Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:52]([NH2:54])=[O:53])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[O:31])[CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH2:24][CH3:25])([CH3:23])[CH3:22])=[CH:17][C:16]=3[C:26]([CH2:29][CH3:30])([CH3:28])[CH3:27])[CH:10]=2)[C:5]([N:32]=NC2C=CC(C(O)=O)=CC=2)=[C:4]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:3]1[CH2:49][CH2:50][CH3:51].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[OH:1][C:2]1([C:52]([NH2:54])=[O:53])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[O:31])[CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH2:24][CH3:25])([CH3:23])[CH3:22])=[CH:17][C:16]=3[C:26]([CH2:29][CH3:30])([CH3:27])[CH3:28])[CH:10]=2)[C:5]([NH2:32])=[C:4]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:3]1[CH2:49][CH2:50][CH3:51]
Reactant: CCCC1C(c2ccccc2)=C(N=Nc2ccc(C(=O)O)cc2)c2ccc(C(=O)COc3ccc(C(C)(C)CC)cc3C(C)(C)CC)cc2C1(O)C(N)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCC1C(c2ccccc2)=C(N)c2ccc(C(=O)COc3ccc(C(C)(C)CC)cc3C(C)(C)CC)cc2C1(O)C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6.15 g of 1-Hydroxy-2-propyl-3-phenyl-4-[(4-carboxy)phenylazo]-7-[(2,4-ditertamyl)phenoxyacetyl]naphthamide prepared in step (7) in 100 ml of ethanol was refluxed under nitrogen with strong stirring. A solution of 6.93 g of sodium hydrosulfite in 36 ml of water was then added. The reaction mixture was stirred for 30 minutes at reflux temperature. After cooling, the reaction mixture was poured into 200 ml of ice water. The organic products were extracted with ethyl ether. The extracts were washed with a sodium bicarbonate saturated aqueous solution and with water. They were finally dried and evaporated to dryness under reduced pressure. After treatment with petroleum ether, the crystals formed were filtered off. The crude product was recrystallized from acetonitrile. The recrystallized product was washed with boiling methanol and with petroleum ether before being dried.
Reaction SMILES: [Cu]C#N.[Cl-].[Li+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([Mg]Cl)[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[CH2:18](Br)[CH:19]=[CH2:20]>C1COCC1>[CH2:20]([C:10]1[CH:9]=[C:8]([O:7][CH3:6])[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=1)[CH:19]=[CH2:18]
Reactant: COc1cc(OC)cc([Mg]Cl)c1
Reactant: C=CCBr
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 1.49 g (16.5 mmol) of copper (I) cyanide and 1.39 g (33 mmol) of lithium chloride in 40 mL of THF was added dropwise 15 mL of a 1 M solution of 3,5-dimethoxyphenylmagnesium chloride in THF at −78° C. After stirring for 5 min, 2.5 mL (3.6 g, 30 mmol) of allyl bromide was added dropwise, and the resulting solution was stirred for 16 h while slowly warming to room temperature. The reaction mixture was quenched by slowly adding saturated NH4Cl(aq) and stirring for 5 min. The layers were separated and the aqueous phase was extracted three times with 50-mL portions ethyl acetate. The combined organic fractions were dried (Na2SO4), filtered through a pad of silica gel (eluted with ethyl acetate) and concentrated in vacuo. The residue was chromatographed over silica gel (eluted with 50:1 hexanes-ethyl acetate) to afford 2.59 g of a pale-yellow oil as a 6:1 mixture of 2:3. The mixture was suitable for further reactions without additional purification: 1H NMR (400 MHz, CDCl3) δ 6.36 (d, J=2.4 Hz, 2H), 6.32 (t, J=2.4 Hz, 1H), 6.81-5.87 (m, 1 H), 5.10 (dd, J=16.8, 1.6 Hz, 1 H), 5.07 (dd, J=9.6, 1.6 Hz, 1H), 3.78 (s, 6H), 3.33 (d, J=6.8 Hz, 2H).
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:20]=1)[CH2:16]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C=O)C>[CH2:1]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:20]=1)[CH2:16][N:33]=[N+:34]=[N-:35])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCC)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCOc1cc(CN=[N+]=[N-])cc(OCCCCCCCCCCC)c1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
3,5-diundecoxybenzyl chloride (13.5 g, 30.1 mmol) was dissolved in DMF (50 mL) in a 250 mL RBF. Sodium azide (3.94 g, 60.2 mmol) and a magnetic stir bar were added to the RBF. A heating mantel was used to gently heat the reaction mixture. After 1 hour, thin layer chromatography indicated that no starting material was present. The contents of the RBF were transferred to a separatory funnel. Ether (250 mL) and distilled H2O (250 mL) were added to the funnel. The aqueous layer was washed 2 times with ether (250 mL). The ether layers were combined and washed 2 times with saturated ammonium chloride solution (125 mL) and once with saturated sodium chloride solution (125 mL). The ether layer was then dried with magnesium sulfate, gravity filtered and concentrated using rotary evaporation. The resulting light yellow oil was then placed under high vacuum where it solidified. This produced a 13.3 g yield or a 97.1% yield of the derivative. The NMR characterization data for the derivative is as follows. 1NMR (300 MHz, CDCl3): 0.88 (t, J=6.3, 6H, CH2CH3), 1.21-1.44 (m, 32H, CH2(CH2)7), 1.77 (p, J=6.6, 4H, OCH2CH2), 3.93 (t, J=6.6, 4H, OCH2), 4.24 (s, 2H, ArCH2Cl), 6.41-6.43 (m, 2H, ArH). 13C NMR (75 MHZ, CDCl3): 14.22, 22.79, 26.13, 29.33, 29.44, 29.49, 29.68, 32.00, 55.00, 68.16, 101.07, 106.50, 137.45, 160.68.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12]C)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:14]#[C:15][Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1C#C)([CH3:23])([CH3:22])[CH3:21].BrC1C=C(S(CC)(=O)=O)C=CC=1F>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:15]#[C:14][C:3]1[CH:4]=[C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCS(=O)(=O)c1ccc(F)c(Br)c1
Product: CCS(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1
Yield: 86 %

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-bromo-4-ethanesulfonyl-1-fluoro-benzene (Intermediate 130), the title compound was obtained as a colorless oil in 86% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH:1]1([B:6]([O:11][CH:12]([CH3:14])[CH3:13])OC(C)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]([Li])#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl.[B].C=C(C)C>C(OCC)C>[CH:1]1([B:6]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[O:11][CH:12]([CH3:13])[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [Li]C#CCCCCCC
Reactant: CC(C)OB(OC(C)C)C1CCCC1
Agent: C=C(C)C
Agent: Cl
Agent: [B]
Solvent: CCOCC
Product: CCCCCCC#CB(OC(C)C)C1CCCC1

Procedure:
Cyclopentyldiisopropoxyborane (2.33 g, 37 mmol) in ethyl ether (37 mL) was added to an ethereal solution of 1-octynyllithium (41 mmoL in 41 mL ethyl ether), then quenched with HCl in ethyl ether (12.0 mL, 41 mmol). Workup as described in Example 14 yielded 6.95 g (76%), bp 100°-102° C. (0.1 mm Hg); n20D 1.4557; proton NMR (CDCl3) δ4.63 (septet, J=18 Hz, 1H), 2.23 (triplet, 1H), 1.17 (d, J=18 Hz, 6H), 0.83 (triplet, 3H); boron NMR (EE) δ+41.2 ppm(s); mass spectrum (chemical ionization, isobutene) m/e 249 (M+H), 40%); IR (thin film) 2186, 1344 cm-1. Anal. Calcd. for C16H29BO: C, 77.42; H, 11.78. Found: C, 77.02; H, 11.92.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:13][CH2:14][C@:15]1([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH2:21][C@@H:20]2[C@H:16]1[CH:17]=[CH:18][CH:19]2[CH2:22][CH3:23]>C1C=CC=CC=1>[C:2]1([CH3:12])[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:9])=[O:10])=[CH:6][CH:7]=1.[NH2:13][CH2:14][C@:15]1([CH2:24][C:25]([OH:27])=[O:26])[CH2:21][C@@H:20]2[C@H:16]1[CH:17]=[CH:18][CH:19]2[CH2:22][CH3:23]
Reactant: CCC1C=C[C@@H]2[C@H]1C[C@]2(CN)CC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCC1C=C[C@@H]2[C@H]1C[C@]2(CN)CC(=O)O

Procedure:
p-Toluenesulfonic acid monohydrate (2.17 g, 11.4 mmol) was added to a benzene solution (20 mL) of tert-butyl(±) [(1S,5R,6S)-6-(aminomethyl)-2-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetate (2.75 g, 10.4 mmol), and the mixture was refluxed for 1 hour. The mixture was allowed to cool, and the deposited solid was then washed with methylene chloride to obtain the compound of interest as a gray solid (3.17 g, 80%, Major/Minor=3/1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[NH:5][N:4]([CH2:14][CH2:15][CH2:16][OH:17])[N:3]=1.[NH2:18][NH2:19]>O1CCOCC1>[NH:18]([C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[NH:5][N:4]([CH2:14][CH2:15][CH2:16][OH:17])[N:3]=1)[NH2:19]
Reactant: OCCCN1N=C(Cl)C=C(N2CCOCC2)N1
Reactant: NN
Solvent: C1COCCO1
Product: NNC1=NN(CCCO)NC(N2CCOCC2)=C1
Yield: 87.6 %

Procedure:
3-(4-Chloro-6-morpholin-4-yl-triazin-2-yl)-propan-1-ol (19.4 mmol) is dissolved in dioxane (30 mL). To the reaction mixture is added anhydrous hydrazine (10 mL, 300 mmol). The reaction is then heated at reflux for five hours. The solvent is removed under reduced pressure, and the crude solid is dissolved in a mixture of dichloromethane (800 mL) and 10% potassium carbonate (40 mL). The organic layer is isolated, dried with sodium sulfate, and evaporated to yield crude 3-(4-hydrazino-6-morpholin-4-yl-triazin-2-yl)-propan-1-ol (4.3 g., 17 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:30][CH2:29][C:26]3[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc(N)cc1)CC3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc(N)cc2)C1

Procedure:
The title compound is prepared from a mixture of 4-(3,4-dihydro-8-methyl-1H-pyrido[4,3-b]indol-2(5H)-yl)benzenamine, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:50][CH3:51])=[C:31]([C:36]([CH2:39][S:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[F:49])(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33].O1C=CC(B(O)O)=C1>>[F:49][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[S:40]([CH2:39][C:36]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]([O:50][CH3:51])[C:29]([C:23]2[CH:27]=[CH:26][O:25][CH:24]=2)=[CH:38][CH:37]=1)(=[O:42])=[O:41]
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2F)ccc(Br)c1OC
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2F)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(2-fluorobenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 100) and furan-3-yl boronic acid.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C#CC(O)CC
Reactant: O=C1Nc2ccc(F)c(I)c2/C1=C/c1ccc[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1ccc[nH]1)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (58.9 mg, 0.7 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.28 mmol) (Starting Material 5, supra) using (Ph3P)4Pd (32 mg) and Cul (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 10 h to yield rac-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 64 mg, 70%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH2:7][C:8]#[CH:9])[C:3]1=[O:18].[CH2:19]([O:21][C:22]1[CH:23]=[CH:24][C:25]([F:36])=[C:26]([C:28]2[CH:33]=[C:32]([CH3:34])[N:31]=[C:30](I)[N:29]=2)[CH:27]=1)[CH3:20].N(CC)CC>C1COCC1.CCOC(C)=O.CCCC(C)C.[Cu](I)I>[CH2:19]([O:21][C:22]1[CH:23]=[CH:24][C:25]([F:36])=[C:26]([C:28]2[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([C:9]#[C:8][CH2:7][C@@:4]3([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:5][CH2:6][N:2]([CH3:1])[C:3]3=[O:18])[N:29]=2)[CH:27]=1)[CH3:20]
Reactant: C#CC[C@@]1(NC(=O)OC(C)(C)C)CCN(C)C1=O
Reactant: CCOc1ccc(F)c(-c2cc(C)nc(I)n2)c1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCCC(C)C
Solvent: CCNCC
Product: CCOc1ccc(F)c(-c2cc(C)nc(C#CC[C@@]3(NC(=O)OC(C)(C)C)CCN(C)C3=O)n2)c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
Copper iodide (26.27 mg, 0.14 mmol), followed by PdCl2(Ph3P)2 (48.41 mg, 0.07 mmol) was added portionwise to a solution of the tert-butyl N-[(3R)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 10) (348 mg, 1.38 mmol), 4-(5-ethoxy-2-fluoro-phenyl)-2-iodo-6-methyl-pyrimidine (which may be prepared as described in D17) (642.17 mg, 1.79 mmol) and Et2NH (0.71 mL, 6.9 mmol) in THF (10 mL) under N2 and the reaction was stirred at 20° C. for 18 hrs. The solvent was evaporated and the residue was dissolved in EtOAc and washed with water. The organic layer was dried (Na2SO4) and the solvent was evaporated to afford an oil. This was purified on a Biotage SP4 using a 25 g SNAP cartridge, eluting with 50 to 100% EtOAc/i-hexane affording the tert-butyl N-[(3R)-3-[3-[4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidin-2-yl]prop-2-ynyl]-1-methyl-2-oxo-pyrrolidin-3-yl]carbamate (D18) (605 mg, 1.2538 mmol, 90.9% yield) as a pale yellow foam.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20].C(N(CC)CC)C>C1COCC1>[CH3:12][O:13][CH2:14][CH2:15][N:16]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:17][CH2:18][O:19][CH3:20]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COCCNCCOC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCN(CCOC)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A solution of p-nitrobenzyl bromide (10 g) in THF (50 ml) was added dropwise to a solution of bis(2-methoxyethyl)-amine (6.8 g) and triethylamine (10 ml) in THF (50 ml). Under nitrogen atmosphere, the mixture was stirred at room temperature overnight, and the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give N,N-bis(2-methoxyethyl)-4-nitrobenzylamine (10.8 g) as yellow oil.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([C@@H:23]1[O:25][CH2:24]1)Cl.Cl([O-])(=O)(=O)=O.[Li+].C[O-].[Na+]>C1(C)C=CC=CC=1.CO.[NH4+].[Cl-]>[CH2:1]([N:8]1[C@H:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH2:10][O:11][C@H:23]([CH2:24][OH:25])[CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](CO)NCc1ccccc1
Reactant: ClC[C@H]1CO1
Agent: C[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CO[C@H](CO)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To (2S)-2-(benzylamino)-3-{[tert-butyl(dimethyl)silyl]oxy}propan-1-ol (1 eq) in Toluene (0.3 M) at rt was added (R)-(−)-epichlorohydrin (1.3 eq.) and Lithium perchlorate (1.3 eq) was then slowly added over 2 hours. The mixture was stirred at rt for 48 hrs and sodium methoxide (2.5 eq of a 25% solution of NaOMe in MeOH) was added. MeOH was then added to the reaction mixture to obtain a 4:1 ratio of toluene:MeOH as solvent. The reaction mixture was stirred for 48 hrs at rt and diluted with saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by automated SiO2 flash chromatography system using solvent gradient of 0% EtOAc/Hex to 25% EtOAc/Hex to afford the desired compound.
Reaction SMILES: C[N:2]([CH3:20])/[CH:3]=[C:4](/[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1[F:18])\[C:5]([O:7][CH2:8][CH3:9])=[O:6].NC[CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C(O)C.C(OCC)C>[F:18][C:12]1[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:11]=1[C:10]([C:4](=[CH:3][NH:2][CH2:20][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:19]
Reactant: NCCN1CCOCC1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=CNCCN1CCOCC1)C(=O)c1cc(I)ccc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
A suspension of ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (WO2006/010733, 294 mg, 0.75 mmol) in ethanol (2.500 mL) and diethyl ether (5 mL) was cooled 0° C. and 4-(2-aminoethyl)morpholine (103 mg, 0.79 mmol) was added dropwise. The reaction mixture was stirred for 3 h, then concentrated under reduced pressure to give the desired product (358 mg). MS (ESP): 477 (M+H+) for C18H22FIN2O4.
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3]1.[OH-].[Na+].[N+:13]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[CH:19]=[CH:20][CH2:21][Cl:22])([O-:15])=[O:14]>O.C(O)C>[ClH:22].[N+:13]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[CH:19]=[CH:20][CH2:21][N:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2]1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cccc(C=CCCl)c1
Reactant: c1ccc2c(c1)CNC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc(C=CCN2Cc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 51.4 %

Procedure:
The process for the preparation of this compound and its physical properties will be given below. A solution of 5.68 grams of isoindoline hydrochloride and 2.86 grams of sodium hydroxide in 15 milliliters of water is added to a solution of 6.8 grams of m-nitrocinnamyl chloride in 160 milliliters of ethanol, and the mixture is stirred for 10 hours at room temperature. After completion of the reaction, the reaction product is concentrated, and the residue is extracted with chloroform. The extract is then purified by silica gel column chromatography, following which the resulting oily product is converted to a hydrochloride in a customary manner and recrystallized from ethanol to obtain 5.6 grams (yield 52%) of N-(m-nitrocinnamyl)-isoindoline hydrochloride as crystals having a melting point of 208°-210° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13][N:14]=[N+]=[N-])[N:10]=[CH:9]1>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13][NH2:14])[N:10]=[CH:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(CN=[N+]=[N-])c3)c(F)c2)C(=O)O1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(CN)c3)c(F)c2)C(=O)O1
Reaction time: 4 h

Procedure:
N-[(5S)-3-(3-Fluoro-4-(4-azidomethylimidazol-1-yl)phenyl)-2-oxooxazolidin-5-yl-methyl]acetamide (1.38 g, 3.67 mM) was dissolved in ethanol (60 ml), treated with Lindlar catalyst (5% Pd on CaCO3 partially poisoned with lead, 650 mg), and stirred under an atmosphere of hydrogen under balloon pressure for 4 hours. After filtration through celite, solvent was evaporated to give the title product as a gum, pure enough for further work (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH:11](OS(C)(=O)=O)[CH3:12])=[CH:8][C:6]=2[N:7]=1.Cl.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].ClCCl>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH:11]([N:32]3[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]3)[CH3:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(OS(C)(=O)=O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(c1cc2nc(Cl)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C

Procedure:
To solution of methanesulfonic acid 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethyl ester (640 mg) and 1-methanesulfonyl-piperazine hydrochloride salt (described above) (511 mg) in acetonitrile (50 mL) was added potassium carbonate (1.170 g) and the reaction mixture was stirred at reflux for 16 h. After cooling to room temperature the reaction mixture was reduced in vacuo, redissolved into dichloromethane and washed with saturated aqueous sodium hydrogencarbonate solution and then brine. The organics were dried (MgSO4), reduced in vacuo and purified on silica to yield 2-chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=1)=O>>[F:27][C:26]([F:28])([F:29])[O:25][C:21]1[CH:20]=[C:19]([C:17]2[N:1]=[C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)[S:14][CH:16]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CBr)c1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(OC(F)(F)F)c3)cs2)c1
Yield: 86.3 %

Procedure:
By a reaction in the same manner as in Example 1c and using the compound (213 mg, 1.00 mmol) obtained in Example 1b and 2-bromo-1-[3-(trifluoromethoxy)phenyl]ethanone (283 mg, 1.00 mmol), the title compound (343 mg, 86%) was obtained as colorless crystals.