Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.BrC1[S:37][C:38]2[C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:43][CH:42]=[CH:41][C:39]=2[N:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:37][C:38]4[C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:43][CH:42]=[CH:41][C:39]=4[N:40]=3)[CH2:14][C@H:13]2[NH:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCN[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN[C@@H]1CN(c2nc3cccc(C(=O)OCC)c3s2)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 47.1 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl trans(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(ethylamino)piperidine-1-carboxylate obtained in Example (207a) (25.0 mg, 0.063 mmol), 4 N hydrochloric acid/1,4-dioxane (1 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (21 mg, 0.075 mmol) and sodium carbonate (66 mg, 0.625 mmol), to obtain 15 mg of the title compound (48%) as a colorless solid.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1>C1C=CC=CC=1>[Br:1][CH2:2][C:3]([N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: c1ccc2c(c1)CCCN2
Solvent: c1ccccc1
Product: O=C(CBr)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 20.2 g. of bromoacetyl bromide in 150 ml. of benzene is added dropwise over 30 minutes, 26.6 g. of 1,2,3,4-tetrahydroquinoline dissolved in 35 ml. of benzene. The reaction mixture is then stirred at room temperature for 18 hours, after which time the precipitate is filtered off. The resultant filtrate is washed successively with 1N HCL solution and with a saturated sodium chloride solution, dried, and the solvent removed under reduced pressure to yield 1-(bromoacetyl)-1,2,3,4-tetrahydroquinoline, b.p. 70°-80° C. (at 0.1 mm. Hg).
Reaction SMILES: [I-].C[S+](C)C.[CH3:6]C(C)([O-])C.[K+].[C:12]([O:16][C:17]([N:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:20]([CH:28]=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(#N)C.O>[C:12]([O:16][C:17]([N:19]([C@@H:20]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C@@H:28]1[O:29][CH2:6]1)[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](C=O)Cc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a suspension of 0.90 g (4.42 mmoles) of trimethylsulfonium iodide in 18 mL of acetonitrile was added 0.495 g (4.42 mmoles) of potassium t-butoxide. A solution of 1.0 g (2.95 mmoles) of N-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninal in 7 mL of acetonitrile was added and the mixture was stirred at room temperature for one hour. The mixture was diluted with 80 mL of water and extracted twice with 80 mL of ethyl acetate. The organic layers were combined and washed with 100 mL water, 30 mL brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1.04 g of a yellow crude oil. The crude product was a mixture of the two diastereomers N,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxiranemethanamine and N,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2R-oxiranemethanamine.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.O.[NH2:25][NH2:26]>C(O)C>[NH:25]([C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1)[NH2:26]
Reactant: NN
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Solvent: CCO
Solvent: O
Product: CCCOc1ccccc1-c1nc2nc(NN)ncc2c(=O)[nH]1

Procedure:
A stirred mixture of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (1.31 g) and hydrazine hydrate (3 ml) in ethanol (30 ml) was heated under reflux for 3 hours to yield a yellow precipitate. The reaction mixture was cooled overnight and the yellow precipitate was collected and washed with ethanol and water to yield the title compound, 0.80 g, m.p. 219°-220° C.
Reaction SMILES: [CH2:1]([C@H:8]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:9]([C:11]([CH:13]1[CH2:15][CH2:14]1)=[O:12])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].[Na+]>C(Cl)Cl>[CH:2]1([CH2:1][C@H:8]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C@@H:9]([OH:10])[C@H:11]([CH:13]2[CH2:14][CH2:15]2)[OH:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reaction time: 2 h
Yield: 73.1 %

Procedure:
2.83 g (8.77 mmol) of tert.-butyl [(1S,2R)-1-benzyl-2-(cyclopropylcarbonyl)-2-hydroxyethyl]carbamate are dissolved in methylene chloride (130 ml), acetic acid (3 ml) is added thereto and the mixture is then treated portionwise at 0°-10° with 332 mg (8.78 mmol) of sodium borohydride. The reaction solution is stirred at 5° for a further 2 hours and then partitioned between 2N sodium bicarbonate solution and methylene chloride. After the usual working-up of the organic phase the residue is crystallized from ether/hexane, whereby there are obtained 2.1 g (74%) of tert-butyl [(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamate, melting point 83°-85°.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21]>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]([OH:21])[CH2:7][C:5]2[O:4][N:3]=[C:2]([CH3:1])[CH:6]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cc(C)on1
Reactant: O=Cc1cccc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CC(O)c2cccc(Cl)c2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-dimethylisoxazole (104 g, 1.07 mol, 1 eq) in THF (1 L) cooled to −78° C. under nitrogen, a solution of lithiumdiisopropylamide (1.8 M ethylbenzene in THF) (630 mL, 1.134 mol, 1.06 eq) was added dropwise. After 1 hr, a solution of 3-chlorobenzaldehyde 100 g, 0.711 mole, 0.66 eq) in THF (300 mL) was added drop wise at −78° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. It was cooled to 0° C., and quenched by saturated ammonium chloride solution (130 mL). The organic layer was concentrated to dryness. Water (1 L) was added to the residue was extracted with ethyl acetate (2×1 L). Combined organic extracts were washed with brine (700 mL) dried over anhydrous sodium sulfate. Concentrated and purified by column chromatography (50% ethyl acetate in hexane) over silica gel using a mixture of ethyl acetate and hexanes as eluant. The title compound was obtained as viscous brown oil (120 g, 0.507 mol, 48%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)=[N:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[CH:17][CH:18]=1.C(N(CC)CC)C.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([O:28][C:14]2[C:13]([NH:12][S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])=[CH:18][CH:17]=[C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[N:15]=2)=[CH:30][CH:31]=1)#[N:36]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: N#Cc1ccc(Oc2ccc(N)c(Oc3ccc(C#N)cc3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Oc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(Oc3ccc(C#N)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.1 %

Procedure:
4-Fluoro benzene sulfonyl chloride (0.15 g, 0.77 mmol), dissolved in 2 ml of tetrahydrofuran (THF), was added to a stirred solution of 3-amino-2,6-bis(4-cyano phenoxy)pyridine (0.25 g, 0.77 mmol), triethylamine (0.155 g, 1.54 mmol) and N,N-diisopropylethylamine (0.1 g, 0.77 mmol), in 10 ml of THF, in an inert atmosphere and stirred at RT for 12 h. The reaction mixture was concentrated and dissolved in 100 ml of ethyl acetate, washed with 1 N HCl followed by saturated brine solution and dried over anhydrous sodium sulphate. The organic phase was concentrated and the crude product was purified by column chromatography to afford 0.3 g of the required compound. 1H NMR (DMSO-d6): δ 6.94 (1H, d), 7.12 (2H, m), 7.25 (1H, d), 7.35 (4H, d), 7.56 (4H, m), 7.80 (4H, m), 8.04 (4H, m).
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[S:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:25][N:26]2[CH:30]=[CH:29][N:28]=[C:27]2[CH3:31])[N:22]=[N:23][CH:24]=1>>[ClH:18].[F:17][CH:2]([F:1])[C:3]1[S:7][CH:6]=[C:5]([C:19]2[CH:20]=[C:21]([CH2:25][N:26]3[CH:30]=[CH:29][N:28]=[C:27]3[CH3:31])[N:22]=[N:23][CH:24]=2)[CH:4]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: CC1(C)OB(c2csc(C(F)F)c2)OC1(C)C
Product: Cc1nccn1Cc1cc(-c2csc(C(F)F)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=307.2 (M+H+), was prepared from 2-(5-difluoromethyl-thiophen-3-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:29]=[CH:30][CH:31]=2)O1>CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.Cl[Pd]Cl.[Fe]>[F:15][C:14]([F:17])([F:16])[O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:30]3[CH:29]=[C:28]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:27]=[CH:26][CH:31]=3)=[N:3]2)=[CH:8][CH:9]=1
Reactant: COC(=O)CCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Product: COC(=O)CCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 10 using 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1), methyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (C13a), and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) at 80° C. and isolated as a dark orange solid (9.86 g, 91%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.12-8.03 (m, 2H), 8.01-7.91 (m, 2H), 7.66-7.58 (m, 2H), 7.49-7.40 (m, 1H), 7.34 (dt, J=7.8, 1.6 Hz, 1H), 3.59 (s, 3H), 2.95 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −57.01; ESIMS m/z 392 ([M+H]+).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:13]CCCC)(=[O:12])[CH:10]=[CH2:11].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O-:13])(=[O:12])[CH:10]=[CH2:11]
Reactant: C=CC(=O)OCCCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: C=Cc1ccccc1
Solvent: Cc1ccccc1C
Product: C=CC(=O)[O-]
Reaction time: 1 h

Procedure:
15 Parts of the above-obtained polymer resin having a higher molecular weight and 100 parts of xylene were charged into a flask, and dissolved. The inner atmosphere of the flask was replaced with nitrogen gas, and the mixture was heated up to the boiling point of xylene. While the mixture was stirred under the reflux of xylene, a mixture containing 72 parts of styrene, 13 parts of n-butyl acrylate and 3.3 parts of benzoyl peroxide (polymerization initiator) were dropwise added over 2 hours to carry out a solution polymerization. After the addition was completed, the reaction mixture was aged for 1 hour with stirring under the reflux of xylene, to give a styrene/acrylate copolymer resin having molecular weight maximal values, measured by GPC, of 6,000 and 1.2×106 and containing 15% by weight of the polymer having a higher molecular weight, for use in an electrophotographic toner of the present invention.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[Br-].[CH3:16][OH:17].C[C:19](N(C)C)=[O:20]>[Pd]>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[C:4](=[O:7])[CH2:5][CH2:6][C:2]=2[C:16]([O:20][CH3:19])=[O:17])=[CH:9][CH:10]=1
Reactant: O=C1CCC(Br)=C1c1ccc(F)cc1
Reactant: CC(=O)N(C)C
Reactant: CO
Agent: [Pd]
Agent: [Br-]
Product: COC(=O)C1=C(c2ccc(F)cc2)C(=O)CC1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To 50 mL of dry dimethylacetamide (DMAC, KF<100 ug/mL) was added 25 g (98 mmol) of 3-bromo-2-(4-fluorophenyl)-2-cyclopenten-1-one as a solid. In a separate 100 mL round-bottom flask was mixed 2.08 g of 5% Pd/C and 40 mL of DMAC. The slurry containing the catalyst was then added to the flask containing the starting bromide and the 100 mL round bottom flask rinsed with an additional 10 mL DMAC. To the reaction mixture was then added 46.7 mL (196 mmol) of N-tributylamine and 20 mL (473 mmol) of MeOH. The resulting reaction flask was purged with nitrogen (5×) and then with CO (5×). The CO pressure was set at 10 psi and the reaction mixture heated at 60° C. for 12 h. The reaction mixture was filtered over a small plug of solka floc to remove the catalyst and the pad washed with MeOH (172 mL). The methanol was removed under reduced pressure. To the mixture was slowly added 8.6 mL of 1N HCl at such a rate to keep the temperature <24° C., and then the batch was seeded with 1 wt % of methyl 2-(4-fluorophenyl)-3-oxo-1-cyclopent-1-enecarboxylate. After aging for 15 min, 163 mL of 1N HCl was added drop-wise over the next 2.5 hours maintaining the temperature <25° C. The slurry was aged at 15–20° C. for 30 min and sampled for supernatant concentration and filtered. The cake is washed with 17 mL of 1 N HCl and then water until the pH of the filtrate was >5. The product is dried under vacuum/nitrogen sweep for 40 h at 25° C. to give methyl 2-(4-fluorophenyl)-3-oxo-1-cyclopent-1-enecarboxylate as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5]N=1.[Cl:12][C:13]1[C:21]2[C:20]([NH:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[N:19][CH:18]=[N:17][C:16]=2[S:15][CH:14]=1.[CH3:32]CN(CC)CC>C(Cl)Cl>[Cl:12][C:13]1[C:21]2[C:20]([NH:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:7](=[O:8])[C:6]4[CH:5]=[CH:32][C:3]([O:2][CH3:1])=[CH:11][CH:10]=4)=[CH:27][CH:26]=3)=[N:19][CH:18]=[N:17][C:16]=2[S:15][CH:14]=1
Reactant: CCN(CC)CC
Reactant: Oc1ccc(CCNc2ncnc3scc(Cl)c23)cc1
Reactant: COc1ccc(C(=O)Cl)cn1
Solvent: ClCCl
Product: COc1ccc(C(=O)Oc2ccc(CCNc3ncnc4scc(Cl)c34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
A solution of 6-methoxynicotinoyl chloride (343 mg, 2 mmol) in CH2Cl2 (5 mL) was added dropwise to a solution of 4-{2-[(5-chlorothieno[2,3-d]pyrimidin-4-yl)amino]ethyl}phenol (611 mg, 2 mmol) and Et3N (1.0g, 10 mmol) in CH2Cl2 (5 mL) and the solution was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 (20 mL) and washed with H2O, 1M NaOH, and brine. The organics were dried (Na2SO4) and filtered through silica gel. The solvent was stripped yielding 200 mg of material which was purified via HPLC giving 48mg, 0.11 mmol, 5 percent yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:14]1([CH2:13][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:16][CH2:15]1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCC1CC1

Procedure:
A solution of 3-hydroxy-4-methoxybenzaldehyde (400 g, 2.63 mole) and bromomethylcyclopropane (426 g, 3.2 mole) in 1 L dimethylformamide (DMF) was stirred with potassium carbonate (K2CO3) (483 g, 3.5 mole) at 55° C. for 3.5 h. Then, 1 L of water was added, the mixture chilled on ice, and Intermediate 1 filtered as a white solid, (535 g, 99%). m/z 207 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1[C:19]2[CH:18]([CH2:20][O:21][C:22](Cl)=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.[Cl:25][C@H:26]1[CH2:30][NH:29][C@@H:28]2[C@@H:31]([OH:34])[CH2:32][O:33][C@H:27]12>O.O1CCOCC1>[Cl:25][C@H:26]1[CH2:30][N:29]([C:22]([O:21][CH2:20][CH:18]2[C:19]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:16]3[C:17]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:23])[C@@H:28]2[C@@H:31]([OH:34])[CH2:32][O:33][C@H:27]12
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O[C@H]1CO[C@H]2[C@@H]1NC[C@@H]2Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1C[C@H](Cl)[C@H]2OC[C@H](O)[C@H]21
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of sodium carbonate (0.49 g, 4.63 mmol) in water (7.5 mL) followed by a solution of 9-fluorenylmethoxycarbonyl chloride (0.55 g, 2.13 mmol) in 1,4-dioxane (2.5 mL) was added dropwise over 15 minutes whilst stirring to a solution of aminoalcohol (69) in 1,4-dioxane (5 mL). The mixture was stirred for 60 minutes then water (50 mL) was added and the product extracted into dichloromethane (3×25 mL), then dried (Na2SO4), filtered and reduced in vacuo to leave a colourless oil. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 10:90 to 45:55 gave alcohol (70) (623 mg, 87%) as a white solid. TLC (Rf=0.45, EtOAc:heptane 1:1), analytical HPLC single main peak, Rt=16.54 min., HPLC-MS 386.1/388.1 [M+H]+, 408.1/410.1 [M+Na]+; [α]D27.5−51.9° (c=2.31, CHCl3); (proton complex) δC (125 MHz, CDCl3) 47.21/47.41 (Fmoc CH), 53.30/53.43 (FmocNCH2), 57.74/58.36 (CHCl), 66.04/67.42 (Fmoc CH2), 67.87/68.52 (FmocNCH), 74.81/75.09 (OCH2CHOH), 74.92/75.51 (OCH2CHOH), 86.57/87.24 (CHCHCl), 119.80/119.82/120.00/120.64/124.55/124.63/124.90/127.04/127.08/127.40/127.51/127.78/127.80/127.87 and 127.91 (aromatic CH), 141.21/141.29/141.38/143.44/143.70/143.88 and 143.91 (aromatic quaternary), 154.13/154.79 (Fmoc C═O).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Si:11]([N:18]1[C@H:21]([CH2:22][C:23](OC)=[O:24])[C@@H:20]([C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH3:28])[C:19]1=[O:37])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[Si:11]([N:18]1[C@H:21]([CH2:22][CH:23]=[O:24])[C@@H:20]([C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH3:28])[C:19]1=[O:37])([C:14]([CH3:17])([CH3:15])[CH3:16])([CH3:13])[CH3:12]
Reactant: COC(=O)C[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Diisobutylaluminum hydride (3.72 ml of 0.91 M in hexane, 3.38 mmol) is added slowly by syringe to a solution of (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-carbomethoxymethyl azetidin-2-one (936 mg, 2.26 mmol) in 25 ml of freshly distilled toluene at -78° C. The resulting solution is stirred at -78° C. for 3 hrs., then quenched by addition of 2.5 N hydrochloric acid (5 ml). The resulting mixture is stirred for 2 min., then poured into a separatory funnel containing 100 ml of ether and 50 ml of 1.25 N hydrochloric acid saturated with tartaric acid. The organic phase is separated and the aqueous phase is extracted with ether (2×50 ml). The combined organic phases are washed with brine and dried over magnesium sulfate. Removal of solvents in vacuo gives a white solid which is recrystallized from ether-petroleum ether to give (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1 -(t-butyldimethylsilyloxy)ethyl]-4-(2-oxoethyl)-azetidin-2-one. m.p. 115°-116° C.; n.m.r. (CDCl3) δ4.1 (m,1), δ4.03 (m,1), δ2.7-3.2 (m,3), δ1.23 (d,3,J=6.4), δ1.08 (s,9), δ0.9 (s,9), δ0.25 (s,6), δ0.1 (s,6), δ9.83 (t,1,J=1.4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[N:9]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH3:37].C(OCC)(=O)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([CH2:24][CH2:25][C:26]([O:28][CH2:36][CH3:37])=[O:27])[N:9]=1
Reactant: CCc1cc2c(s1)-n1c(C)nnc1C(CCC(=O)O)N=C2c1ccccc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCC1N=C(c2ccccc2Cl)c2cc(CC)sc2-n2c(C)nnc21
Reaction time: 4 h

Procedure:
3-(4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-6-yl)propionic acid (13.5 g) was dissolved in dimethylformamide (140 ml). Potassium carbonate (9.1 g) and iodoethane (2.9 ml) were added, and the mixture was stirred for 4 hours. Ethyl acetate and water were added thereto. The organic layer was taken out, washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was crystallized from diisopropyl ether to give 11.2 g of ethyl 3-(4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-6-yl)propionate.
Reaction SMILES: [C:1]([C:5]1[CH:55]=[CH:54][C:8]2[NH:9][C:10]([CH2:12][CH2:13][CH:14]3[CH2:17][CH:16]([N:18]([CH2:22][C@@H:23]4[C@H:27]5[O:28]C(C)(C)[O:30][C@H:26]5[C@H:25]([N:33]5[C:37]6[N:38]=[CH:39][N:40]=[C:41]([NH:42]CC7C=CC(OC)=CC=7OC)[C:36]=6[CH:35]=[CH:34]5)[CH2:24]4)[CH:19]([CH3:21])[CH3:20])[CH2:15]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>FC(F)(F)C(O)=O.O.CO>[NH2:42][C:41]1[C:36]2[CH:35]=[CH:34][N:33]([C@@H:25]3[CH2:24][C@H:23]([CH2:22][N:18]([CH:16]4[CH2:15][CH:14]([CH2:13][CH2:12][C:10]5[NH:9][C:8]6[CH:54]=[CH:55][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=6[N:11]=5)[CH2:17]4)[CH:19]([CH3:20])[CH3:21])[C@@H:27]([OH:28])[C@H:26]3[OH:30])[C:37]=2[N:38]=[CH:39][N:40]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CC(C)N(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
7-((3aS,4R,6R,6aR)-6-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (390 mg, 0.52 mmol) was dissolved in a mixture of Trifluoroacetic Acid (7.2 ml) and Water (0.8 ml) which had been pre-cooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, then warmed to RT After 2.5 at RT the residue was taken up in 15 ml MeOH and concentrated. This procedure was repeated twice and the residue placed on high vacuum. The material was taken up in 15 ml MeOH (gave a slurry) and was treated with 500 mg K2CO3 and 8 drops of water. The mixture was allowed to stir for 1 hr, during which time the solution was found to be basic. The mixture was filtered through a finefrit, the solids were washed with 10 ml MeOH and the filtrate was concentrated to yield an off white solid. The material was left on high vacuum overnight. The crude material was purified by flash chromatography (SiO2, eluting with 8-10% 7N NH3 in CH3OH/CH2Cl2) to give a glass/stiff foam (0.22 g). 1H NMR (400 MHz, MeOD) δH ppm 8.06 (s, 1H), 7.48 (br. s., 1H), 7.39 (m, 1H), 7.27 (m, 1H), 7.20 (d, J=3.52 Hz, 1H), 6.60 (m, 1H), 4.32 (t, J=6.43 Hz, 1H), 3.93 (t, J=5.29 Hz, 1H), 3.54 (m, 0.2H), 3.11 (t, J=9.33 Hz, 1H), 3.02 (m, 1H), 2.82 (m, 2H), 2.66 (dd, J=13.68, 8.09 Hz, 1H), 2.46 (m, 1H), 2.36 (m, 1H), 2.23 (m, 3H), 2.05 (m, 1H), 1.91 (m, 3H), 1.59 (m, 3H), 1.36 (s, 9H), 1.02 (m, 6H).