C)=O.OI1(=O)C2C=CC=CC=2C(=O)O1>C(Cl)Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[S:13][C:9]3[C:7](=[O:8])[N:6]([CH2:5][C:4]4[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:3]=4[O:2][CH3:1])[CH:22]=[CH:21][C:10]=3[N:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(CNC(=O)c2sc(-c3ccc(Cl)cc3)nc2CCO)c(OC)c1
Agent: O=C1OI(=O)(O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)c(OC)c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
Mix 2-(4-chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid 2,4-dimethoxy-benzylamide (19.7 g, 45.5 mmol) with EtOAc (400 mL) and treat the resulting slurry with 1-hydroxy-1-oxo-1H-benzo[d][1,2]iodoxol-3-one (36.0 g, 57.8 mmol). Stir the mixture at 60° C. for 1.5 h. Add additional 1-hydroxy-1-oxo-1H-benzo[d][1,2]iodoxol-3-one (18.0 g, 28.9 mmol) and stir the mixture at 70° C. overnight. Cool the mixture to room temperature and then dilute with CH2Cl2 (600 mL). Filter the mixture and wash the solids with additional CH2Cl2 (3×500 mL). Wash the filtrate with NaHCO3 (4×300 mL) and water (300 mL). Dry the organic portion, filter, and concentrate in vacuo. Purify the crude material by flash chromatography, using 0.5% MeOH/CH2Cl2 as eluent, to give 13.1 g (70%) of the title compound as a light yellow-orange solid. 1H NMR (400 MHz, CDCl3) δ7.99 (d, 2H, J=8.1), 7.50 (d, 1H, J=7.4), 7.45 (d, 2H, J=8.8), 7.38 (d, 1H, J=8.8), 6.84 (d, 1H, J=6.4), 6.46 (m, 2H), 5.16 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[N:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1
Reactant: O=C1CNCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(c2ccc([N+](=O)[O-])cc2F)CN1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A solution of 4-imidazolidinone (9.5 g, 110.5 mmol), 3,4-difluoro nitrobenzene (12.2 ml, 110.5 mmol) and diisopropyl ethylamine (28.6 ml, 165 mmol) in dry DMF (80 ml) was heated to 60° C. overnight under argon. The reaction mixture was allowed to cool to room temperature and ice pieces were added. The solid formed was filtered and washed with water. The solid was dried under air to yield the nitro compound (19.5 g, 78.5%) as yellow crystals.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[S:10]([CH3:13])(=[O:12])=[O:11].C(O)(=O)C>CCOCC>[OH:4][CH:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:6][CH2:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:3])=[O:21])[S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: C=[N+]=[N-]
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)S(C)(=O)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCC(O)CCCN(CCCCCCC(=O)OC)S(C)(=O)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approx. 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 7-[N-(4-hydroxynonyl)methanesulfonamido]heptanoic acid (10.8 g., 0.03 mole) (Example 1, Step B) in ether (50 ml.). The resulting solution is allowed to stand at room temperature for 4 hours. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 7-[N-(4-hydroxynonyl)methanesulfonamido]heptanoate as a viscous oil.