Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl>[N:11]1([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: N#Cc1ccc(CN2CCOCC2)cc1
Yield: 79.2 %

Procedure:
Dissolve 4-cyanobenzaldehyde (5 g, 38.1 mmol), morpholine (4.15 g, 47.7 mmol) and acetic acid (2.2 mL, 38.1 mmol) in DCE (100 mL). Add sodium cyanoborohydride (3.59 g, 57.2 mmol), and stir the mixture overnight. Add water (100 mL), separate the layers and extract the aqueous layer with DCM (3×50 mL). Wash the combined organic extracts with brine, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:2 over 1.25 h, 80 mL/min) to obtain the desired intermediate as a colorless oil (6.1 g, 79%). MS (APCI+) m/z: 203 (M+H)+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]1[CH2:19]CN2C(=NCCC2)C[CH2:10]1.C(Br)(C)C.C(O)(=O)C>C1COCC1>[CH:9]([O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)([CH3:19])[CH3:10]
Reactant: Oc1cccc(O)c1
Reactant: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CC(C)Br
Solvent: CC(=O)O
Product: CC(C)Oc1cccc(O)c1

Procedure:
In 10 ml of THF, 1.5 g of resorcinol was dissolved and 2.24 ml of DBU was added under ice cooling. The resultant mixture was stirred for 10 min at room temperture. To the mixture, 1.92 ml of isopropyl bromide was added and refluxed for 2 hr. The reaction mixture was neutralized with acetic acid and evaporated under reduced pressure. The evaporated residue was redissolved in ethyl acetate and washed with 5% aqueous citric acid solution and saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and the residue was subjected to a silica gel column chromatography (chloroform:methanol=40:1) to give 466 mg of the title compound.
Reaction SMILES: [CH2:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH2:4][CH2:3]1.[H][H]>CO.CCOC(C)=O.[Pd]>[CH3:1][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: C=C1CCc2c(O)cccc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1CCc2c(O)cccc21
Yield: 93579.3 %

Procedure:
A mixture of 1-methylene-indan-4-ol (200 mg, 1.37 mmol) and 10% Pd/C (60 mg, 10% weight) in methanol (6 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 1-methyl-indan-4-ol (190 g, 94%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>C(Cl)Cl>[Br:34][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(F)ccc1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)ccc1CCBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2-(4-fluoro-2-nitro-phenyl)-ethanol (20.7, 0.11 mole) in methylene chloride (500 mL) was added triphenylphosphine (30.0 g, 0.11 mole) and the mixture was cooled to 0° C. Carbon tetrabromide (40.0 g, 0.12 mole) in methylene chloride (100 mL) was added dropwise through an addition funnel. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by flash column chromatography (silica gel, ethyl acetate:hexanes 3:7) to provide 24.0 g of the title compound as a yellow solid. 1H NMR (CDCl3): 7.70 δ (d, 1H); 7.40 δ (dd, 1H); 7.30 δ (d of t, 1H); 3.65 δ (t, 2H); 3.40 δ (t, 2H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[CH:23])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:10]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[C:23][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1ccccc1Br
Reactant: C#CCCCCCCC1CCCCC1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=Cc1ccccc1C#CCCCCCCC1CCCCC1

Procedure:
To an ice cold solution of 1-hexyne (49.6 mmoles) in freshly distilled tetrahydrofuran (50 ml) containing a trace of triphenylmethane was added dropwise n-butyl lithium in hexane (49.5 mmoles). About 10 minutes after the addition was stopped, sieve dried hexamethylphosphoramide (57.5 mmoles) was added and the solution stirred for 10 minutes. A solution of 2-cyclohexylethyl bromide (51.3 mmoles) in tetrahydrofuran (10 ml) was added and the reaction mixture was stirred for about 3 hours as the temperature rose to room temperature. The mixture was taken up in ether (100 ml) and washed with water (3×100 ml) and sodium chloride solution (100 ml). The organic phase was dried over magnesium sulfate and evaporated to leave an oil which was purified by flash chromatography to give 1-cyclohexyloct-3-yne. This compound (20.8 mmoles) was treated with potassium hydride (36.8 mmoles) in propylene diamine to obtain the isomeric 8-cyclohexyloct-1-yne as an oil. A mixture of 2-bromobenzaldehyde (12.59 mmoles), 8-cyclohexyloct-1-yne (14.87 mmoles), cuprous iodide (0.17 mmoles) and bis(triphenylphosphine) palladium (II) chloride (0.26 mmoles) in triethylamine (35 ml) was refluxed under argon for 1.5 hours. The reaction mixture was cooled, filtered and the filtrate evaporated. The resulting residue was dissolved in ether (100 ml), washed with 3N hydrochloric acid (50 ml) and saturated sodium chloride solution (50 ml) and then dried over anhydrous magnesium sulfate and charcoal. The solution was evaporated to afford an oil which was purified by flash chromatography (2% ether/hexane) to yield 2-(8-cyclohexyl-1-octynyl)benzaldehyde an an oil. This benzaldehyde (10.22 mmoles) was hydrogenated with 10% palladium on charcoal in ethyl acetate to give the desired product as an oil, after chromatography (3% ether/hexane).
Reaction SMILES: [BH4-].[Na+].CO.[O:5]1[C:9]2([CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[O:8][CH2:7][CH2:6]1>O>[O:5]1[C:9]2([CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[O:8][CH2:7][CH2:6]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1CCC2(CC1)OCCO2

Procedure:
NaBH4 (370 mg, 10 mmol) in 5 mL H2O was slowly added to 10 mL of MeOH solution of 1,4-dioxaspiro[4.5]decan-8-one (1.56 g, 10 mmol) at 0° C. After the addition, the methanol was removed and the residue was extracted with EtOAc (2×20 mL). The EtOAc layer was dried over MgSO4, filtered, and evaporated to give 1,4-dioxaspiro[4.5]decan-8-ol (compound 35-1), which was used in next step without further purification (1.56 g, yield 100%).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.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>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:21]1[CH:22]=[C:23]([F:25])[CH:24]=[C:19]([Cl:18])[CH:20]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Reactant: OB(O)c1cc(F)cc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cc(F)cc(Cl)c3)c(=O)n12
Temperature: 100 °C
Yield: 55.7 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.12 g, 0.38 mmol) and (3-chloro-5-fluorophenyl)boronic acid (0.080 g, 0.46 mmol) in 1,4-dioxane (3 mL) was added a 1N solution of sodium carbonate in water (0.5 mL, 0.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol). The mixture was heated at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, concentrated and purified on silica gel (0-25% ethyl acetate/hexanes) to give the desired product (0.077 g, 55%). LCMS calculated for C15H12ClFN5OS (M+H)+: m/z=364.0. Found: 364.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[N+:16]([C:4]1[CH:3]=[C:2]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([O-:18])=[O:17]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Yield: 53.4 %

Procedure:
A solution of tert-butyl 4-bromo-2-nitrophenylcarbamate 175 (3.97 g, 12.5 mmol), 2-thiophene boronic acid 176 (1.68 g, 13.4 mmol), sodium carbonate (3.98 g, 37.56 mmol) and Pd(PPh3)4 (0.94 g, 0.814 mmol) were stirred at 110° C. in a mixture of DME and water (2:1, 70 mL overnight. The solution was evaporated to dryness, diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to provide the crude product which was purified by flash chromatography (10% ethyl acetate in hexane) to provide the title compound 177 (2.14 g, 53% yield). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.63 (s, 1H), 8.12 (d, J=2.3 Hz, 1H), 7.92 (dd, J=8.4, 2.2 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.61 (q, J=2.2 Hz, 2H), 7.15 (dd, J=5.1, 3.7 Hz, 1H), 1.46 (s, 9H). MS: (calc.) 320.08; (obt.) 343.1 (M+Na).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21]([C:24]1[N:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:14]([F:15])=[C:13]([CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[O:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[N:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1OCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2F)cn1
Temperature: 90 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
A mixture of 2-(benzyloxy)-3,4-difluoro-1-nitrobenzene (7.65 g), 6-(methylsulfonyl)pyridin-3-ol (5.0 g) and potassium carbonate (4.4 g) in N,N-dimethylformamide (40 mL) was stirred at 90° C. for 5 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with successively water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=25:75 to 40:60, volume ratio) to give light yellow crystals, which were washed with ethyl acetate-hexane to give the title compound (8.4 g, 69%) as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:17][CH2:16][C:15](=O)[CH2:14]1)([O-:3])=[O:2].CC(O)=O.[CH2:23]([NH2:25])[CH3:24].Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:23]([NH:25][CH:15]1[CH2:16][CH2:17][CH:13]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)[CH2:14]1)[CH3:24]
Reactant: CCN
Reactant: O=C1CCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCNC1CCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(5-nitro-1H-indol-3-yl)cyclopentanone (1.6 g, 6.55 mmol) in 1,2-dichloroethane (50 mL) was added AcOH (0.40 mL, 6.55 mmol), EtNH2.HCl (0.53 g, 6.55 mmol) and NaBH(OAc)3 (2.1 g, 9.83 mmol) and the mixture left to stir overnight at room temperature. The reaction mixture was extracted with 2N NaOH (10 mL) and washed with dichloromethane (2×10 mL). The dichloromethane layer was separated and evaporated. The crude material was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain the product as a yellow solid as a mixture of diastereomers (1.2 g, 67%). 1H-NMR (CDCl3) δ 1.10-1.16 (m, 6H), 1.45-1.92 (m, 10H), 1.96-2.13 (m, 3H), 2.13-2.36 (m, 3H), 2.50-2.58 (m, 1H), 2.65-2.76 (m, 4H), 3.28-3.43 (m, 3H), 3.49-3.60 (m, 1H), 7.11 (d, 1H, J=1.8 Hz), 7.15 (d, 1H, J=1.5 Hz), 7.35 (s, 1H), 7.38 (s, 1H), 8.08 (d, 1H, J=2.1 Hz), 8.11 (d, 1H, J=2.1 Hz), 8.32 (brs, 1H, NH), 8.41 (brs, 1H, NH), 8.61 (d, 1H, J=2.1 Hz), 8.63 (d, 1H, J=2.1 Hz); EI-MS (m/z, %) 273 (M+, 90).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C-:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=O)=[O:7])=[CH:4][CH:3]=1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26].S(=O)(=O)(O)O.O>C(O)(=O)C>[C-:14]1([C:12]2[CH2:11][CH2:10][CH2:9][C:8]=2[C:6](=[O:7])[C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15]1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]
Reactant: O=C(CCCCC(=O)[c-]1cccc1)c1ccc(Cl)cc1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Solvent: O
Product: O=C(C1=C([c-]2cccc2)CCC1)c1ccc(Cl)cc1

Procedure:
5-(4-Chlorobenzoyl)pentanoyl ferrocene (8.2g; 0.02 mole) and 5% (v/v) concentrated sulphuric acid in glacial acetic acid (200 ml) were stirred at room temperature for 1 hour, the mixture was poured into water and extracted with chloroform (3 × 100 mls.). The combined extracts were washed with saturated aqueous sodium bicarbonate, and water, dried (magnesium sulphate) and evaporated under vacuum to yield a red-brown oil which crystallized from pentane at 0°-5°. The solid was filtered off to yield pure 1-ferrocenyl-2-(4-chlorobenzoyl)cyclopent-1-ene; 2.5g (35%) mp 121°-123°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:28])[CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:25]3[CH2:26][CH2:27][CH:22]([CH2:21][N:20]([CH3:28])[CH3:19])[CH2:23][CH2:24]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)CC1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN(C)CC1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with dimethyl-piperidin-4-ylmethyl-amine using standard reductive amination conditions. The resulting crude solid was triturated with methanol to give [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-ylmethyl]-dimethyl-amine as an off white solid (51% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with methanol to give 332 as an off white solid (36% yield). NMR (CDCl3, 400 MHz), 1.29-1.35 (2H, m), 1.46-1.51 (1H, m), 1.77 (2H, d, J=11.8), 2.08-2.15 (4H, m), 2.22 (6H, s), 2.99 (2H, d, J=11.5), 3.82 (2H, s), 3.88-3.91 (4H, m), 4.03-4.06 (4H, m), 5.21 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=469
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[CH2:10][CH2:11][C:12]#[N:13].C(N(CC)[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[CH3:25])C>>[OH:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[CH2:10][CH2:11][C:12]1[NH:13][C:17](=[O:26])[C:18]2[C:19]([CH:25]=1)=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: C[C@H]1CCCN(CCC#N)[C@H]1CO
Product: Cc1cccc2c(=O)[nH]c(CCN3CCC[C@H](C)[C@@H]3CO)cc12

Procedure:
In the same manner as in Example 10b (a) and using cis-2-hydroxymethyl-3-methylpiperidine described in J. Heterocycl. Chem., vol. 9, pp. 875–878 (1972), 3-(cis-2-hydroxymethyl-3-methylpiperidin-1-yl)propionitrile is obtained. In the same manner as in Example 1b (e) and using 3-(cis-2-hydroxymethyl-3-methylpiperidin-1-yl)propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-[2-(cis-2-hydroxymethyl-3-methylpiperidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6](I)=[C:7]([CH:19]=1)[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])#[N:2].[C:21]([NH:24][C:25](=[CH2:30])[C:26]([O:28][CH3:29])=[O:27])(=[O:23])[CH3:22].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:21]([NH:24][C:25](=[CH:30][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:19][C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18])[C:26]([O:28][CH3:29])=[O:27])(=[O:23])[CH3:22]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(=Cc1ccc(C#N)cc1OCCNC(=O)OC(C)(C)C)NC(C)=O

Procedure:
15.3 g (39.5 mmol) of t-butyl [2-(5-cyano-2-iodophenoxy)ethyl]carbamate, 9.05 g (63.2 mmol) of methyl 2-acetamidoacrylate, 11 ml (79 mmol) of triethylamine, 1.3 g of palladium (II) acetate and 7.30 g of tris(2-methylphenyl)phosphine were stirred in 150 ml of acetonitrile overnight. The solvent was distilled off, and the residue was treated by the silica gel chromatography (ethyl acetate/hexane) to obtain the crude product, which was washed with hexane and a mixed solvent of hexane/ethyl acetate, and then vacuum-dried to obtain the title compound.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][O:8][CH:9]1[CH2:12][NH:11][CH2:10]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:44]=[C:45]1[NH:58][C:48]2=[N:49][CH:50]=[C:51](/[CH:53]=[CH:54]/[C:55](O)=[O:56])[CH:52]=[C:47]2[NH:46]1>CN(C)C=O>[O:56]=[C:55]([N:11]1[CH2:12][CH:9]([O:8][CH2:7][C:3]2[S:2][CH:6]=[CH:5][CH:4]=2)[CH2:10]1)/[CH:54]=[CH:53]/[C:51]1[CH:52]=[C:47]2[NH:46][C:45](=[O:44])[NH:58][C:48]2=[N:49][CH:50]=1
Reactant: O=C(O)/C=C/c1cnc2[nH]c(=O)[nH]c2c1
Reactant: c1csc(COC2CNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C/c1cnc2[nH]c(=O)[nH]c2c1)N1CC(OCc2cccs2)C1
Reaction time: 8 h
Yield: 14.4 %

Procedure:
3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (127 mg, 0.62 mmol), EDCI (120 mg, 0.62 mmol), HOBt (86 mg, 0.62 mmol) and diisopropylethylamine (180 μL, 1.03 mmol) were successively added to a solution of (E)-3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)acrylic acid hydrochloride (100 mg, 0.41 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred overnight then partitioned between ethyl acetate (20 mL) and water (30 mL). The aqueous layer was separated and successively extracted with ethyl acetate (2×20 mL) and dichloromethane (2×20 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (98:2 to 93:7) as eluent. The residue was triturated in pentane to afford the title product as a pale orange solid (21 mg, 14%).
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[S:19][CH2:20][CH2:21][OH:22])=CC=2)C=CC=1)=O)C.[CH2:23]([O:25][C:26]([C:28]1[C:29]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]Br)[CH:35]=2)=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24].SCCO.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:23]([O:25][C:26]([C:28]1[C:29]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][S:19][CH2:20][CH2:21][OH:22])[CH:35]=2)=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCO)cc2)c1
Reactant: CCOC(=O)c1ccccc1-c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: OCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1-c1cccc(CSCCO)c1

Procedure:
3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester was prepared as described for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 3′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester (5.4 g, 16.92 mmol, 1 eq.). in anhydrous DMF was treated with 2-mercaptoethanol (1.59 g, 20.30 mmol, 1.2 eq.) and potassium carbonate (7.02 g, 50.76 mmol, 3 eq.). When complete, the reaction was worked up as described leaving a light yellow oil.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:19])[NH2:18])=O)C1C=CC=CC=1.[CH3:23][S:24]([Cl:27])(=[O:26])=[O:25].[C:28]([C@@H:30]1[CH2:34][S:33][CH2:32][NH:31]1)#[N:29]>>[ClH:27].[C:28]([C@@H:30]1[CH2:34][S:33][CH2:32][N:31]1[C:20](=[O:22])[C@H:12]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:19])[NH:18][S:24]([CH3:23])(=[O:26])=[O:25])[NH2:11])#[N:29]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N#C[C@@H]1CSCN1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N1CSC[C@H]1C#N
Product: Cl

Procedure:
Starting from (S)-N2-(benzyloxycarbonyl)-arginine, methanesulphonyl chloride and (R)-4-cyano-1,3-thiazolidine, the expected product is obtained according to the procedure described in Example 1.
Reaction SMILES: [C:1]1([C@H:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=O.C(O)(=O)C.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.O>[C:1]1([C@H:11]([NH:13][CH:20]2[CH2:21][CH2:22][C:23]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2ccccc2C1
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](NC1CCc2ccccc2C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of (R)-1-(naphthalen-1-yl)ethanamine (4.77 ml, 29.5 mmol) in methanol (50 mL) was added 3,4-dihydronaphthalen-2(1H)-one (4.80 g, 32.8 mmol) at 0° C. Acetic acid (2.349 mL, 41.0 mmol) was added and the reaction was stirred for 5 min. After that the reaction was warmed to RT and further stirred for 20 minutes. Again reaction was cooled to 0° C. and sodium cyanoborohydride (3.09 g, 49.2 mmol) was added stirred overnight at RT. After completion of reaction, —NaHCO3 solution (20 mL) and water (50 mL) were added and the mixture was extracted with ethyl acetate (50 mL×2). The extract was washed with saturated brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure to get the crude compound. This was used directly in the next reaction (11.1 g, 36.8 mmol); m/z 302.65.