Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH:26]([CH2:30][OH:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[C:5]1=[O:32].[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH:26]([CH2:30][OH:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[C:5](=[O:32])[N:4]3[CH2:3][CH2:2][NH:1][C:39]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:40])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: CC(C)C(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Reactant: O=C(Cl)N1CCOCC1
Product: CC(C)C(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[1-(hydroxymethyl)-2-methylpropyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 4-morpholinecarbonyl chloride employing methods similar to those described in Example 450 and was obtained as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88-0.96 (m, 6 H), 1.92-2.04 (m, 2 H), 3.12-3.21 (m, 4 H), 3.27-3.31 (m, 2 H), 3.44-3.51 (m, 5 H), 3.51-3.61 (m, 1 H), 3.86 (ddd, J=14.64, 5.30, 5.19 Hz, 1 H), 4.14 (s, 2 H), 4.29 (t, J=6.25 Hz, 2 H), 4.88 (t, J=5.05 Hz, 1 H), 6.77 (t, J=5.76 Hz, 1 H), 7.11-7.18 (m, 2 H), 7.39-7.45 (m, 2 H), 8.25 (d, J=1.54 Hz, 1 H), 8.54 (d, J=0.98 Hz, 1 H), 10.44 (d, J=9.13 Hz, 1 H); ES+ MS: 556 (M+H+).
Reaction SMILES: FC1C=CC2C(C3CCN([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([CH:22](C)[CH3:23])[C:18]4=[O:25])CC3)=NOC=2C=1.[F:28][C:29]1[CH:43]=[CH:42][C:32]2[C:33]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:34][O:35][C:31]=2[CH:30]=1.BrCC.Cl>>[F:28][C:29]1[CH:43]=[CH:42][C:32]2[C:33]([N:36]3[CH2:41][CH2:40][N:39]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[C:18]4=[O:25])[CH2:38][CH2:37]3)=[N:34][O:35][C:31]=2[CH:30]=1
Reactant: CC(C)N1CCN(CCN2CCC(c3noc4cc(F)ccc34)CC2)C1=O
Reactant: Fc1ccc2c(N3CCNCC3)noc2c1
Agent: Cl
Solvent: CCBr
Product: CCN1CCN(CCN2CCN(c3noc4cc(F)ccc34)CC2)C1=O

Procedure:
This product is prepared in the same manner as the compound of Example 1 but using 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperazine instead of 4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidine in Step 1, and using bromoethane instead of 2-bromopropane in Step 2. The hydrochloride of the title compound so obtained melts at 201°-204° C.
Reaction SMILES: [CH2:1](O)[CH2:2]SCCO.[CH2:8]([N:23]=[C:24]=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)COCCO>[CH2:8]([N:23]=[C:24]=[O:25])[CH2:9][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][CH2:1][CH3:2]
Reactant: OCCSCCO
Reactant: CCCCCCCCCCCCCCCN=C=O
Solvent: OCCOCCO
Product: CCCCCCCCCCCCCCCCCN=C=O

Procedure:
Following the procedure described in preparation 4, but using thiodiethylene glycol and n-pentadecylisocyanate, instead of diethylene glycol and n-heptadecylisocyanate, respectively, the title compound of this preparation was obtained in a similar yield.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][OH:22].O>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:20][CH2:21][OH:22])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: O=c1[nH]ccc2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cc(Br)ccc2ccn1CCO
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A solution of compound 5 (19.8 g, 88.4 mmol), potassium carbonate (18.3 g, 133 mmol) and 2-bromoethanol (13.3 g, 106 mmol) in dimethylforamide (200 mL) was stirred at 80° C. for 12 h. Then the mixture was cooled to room temperature and poured into water. The mixture was extracted with ethyl acetate (three times 500 mL), dried (sodium sulfate), concentrated and purified by chromatography on silica gel to give 6 (16.2 g, 68%)
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:14]([SH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CS(C)=O>[CH2:14]([S:21][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: SCc1ccccc1
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: c1ccc(CSc2cnccn2)cc1
Yield: 45.6 %

Procedure:
In a similar fashion using route 38 general procedure 92, 2-chloropyrazine (1 g, 8.73 mmol), K2CO3 (1.80 g 13.1 mmol), benzylmercaptan (1.62 g 13.1 mmol) and DMSO (8 ml) at 150° C. for 4 h in sealed tube gave the title compound (805 mg, 45%) after purification by column chromatography with n-hexane/EtOAc (97:3) as the eluent.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)#[N:2].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:26]=[C:25]([C:27]#[N:28])[N:24]([C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=3)[N:23]=2)[CH:17]=1>>[C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:35][C:32]2[CH:31]=[CH:30][C:29]([N:24]3[C:25]([C:27]#[N:28])=[CH:26][C:22]([C:18]4[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=4)=[N:23]3)=[CH:34][CH:33]=2)=[O:13])=[CH:14][CH:15]=1)#[N:2]
Reactant: N#CCCCOc1ccc(C(=O)O)cc1
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Product: N#CCCCOc1ccc(C(=O)Nc2ccc(-n3nc(-c4cccnc4)cc3C#N)cc2)cc1

Procedure:
The 4-(cyanopropyloxy)benzoic acid (0.75 mmol) was coupled with 3-(3-pyridyl)-5-cyano-1-(4′-aminophenyl)-pyrazole (0.5 mmol) under standard EDC mediated conditions (Method A). The crude product was recrystallized from hot benzene/methanol, m.p. 193-194° C. 1H NMR(CDCl3): δ 2.04-2.11 (m, 2H), 2.68-2.71 (7, J=7.1 Hz, 2H), 4.14-4.17 (t, J=6 Hz, 2H), 7.11-7.13 (d, J=8.6 Hz, 2H), 7.53-7.56 (m, 1H), 7.79-7.82(d, J=8.7 Hz, 2H), 8.00-8.05 (m, 4H), 8.1 (s, 1H), 8.30-8.32 (d, J=8 Hz, 1H), 8.63-8.64(d, J=4.6 Hz, 1H), 9.15 (s, 1H), 10.4 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]([CH2:11][CH2:12][CH3:13])=[CH:8][C:4]([C:5](O)=[O:6])=[CH:3]1.Cl.O>C1COCC1>[OH:6][CH2:5][C:4]1[CH:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:2](=[O:1])[CH:3]=1
Reactant: CCCc1cc(C(=O)O)cc(=O)[nH]1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(CO)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
27.8 ml and, after 1 hour at room temperature, a further 27.8 ml of a 1M solution of BH3 in THF are added dropwise at 0° C. to a suspension of 3.0 g (16.6 mmol) of 2-oxo-6-propyl-1,2-dihydroisonicotinic acid and the mixture is stirred for a further hour at room temperature. 66.8 ml of 1N hydrochloric acid and 100 ml of water are added to the now clear solution, and it is stirred at room temperature for 1 hour and extracted three times with 75 ml of ethyl acetate each time. The organic phase is discarded, the aqueous phase is adjusted to a pH of about 7 with satd. NaHCO3 solution and the deposited precipitate is filtered off with suction. The aqueous filtrate is concentrated to dryness in a rotary evaporator and recrystallised from about 80 ml of water together with the first precipitate. 1.28 g (46%) of colourless crystals of m.p. 167° C. are obtained.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([C:28](=[O:29])[C:27]5[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=5)[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C1CCNC[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(C(F)(F)F)c1)N1CCC(=O)N2C[C@H](Oc3cnc(C4CC4)cn3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
(8R,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (27.6 mg, 0.085 mmol, 1 equivalent, prepared as described in Example 55, Part B) was suspended in dichloromethane (1.0 mL) in a 4-mL scintillation vial. 3-(Trifluoromethyl)benzoyl chloride (23.05 mg, 0.111 mmol, 1.3 equivalents) was added as a solution in dichloromethane (0.1 mL) followed by the addition of triethylamine (0.059 mL, 0.425 mmol, 5.0 equiv) and 4-(dimethylamino)pyridine (1.0 mg, 0.0085 mmol, 0.1 equivalent). The resulting solution was stirred at room temperature for an additional 30 minutes. The reaction was loaded directly onto a 4 g silica gel column eluted with 50:50 to 100:0 ethyl acetate:heptanes (flow rate=18 mL/minute) over 20 minutes to give the title compound as a white solid (25 mg, 64%). 1H NMR (400 MHz, pyridine-d5, 90° C.) δ ppm 8.06 (s, 1H), 7.97 (d, J=1.3 Hz, 1H), 7.89 (s, 1H), 7.68 (dd, J=18.2, 7.8 Hz, 2H), 7.47 (t, J=7.8 Hz, 1H), 5.40 (dq, J=8.0, 4.0 Hz, 1H), 4.53-4.10 (m, 1H), 4.13 (td, J=8.8, 3.6 Hz, 2H), 3.96 (d, J=4.1 Hz, 2H), 3.41 (dd, J=13.9, 10.0 Hz, 1H), 3.32-3.17 (m, 1H), 2.90-2.67 (m, 2H), 2.55 (ddd, J=14.2, 8.8, 5.5 Hz, 1H), 2.07-1.91 (m, 2H), 1.06-0.97 (m, 2H), 0.92-0.79 (m, 2H); MS (ESI+) m/z 461.1 (M+H)+; [α]D23.7=0.10 (c=0.12, CH3OH).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].C(OCC)(=O)C>CCO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in EtOH (15 ml). The mixture was stirred at about 70° C. for 4 h (it became clear and turned to a slurry), after which the starting material was not detected by HPLC. Then, 40 ml of ethyl acetate was dripped into the mixture and it was cooled slowly to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with ethyl acetate (10 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain fluvastatin sodium Form XXXVIII (1.78 g, 87.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn12
Reactant: FC(F)(F)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(CCCC(F)(F)F)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 80 °C
Yield: 27.9 %

Procedure:
To a stirring mixture of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (50 mg, 0.14 mmol) and K2CO3 (40 mg, 0.28 mmol) in DMF (0.47 mL) at 20° C. was added 4-bromo-1,1,1-trifluorobutane (50 mg, 0.28 mmol). The resulting reaction mixture was heated at 80° C. for 60 min. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature, diluted with water, and extracted twice with diethyl ether. The combined organic extract was washed with saturated aqueous NaHCO3 solution, then brine, then dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (18 mg, 0.039 mmol) as a yellow oil. MS: [M+H]+=466.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:37])[C:22]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=1)([OH:27])[C:23]([F:26])([F:25])[F:24])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.Cl([O-])=[O:39].[Na+].Cl>C(O)(C)(C)C.CC(=CC)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:37])[C:22]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=1)([OH:27])[C:23]([F:25])([F:26])[F:24])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:39])=[O:11])=[C:8]([C:14]([F:17])([F:15])[F:16])[CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C=O)c(C(F)(F)F)c3)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C(=O)O)c(C(F)(F)F)c3)cc2Cl)C(F)(F)F)cn(C)c1=O
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 96.2 %

Procedure:
To a solution of 4-{3-chloro-4-[2-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-2-trifluoromethyl-benzaldehyde (105 mg) in tert.-butanol (1 ml) and 2-methyl-2-butene (0.12 ml) was added a solution of sodium chlorite (28 mg) and sodiumdihydrogenphosphate-dihydrate (34 mg) in water (0.8 ml) at 0° C. The mixture was stirred for 10 minutes at 0° C. and for 4.5 h at room temperature. The mixture was acidified with 1 M aqueous HCl and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated to give the title compound (104 mg) as a colorless solid. MS (m/e, ISP neg. ion)=562.1 [M−H+].
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][CH:23]([CH3:39])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=1)=[O:25]>>[C:16]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH2:12][N:36]3[CH2:37][CH2:38][CH:33]([C:29]4[CH:28]=[C:27]([NH:26][C:24](=[O:25])[CH:23]([CH3:39])[CH3:22])[CH:32]=[CH:31][CH:30]=4)[CH2:34][CH2:35]3)=[CH:10][CH:9]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(N(c4ccccc4)c4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(diphenylamino)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 504.2 (M+H)+.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][CH:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]([OH:25])=O)[C:18]1=[O:26].[CH3:27][C@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([CH3:34])[N:29]1[CH2:35][CH2:36][NH2:37].O>CN(C)C=O>[CH3:27][C@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([CH3:34])[N:29]1[CH2:35][CH2:36][NH:37][C:23](=[O:25])[CH2:22][N:19]1[CH2:20][CH2:21][CH:17]([OH:16])[C:18]1=[O:26]
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Reactant: O=C(O)CN1CCC(O)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1.30 g of dicyclohexylcarbodiimide dissolved in 6 ml of dimethylformamide are added dropwise at 0° to 1.0 g of (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetic acid and 1.03 g of 94.7% cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine dissolved in 20 ml of dimethylformamide. The mixture is left to stir at room temperature for 4 days, treated with 0.23 g of ion-free water and evaporated in a water-jet vacuum. The residue is treated five times with toluene and in each case again evaporated. The constituents of the residue which are soluble in chloroform are chromatographed on 60 g of aluminum oxide (activity grade III, neutral). The alcohol eluate is again chromatographed on 15 g of aluminum oxide (activity grade III, neutral). The fractions which are eluted with acetonitrile and ethanol contain, according to the gas chromatogram and mass spectrum, (R/S)-cis-N-[2-(2,6-dimethyl-1piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH3:12])=[C:4]([CH3:13])[CH:3]=1.[CH2:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=[CH2:16]>Cl[Pd](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH2:11][CH3:12])=[C:4]([CH3:13])[CH:3]=1)[CH:15]=[CH2:14]
Reactant: CCOCOc1ccc(Br)cc1C
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=CCc1ccc(OCOCC)c(C)c1

Procedure:
In a manner similar to Example 1c, by reacting 16 g (65 mmol) of 4-bromo-1-ethoxymethoxy-2-methylbenzene with 30 ml (97 mmol) of allyltributyltin and 1.35 g (2 mmol) of dichlorobis (triphenylphosphino)palladium. A yellow oil is obtained (m=12:1 g, y=89%).
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[SH:22][CH2:23][CH2:24][OH:25].[H-].[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]=3[C:14]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[CH:13][C:12]=2[S:22][CH2:23][CH2:24][OH:25]
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Reactant: OCCS
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1Nc2ccc(F)c3c(SCCO)cc(-c4ccc[nH]4)c1c23
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A mixture of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (300 mg, 0.60 mmol) and neat 2-mercaptoethanol (Sigma, 4 mL) was treated with NaH (Aldrich, 98%, 210 mg that was emulsified with 0.4 mL of mineral oil) in small portions at room temperature. After the evolution of gas stopped, the mixture was heated gradually to 120° C. and stirred at this temperature for 6 hours. The reaction mixture was then poured in a mixture of ethyl acetate and water. The aqueous layer was extracted few more times with ethyl acetate and the combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by HPLC (silica gel, with 25% ethyl acetate in hexanes) and then precipitated out of THF with excess pentane to give 6-fluoro-5-(2-hydroxy-ethylsulfanyl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 98 mg, 49%).
Reaction SMILES: [CH3:1][C:2]1([O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CB1N2CCC[C@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[OH:22][C@H:20]([CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:2]1([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(=O)CCCCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@@H](O)CCCCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a stirred yellow solution of tert-butyl 4-methyl-4-((5-oxohexyl)oxy)piperidine-1-carboxylate (5.8 g, 18.50 mmol) in anhydrous toluene (100 mL) was added (S)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (2.052 g, 7.40 mmol). The mixture was cooled to −35° C. and a solution of 50% catechoborane (6.35 mL, 25.9 mmol) in toluene was added over 5 min. After 30 min, the reaction mixture was slowly warmed to −15° C. and stirred for additional 2 h. At his point LCMS indicated completion of reaction. Mixture was then diluted with EtOAc (200 mL) and sat. Na2CO3 (100 mL). The mixture was stirred vigorously for 30 min, and the organic phase washed with sat Na2CO3 (2×50 mL), dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel chromatography (5-70% EtOAc/hexane) to afford desired (R)-tert-butyl 4-((5-hydroxyhexyl)oxy)-4-methylpiperidine-1-carboxylate (4.6 g, 14.58 mmol, 79% yield) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 3.90-3.80 (m, 1H), 3.78-3.64 (m, 2H), 3.33 (t, J=6.4 Hz, 2H), 3.14 (t, J=11.4 Hz, 2H), 1.74 (d, J=13.2 Hz, 2H), 1.66-1.54 (m, 3H), 1.53-1.46 (m, 12H), 1.46-1.38 (m, 3H), 1.22 (d, J=6.3 Hz, 3H), 1.17 (s, 3H). LCMS (M+Na)=338.4.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)[CH3:2].C(=O)([O-])[O-:14].[K+].[K+].C1OC1>CO>[OH:14][CH2:2][CH2:1][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CO1
Solvent: CO
Product: C=Cc1ccc(OCCO)cc1

Procedure:
Para-(hydroxyethoxy)styrene was prepared using the method described in Example 1, except that the following amounts of reagents were used: 86 g (0.53 mol, 1 eq) of p-acetoxystyrene, 3.7 g (26.77 mmol, 0.05 eq) of anhydrous potassium carbonate, and 35 g (0.795 mol, 1.5 eq) of ethylene oxide in 530 mL of methanol. The isolated product yield was 61.9%.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[C:9]([O:13][C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])([CH3:12])([CH3:11])[CH3:10].CI>C1COCC1>[C:9]([O:13][C:14](=[O:20])[CH:15]([CH3:2])[CH2:16][C:17]([OH:19])=[O:18])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)CCC(=O)O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(CC(=O)O)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of LDA (6.3 mmol, 2M in hexane) in THF (5 mL) at −78° C. is added a solution of succinic acid mono-tert-butyl ester (523 mg, 3 mmol) in THF (2 mL) dropwise. After the addition, the mixture is warmed to −20° C. slowly and stirred at −20° C. for 30 minutes. The solution is re-cooled to −78° C. and MeI (511 mg, 3.6 mmol) is added dropwise. The mixture is warmed to room temperature and stirred for 18 hours. The mixture is quenched with water and extracted with ethyl acetate. The organic layer is washed with water, brine, dried over MgSO4 and filtered. The solvent is removed under reduced pressure to give 2-methyl-succinic acid 1-tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Mg+].[Br-].[CH3:26]C(O)=O>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]([OH:22])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CC(O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1.75 h

Procedure:
To a solution of 1J (˜0.05 M in THF) at −78° C. was added dropwise MeMgBr (3.0M in Et2O, 3 equiv). The reaction was stirred at −78° C. for 1.5-2 h (quench small aliquot in 10% MeOH/DCM, spot TLC-silica gel, 30% EtOAc/Hex-stain with 5% HCl/MeOH, heat and then ninhydrin, heat). Quench reaction by addition of HOAc (3 equiv) at −78° C. Warm to rt, dilute with EtOAc and wash with a 1:1 mixture of saturated aq. NaHCO3 and brine. Back extract aqueous layer. Combine organic extracts, dry over MgSO4, filter and concentrate. Purification by flash chromatography (silica gel, step gradient 0-10-20% EtOAc in hexane) provided the title compound.