Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CN(C)C=O>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:11]1
Reactant: Nc1ccnc(Cl)n1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CN1CCN(c2nccc(N)n2)CC1
Temperature: 220 °C
Yield: 67 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (300 mg, 2.316 mmol) and 1-methylpiperazine (771 μl, 6.95 mmol) in N,N-dimethylformamide (DMF) (3 ml) was heated to 220° C. via a microwave reactor for 60 min. The reaction was purified by RP-HPLC to yield 2-(4-methyl-1-piperazinyl)-4-pyrimidinamine (300 mg, 1.552 mmol, 67% yield). MS (ES+) m/z 194.2 (MH+).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[N:30]=[CH:29][C:28]2[CH:27](O)[CH2:26][CH2:25][CH2:24][C:23]=2[N:22]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P([N:46]=[N+:47]=[N-:48])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:46]([CH:27]1[CH2:26][CH2:25][CH2:24][C:23]2[N:22]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:30]=[CH:29][C:28]1=2)=[N+:47]=[N-:48]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2N=[N+]=[N-])(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydro-quinazolin-5-ol (2.0 g, 4.63 mmol) in 25 mL of toluene at −10° C. was added DPPA (1.2 mL, 5.56 mmol). To this stirred solution was then added DBU (0.83 mL, 5.56 mmol) dropwise while keeping the temperature below 0° C. After stirring at room temperature for 16 h, the reaction was evaporated to dryness and directly submitted to flash chomatography (SiO2, hexane/DCM=1:2) to afford the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=[O:12].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[CH2:25]([Mg]Br)[CH2:26][CH3:27].[NH4+].[Cl-]>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH2:25][CH2:26][CH3:27])[CH2:6][C:5]2=[O:12]
Reactant: O=c1ccoc2ccc(Br)cc12
Reactant: CCC[Mg]Br
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCC1CC(=O)c2cc(Br)ccc2O1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a solution of 6-bromo-4H-chromen-4-one (12 g, 53 mmol) in CH2Cl2 (24 mL) was added TMSOTf (12.5 mL, 69.18 mmol) at ambient temperature. After stirring for 1 hour, THF (210 mL) was added to the mixture at ambient temperature and cooled to −78° C. To the mixture was added n-propylmagnesium bromide (1.05M solution in THF, 66 mL, 69 mmol). After stirring for 1 hour at −78° C., 1M aqueous NH4Cl was added to the mixture. The mixture was warmed to ambient temperature and stirred overnight. The organic and the aqueous layers were separated, and the organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silicagel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 0 to 10%) to afford 6-bromo-2-propyl-2,3-dihydro-4H-chromen-4-one (11.42 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(Cl)Cl>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:2]([NH:1][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=2)[C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(CC(N)C(=O)OC(C)(C)C)ccc1O
Solvent: ClCCl
Product: COc1cc(CC(NC(=O)c2ccc([N+](=O)[O-])cc2)C(=O)OC(C)(C)C)ccc1O
Reaction time: 1 h
Yield: 44 %

Procedure:
Prepared using General Procedure 5: To a stirred solution of tert-butyl 2-amino-3-(4-hydroxy-3-methoxyphenyl)propanoate INT-1 (1.85 g, 6.93 mmol) and TEA (1.93 mL, 13.9 mmol) in DCM (15 mL) at 0° C. was added 4-nitrobenzoyl chloride (1.29 g, 6.93 mmol) in DCM (10 mL) dropwise. The reaction mixture was stirred for 1 h, diluted with DCM (100 mL) and washed with saturated aqueous NaHCO3 (100 mL). The organic layer was dried over MgSO4, and concentrated. The product was purified by chromatography (EA/hexanes) to afford 1.38 g (44%) of tert-butyl 3-(4-hydroxy-3-methoxyphenyl)-2-(4-nitrobenzamido)propanoate INT-7. LCMS-ESI (m/z) calculated for C21H24N2O7: 416. Found 415 [M−H]−, tR=2.18 min (Method 4).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH2:25](O)[CH2:26][CH2:27]/[CH:28]=[CH:29]/[CH3:30]>CC(OC)(C)C>[CH2:30]([O:23][C:22](=[O:24])[CH2:21][NH:20][C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19])[CH2:29][CH2:28]/[CH:27]=[CH:26]/[CH3:25]
Reactant: C/C=C/CCCO
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: COC(C)(C)C
Product: C/C=C/CCCOC(=O)CNC(=O)OC(C)(C)C
Temperature: 40 °C

Procedure:
To a vessel maintained at 40° C. was charged CDI (2.75 g, 0.95 eq) and TBME (9 mL). To this mixture was added with stirring a solution of N-(t-butoxycarbonyl)glycine (3.1 g, 1.0 eq) dissolved in TBME (12 mL) over 30 min. Stirring was continued for an additional 30 min, whereupon trans-4-hexen-1-ol (1.7 g, 0.95 eq) was added over 30 min. The mixture was maintained with stirring at 40° C. for an additional 3.5 h, then cooled to ambient temperature and stirred a further 14 h. The mixture was washed with 1N HCl (2×7.8 mL) then water (1×7.8 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give (E)-hex-4-en-1-yl2-((tert-butoxycarbonyl)amino)acetate as an oil. The oil was dissolved in DCM (12 mL) and 4.0 M HCl in dioxane (2.8 mL) was added drop-wise. The mixture was stirred at ambient temperature for 1.5 h then the mixture was heated to 35° C. and stirred for 3 h. 4.0 M HCl in dioxane (2.8 mL) was added drop-wise. After 6 h at 35° C. a further dose of 4.0 M HCl in dioxane (2.8 mL) was added drop-wise and the mixture was stirred for a further 4 h. The mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. A portion of the residue (1.0 g) was dissolved in DCM (8 mL) and methyl 2-chloro-2-oxoacetate (0.63 g) was added. Triethylamine (1.0 g) was added drop-wise over 20 min. The mixture was stirred for 1 h before being quenched by 1N HCl (2.5 mL) to form a biphasic mixture. The layers were separated and the organic layer was washed with 1N HCl (1×2.5 mL), water (1×2.5 mL) and concentrated under reduced pressure to provide an oil. Flash column chromatography (SiO2, 10→60% EtOAc/Hex gradient) provided the title compound as an oil as a 95:5 mixture of trans:cis isomers. 1H NMR (300 MHz, CDCl3) δ ppm 7.57 (s, 1H), 5.31-5.55 (m, 2H), 4.17 (t, J=6.69 Hz, 2H), 4.12 (d, J=5.51 Hz, 2H), 3.92 (s, 3H), 1.97-2.10 (m, 2H), 1.67-1.77 (m, 2H), 1.62-1.67 (m, 3H); 13C NMR (75 MHz, CDCl3) δ ppm 168.60, 160.35, 156.28, 129.49, 126.12, 65.34, 53.68, 41.47, 28.62, 28.17, 17.84; HRMS (M+H) m/z, calcd for C11H18NO5, 244.1185; found 244.1187.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH:28]1([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:28]1(=[CH:34][C:35]2[CH:36]=[CH:37][C:38]([NH:39]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:40][CH:41]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(CC2CCCCC2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(C=C2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(cyclohexyl-methyl)-aniline (Eur. J. Med. Chem. Chim. Ther. 1992, 27, 537-544) Rf value: 0.6 (silica gel, methylene chloride/methanol=10:1) C30H30N2O3
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[O:7]=[C:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH3:16])=[O:14].S(=O)(=O)(O)O>>[C:1]([O:5][O:6][C:8]1([O:7][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH3:16])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CCCC1=O
Reactant: CC(C)(C)OO
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCCC1(OOC(C)(C)C)OOC(C)(C)C
Temperature: -5 °C

Procedure:
Methyl 2,2-di(tertiary-butylperoxy)-1-cyclopentanecarboxylate was prepared by the addition of 92.28% TBHP (tertiary butyl hydroperoxide) (36.62 g, 0.3750 mol) to 97% methyl 2-oxo-1-cyclopentanecarboxylate (14.65 g, 0.1000 mol) at room temperature in a three necked 250-mL round bottomed flask equipped with a thermometer and mechanical stirrer. The solution was then cooled via a dry ice-acetone bath to −5° C. and 78% sulfuric acid (15.09 g, 0.1200 mol) was added dropwise to the solution with temperature at −5° C. Upon completion of the addition of sulfuric acid, the solution was allowed to reach 5° C. where it was maintained by an ice-water bath for three hours with mechanical stirring. The reaction was transferred to a separatory funnel and the lower acidic aqueous layer separated and discarded. The organic layer was then washed with saturated NaCl solution until the aqueous washings had a pH of 4.0 to 4.5. The organic layer was then dried over MgSO4, filtered through a Buchner funnel and analyzed for purity by gas chromatography (88% by area): 1H NMR (300 MHz, CDCl3) δ 3.7 (s, 3H, CH3), 3.3-3.4 (m, 1H, cyclic H), 1.9-2.2 (m, 6H, cyclic H), 1.3 (s, 9H, CH3), 1.2 (s, 9H, CH3); 13C NMR (75 MHz, CDCl3) δ 172.4 (C═O). 116.9 (O—C—O, cyclic), 79.7 (CCH3)3), 79.4 (C(CH3)3), 51.1 (CH, cyclic), 49.1 (CH3—O), 32.9 (CH2, cyclic), 27.7 (CH2, cyclic), 26.2 (C(CH3)3, (2x)), 22.1 (CH2, cyclic); IR (neat) 1740, 1364, 1198, 878 cm−1.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([C:15]1[CH:16]=[C:17]([C:21]2[C:22]([N:42]([CH3:47])[S:43]([CH3:46])(=[O:45])=[O:44])=[CH:23][C:24]3[O:28][C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[C:26]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:25]=3[CH:41]=2)[CH:18]=[CH:19][CH:20]=1)=[O:14])(C)(C)C>ClCCCl>[CH2:39]([O:38][C:36]([C:26]1[C:25]2[CH:41]=[C:21]([C:17]3[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=3)[C:13]([OH:14])=[O:12])[C:22]([N:42]([CH3:47])[S:43]([CH3:46])(=[O:45])=[O:44])=[CH:23][C:24]=2[O:28][C:27]=1[C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(C(=O)O)c3)cc12
Yield: 102.2 %

Procedure:
TFA (2 mL, 26.0 mmol) was added to a stirring solution of ethyl 5-(3-(tert-butoxycarbonyl)phenyl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylate (100 mg, 0.176 mmol) in DCE (9 mL) at 25° C. It was allowed to stir for several hours then concentrated to give the titled compound (92 mg, quant). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05-8.12 (3H, m), 7.92-8.03 (3H, m), 7.65-7.75 (1H, m), 7.53-7.64 (1H, m), 7.44 (2H, t, J=8.91 Hz), 4.33 (2H, q, J=7.03 Hz), 3.12 (3H, s), 2.93 (3H, s), 1.26 (3H, t, J=7.15 Hz). LC-MS retention time: 1.17 min; m/z (MH−): 510. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][C:40](O)=[O:41].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:40](=[O:41])[CH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)Cc1ccccn1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccn1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4 with 98 mg (0.561 mmol) of 2-pyridylacetic acid hydrochloride, 143 mg (0.562 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 209 μl (1.50 mmol) of triethylamine. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.60, FD-MS: M+ =546.
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7]1.CN(C)[CH:17]=[O:18].Cl>CCCCCC.C(OCC)C>[S:6]1[C:7]([CH:17]=[O:18])=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: CN(C)C=O
Reactant: c1ccc2sccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1cc2ccccc2s1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a solution of 31.25 ml of a 1.6M solution of n-butyl lithium in hexane and 100 ml of dry diethyl ether at -20° C. was added a solution of 6.7 g of 1-benzothiophene in 100 ml of dry diethyl ether. The mixture was stirred at -20° C. for 2 hours. A solution of 3.8 ml of dimethylformamide and 10 ml of dry diethyl ether was added and the reaction was allowed to warm to 0° C. The reaction was stirred an additional 1 hour at 0° C., at which time 75 ml of 1N hydrochloric acid were added. After stirring for 15 minutes, the layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate and evaporated to dryness. The resulting oil was stored at about 0° C. for 3 days, at which time a solid formed. The solid weighed 8.5 g and was identified as the desired subtitled intermediate based upon the mass spectral and proton NMR data.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:16]([OH:18])=O)[C:11](=[O:26])[CH:10]=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:16]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=2)=[O:18])[C:11](=[O:26])[CH:10]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)C(Cc1cccnc1)n1ccc(-c2cc(Cl)ccc2Br)cc1=O
Product: COC(=O)c1ccc(NC(=O)C(Cc2cccnc2)n2ccc(-c3cc(Cl)ccc3Br)cc2=O)cc1

Procedure:
244 mg (purity 57%, 0.32 mmol) of 2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-3-yl)propanoic acid (racemate) and 1.2 eq. of methyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 65 mg (purity 85%, 30% of theory)
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.O1CCCC1>O>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([CH:7]2[CH2:8][CH2:9][CH:4]([CH:3]=[O:2])[CH2:5][CH2:6]2)=[CH:11][CH:12]=1)#[N:15]
Reactant: COC=C1CCC(c2ccc(C#N)cc2)CC1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C2CCC(C=O)CC2)cc1
Yield: 99 %

Procedure:
A mixture of 4.2 g of p-[4-(methoxymethylene)cyclohexyl]benzonitrile and 100 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) was heated to reflux for 30 minutes in a round flask. The mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time The organic phases were washed once with 100 ml of water, dried over magnesium sulphate and concentrated There were obtained 3.9 g (100%) of 4-(p-cyanophenyl)cyclohexanecarboxaldehyde as a colourless oil which was used in the next step without further purificarion: trans/cis ratio about 3:1, Rf-value (ethyl acetate/petroleum ether, vol. 3:7) 0.41. By recrystallization from hexane there could be obtained pure trans-4 (p-cyanophenyl)cyclohexanecarboxaldehyde; m.p. 57.1° C.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Br[C:27]1[C:32]2=[CH:33][CH:34]=[C:35]3[C:44](C=C4[C:37](C=CC=C4)=[CH:36]3)=[C:31]2[CH:30]=[CH:29][CH:28]=1>>[CH:13]1[C:12]2=[C:25]3[C:16](=[CH:9][CH:10]=[C:11]2[C:2]([C:3]2[C:8]4=[CH:37][CH:36]=[C:35]5[C:34]([CH:33]=[C:32]6[C:31]([CH:30]=[CH:29][CH:28]=[CH:27]6)=[CH:44]5)=[C:7]4[CH:6]=[CH:5][CH:4]=2)=[CH:15][CH:14]=1)[CH:17]=[C:18]1[C:23]([CH:22]=[CH:21][CH:20]=[CH:19]1)=[CH:24]3
Reactant: Brc1cccc2c1ccc1cc3ccccc3cc12
Reactant: Brc1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Product: c1ccc2cc3c(ccc4c(-c5cccc6c5ccc5cc7ccccc7cc56)cccc43)cc2c1

Procedure:
Preparation analogous to Example 7. 9-Bromo-10-(2-naphthyl)anthracene is replaced by 15.4 g (50 mmol) of 4-bromobenz[a]anthracene. Recrystallisation four times from o-dichlorobenzene (about 15 ml/g); sublimation (p=5×10−5 mbar, T=320° C.). Yield: 16.8 g (37 mmol), 74.0%, purity 99.9% (HPLC), Tg=130.3° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[S:11][C:12]([CH:15]=O)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:26][OH:27]>O>[CH:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[S:11][C:12]([CH:15]=[N:26][OH:27])=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)Oc1ccc(Oc2ncc(C=O)s2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)Oc1ccc(Oc2ncc(C=NO)s2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.5 %

Procedure:
To a solution of Example 1C (2.5 g, 0.0095 mol) in pyridine (15 mL, 0.19 mol) was added hydroxylamine hydrochloride (6.6 g, 0.095 mol) portion wise and the mixture was stirred at room temperature for 5 minutes and it solidified. The mixture was then heated at 70° C. for 0.5 hours. Water (300 mL) was added and the reaction was stirred for 20 minutes. The solid was filtered and air-dried to give 2.26 g of product as a white solid (85% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.28 (d, J=5.49 Hz, 6H) 4.54-4.68 (m, 1H) 7.00 (d, J=9.16 Hz, 2H) 7.28 (d, J=9.16 Hz, 2H) 7.68 (s, 1H) 7.77 (s, 1H) 11.89 (s, 1H). MS (ESI), m/z 279.0 (M+H)+.
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:32])=[C:11]([CH3:31])[C:12]2[O:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[C:13]=2[C:29]=1[CH3:30])C1C=CC=CC=1>CCCCCC>[CH:23]1([C:20]2[CH:19]=[CH:18][C:17]([C:14]3[C:13]4[C:29]([CH3:30])=[C:9]([NH2:8])[C:10]([CH3:32])=[C:11]([CH3:31])[C:12]=4[O:16][CH:15]=3)=[CH:22][CH:21]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Cc1c(NCc2ccccc2)c(C)c2c(-c3ccc(C4CCCCC4)cc3)coc2c1C
Solvent: CCCCCC
Product: Cc1c(N)c(C)c2c(-c3ccc(C4CCCCC4)cc3)coc2c1C
Yield: 79 %

Procedure:
Using N-benzyl-3-(4-cyclohexylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine obtained in Reference Example 283, the title compound was synthesized in the same manner as in Reference Example 30. Yield 79%. Melting point: 139-140° C. (hexane).
Reaction SMILES: O[C:2]1([C:15]#[N:16])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[C:7]([O:11][CH3:12])[CH:8]=2)[CH2:3]1>Cl>[CH3:14][O:13][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][C:7]=1[O:11][CH3:12])[CH2:10][C:2]([C:15]#[N:16])=[CH:3]2
Reactant: COc1cc2c(cc1OC)CC(O)(C#N)C2
Agent: Cl
Product: COc1cc2c(cc1OC)CC(C#N)=C2
Temperature: 75 °C
Yield: 80.3 %

Procedure:
The crude alcohol (17.1 g) was suspended in hydrochloric acid (5M, 170 ml) and the mixture was stirred and heated to 75° C. After 30 min. the dark solution was cooled in an ice-bath and the resultant green solid was filtered off and dried at 60° C. The product was dissolved in dichloromethane and the solution was passed through a column of coarse silica (0.2-0.5 mm, Merck, 80 g). The appropriate fractions were combined and evaporated to dryness to give 5,6-dimethoxy-1H-indene-2-carbonitrile (12.6 g), m.p. 140°-141° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:16][C:15]([F:17])([F:18])[C:11]1[CH:10]=[C:9]([CH:7]2[CH2:8][CH:6]2[CH2:4][OH:3])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C1CC1c1cccc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CC1c1cccc(C(F)(F)F)c1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
2-(3-Trifluoromethyl-phenyl)-cyclopropanecarboxylic acid ethyl ester (prepared as per literature procedure) (0.70 g, 2.7 mmol) in THF (5 ml) was added to a solution of lithium aluminium hydride (0.123 g, 3.25 mmol) in THF (5 ml) at 0° C. over a period of 10 min. and stirred further at 20-25° C. for 2 hours. The reaction mixture was diluted with THF (15 ml) and quenched with 10% NaOH solution (5 ml) and water (10 ml). The aqueous layer was extracted with ethyl acetate, washed with saturated brine solution and dried over Na2SO4. The organic layer was evaporated to afford [2-(3-trifluoromethyl-phenyl)-cyclopropyl]-methanol as a colorless oil (0.54 g, 92%).
Reaction SMILES: C(N[C:6](=[O:13])[C:7]([C:9]1([CH3:12])[CH2:11][CH2:10]1)=O)(C)(C)C.[NH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17].Cl.C(O)C>O>[NH2:14][N:15]1[C:6](=[O:13])[C:7]([C:9]2([CH3:12])[CH2:11][CH2:10]2)=[N:19][N:18]=[C:16]1[SH:17]
Reactant: CC(C)(C)NC(=O)C(=O)C1(C)CC1
Reactant: NNC(=S)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1(c2nnc(S)n(N)c2=O)CC1

Procedure:
183 g of (1-methylcyclopropyl)-glyoxylic acid tert-butylamide and 112 g of thiocarbohydrazide are added to a mixture of 1 liter of 1 N HCl and 1 liter of ethanol. The mixture is refluxed for 8 hours; it is subsequently cooled and diluted with 2 liters of H2O and the crystals are filtered off with suction. White crystals having a yellow lustre are obtained and these are dried.
Reaction SMILES: C([O:4][C@H:5]([CH3:26])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][CH2:22][NH:23][C:15]3=[N:14][C:13]=2[N:12]([CH3:24])[C:11]1=[O:25])(=O)C.Cl.C(OCC)C>CO>[OH:4][C@H:5]([CH3:26])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][CH2:22][NH:23][C:15]3=[N:14][C:13]=2[N:12]([CH3:24])[C:11]1=[O:25]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc3n2CCCN3)n(C)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2c(nc3n2CCCN3)n(C)c1=O
Yield: 80 %

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-1-methyl-6,7,8,9-tetrahydro-pyrimido[2,1-f]purine-2,4(1H,3H)-dione (100 mg, 0.276 mmol) and a 1.0 M solution of hydrogen chloride in diethylether(1.0 ml, 1.0 mmol) in methanol (15 ml) was stirred at 70° C. for 3 hours. Concentration under reduced pressure provided (R)-3-(5-hydroxyhexyl)-1-methyl-6,7,8,9-tetrahydro-pyrimido[2,1-f]purine-2,4(1H, 3H)-dione (CT-13431) (71 mg, 80% yield) as a white powder.