Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:7])[CH2:4][CH2:5]Br.[CH3:8][O:9][C:10]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[C:51]([O:57][CH3:58])[C:11]=1/[CH:12]=[CH:13]/[CH:14]([S:24]([CH:27](/[CH:37]=[CH:38]/[C:39]1[C:44]([O:45][CH3:46])=[CH:43][C:42]([O:47][CH3:48])=[CH:41][C:40]=1[O:49][CH3:50])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([NH2:36])[CH:29]=1)(=[O:26])=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH2:23])[CH:16]=1>>[CH3:58][O:57][C:51]1[CH:52]=[C:53]([O:55][CH3:56])[CH:54]=[C:10]([O:9][CH3:8])[C:11]=1/[CH:12]=[CH:13]/[CH:14]([S:24]([CH:27](/[CH:37]=[CH:38]/[C:39]1[C:40]([O:49][CH3:50])=[CH:41][C:42]([O:47][CH3:48])=[CH:43][C:44]=1[O:45][CH3:46])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([NH:36][CH2:5][CH2:4][C:3]([OH:7])=[O:2])[CH:29]=1)(=[O:26])=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH:23][CH2:5][CH2:4][C:3]([OH:2])=[O:7])[CH:16]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: COC(=O)CCBr
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NCCC(=O)O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NCCC(=O)O)c2)c(OC)c1

Procedure:
A solution of methyl-3-bromopropionate (40 mmol) and (E)-2,4,6-trimethoxy styryl-3-amino-4-methoxybenzylsulfone (10 mmol) was reacted according to General Method B. The product obtained was purified by recrystallization from acetone. (m.p. 156-158° C.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:11]([N:17]=2)=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.[CH3:18][S:19][C:20]1[N:25]=[C:24](I)[CH:23]=[CH:22][N:21]=1>C1(C)C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:22]3[CH:23]=[CH:24][N:25]=[C:20]([S:19][CH3:18])[N:21]=3)[C:10]3[C:11]([N:17]=2)=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[CH:6][CH:7]=1
Reactant: Nc1ccc2[nH]c(-c3ccc(F)cc3)nc2n1
Reactant: CSc1nccc(I)n1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N)ccc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
KN(TMS)2 (688 mg 3.65 mmol) in toluene (3.5 ml) is added at 0° C. to a solution of 2-(4-fluorophenyl)-5-aminoimidazo[4,5-b]pyridine (684 mg 3 mmol) in DMF (10 ml). After stirring 1 h at room temperature, 2-methylthio4-iodopyrimidine (832 mg 3.3 mmol) in toluene (3.3 ml) is added dropwise and heated for 18 h at 120° C. The reaction mixture is poured on water and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crude product, which is purified by SiO2 chromatography (acetone/cyclohexane 20/80 to 60/40) and renders the title compound as a yellow foam (300 mg 27%)
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:22]=[C:23]3[C:28]=2[CH2:27][CH2:26][CH2:25][CH2:24]3)([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O:12][CH3:13])=[CH:7][CH:6]=1)C.[OH-].[Li+]>C1COCC1.CO>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([N:21]2[C:20]([C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)([O:12][CH3:13])[C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:36])=[O:3])=[CH:10][CH:9]=3)=[C:28]3[C:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:22]2)=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1ccc(C(OC)(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(c1ccc(C(=O)O)cc1)(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-4-{[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-methoxymethyl}-benzoic acid ethyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as off-white solid. MS: m/e=479.3 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=1)[NH:5][C:6]([C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]>C(O)C>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=1)[NH:5][C:6]([C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(c2ccccc2)CCCC1
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(c2ccccc2)CCCC1
Yield: 89.1 %

Procedure:
A suspension of N-[(1-phenylcyclopentyl)carbonyl]-4-nitro-L-phenylalanine methyl ester (3.5 g, 8.88 mmol) and stannous chloride (10 g, 44 mmol) in 60 mL of ethanol was refluxed for 50 min under argon. The ethanol was then removed under reduced pressure and the residue was treated with 50 mL of saturated NaHCO3 followed by sodium carbonate to adjust pH above 9. The white slurry was extracted with ethyl acetate (3×300 mL). The combined extracts were washed with water (100 mL) and brine (100 mL) and were dried (MgSO4). Removal of the solvent afforded 4-amino-N-[(1-phenylcyclopentyl)carbonyl]-L-phenylalanine methyl ester (2.9 g, 89%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7]CC)=O.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][NH2:16].C(N(CC)C(C)C)(C)C>C1C=CC=CC=1>[N:16]1([CH2:15][C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)[CH2:2][CH2:3][CH2:4][C:5]1=[O:7]
Reactant: CCOC(=O)CCCBr
Reactant: NCc1cccs1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCN1Cc1cccs1
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A mixture of ethyl 4-bromobutyrate (5.85 g, 30.0 mmol), 2-thiophenemethylamine (13.6 g, 120 mmol), and N,N-diisopropylethylamine (3.88 g, 30.0 mmol) in benzene (100 mL) was stirred under N2 at reflux for 2 hours. The reaction mixture was cooled to ambient temperature and filtered. The residue was concentrated in vacuo, dissolved in ether, and washed twice with 2N aqueous HCl, and once with brine, then dried over MgSO4, filtered, and concentrated in vacuo to give 2-(pyrrolodin-2-one-1-ylmethyl)thiophene (2.59 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:11][CH:10]=2)[C:5]([C:28]2[CH:47]=[CH:46][C:31]([O:32][C@H:33]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]([O:36]CC)=[O:35])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][CH:14]=2)[C:5]([C:28]2[CH:29]=[CH:30][C:31]([O:32][C@H:33]([CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]([OH:36])=[O:35])=[CH:46][CH:47]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)Oc1ccc(-c2ccc(C)n2CCc2ccc(OCCCCCCc3ccccc3)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)n1CCc1ccc(OCCCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-{2-[4-(6-phenylhexyloxy)phenyl]ethyl}-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate (760 mg, 1.21 mmol) in THF (30 ml) and methanol (15 ml) was added 1N aqueous potassium hydroxide solution (7 ml, 7 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the object compound as an oily substance. 561 mg (yield: 77.1%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11]Cl)[CH3:2].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][N:18]1[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]2[C:14]1=[O:24])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)COCCOCCCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)COCCOCCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
A solution of 10.5 g (50 mmol) of 2-[2-(chloroethoxy)-ethoxy]-acetic acid ethyl ester (Chemical Abstracts-Registry No. 82227-25-6) in 100 ml of DMF is reacted with 9.25 g (50 mmol) of potassium phthalimide (Fluka, Buchs, Switzerland) and 50 mg of 18-crown-6 ether (1,4,7,10,13,16-hexaoxacyclooctadecane, Fluka, Buchs, Switzerland) and the mixture is stirred for 2.5 h at 100° C. The reaction mixture is cooled and then concentrated under reduced pressure. The residue is taken up in ether and washed twice in each case with water and brine. After drying and concentrating, the title compound is obtained by column chromatography (SiO2, ethyl acetate/hexane: 1/1); TLC Rf (ethyl acetate/hexane: 4/1)=0.45;
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28]Br)[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:38]([O-:41])(=[S:40])[CH3:39].[K+]>CC(C)=O.CCCCCC>[C:38]([S:40][CH2:28][C:20]1[C@:21]2([CH2:23][CH2:24][C@H:25]3[C:16](=[CH:15][CH:14]=[C:13]4[C@:26]3([CH3:27])[C@@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2])[CH2:10][C@H:11]([O:30][Si:31]([C:34]([CH3:36])([CH3:37])[CH3:35])([CH3:33])[CH3:32])[CH2:12]4)[C@@H:17]2[CH2:18][CH:19]=1)[CH3:22])(=[O:41])[CH3:39]
Reactant: CC([O-])=S
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CBr)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC(=O)SCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (100 mg, 0.183 mmol), triphenylphosphine (96.0 mg, 0.366 mmol) and imidazole (49.8 mg, 0.732 mmol) in dichloromethane (2 ml), N-bromosuccinimide (65.1 mg, 0.366 mmol) was added at 0° C. and stirred at room temperature. After 1 hour, hexane was added to the reaction mixture, which was then washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give a mixture (150 mg) containing 1α,3β-bis(tert-butyldimethylsilyloxy)-17-(bromomethyl)androsta-5,7,16-triene. This mixture was dissolved in acetone (1.5 ml), followed by addition of potassium thioacetate (31.4 mg, 0.275 mmol) and stirring for 30 minutes. The reaction mixture was diluted with hexane and filtered. The resulting filtrate was evaporated under reduced pressure to remove the solvent and the residue was purified by preparative thin layer chromatography (0.5 mm×2 plates, hexane:ethyl acetate=20:1, developed once) to give the titled compound (70.2 mg, 64%) as a colorless oil.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[CH3:5][S:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[CH:11]=1)(=[O:8])=[O:7]>C1(C)C=CC=CC=1>[CH3:5][S:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][S:1](=[O:2])[O:19][CH2:18][C:17]([CH3:20])([CH3:21])[C:12]=2[CH:11]=1)(=[O:8])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(CO)c1cc(OS(C)(=O)=O)ccc1O
Solvent: Cc1ccccc1
Product: CC1(C)COS(=O)Oc2ccc(OS(C)(=O)=O)cc21
Temperature: 50 °C
Yield: 90 %

Procedure:
Thionyl chloride (12 parts) was added dropwise at room temperature to a suspension of 4-hydroxy-3-(2-hydroxy-1,1-dimethylethyl)phenyl methanesulphonate (5 parts) (from Example 1) in toluene (50 parts). The mixture was gently warmed to 50° C. when reaction commenced, then maintained at this temperature for 15 minutes. The temperature was then raised to boiling point and the mixture boiled under reflux for 2 hours. The solvent was then evaporated off under reduced pressure to give crude 4,5-dihydro-5,5-dimethyl-2-oxido-1,3,2-benzodioxathiepin-7-yl methanesulphonate (5.2 parts, 90% yield). Recrystallization from ethanol gave the pure product (2.4 parts), melting point 96°-98° C.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([C:16]3[N:24]4[C:19]([CH:20]=[N:21][C:22](O)=[N:23]4)=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[N:38]([CH3:39])[CH2:37][CH2:36][N:35]([CH3:40])[C:34]2=[O:41])=[CH:29][CH:28]=1>>[CH3:40][N:35]1[CH2:36][CH2:37][N:38]([CH3:39])[CH:33]([C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:22]3[N:21]=[CH:20][C:19]4=[CH:18][CH:17]=[C:16]([C:12]5[CH:13]=[CH:14][CH:15]=[C:10]([S:7]([N:1]6[CH2:2][CH2:3][O:4][CH2:5][CH2:6]6)(=[O:9])=[O:8])[CH:11]=5)[N:24]4[N:23]=3)=[CH:28][CH:29]=2)[C:34]1=[O:41]
Reactant: CN1CCN(C)C(c2ccc(N)cc2)C1=O
Reactant: O=S(=O)(c1cccc(-c2ccc3cnc(O)nn23)c1)N1CCOCC1
Product: CN1CCN(C)C(c2ccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)N6CCOCC6)c5)n4n3)cc2)C1=O

Procedure:
1,4-Dimethyl-3-(4-{7-[3-(morpholine-4-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-phenyl)-piperazin-2-one was prepared from 7-[3-(morpholine-4-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 3-(4-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1052a. Product isolated as an orange foam (91 mg, 55%). LCMS (m/e) 562 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.75 (s, 1H), 8.57 (d, 1H, J=7.5 Hz), 8.30 (s, 1H), 7.78-7.65 (m, 2H), 7.58 (d, 2H, J=8.3 Hz), 7.38 (d, 2H, J=8.3 Hz), 7.05 (d, 1H, J=4.7 Hz), 6.90 (bs, 1H), 6.86 (d, 1H, J=4.7 Hz), 3.80-3.68 (m, 6H), 3.27-3.19 (m, 1H), 3.12-3.00 (m, 5H), 3.00 (s, 3H), 2.74-2.63 (m, 1H), 2.21 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[Cl:16])[OH:9].[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20].[H-].[Na+].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[Cl:16])[O:9][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17]
Reactant: OC(c1cnccc1Cl)c1cnccc1Br
Reactant: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OC(c1cnccc1Cl)c1cnccc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
0.4 grams of 1-(4-bromopyrid-3-yl)-1-(4-chloropyrid-3-yl)methanol were dissolved in 50 ml of tetrahydrofuran (THF) and cooled to 0° C. One gram of trimethylacetyl chloride was added followed by the portionwise addition of 0.5 grams of sodium hydride (60%) over a period of 15 minutes. The reaction mixture was then allowed to warm to room temperature and then stirred overnight. 50 ml of a saturated ammonium chloride solution were added and then this mixture was extracted twice with ethyl ether. The combined ether extracts were washed with a 5% aqueous solution of potassium carbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 0.5 g of 1-(4-bromopyrid-3-yl)-1-(4-chloropyrid-3-yl)-1-trimethylacetoxymethane as a waxy solid.
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH2:23][O:24][CH2:25][CH2:26][CH3:27])[CH:3]=[CH:4][CH:5]1[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH:6]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].CC(C)=O.O.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[OH:1][C:2]([CH3:28])([CH2:23][O:24][CH2:25][CH2:26][CH3:27])[CH:3]=[CH:4][CH:5]1[CH:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:7](=[O:8])[CH2:12][CH2:13]1
Reactant: CCCOCC(C)(O)C=CC1CCC2(OCCO2)C1CCCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCCOCC(C)(O)C=CC1CCC(=O)C1CCCCCCC(=O)O
Reaction time: 24 h
Yield: 9.7 %

Procedure:
Crude 7-{7-(3-hydroxy-3-methyl-4 -propoxybut-1-enyl)-1,4-dioxaspiro[4,4]non-6-yl}heptanoic acid [1.04 g.; prepared as hereinbefore described in Example 1 (viii)], undried acetone (50 ml.) containing a small amount of water and p-toluenesulphonic acid dihydrate (0.1 g.) were left to stand together at room temperature for 24 hours. The mixture was then added to excess diethyl ether and washed with water until the washings were neutral. The ether solution was dried over sodium sulphate and evaporated, to give crude 7-[5-(3-hydroxy-3-methyl-4-propoxybut-1-enyl)-2-oxocyclopentyl] heptanoic acid (0.83 g.). This material was purified by preparative thin layer chromatography on silica gel, using a mixture of toluene, dioxan and acetic acid (65:15:1 by volume) as eluant, to give 7-[5-(3-hydroxy-3-methyl-4-propoxybut-1-enyl)2-oxocyclopentyl] heptanoic acid (90 mg.). Elemental analysis: found C, 67.3; H, 9.9%; C20H34O5 requires C, 67.7; H, 9.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][S:15]([C:18]3[CH:49]=[CH:48][C:21]([CH2:22][CH2:23][NH:24][CH2:25][C@H:26]([OH:47])[CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][Si](C(C)C)(C(C)C)C(C)C)=[C:31]([CH3:46])[CH:30]=4)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[N:10]=2)=[CH:5][CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[Cl-].[NH4+]>[OH:47][C@@H:26]([CH2:25][NH:24][CH2:23][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([S:15]([CH2:14][C:11]2[N:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[O:13][N:12]=2)(=[O:17])=[O:16])=[CH:49][CH:48]=1)[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([CH3:46])[CH:30]=1
Reactant: COc1ccc(-c2nc(CS(=O)(=O)c3ccc(CCNC[C@H](O)COc4ccc(O[Si](C(C)C)(C(C)C)C(C)C)c(C)c4)cc3)no2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(CS(=O)(=O)c3ccc(CCNC[C@H](O)COc4ccc(O)c(C)c4)cc3)no2)cc1
Reaction time: 6 h
Yield: 72.7 %

Procedure:
To a solution of the amino alcohol of Example 18(0.630 g, 0.887 mmol) in THF (12 mL) was added a 1M solution of TBAF (0.18 mL, 0.18 mmol). The reaction mixture was stirred for 6 h. TLC shows the absence of starting material, so 4 drops of a saturated aqueous ammonium chloride solution was added. The reaction mixture was evaporated in vacuo to dryness and the residue was flash chromatographed (silica gel; dichloromethane/chloroform/methanol: 5/4/1) to afford 0.357 g of the title compound as a white crystalline solid.
Reaction SMILES: [F:1][CH2:2][C:3]([NH2:11])([CH2:6][CH2:7][CH2:8][O:9][CH3:10])[C:4]#[N:5].C(N(CC)CC)C.[C:19](Cl)(=[O:29])[C:20]1[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:22](Cl)=[O:23]>C(Cl)Cl>[F:1][CH2:2][C:3]([N:11]1[C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]2[C:19]1=[O:29])([CH2:6][CH2:7][CH2:8][O:9][CH3:10])[C:4]#[N:5]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: COCCCC(N)(C#N)CF
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a solution of 2-fluoromethyl-2-amino-5-methoxy-valeronitrile (1.62 g, 10 mmol) and triethylamine (2.02 g, 20 mmol) in methylene chloride (30 ml), cooled to -20° C., is added phthaloyldichloride (2.03 g, 10 mmol) in methylene chloride (10 mL). The mixture is allowed to warm up to room temperature overnight. After washing with water, 1 N HCl, water again, and drying (Na2SO4), the solvent is removed under reduced pressure to give 2.4 g of crude material. This is purified by chromatography on silica (ethyl acetate/petroleum ether 3:7).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[O:22]1C2C(=CC=CC=2)C(N)CC1>>[O:22]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]([NH:11][C:4]2[C:3]([CH2:1][CH3:2])=[N:8][CH:7]=[C:6]([CH2:9][CH3:10])[N:5]=2)[CH2:13][CH2:14]1
Reactant: NC1CCOc2ccccc21
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2CCOc3ccccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,4-dihydro-2H-chromen-4-ylamine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.71, 7.31-7.21, 6.95, 6.91, 5.34, 4.54, 4.32-4.24, 2.71, 2.56, 2.25, 1.36-1.26; HRMS (FAB) calcd for C17H21N3O+H 284.1763, found 284.1768.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11]N1C(=O)CCC1=O>>[Br:11][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[OH:10]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C1CCC(=O)N1Br
Product: O=[N+]([O-])c1ccc(O)c(Br)c1

Procedure:
2-bromo-4-nitrophenol is prepared by reaction of 4-nitrophenol with N-brom-succinimide, according to the paper by T. Oberhouser in J. Org. Chem. 62, pp. 4504 and following (1997).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[CH:8]=[C:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:30][NH:31][C:32](=O)[O:33]C1C=CC=CC=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH2:23]([O:30][NH:31][C:32]([N:11]1[CH2:12][CH2:13][C:9](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[C:10]1=[O:14])=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(NOCc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)c1cc(C=C2CCNC2=O)cc(C(C)(C)C)c1O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(C=C2CCN(C(=O)NOCc3ccccc3)C2=O)cc(C(C)(C)C)c1O
Yield: 61 %

Procedure:
3-(3,5-Di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (600 mg, 2 mmole) and phenyl N-benzyloxycarbamate (490 mg, 2.01 mmole) were dissolved into 8 ml of pyridine and the solution was heated under reflux for 12 hours. The reaction mixture was evaporated and the obtained residue was dissolved into ethyl acetate, which was washed with an aqueous solution of 0.1N hydrochloric acid, water, and saturated brine, dried over magnesium sulfate, and evaporated. The obtained residue was separated by using silica gel chromatography (toluene:ethyl acetate=10:1) and recrystallized from dichloromethane/n-hexane, whereby 550 mg of the objective compound (Ia-10) was obtained in 61% yield.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].N1C=CC=CC=1.[C:15](Cl)([CH3:17])=[O:16]>C(Cl)Cl>[C:15]([O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1)(=[O:16])[CH3:17]
Reactant: Cc1cccc(O)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(C)c1

Procedure:
To a solution of m-cresol (Aldrich) (80 g, 0.74 mol) in dry CH2Cl2 (300 mL) and pyridine (71 mL, 0.89 mol) at 0° C. was added dropwise AcCl (58 mL, 0.81 mol). The reaction mixture was stirred for ca 1 h and then diluted with more CH2Cl2. The organic phase was washed successively with HCl 1N (3×), brine, dried over MgSO4 and evaporated. The residue was distilled under vacuum to give the title compound.