Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]([CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH:9]=[C:10]([Br:20])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16](=[O:19])[NH:15][N:14]=1>>[Br:5][C:6]1[CH:7]=[C:8]([CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH:9]=[C:10]([Br:20])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16](=[O:19])[N:15]([CH:1]([CH3:3])[CH3:2])[N:14]=1
Reactant: CC(C)I
Reactant: CC(=O)OCCc1cc(Br)c(Oc2ccc(=O)[nH]n2)c(Br)c1
Product: CC(=O)OCCc1cc(Br)c(Oc2ccc(=O)n(C(C)C)n2)c(Br)c1
Temperature: 50 °C
Yield: 79 %

Procedure:
This compound was prepared by a similar method to that described in Example 10, Step 2 except that isopropyl iodide was used in place of methyl iodide and acetic acid 2-[3,5-dibromo-4-(6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-ethyl ester (39) was used in place of acetic acid 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-ethyl ester (34). The method was similar except that the reaction was heated to 50° C. for 24 h. The product was purified by column chromatography using silica gel eluted with 10% ethyl acetate in hexanes to 100% ethyl acetate to afford 2-[3,5-dibromo-4-(1-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-ethyl ester (40) (79%) as a white solid; LRMS for C17H18Br2N2O4 (M+CH3CN+H) m/z=516. Molecular Weight=474.1520; Exact Mass=471.9633
Reaction SMILES: [C:1]1(=O)[NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[CH2:15]([NH2:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1C=CC=CC=1>[CH2:15]([N:27]=[C:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1CCCCCCN1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCN=C1CCCCCCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 28.3 g (0.223 mole) of an enantholactam in 250 ml of benzene is added 34.1 g (0.223 mole) of phosphorous oxychloride over 30 minutes. The mixture is stirred at room temperature for 4 hours after which 41.2 g (0.223 mole) of dodecylamine is added. The reaction mixture is stirred at room temperature for 1 hour and refluxed for 4 hours then allowed to stand overnight. The resulting precipitate is washed with benzene, and the benzene wash is extracted with aqueous 2 N hydrochloric acid and combined with the precipitate. The combined fractions are made alkaline with 2N sodium hydroxide, extracted into ether-methylene chloride, dried and recrystallized from isopropyl alcohol to give 2-dodecyliminooctahydroazocine.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11](SC)[N:12]=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.OC1CCNCC1.N1C=CN=CN=1>O>[CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([N:31]3[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]3)[N:12]=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CSc1nnc(-c2ccc(N(C)C)cc2)c(-c2ccc(N(C)C)cc2)n1
Reactant: OC1CCNCC1
Agent: c1cnncn1
Solvent: O
Product: CN(C)c1ccc(-c2nnc(N3CCC(O)CC3)nc2-c2ccc(N(C)C)cc2)cc1

Procedure:
Three grams of 5,6-bis(4-dimethylaminophenyl)-3 -methylthio-1,2,4-triazine and 1.5 g. of 4-hydroxypiperidine were heated at about 150° C. for 12 hours. The reaction mixture was treated with water and the product was collected. The product was dissolved in benzene and the solution was slowly added to n-hexane. The solid which precipitated was recrystallized from ethyl acetate to yield 1.6 g. of 5,6-bis(4-dimethylaminophenyl)-3-(4-hydroxypiperidine-1,2,4-triazine, mp about 186°-188° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[CH:24]=[CH2:25]>CN1C(=O)CCC1.O>[CH3:1][N:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:25][CH2:24][C:20]3[S:21][CH:22]=[CH:23][C:19]=3[CH3:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1sccc1C
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2sccc2C)C=CN(C)C1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (250 mg, 1.25 mmol) in NMP (1 mL) were added powdered KOH (490 mg, 8.75 mmol) and 3-methyl-2-vinyl-thiophene (310 mg, 2.25 mmol), and the reaction mixture stirred at 90° C. for 5 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was washed with water (5×25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-[2-(3-methyl-thiophen-2-yl)-ethyl]-2,5-dihydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.25 (d, 1H), 7.22 (s, 1H), 7.1 (d, 1H), 7.02 (d, 1H), 6.7 (d, 1H), 4.41 (s, 2H), 4.3 (t, 2H), 2.42 (bs, 2H), 3.2 (t, 2H), 3.0 (s, 3H), 2.61 (bs, 2H), 2.4 (s, 3H), 1.6 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Li])CCC.[Br-].[Mg+2].[Br-].[S:24]1[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25]1>O1CCCC1.ClCCl.CCCCCC>[Si:6]([O:5][C:4]1[CH:3]=[C:2]([CH:15]=[CH:14][CH:13]=1)[CH:29]([OH:30])[C:26]1[CH:27]=[CH:28][S:24][CH:25]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Reactant: O=Cc1ccsc1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(O)c2ccsc2)c1
Temperature: -78 °C
Yield: 68.8 %

Procedure:
3-Bromophenoxy-tert-butyldimethylsilane (57.5 g, 0.20 mol, Example 1, infra) was dissolved in 300 mL of dry tetrahydrofuran under nitrogen and cooled to -78° C. A solution of 1.6M n-butyllithium in hexane (125 mL, 0.20 mol) was added dropwise at a rate to maintain a temperature below -70° C. The reaction was stirred for thirty minutes after the addition was complete and the cold solution was transferred to another vessel containing a -40° C. solution of magnesium bromide (37.8 g, 0.205 mol) in 600 mL of dry tetrahydrofuran under nitrogen. The resulting solution was allowed to warm to -15° C. while stirring. After one hour a solution of thiophene-3-carboxaldehyde (22.4 g, 0.20 mol) in 200 mL of dry tetrahydrofuran was added slowly at a rate to maintain a temperature below 25° C. The resulting solution was stirred for 30 minutes at room temperature, then washed twice with aqueous ammonium chloride, dried over sodium sulfate and evaporated to give a brown oil. Chromatography on silica gel with hexane:dichloromethane (gradient from 3:1 to 1:1) gave 44.1 g (69%) of 3-((tert-butyldimethylsilyl)oxy)-α-(3-thienyl)benzyl alcohol as a viscous yellow oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[H-].[Na+].Cl[C:24]1[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[N:28][CH:29]=1>CN(C=O)C.CO>[F:20][C:2]([F:1])([F:19])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([O:18][C:24]4[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[N:28][CH:29]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: N#Cc1ccc(Cl)cn1
Reactant: OC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1ccc(OC2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cn1
Temperature: 50 °C
Reaction time: 18 h
Yield: 27.2 %

Procedure:
A solution of 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (150 mg, 0.52 mmol) and sodium hydride (60% dispersion in oil, 22.98 mg, 0.57 mmol) in DMF (5 mL) was stirred for 30 minutes at ambient temperature under nitrogen. 5-Chloropicolinonitrile (80 mg, 0.57 mmol) was added to the reaction mixture. The resulting solution was stirred at 50° C. for 18 hours. The reaction mixture was diluted with a few drops of MeOH. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 5-[[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]oxy]pyridine-2-carbonitrile (55.0 mg, 27%) as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC=CC=3)(=O)=O)[C:9]([CH3:11])=[CH:10][C:3]=12.[CH3:21][N:22]1[CH:26]=[C:25]([CH3:27])[C:24]([C:28]([NH:30][C:31]2[CH:39]=[C:38]([Sn](C)(C)C)[CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][N:35]3S(C2C=CC=CC=2)(=O)=O)=[O:29])=[N:23]1.C1(S)C=CC=CC=1>CN(C=O)C>[CH3:21][N:22]1[CH:26]=[C:25]([CH3:27])[C:24]([C:28]([NH:30][C:31]2[CH:39]=[C:38]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[NH:8][C:9]([CH3:11])=[CH:10][C:3]=34)[CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)=[O:29])=[N:23]1
Reactant: Cc1cn(C)nc1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: Cc1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Agent: Sc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc2c(-c3cc(NC(=O)c4nn(C)cc4C)c4cn[nH]c4c3)ccnc2[nH]1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
4-Bromo-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (63 mg) in DMF (0.4 ml) was added to 1,4-dimethyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1H-pyrazole-3-carboxamide (100 mg) in DMF (0.4 ml). Solvias catalyst (4 mg) was added and the sealed vessel was heated in the Anton Paar microwave at 135° C. for 20 min. PS-thiophenol resin was added and the reaction was stirred overnight before being filtered onto a C18 SPE cartridge, pre-washed with 0.1% TFA, with acetonitrile. The cartridge was washed with 0.1% TFA in acetonitrile and the collected solvent was removed under a stream of nitrogen. The residue was dissolved in DMSO (1 ml) and purified by MDAP (method C). The solvent was evaporated in vacuo. The residue was dissolved in isopropanol (0.3 ml), 2M sodium hydroxide (aq) (0.3 ml) was added and the reaction was left at room temperature overnight, then heated to 60° C. for 2 h. The solvent was removed under a stream of nitrogen and the residue was dissolved in DMSO (0.5 ml) and purified by MDAP (method C). The solvent was evaporated in vacuo to give title compound, 8 mg.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([Cl:9])[S:6][C:5]=1[S:10]([NH2:13])(=[O:12])=[O:11])(=[O:3])[CH3:2].C(OCC)(=O)C.C1C=C[NH+]=CC=1.[Br:26][Br-]Br.S(=O)(=O)(O)O>O>[Br:26][CH2:2][C:1]([C:4]1[CH:8]=[C:7]([Cl:9])[S:6][C:5]=1[S:10]([NH2:13])(=[O:11])=[O:12])=[O:3]
Reactant: CC(=O)c1cc(Cl)sc1S(N)(=O)=O
Agent: O=S(=O)(O)O
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: O
Product: NS(=O)(=O)c1sc(Cl)cc1C(=O)CBr
Temperature: 1 °C
Reaction time: 1 h

Procedure:
A 50-L, 5-necked flask equipped with a mechanical stirrer, a thermometer, and a 1-L addition funnel was charged with 3-acetyl-5-chloro-2-thiophenesulfonamide (3, 1.087 kg, 4.55 mol) and ethyl acetate (22L). The pale yellow suspension was cooled to 1° C. over 45 minutes using an ice-water bath, and 90% pyridinium bromide perbromide (1.305 kg, 3.67 mol) was added in one portion. Sulfuric acid (544 mL) was added via the addition funnel over 10 minutes causing the temperature to rise to 5° C. The reaction mixture was stirred for 1 hour, after which TLC analysis indicated complete reaction. Thirty minutes later, water (5L) was added and the mixture was stirred for 5 minutes before the phases were split. The organic phase was washed with saturated aqueous sodium chloride until the pH of the wash was 3 (4×5L required), dried over sodium sulfate (1 kg), filtered, and stripped of solvent by rotary evaporation. The residue was triturated with methylene chloride (2L) and chilled for 15 minutes before the solid was collected by filtration, washed with cold methylene chloride (2L), and dried in air at ambient temperature to a constant weight of 1.041 kilograms (72%) of 4: mp 147°-148° C.; IR (KBr) 3381, 3263, 3093, 1694, 1532, 1403, 1336, 1163, 1102 cm-1 ; 1H NMR (acetone-d6) δ 7.76 (s, 1H), 7.11 (br, 2H), 4.76 (s, 2H); Analysis for C6H5BrClNO3S2 : Calcd: C, 22.62; H, 1.58; N, 4.40; S, 20.13. Found: C, 22.66; H, 1.60; N, 4.35; S, 20.12.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH3:30])([CH3:29])[CH2:15][N:16]3[Si](C(C)C)(C(C)C)C(C)C)=[CH:12][C:11]=2[F:31])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]1([S:7]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH3:29])([CH3:30])[CH2:15][NH:16]3)=[CH:12][C:11]=2[F:31])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)N1CC(C)(C)c2cc(F)c(S(=O)(=O)c3ccccc3)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)CNc2cc(S(=O)(=O)c3ccccc3)c(F)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
6-Benzenesulfonyl-5-fluoro-3,3-dimethyl-1-triisopropylsilanyl-2,3-dihydro-1H-indole (1.43 mg, 3.1 mmol) was treated with TBAF (1M solution in THF, 4.0 mL) in dry THF (20 mL) and the resulting solution stirred at room temperature for 1.5 hours. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The crude material was purified by chromatography (petrol:EtOAc 1:1) to give the title compound (810 mg) as a colourless oil. MS: [M+H]+=306.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].C(=O)(O)[O-].[Na+].[CH2:11]([C:13]1[CH:25]=[CH:24][C:16]([O:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:15][CH:14]=1)[CH3:12].O>ClCCl>[Br:1][CH2:2][C:3]([N:21]1[CH2:22][CH2:23][CH:18]([O:17][C:16]2[CH:24]=[CH:25][C:13]([CH2:11][CH3:12])=[CH:14][CH:15]=2)[CH2:19][CH2:20]1)=[O:4]
Reactant: CCc1ccc(OC2CCNCC2)cc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCc1ccc(OC2CCN(C(=O)CBr)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.7 %

Procedure:
To a stirred suspension of 6.03 ml (69.3 mmol) of bromoacetyl bromide, 13.0 g (155 mmol) of sodium bicarbonate and 160 ml of dry dichloromethane in an ice bath was added dropwise a solution of 13.0 g (63.4 mmol) of 4-(4-ethylphenoxy)piperidine in 140 ml of dry dichloromethane. The mixture was stirred 1 hour at 0° and 45 minutes at room temperature. The mixture was subsequently poured into water, extracted twice with dichloromethane, washed with saturated sodium chloride and dried over potassium carbonate. Filtration followed by evaporation of the solvent provided 20.0 g (61.3 mmol) of 1-(2-bromoacetyl)-4-(4-ethylphenoxy)piperidine as an oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Sc1ccc2ccccc2c1
Product: O=C1CCc2cc(OCCCCSc3ccc4ccccc4c3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 2-naphthyl-mercaptan and 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:12])[CH2:7][CH2:6]1)=O.C([O-])([O-])=O.[K+].[K+]>CO.O>[N:8]1([C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:12])[CH2:7][CH2:6][NH:5][CH2:10][CH2:9]1
Reactant: O=C(c1nccs1)N1CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(c1nccs1)N1CCNCC1
Yield: 238.7 %

Procedure:
A solution of compound 7a (3.8 g, 0.013 mol) and K2CO3 (3.5 g, 0.026 mol) in MeOH (40 mL) and water (10 mL), was stirred for 4 h. The solid was collected by filtration and the solvent evaporated in vacuo to give compound 7b (6.12 g). MS m/z (M+H+) 198.1.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([OH:55])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])[CH2:4][CH2:3]1.N1C(C)=CC=CC=1C.S(O[CH2:82][CH2:83][O:84][CH2:85][CH3:86])(C(F)(F)F)(=O)=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:82][CH2:83][O:84][CH2:85][CH2:86][O:55][C@H:50]1[C@H:51]([O:53][CH3:54])[CH2:52][CH:47]([CH2:46][C@H:44]([CH:27]2[O:28][C:29](=[O:30])[C@H:31]3[N:36]([CH2:35][CH2:34][CH2:33][CH2:32]3)[C:37](=[O:38])[C:39](=[O:40])[C@:41]3([OH:43])[O:42][C@@H:5]([CH2:4][CH2:3][C@H:2]3[CH3:1])[CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17](=[O:18])[C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24](=[O:25])[CH2:26]2)[CH3:45])[CH2:48][CH2:49]1
Reactant: CCOCCOS(=O)(=O)C(F)(F)F
Reactant: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C
Agent: CCOCCO[C@@H]1CCC(C[C@@H](C)C2CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)CC(C)/C=C/C=C/C=C(\C)[C@@H](OC)C[C@@H]3CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)C[C@H]1OC
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOCCO[C@@H]1CCC(C[C@@H](C)C2CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)CC(C)C=CC=CC=C(C)[C@@H](OC)C[C@@H]3CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)C[C@H]1OC
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1 g rapamycin, and 7.66 g 2,6-lutidine in 14.65 mL toluene held at 60° C. was added 5.81 g 2-ethoxyethanol triflate. Stirring was continued for 90 minutes after which 50 mL ethyl acetate was added to the reaction and the solution was washed with 50 mL 1M HCl. The organic material was washed with D.I. water until pH of wash solution was neutral and the organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, 200–400 mesh (40:60 hexane-ethyl acetate (v/v) to give 210 mg 42-O-(2-ethoxyethyl) rapamycin. TLC Rf=0.41 using 40:60 hexane-ethyl acetate (v/v). MS (ESI) m/z 1008.5 C55H87NNaO14. A mass spectrum of the title compound is shown in FIG. 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]([C:11]1[C:15]([CH3:16])=[CH:14][S:13][C:12]=1[CH3:17])[CH:7]([CH3:10])[C:8]#[CH:9])=[O:5].[OH-].[Na+].[I:20]I.Cl>CO>[CH3:1][O:2][CH2:3][C:4]([N:6]([C:11]1[C:15]([CH3:16])=[CH:14][S:13][C:12]=1[CH3:17])[CH:7]([CH3:10])[C:8]#[C:9][I:20])=[O:5]
Reactant: C#CC(C)N(C(=O)COC)c1c(C)csc1C
Reactant: II
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCC(=O)N(c1c(C)csc1C)C(C)C#CI

Procedure:
A mixture of 2.51 g (0.01 mol) 2-methoxy-N-(2,4-dimethylthien-3-yl)-N-(1-butin-3-yl)-acetamide, 1.3 g (0.0325 mol) NaOH and 100 ml methanol are cooled with stirring to 10°, and 2.65 g (0.01 mol) powdered iodine is then slowly added. The mixture is then stirred for 3 hours at room temperature, neutralized with methanolic HCl-solution, and the solvent evaporated to yield, after chromatography, the title compound.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20](OC)=[O:21])=[CH:14][C:13]=2[C:24]([F:27])([F:26])[F:25])=[C:8]([C:28]([F:31])([F:30])[F:29])[CH:7]=1.[BH4-].[Na+]>O>[OH:21][CH2:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][OH:2])=[CH:7][C:8]=2[C:28]([F:29])([F:30])[F:31])=[C:13]([C:24]([F:25])([F:26])[F:27])[CH:14]=1
Reactant: COC(=O)C=Cc1ccc(-c2ccc(C=CC(=O)OC)cc2C(F)(F)F)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: OCCCc1ccc(-c2ccc(CCCO)cc2C(F)(F)F)c(C(F)(F)F)c1
Yield: 35 %

Procedure:
2,2′-Bistrifluoromethylbiphenyl-4,4′-diacrylic acid dimethyl ester (11.5 g, 25.1 mmol) was dissolved in 200 ml polyethylene glycol (PEG 400) and sodium borohydride (6.5 g, 172 mmol) was added gradually during 30 min at 130° C. The mixture was heated at this temperature for 6 h. After cooling water was added, the mixture was extracted with chloroform, dried (MgSO4) and evaporated to give a residue which was submitted to chromatography on silica gel. Elution with ethyl acetate afforded 3.57 g (35%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[N+:19]([O-])=O)[OH:10].Cl.[Sn]>C(O)C>[NH2:19][C:12]1[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=1[CH:9]([C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[OH:10]
Reactant: COc1cccc(C(O)c2c(F)cccc2F)c1[N+](=O)[O-]
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: COc1cccc(C(O)c2c(F)cccc2F)c1N
Reaction time: 18 h

Procedure:
13.3 g of (2,6-difluorophenyl)(3-methoxy-2-nitro-phenyl)methanol are dissolved in 75 ml of ethanol. At 0° C., 37 ml of concentrated hydrochloric acid (10 eq.) are slowly added to 10.5 g of tin (2.2 eq.) (exothermic reaction). After 18 hours, the ethanol is evaporated, the residue is taken up in ethyl acetate before being alkalinized with a 3N aqueous sodium hydroxide solution until the pH is close to 14. After decantation, the organic phase is dried over anhydrous sodium sulfate and concentrated in order to obtain 8.7 of the expected product.
Reaction SMILES: [C:1]([O:19][CH3:20])(=[O:18])[C:2]1[C:3](=[CH:7][C:8](=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])[C:9]([O-:11])=[O:10])[C:4]([O-:6])=[O:5].S(Cl)([Cl:23])=O>CN1CCCC1=O>[Cl-:23].[Cl-:23].[C:13]([O:15][CH3:16])(=[O:14])[C:12]1[C:8](=[CH:7][C:3](=[C:2]([CH:17]=1)[C:1]([O:19][CH3:20])=[O:18])[C:4]([O-:6])=[O:5])[C:9]([O-:11])=[O:10]
Reactant: O=S(Cl)Cl
Agent: COC(=O)c1cc(C(=O)OC)c(C(=O)[O-])cc1C(=O)[O-]
Solvent: CN1CCCC1=O
Product: [Cl-]
Temperature: 0 °C

Procedure:
Next, the NMP solution (β) of dimethyl pyromellitate was added to the NMP solution (α) of di-n-butyl 3,3′,4,4′-diphenylether-tetracarboxylate, and the flask containing them was cooled to 0° C., to which was dropwise added 17.13 g (0.144 mols) of thionyl chloride, and reacted therewith for 1 hour to obtain a mixed solution (γ) of di-n-butyl 3,3′,4,4′-diphenylether-tetracarboxylate dichloride and dimethyl pyromellitate dichloride.
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].[C:7]([O:11][C:12](=[O:21])[CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C@@H:18]([OH:20])[CH3:19])([CH3:10])([CH3:9])[CH3:8].O>CO.ClCCl>[C:7]([O:11][C:12](=[O:21])[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][C@@H:18]([OH:20])[CH3:19])[CH3:3])([CH3:8])([CH3:10])[CH3:9]
Reactant: C[C@H](O)CNCCCC(=O)OC(C)(C)C
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: C[C@H](O)CN(C)CCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Add 0.62 ml (670 mg, 7.81 mmol) of 35% aqueous formaldehyde solution and 101 mg (1.61 mmol) sodium cyanoborohydride to a solution of 350 mg (1.61 mmol) 4-{[(2S)-2-hydroxypropyl]amino}butyric acid tert.-butyl ester in 10 ml methanol. Stir the reaction mixture for 16 h at room temperature. After adding 30 ml water and 40 ml dichloromethane, dry the organic phase over sodium sulphate, and filter. Concentrate the filtrate by vacuum evaporation, and dry. 323 mg (81% of theor.) of the desired product is obtained.