Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:11][C:10]1=[O:22])[CH2:5][CH:6]([F:8])[F:7].O1CCCC1.O.[OH-].[Li+]>O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:12]1[CH2:13][N:9]([CH:4]([CH2:5][CH:6]([F:8])[F:7])[C:3]([OH:23])=[O:2])[C:10](=[O:22])[CH:11]=1
Reactant: COC(=O)C(CC(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
A mixture of 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-butyric acid methyl ester (790 mg, 2.28 mmol) in a 1:1 solution of tetrahydrofuran:water (20 mL) was treated with lithium hydroxide monohydrate (230 mg, 4.56 mmol). The mixture was stirred for 2 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran and then diluted with water, and the pH adjusted to pH=5 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4,4-difluoro-butyric acid (571 mg, 75%) as a cream colored solid: HR-ES-MS m/z calculated for C14H12NO4ClF2 [M+H]+ 332.0496, observed 332.0496.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)(C)C(C)=O)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(=O)C(C)(C)c1cccc(O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of 3-(3-methoxy-phenyl)-3-methyl-butan-2-one (6.570 g, 34.172 mmol) in methylene chloride (100 mL) cooled to −78° C. was added boron tribromide (102 mL, 1 M solution in methylene chloride, Aldrich). The mixture was stirred at −78° C. for 1 h, warmed up to 0° C. for 1 h then put in the freezer (−20° C.) for 72 h. At 0° C., water was added to quench the excess boron tribromide (CAUTION: Violent reaction). The product was extracted with petroleum ether. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by flash chromatography (40 g of silica gel, eluting with 5-20% ethyl acetate in hexane) to give 3-(3-hydroxy-phenyl)-3-methyl-butan-2-one as a yellow oil (5 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[CH3:12].Br[C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(B(O)O)cc1C
Reactant: Cn1cc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cnn(C)c2)cc1C
Yield: 65.9 %

Procedure:
Under nitrogen atmosphere, a mixture of 4-methoxy-3-methyl-phenylboronic acid 1.62 g, 4-bromo-1-methyl-1H-pyrazole 1.57 g, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex 0.79 g, sodium carbonate 3.51 g, dioxane 100 ml and water 30 ml was stirred with heating under reflux for four hours. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 4-(4-methoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole 1.3 g.
Reaction SMILES: S(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(=O)(=O)C.[NH:20]1[CH2:26][CH2:25][CH2:24][C@@H:21]1[CH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[OH:23][CH2:22][C@H:21]1[CH2:24][CH2:25][CH2:26][N:20]1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: OC[C@H]1CCCN1
Reactant: CS(=O)(=O)OCCc1ccc(N2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: OC[C@H]1CCCN1CCc1ccc(N2CCOCC2)cc1
Temperature: 70 °C

Procedure:
4-Morpholinophenethyl mesylate (0.43 g, 1.51 mmol), D-prolinol (0.17 g, 1.66 mmol) and sodium carbonate (0.40 g, 2.89 mmol) were added to acetonitrile (20 ml), and they were stirred under heating at 70° C. overnight. The reaction mixture was cooled and then filtered. The filtrate was evaporated to dryness under reduced pressure, and the residue was distributed into water and ethyl acetate. The intended product was extracted from ethyl acetate layer with 1 M hydrochloric acid. The aqueous layer was neutralized and the product was again extracted with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure to obtain (R)-2-hydroxymethyl-1-(4-morpholinophenethyl)pyrrolidine in the form of a light yellow solid (0.44 g, 1.5 mmol, 100%). This product was dissolved in dichloromethane (10 ml). Triethylamine (0.29 ml, 2.1 mmol) and methanesulfonyl chloride (0.15 ml, 1.9 mmol) were added to the obtained solution at 0° C., and they were stirred at room temperature for 1 hour. The reaction mixture was distributed into 5% aqueous sodium hydrogencarbonate solution and dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (1:1), suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(morpholinophenethyl)piperidine in the form of a white solid (0.30 g, 64%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][O:23][C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[N:31][C:30]([O:34][CH3:35])=[CH:29][CH:28]=3)[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[CH3:35][O:34][C:30]1[N:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][C@H:18]1[CH2:17][CH2:16][C@H:15]([NH2:14])[CH2:20][CH2:19]1)=[CH:33]2
Reactant: COc1ccc2ncc(OCC[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)cc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ncc(OCC[C@H]3CC[C@H](N)CC3)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (6.33 mL, 82.2 mmol, 20 eq) is added at room temperature to a stirred solution of {trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.65 g, 4.11 mmol, 1.0 eq) in dichloromethane (100 mL). After 2 hours stirring at room temperature, the reaction mixture is partitioned between saturated sodium hydrogen carbonate aqueous solution and dichloromethane and the pH value is about 10. The combined organic layers are dried over sodium sulfate and concentrated to afford trans-4-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-cyclohexylamine as a yellow solid (1.24 g, 95% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(OC)cc1
Solvent: ClCCl
Product: CCOC(=O)Cn1c(-c2ccc(OC)cc2)nc2cccnc21
Yield: 29.5 %

Procedure:
Solid N-[3-[(4-methoxybenzoyl)amino]-2-pyridinyl]glycine ethyl ester, 12.8 g (0.039 mole) was heated in glass in a Wood's metal bath at 210°-220° C. for 6 minutes. The residue was dissolved in methylene chloride, treated with charcoal, and filtered through a Celite pad. The filtrate (dark orange) was treated with Florisil® to give a pale orange filtrate. The filtrate was evaporated to a solid, which was recrystallized from tetrahydrofuran-petroleum ether. The solid was collected, washed with tetrahydrofuran-petroleum ether and dried under high vacuum at 50° C. overnight to give 3.58 g (29.5%) of title compound, mp 107°-8° C.
Reaction SMILES: C(O[K])(C)(C)C.[CH3:7][O:8][C:9](=[O:23])[CH:10]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12].[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28]Br)[CH3:25]>CN(C=O)C>[CH3:14][O:13][C:11](=[O:12])[C:10]([CH2:28][CH:27]([O:30][CH2:31][CH3:32])[O:26][CH2:24][CH3:25])([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[C:9]([O:8][CH3:7])=[O:23]
Reactant: CCOC(CBr)OCC
Reactant: CCOC(CC(C(=O)OC)C(=O)OC)OCC
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: CCOC(CC(CC(OCC)OCC)(C(=O)OC)C(=O)OC)OCC
Temperature: 60 °C
Reaction time: 10 h

Procedure:
4.97 g (44.3 mmol) of tBuOK are placed in a 0.5 L reactor with 80 mL DMF (solvent). 10.0 g (40.27 mmol) of 2-(2,2-diethoxy-ethyl)-malonic acid dimethyl ester, as prepared in example 2, dissolved in DMF (10 mL) are added slowly to the previous mixture keeping the temperature around 25° C. Once the addition has finished the temperature is raised to 60° C. and 7.94 mL (40.27 mmol) of bromoacetaldehyde diethyl acetal are added. The temperature is raised to 120° C. and kept during 10 h.
Reaction SMILES: [CH3:1][C:2]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:27])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:26])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])=[CH:3][C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5]>O1CCOCC1.[C].[Pd]>[CH3:1][CH:2]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:27])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:3][C:4]([N:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)=[O:5]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)N1CCOCC1
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(=O)N1CCOCC1
Yield: 88.1 %

Procedure:
In 100 ml of dioxane was dissolved 10 g of the compound obtained in step (a) above, and 1 g of 10% palladium-carbon was added to the solution. Reaction was carried out in an autoclave under a hydrogen gas pressure of 10 atmospheres at room temperature for 3 hours. The liquid reaction mixture was filtered, and the solvent was removed from the filtrate by distillation. The residue was purified by column chromatography using silica gel to obtain 9 g of the intended compound in the form of an oil.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27].Cl>>[ClH:19].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCc1ccccn1
Agent: Cl
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3ccccn3)s2)c(C)[nH]c1=O
Yield: 38 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (pyridin-2-yl)methylamine as described in Step 5, Example 24 and the resulting sulfonamide is converted to hydrochloride following the procedures as set forth in Step 6, Example 24 to give the title compound as a solid (38% yield). LC/MS: RT 2.28 min; me 390 (M+H).
Reaction SMILES: C(S[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)CCC.[Li]>>[CH2:8]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1)[CH2:7][CH2:6][CH2:14][CH3:13]
Reactant: CCCCSc1ccc(C(=O)O)cc1
Agent: [Li]
Product: CCCCCc1ccc(C(=O)O)cc1

Procedure:
The experimental procedure was as described for the preparation of e.g. compound 2 (i.e. pour the lithium salt onto cardice and acidify). A white solid was obtained.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([O:39][C:40]([N:42]1[CH2:46][CH2:45][CH:44]([NH:47][CH3:48])[CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[CH2:46][CH2:45][CH:44]([N:47]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[CH:28][C:3]=3[C:2]([F:34])([F:1])[F:33])[N:7]=[CH:8]4)[C:17](=[O:24])[N:18]=2)[CH3:48])[CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)C1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)C1CCN(C(=O)OC(C)(C)C)C1

Procedure:
3-({5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 3-Methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:32]([NH2:34])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:32]([NH:34][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)=[CH:26][CH:25]=1)[CH3:33]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cc1
Reaction time: 2 h
Yield: 53.3 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (20 mg, 0.046 mmol) in DMSO and acetic acid was added ethylamine (32 μL, 0.547 mmol). After 2 h, sodium triacetoxyborohydride (120 mg, 1.10 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 11.5 mg of the title compound (55%).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH2:11][C@H:10]2[N:7]([C:8](=[O:15])[C@@H:9]2[C@H:12]([OH:14])[CH3:13])[C:6]=1[C:16]([OH:18])=[O:17])[CH2:3][NH2:4].Cl.[C:20](=N)(OCC)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>O.O1CCCC1>[OH:14][C@@H:12]([C@H:9]1[C:8](=[O:15])[N:7]2[C@@H:10]1[CH2:11][C:5]([C@H:2]1[CH2:3][NH:4][C:20]([CH3:21])=[N:1]1)=[C:6]2[C:16]([OH:18])=[O:17])[CH3:13]
Reactant: CCOC(C)=N
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C([C@H](N)CN)C[C@H]12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1=N[C@@H](C2=C(C(=O)O)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)CN1
Yield: 7.3 %

Procedure:
To a solution of (5R,6S)-3-[(1S)-1,2-diaminoethyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (1.00 g) in a mixture of water (100 ml) and tetrahydrofuran (100 ml) was added portionwise ethyl acetimidate hydrochloride (1.00 g) under ice-cooling with stirring, keeping the pH between 8.0 and 8.5 with saturated aqueous potassium carbonate. After stirring for 2 hours, the mixture was concentrated under reduced pressure to be about 10 ml-volume. The aqueous solution was subjected to a column chromatography on silica gel (100 g) and eluted with a mixture of water and acetonitrile (6:4, V/V). The fractions containing the object compound were collected, concentrated under reduced pressure, and lyophilized to give a solid. A solution of the solid in water (10 ml) was subjected to a column chromatography on "Diaion HP-20" and eluted with water. The fractions containing the objected compound were collected, concentrated under reduced pressure, and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[(4S)-2-methyl-2-imidazolin-4-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.08 g) as a solid.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23]>CC(O)C>[N:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: N#CCCCCBr
Reactant: Oc1ccc(C=Cc2ccncc2)cc1
Agent: [Na]
Solvent: CC(C)O
Product: N#CCCCCOc1ccc(C=Cc2ccncc2)cc1
Yield: 85.5 %

Procedure:
To the solution of 1.16 g (50 mmol) sodium in 250 ml 2-propanol one adds 10.0 g (50 mmol) 4-[2-(4-pyridinyl)-ethenyl]-phenol, heats under reflux for 10 min, allows to cool, adds thereto 8.1 g (50 mmol) 5-bromovaleronitrile and heats to reflux for 16 h. One evaporates, mixes with water, extracts with dichloromethane, dries the extract, evaporates and triturates the residue with ether. One obtains 11.9 g of title compound (86% of theory) of the m.p. 85°-87° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:17][CH2:18][OH:19].C([O-])(O)=O.[Na+]>CO>[CH2:1]([N:8]([C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[CH2:17][CH2:18][OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNc1cccc(O)c1
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCCCN(CCO)c1cccc(O)c1
Yield: 54 %

Procedure:
0.1 mol of 3-(n-heptylamino)phenol in 100 ml of methanol is heated under reflux for 10 h with 0.11 mol of 2-bromoethanol and 0.1 mol of NaHCO3. After cooling, the reaction mixture is filtered, the solvent removed under reduced pressure and the residue fractionated to give 3-[N-(n-heptyl)-N-(2-hydroxyethyl)amino]phenol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[F:25][C:26]1[CH:40]=[CH:39][C:29]([CH2:30][N:31]2[CH2:36][C@H:35]([CH3:37])[NH:34][CH2:33][C@H:32]2[CH3:38])=[CH:28][CH:27]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]([N:34]1[CH2:33][C@H:32]([CH3:38])[N:31]([CH2:30][C:29]2[CH:39]=[CH:40][C:26]([F:25])=[CH:27][CH:28]=2)[CH2:36][C@H:35]1[CH3:37])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a solution of tert-butoxycarbonylamino-acetic acid (0.71 g, 4.05 mmol) in dichloromethane (40 mL) was added 4-dimethylaminopyridine (0.74 g, 6.07 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.16 g, 6.07 mmol) and 1-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazine (0.90 g, 4.05 mmol). The reaction was stirred overnight at ambient temperature. The reaction was diluted with dichloromethane and washed with brine. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (1.45 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[N:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>C(Cl)Cl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@@H:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32]([NH:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=4)=[O:33])=[CH:3][CH:4]=3)[C:16]=12
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(-c2nn([C@@H]3CCOC3)c3ncnc(N)c23)cc1
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc1)nn2[C@@H]1CCOC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(4-aminophenyl)-1-((R)-tetrahydrofuran-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.075 g, 0.25 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)phenyl isocyanate (0.035 mL, 0.25 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 12 hours. The reaction proceeded until completion as judged by TLC and LC-MS, was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD69. ESI-MS m/z [M+H]+ found 484.4, calculated 484.4.
Reaction SMILES: [C@@H:1]1([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([OH:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.F[P-](F)(F)(F)(F)F.[N:26]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:26]1([O:14][C:13]2[C:12]3[N:11]=[CH:10][N:9]([C:18]=3[N:17]=[CH:16][N:15]=2)[C@@H:1]2[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 26 h
Yield: 57 %

Procedure:
In a 50 mL round-bottomed flask equipped with a stirring bar were placed 2′-deoxyinosine 24 (0.504 g, 2.00 mmol) and BOP (1.770 g, 4.00 mmol). DMF (20 mL) and DIPEA (0.70 mL, 4.00 mmol) were added and the mixture was allowed to stir at room temperature for 26 h. The reaction mixture was evaporated with toluene several times. The crude product was dissolved in EtOAc and washed with water. The organic layer was separated, dried over Na2SO4 and concentrated. Chromatographic purification (SiO2, elution with 10% MeOH in CH2Cl2) afforded 0.421 g (57% yield) of compound 28 as a pale brownish-white foam. Rf (10% MeOH in CH2Cl2)=0.38. 1H NMR (500 MHz, CDCl3): δ 8.43 (s, 1H, Ar—H), 8.24 (s, 1H, Ar—H), 8.16-8.14 (m, 1H, Ar—H), 7.57-7.54 (m, 1H, Ar—H), 7.49-7.46 (m, 1H, Ar—H), 6.46 (dd, 1H, H-1′, J=9.2, 5.5), 5.10 (dd, 1H, OH, J=11.3, 2.3, CD3OD exchangeable), 4.83 (br m, 1H, H-3′), 4.25 (br s, 1H, H-4′), 3.97 (dt, 1H, H-5′, J=12.8, 2.0), 3.82 (app td, 1H, H-5′, Japp˜11.9, 1.8), 3.07 (ddd, 1H, H-2′, J=13.4, 9.5, 4.9), 2.42 (dd, 1H, H-2′, J=13.6, 5.7), 2.05 (d, 1H, OH, CD3OD exchangeable). 13C NMR (126 MHz, DMSO-d6): δ 159.1, 153.1, 151.1, 144.8, 143.2, 129.1, 128.8, 125.2, 120.5, 120.3, 108.7, 88.9, 86.9, 72.2, 62.7, 40.9. FAB HRMS calcd for C16H16N7O4 (M++H) 370.1264. found 370.1258.
Reaction SMILES: [CH2:1]([SiH:13]([Cl:15])[Cl:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:16]=[CH2:17]>C(O)(C)C>[CH2:1]([Si:13]([CH2:16][CH3:17])([Cl:15])[Cl:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC[SiH](Cl)Cl
Reactant: C=C
Solvent: CC(C)O
Product: CCCCCCCCCCCC[Si](Cl)(Cl)CC
Reaction time: 25 h

Procedure:
Resultant n-dodecyldichlorosilane in an amount of 161.4 g (0.6 mol), 22.4 g of ethylene (0.8 mol) and a solution of H2PtCl6 ·6H2O in isopropanol (0.05 mol % relative to n-dodecyldichlorosilane) were charged in a pressure-proof stainless steel reactor. After sealing, reaction was carried out at 50° C. for 25 hours to give n-dodecylethyldichlorosilane [(n--C12H25)(C2H5)SiCl2 ].
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)(=[O:3])[CH3:2].[OH-].[Na+].[BH4-].[Na+].Cl>O.CO>[CH3:2][CH:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)[OH:3]
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)C12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a mixture of 45.0 g of 1-acetyladamantane obtained according to the process of Production Example 1, 100 ml of methanol, and 20 ml of a 0.1 N sodium hydroxide aqueous solution on a water bath, 4.8 g of sodium borohydride was gradually added over 30 minutes. The mixture was stirred for further 30 minutes, was neutralized with a 1 N hydrochloric acid aqueous solution, and 200 ml of water was added to the neutralized mixture. The obtained crystal was filtrated, was washed with water, and was dried in vacuo to yield 45.0 g of α-methyl-1-adamantanemethanol.