Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:3](=[O:17])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=O)[S:4][CH2:5][CH2:6][CH3:7])[CH3:2].[F:18][C:19]([F:31])([F:30])[C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=1>CO.C(Cl)Cl>[CH2:1]([P:3](=[O:17])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[N:27][NH:26][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:31])[F:30])=[CH:29][CH:28]=1)[S:4][CH2:5][CH2:6][CH3:7])[CH3:2]
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCCSP(=O)(CC)Oc1ccccc1C=O
Solvent: CO
Solvent: ClCCl
Product: CCCSP(=O)(CC)Oc1ccccc1C=NNC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of S-propyl O-(2-formylphenyl) ethylthiophosphonate (0.02 mole) in methanol (50 ml) and 4-trifluoromethylbenzoylhydrazine (0.02 mole) are charged into a glass reaction vessel and the mixture is stirred at room temperature for a period of about 12 hours. After this time the reaction mixture is stripped of methanol under vacuum and the residue is dissolved in methylene chloride (100 ml) and the resulting solution is washed with water (75 ml) with aqueous sodium hydroxide (75 ml; 0.1 N) and again with water (75 ml). The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product S-propyl O-[2-(4-trifluoromethylbenzoylhydrazonomethyl)phenyl] ethylthiophosphonate.
Reaction SMILES: [CH:1]([C:3]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2].C1(=O)CCCCCCCCC1>>[C:3]1(=[O:13])[CH2:1][CH2:2][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: C=CC1(O)CCCCCCCCC1
Agent: O=C1CCCCCCCCC1
Product: O=C1CCCCCCCCCCC1
Yield: 52.8 %

Procedure:
0.5 g (2.7 mmol) of 1-vinyl-1-cyclodecanol (cf. I.1.3, comprises also about 8-10% cyclodecanone), quartz reactor 25/400 mm, temperature 670° C.±10, vaporization at 95-100° C. (airbath temperature) in about 10 min. Nitrogen stream about 2-2.5 l/h, vacuum 5-6 mbar. 0.45 g (90% crude yield) of a pure white condensate were obtained which partially crystallized into small fine needles. According to GC and GC/MS analyses, the mixture comprises, as main component, about 70% cyclododecanone, as well as 6-8% cyclodecanone and 2-3% starting material. Chromatographic separation of the mixture over silica gel (hexane/TBME 97:3) gave 0.26 g of cyclododecanone (52% isolated yield), which has identical retention times and spectroscopic properties as the commercially available compound (Fluka).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS(O[CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])(=O)=O>CN(C=O)C.CCOC(C)=O>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=3)[O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:13]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)COc1cccc(OCCCOS(C)(=O)=O)c1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(OCCCn2nc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a solution of 6-(diphenylmethyl)pyridazin-3(2H)-one (158 mg) in DMF (2 mL) was added NaH (60% in oil, 26 mg) at 5° C. After stirring for an hour at ambient temperature, to the reaction mixture was added a solution of ethyl (3-{3-[(methylsulfonyl)oxy]propoxy}phenoxy)acetate (200 mg) in DMF (0.5 mL), and the resulting mixture was stirred at ambient temperature for 12 hours and then was stirred at 50° C. for 5 hours. After cooling, the reaction mixture was diluted with EtOAc (5 mL) and washed with water (5 mL) and brine (5 mL) two times. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to give crude oil. The crude oil was purified by silica gel column chromatography (EtOAc:n-hexane=3:1) to give ethyl (3-{3-[3-(diphenylmethyl)-6-oxopyridazin-1(6H)-yl]propoxy}phenoxy)acetate (230 mg) as a pale yellow oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:18](Cl)=[C:13]([O:14][CH:15]([CH3:17])[CH3:16])[C:12](Cl)=[C:7]([O:8][CH:9]([CH3:11])[CH3:10])[C:6]=1Cl)([CH3:3])[CH3:2].[Na].Cl>C(O)(C)C.O.C(OCC)C>[CH:9]([O:8][C:7]1[CH:12]=[C:13]([O:14][CH:15]([CH3:17])[CH3:16])[CH:18]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=1)([CH3:10])[CH3:11]
Reactant: CC(C)Oc1c(Cl)c(OC(C)C)c(Cl)c(OC(C)C)c1Cl
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1cc(OC(C)C)cc(OC(C)C)c1
Yield: 97.9 %

Procedure:
3.55 g (0.01 mol) trichlorophloroglucinol triisopropylether in 100 ml isopropanol were mixed with 5 g sodium. Heating with reflux was continued until all sodium had been dissolved. This was followed by diluting with 100 ml water, neutralizing with hydrochloric acid of 15% by weight, taking up of the organic phase in ethyl ether, drawing off of the ethyl ether and distilling of the residue on a bulb tube (2-3 mbar, airbath temperature 130° to 150° C.). 2.47 g phloroglucinol triisopropylether were obtained, which corresponds to a yield of 98% of theoretical.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1.Cl.[CH3:21][O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][NH2:27].B(F)(F)F.CCOCC>C1(C)C(C)=CC=CC=1>[CH3:21][O:22][C:23]([CH2:24][CH2:25][CH2:26][N:27]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1)=[O:28]
Reactant: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Reactant: COC(=O)CCCN
Agent: Cl
Agent: FB(F)F
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: COC(=O)CCCN=C1Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 135 °C

Procedure:
To a suspension of 0.2 g (0.79 mmol) of 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide and 0.1 g (0.67 mmol) of methyl-4-aminobutyrate hydrochloride in 5 mL of xylene was added 0.07 g (0.49 mmol) of boron trifluoride diethyl etherate. The resulting mixture was heated at 135° C. for seven hours and then allowed to cool to room temperature. The mixture was then filtered and the residue was extracted with toluene. The combined extracts were evaporated under reduced pressure and the residue chromatographed on silica gel using a 4:1 mixture of petroleum ether-ethyl acetate. Chromatographically homogenous fractions were pooled and the solvents were removed under reduced pressure to give the desired product as a yellow oil which crystallised on standing to give yellow crystals which decomposed on heating without melting.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21]C)=[C:16]([O:19]C)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])=[C:4]([F:25])[CH:3]=1.Cl.N1C=CC=CC=1>[OH-].[NH4+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])=[C:4]([F:25])[CH:3]=1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(Cl)cc3F)c2cc1OC
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: N#Cc1cnc2cc(O)c(O)cc2c1Nc1ccc(Cl)cc1F
Temperature: 215 °C
Reaction time: 0.33 h
Yield: 91.5 %

Procedure:
A mixture of 0.358 g of 4-(4-chloro-2-fluoro-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile and 3 g of pyridine hydrochloride was stirred under nitrogen at 210-220° C. for 20 minutes. The mixture was cooled and added to 50 ml of 3% ammonium hydroxide solution. The product was collected, washed with water, and dried to give 0.302 g of 4-(4-chloro-2-fluoro-phenylamino)-6,7-dihydroxy-quinoline-3-carbonitrile as a solid, mp 270-272° C.; mass spectrum (EI, m/e): M 329.0363.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:20][CH2:19]1
Reactant: IC1CCCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(C4CCCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 35 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and iodocyclohexane.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH3:29][NH:30][CH3:31].C(N(CC)CC)C>C(#N)C>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([N:30]([CH3:31])[CH3:29])=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)O)C1(C)C
Reactant: CNC
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)N(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
To a 20-mL scintillation vial were added the product from Example 96 (118 mg, 0.300 mmol), dimethylamine hydrochloride (Aldrich, 36.7 mg, 0.450 mmol), and 2-(1H-benzo[d][1,2,3]tria-zol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TBTU, Bachem, 144 mg, 0.450 mmol). Anhydrous acetonitrile (3 mL) was added to form a yellow slurry. Neat triethylamine (Aldrich, 182 mg, 1.80 mmol) was added to form a tan solution. The reaction was stirred at 25° C. in a shaker block for 24 hr. The volatiles removed by rotary evaporator to give a brown oil. The product was purified by flash chromatography (silica gel: 10-45% ethyl acetate in hexanes). The product was recrystallized from hexanes to afford 67.0 mg (53%) of the title compound. 1H NMR (DMSO-d6) δ ppm 0.49 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.25 (s, 3H), 1.26 (s, 3H), 1.28-1.33 (m, 2H), 1.37-1.46 (m, 1H), 1.57 (s, 9H), 1.57-1.70 (m, 3H), 2.01-2.10 (m, 1H), 2.62-2.67 (m, 2H), 2.74-2.83 (m, 1H), 2.83 (s, 3H), 3.05 (s, 3H), 3.33-3.39 (m, 1H), 8.49 (s., 1H). MS (ESI+) m/z 422 (M+H)+. Anal. calcd. for C23H39N3O2S: C, 65.52; H, 9.32; N, 9.97. Found: C, 65.13; H, 9.22; N, 9.55.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:18][CH:17]=[CH:16][CH2:15][N:14]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:13]1[C:30](O)=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([NH:40][OH:41])(C(C)(C)C)(C)C.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]1[CH2:18][CH:17]=[CH:16][CH2:15][N:14]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:13]1[C:30](=[O:31])[NH:40][OH:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)NO
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[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: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid (21 mg, 0.043 mmol) is dissolved in dry Dimethylformamide (DMF) and cooled to -20° C. tert-Butyldimethylsilylhydroxyl amine (7 mg, 0.05 mmol), Hunigs Base (9.8 μl, 0.05 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) (18 mg, 0.05 mmol) are added. The reaction solution is stirred for 1 h and then allowed to warm to room temp. The solvent is evaporated. The residue is purified by flash-chromatography, Dichloromethane/Methanol (9:1), to afford the desired hydroxamide: Cal. 476.5, Found (MH)+ 476.
Reaction SMILES: Cl[CH:2]([CH3:21])[CH2:3][N:4]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:20].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH2:22]([NH:29][CH:2]([CH3:21])[CH2:3][N:4]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(Cl)Cn1cc(-c2ccccc2)c2ccccc2c1=O
Reactant: NCc1ccccc1
Solvent: CO
Product: CC(Cn1cc(-c2ccccc2)c2ccccc2c1=O)NCc1ccccc1
Yield: 82 %

Procedure:
29.8 g of 2-(2-chloropropyl)-4-phenyl-1(2H)-isoquinolone was mixed with 20 ml of benzylamine, and the mixture was heat-melted in a nitrogen stream. After completion of the reaction, the mixture was dissolved in methanol while hot, and the solution was poured into crashed ice. The resulting precipitate was collected by filtration, washed with water, dried and recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 30.2 g (82% yield) of 2-(2-benzylaminopropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 118° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[NH:15][N:14]=[N:13][C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.[CH2:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[NH2:12][C:10]1[N:11]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:7]2[N:15]=[N:14][N:13]([C:24]([NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[C:8]=2[N:9]=1
Reactant: Nc1nc(-c2ccco2)c2[nH]nnc2n1
Reactant: O=C=NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nc(-c2ccco2)c2nnn(C(=O)NCc3ccccc3)c2n1
Yield: 18.5 %

Procedure:
A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (202 mg, 1.0 mmol) in DMF (3 mL) was treated with benzyl isocyanate (123 mL, 1.0 mmol) and a catalytic amount of DMAP, stirred at room temperature overnight, diluted with EtOAc and filtered to give the title compound (62 mg, 19%) as a peach coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1COc1cc(F)ccc1F
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2cc(F)ccc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(2,5-difluorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][CH2:17][CH2:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C@H:26]2[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]2)[CH2:22][CH2:21]1.[C:35](O)(=[O:38])[CH:36]=[CH2:37]>CN(C)C1C=CN=CC=1.ClCCl>[C:35]([O:16][CH2:17][CH2:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C@H:26]2[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]2)[CH2:22][CH2:21]1)(=[O:38])[CH:36]=[CH2:37]
Reactant: O=C(O)[C@H]1CC[C@H]([C@H]2CC[C@H](CCCO)CC2)CC1
Reactant: C=CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Reaction time: 8 h

Procedure:
4.2 g of N,N'-dicyclohexylcarbodiimide were added within 5 minutes while stirring to a solution of 5.2 g of trans-4-(trans-4-[3-hydroxypropyl]cyclohexyl)cyclohexanecarboxylic acid, 1.2 g of acrylic acid and 0.2 g 4-(dimethylamino)pyridine in 25 ml of dichloromethane. The reaction mixture was stirred overnight, filtered and then concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 8:2) and recrystallization from ethyl alcohol of the fractions which were pure according to thin-layer chromatography gave 4.2 g of trans-4-(trans-4-[3-acryloyloxypropyl]cyclohexyl)cyclohexanecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17]>>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1nc[nH]c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: Cc1ncn(COCC[Si](C)(C)C)c1-c1ccccc1
Yield: 44.3 %

Procedure:
Reaction of 4-methyl-5-phenyl-1H-imidazole (400 mg, 2.53 mmol), NaH (60%, 98 mg, 2.46 mmol), and SEMCl (474 uL, 2.68 mmol) followed by column chromatography on silica gel (hexane/EtOAC 3:2) gave the title compound (323 mg, 46%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.92 (t, 2H, J=7.5 Hz), 2.47 (s, 3H), 3.52 (t, 2H, J=7.5 Hz), 5.26 (s, 2H), 7.26–7.27 (m, 1H), 7.41 (dd, 2H, J=7.5, 7.5 Hz), 7.57 (s, 1H), 7.68 (d, 2H, J=9.0 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:30][CH2:31][N:32]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:3]=3)[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCc2cccnc2)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCc2cccnc2)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 47b, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile (example 49a) was treated with the 4-(4-fluorophenyl)-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, light brown; MS: [M+H]+=448.
Reaction SMILES: [Cl:1][C:2]1([CH3:13])[CH2:5][C:4]([C:9]([F:12])([F:11])[F:10])([C:6]([OH:8])=O)[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([CH3:29])[NH2:28])=[CH:23][CH:22]=1.O>S(Cl)(Cl)=O.O1CCOCC1.O>[Cl:1][C:2]1([CH3:13])[CH2:3][C:4]([C:9]([F:12])([F:11])[F:10])([C:6]([NH:28][C@@H:27]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)[CH3:29])=[O:8])[CH2:5]1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Reactant: CC1(Cl)CC(C(=O)O)(C(F)(F)F)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](NC(=O)C1(C(F)(F)F)CC(C)(Cl)C1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 0.240 g (1.11 mmol) of 3-chloro-3-methyl-1-(trifluoromethyl)cyclobutane carboxylic acid (prepared according to the method described by H. K. Hall, Jr., E. P. Blanchard Jr. and E. L Martin in Macromolecules 4(2) 142-146 (1971)) in 5 mL thionyl chloride was heated at reflux for 1 h. Solvent was removed in vacuo. The residue was added to a solution of 0.176 g (1.66 mmol) sodium carbonate and 0.172 g (1.11 mmol) (R)-4-chloro-α-methylbenzenemethanamine in 6 mL of 1:1 dioxane-water, pre-cooled to 0° C. After stirring at room temperature overnight, the mixture was poured into 50 mL water and extracted two times with 50 mL ethyl acetate (EtOAc). Drying (magnesium sulfate) and removal of the solvent gave an oil which was chromatographed on silica gel, eluting with 25% hexane-dichloromethane, to afford 43 mg of the cis isomer of the title compound: mp 129-130° C., 1H NMR (CDCl3) δ1.49 (d, 3H), 1.69 (s, 3H), 2.86-2.95 (m, 2H), 2.98-3.05 (m, 2H), 5.05-5.12 (q, 1H), 5.86 (s, 1H), 7.20 (d, 2H), 7.32 (d, 2H), and 77 mg of the trans isomer of the title compound: mp 145-146 C, 1H NMR (CDCl3) 1.54 (d, 3H), 1.74 (s, 3H), 2.79-2.86 (m, 2H), 3.13 (d, 2H), 5.14 (q, 1H), 5.85 (s, 1H), 7.23 (d, 2H), 7.31 (d, 2H).
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[C:12]([O:16][C:17]([N:19]1[C@@H:27]2[C@@H:22]([CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:21][C@H:20]1[CH2:28][NH2:29])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:12]([O:16][C:17]([N:19]1[C@@H:27]2[C@@H:22]([CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:21][C@H:20]1[CH2:28][NH:29][CH2:6][C:5]1[S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[CH:4]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=Cc1cc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2CCCC[C@@H]21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](CNCc2cc3ccccc3s2)C[C@@H]2CCCC[C@@H]21

Procedure:
Experimental conditions analogous to Example 1, from 0.1 g (0.63 mmol) of benzo[b]thiophene-2-carbaldehyde, 0.16 g (0.63 mmol) of (2S,3aS,7aS)-2-aminomethyl-octahydro-indole-1-carboxylic acid tert-butyl ester, 10 mL dichloromethane, and 0.2 g (0.94 mmol) of sodium triacetoxyborohydride. The reaction was quenched with aqueous sodium bicarbonate. The residue from the organic layer was purified using flash chromatography (ethyl acetate in hexane), yield 130 mg of the free base as colorless oil. LC-MSD, m/z for C23H32N2O2S [M+H]+: 401.6, [M+H-isobutylene]+: 345.5.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[C:7](=[CH:15][CH:16]=1)[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])([O-])=O.Cl.O.[OH-].[Na+]>C1C=CC=CC=1.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[C:7](=[CH:15][CH:16]=1)[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9]
Reactant: CCCCOC(=O)c1ccc([N+](=O)[O-])cc1C(=O)OCCCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCCCOC(=O)c1ccc(N)cc1C(=O)OCCCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
Compound 403 (1.5 g, 4.6 mmol) was dissolved in 230 ml of benzene and then 2.8 g of purified zinc dust was added. Concentrated hydrochloric acid (8.2 ml) was added in portions. After 15 minutes of stirring at room temperature, another 2.8 g of zinc dust was added and the mixture was stirred at room temperature for 12 hours. Then 280 ml of water was added to the reaction mixture and the mixture was neutralized with 1N NaOH solution. The mixture was transferred to a separatory funnel and the benzene layer was removed. The aqueous layer was extracted with benzene. The combined benzene extracts were washed with water and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (n-hexane: acetic acid =10:1) to give 980 mg (89.6%) of di-n-butyl 4-aminophthalate (compound 404).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[CH:7]=1)(=O)C.[OH-].[Na+].O>O1CCCC1>[C:13]([NH:12][C:8]1[CH:7]=[C:6]([CH2:5][OH:4])[CH:11]=[CH:10][N:9]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1cc(COC(C)=O)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(CO)ccn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 86 %

Procedure:
4-Acetoxymethyl-2-acetylaminopyridine (Reference compound No. 11-1, 6.6 g, 32 mmol) was dissolved in tetrahydrofuran (20 mL), and 2N aqueous sodium hydroxide solution (19 mL, 38 mmol) was added dropwise thereto under ice-cooling. The mixture was stirred for 40 minutes at room temperature, and water (100 mL) was added thereto. The whole was extracted with ethyl acetate (80 mL) six times, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was filtered off with the mixed solvent of ethyl acetate and hexane, and then the solid was dried under reduced pressure at 40° C. to give 4.5 g of the title reference compound as a colorless solid. (Yield 86%)