Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH2:17])=[O:16])[CH2:10][CH2:9]2)=[C:4]([N+:18]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C1COCC1.O.[Zn]>[NH2:18][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH2:17])=[O:16])[CH2:10][CH2:9]1
Reactant: NC(=O)CN1CCN(c2ccc(Br)cc2[N+](=O)[O-])CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)CN1CCN(c2ccc(Br)cc2N)CC1
Yield: 93.2 %

Procedure:
Using similar reaction conditions as described in step ii of Intermediate-27, 2-(4-(4-bromo-2-nitrophenyl)piperazin-1-yl)acetamide (600 mg, 1.74 mmol) was reduced using zinc dust (568 mg, 8.74 mmol) and ammonium chloride (461 mg, 8.74 mmol) in THF/water 10/10 ml to afford 508 mg (93% yield) of the titled product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO.O1CCCC1>[CH3:20][S:17]([C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=1)(=[O:18])=[O:19]
Reactant: COC(=O)c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1cccc(-c2ccc(C(=O)O)cc2)c1

Procedure:
Procedure HH: To a stirring solution of 3′-Methanesulfonyl-biphenyl-4-carboxylic acid methyl ester (1.0 mmol) in 1:1 methanol/tetrahydrofuran (0.15M), add 2N sodium hydroxide (3.0 mmol) and heat to reflux for 1 hour. After this time, remove the heat and concentrate in vacuo. Wash with 1N hydrochloric acid and water while extracting with 10% isopropanol/dichloromethane. Concentrate the organic layer in vacuo to yield the title compound. MS (m/e): 275.1 (M−1)
Reaction SMILES: N1C=C2C(N=CN2)=NC=1.[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([NH:15][CH:16]=[N:17]2)=[C:13]([Cl:20])[N:12]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(N(CC)CC)C>ClCCl>[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)=[C:13]([Cl:20])[N:12]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: c1ncc2[nH]cnc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-n2cnc3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
Purine N9 arylation via boronic acids/cupric acetate: A 20 mL glass vial equipped with a magnetic stir bar was charged with 2,6-dichloropurine (0.200 g, 1.06 mmol, 1.0 equiv), 4-methylphenylboronic acid (0.288 g, 2.12 mmol, 2.0 equiv), anhydrous cupric acetate (0.384 g, 2.12 mmol, 2.0 equiv.), 4 Å activated molecular sieves (0.500 g), triethylamine (0.443 mL, 3.18 mmol, 3.0 equiv.) and dichloromethane (5.0 mL). The reaction was stirred under air at ambient temperature and monitored by TLC. When the reaction was complete after 24 hours, it was filtered through Celite, washed with methanol and purified by flash column chromatography (1% methanol in dichloromethane) to afford desired 2,6-dichloro-9-(4-methylphenyl)-purine (0.136 g, 47%). 1H NMR (400 MHz, CDCl3) δ 2.47 (s, 3H), 7.41 (d, 2H, J=8.1 Hz), 7.54 (d, 2H, J=8.1 Hz), 8.35 (s, 1H); HRMS (MALDI-FTMS) C12H8Cl2N4 [MH+] 279.0199, found: 279.0208.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[CH3:15][O:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:25][CH2:26][CH3:27])[C:19]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:15][O:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:2][CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=2)=[C:20]([CH2:25][CH2:26][CH3:27])[C:19]=1[OH:28]
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Reactant: COc1ccc(CCCBr)cc1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCc2ccc(OC)c(OC)c2)ccc(C(=O)OC)c1O
Yield: 56.2 %

Procedure:
A mixture of 9.5 g (0.037 mol) of 1-(3-bromopropyl)-3,4-dimethoxybenzene [G. H. Douglas, C. R. Walk and H. Smith, J. Med. Chem., 9, 27 (1966)], 7.0 g (0.033 mol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester, 6.9 g (0.05 mol) of potassium carbonate and 8.3 g (0.05 mol) of potassium iodide in 250 mL of acetone was stirred at reflux for 24 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to an oil which was purified by high pressure liquid chromatography using 15% ethyl acetate-hexane to give 7.2 g (56% yield) of 4-[3-(3,4-dimethoxyphenyl)propoxy]-2-hydroxy-3-propylbenzoic acid methyl ester as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([NH:11][NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28].C(O)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:23][O:22][C:20](=[O:21])[C:17]1[CH:18]=[CH:19][C:14]([C:13]2[S:28][C:9]([C:8]3[CH:25]=[CH:26][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:6][CH:7]=3)=[N:11][N:12]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(C(=O)NNC(=O)c2ccc(C(=O)OC)cc2)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(C(=O)OC)cc3)s2)cc1

Procedure:
1,2-di(4-Carbomethoxybenzoyl)hydrazine (A), prepared as in Example 1, in pyridine was refluxed with phosphorus pentasulfide for 15 hours. The mixture was cooled and poured into 20% ethanol. After the solution was neutralized with sodium bicarbonate, the product, dimethyl-4,4'-(1,3,4-thiadiazol-2,5-diyl)dibenzoate (D), was obtained by filtration (m.p. 268°-270°, yiled 60%). Then III was obtained by reacting D in a similar manner as in Example 1 (m.p. >300°, 60%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]2[N:10]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]4Cl)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.C1(N2C3C=CC(C(O)=O)=CC=3N=C2C2C=C3C(=CC=2)N=C(C2C=CC=CC=2)C=C3N(C)C)CCCCC1.[CH:75]1[C:84]2[C:79](=[CH:80][CH:81]=[C:82]([OH:85])[CH:83]=2)[CH:78]=[CH:77][C:76]=1[OH:86]>>[CH:30]1([N:10]2[C:9]3[CH:36]=[CH:37][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=3[N:12]=[C:11]2[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[C:16]3[O:86][C:76]2[CH:77]=[CH:78][C:79]3[C:84](=[CH:83][C:82]([OH:85])=[CH:81][CH:80]=3)[CH:75]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Cl)c3c1)n2C1CCCCC1
Reactant: Oc1ccc2ccc(O)cc2c1
Agent: CN(C)c1cc(-c2ccccc2)nc2ccc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)cc12
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Oc4ccc5ccc(O)cc5c4)c3c1)n2C1CCCCC1

Procedure:
In this reaction 51 mg (0.1 mmol) of crude 2-(4-chloro-2-phenyl-quinolin-6-yl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester were used in the same reaction sequence as that used for Compound 481. The nucleophile used was naphthalene-2,7-diol. Yield: 6.2 mg.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][N:24]=1)=[O:21].[CH2:32]1[C:40]2[C:35](=[CH:36]C=CC=2)[CH2:34][N:33]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:34][CH:35]([CH3:36])[CH2:40][CH2:32][NH:33][C:27]([C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:21])=[N:24][CH:25]=1)=[O:29]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)nc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: NCCCc1ccccc1
Product: CC(C)CCNC(=O)c1ccc(NC(=O)N2Cc3ccccc3C2)nc1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-methylbutan-1-amine for 3-phenylpropan-1-amine and 6-(isoindoline-2-carboxamido)nicotinic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (s, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.42 (t, J=5.5 Hz, 1H), 8.13 (dd, J=8.8, 2.4 Hz, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.25-7.37 (m, 4H), 4.71-4.95 (bs, 4H), 3.24-3.32 (m, 2H), 1.57-1.68 (m, 1H), 1.43 (q, J=7.1 Hz, 2H), 0.91 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 353 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].I[CH:19]([CH3:21])[CH3:20]>CN(C=O)C.C(#N)C>[CH:19]([N:3]1[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]1=[O:1])([CH3:21])[CH3:20]
Reactant: CC(C)I
Reactant: COC(=O)c1cc[nH]c(=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(C(C)C)c(=O)c1
Temperature: 60 °C
Yield: 25.8 %

Procedure:
To methyl 2-oxo-1H-pyridine-4-carboxylate (700 mg, 4.57 mmol) in dry DMF (4.4 mL) was added finely ground K2CO3 (2.53 g, 18.3 mmol) followed by 2-iodopropane (914 μL, 9.14 mmol). The mixture was heated at 60° C. (external) for 1 h. The mixture was diluted with acetonitrile (10 mL) and was filtered. The filtrate was evaporated onto Celite and was purified by column chromatography (0-100% EtOAc/DCM) to give methyl 1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate (230 mg). ESI-MS m/z calc 195.1. found 196.3 (M−1)−. Retention time: 1.09 minutes (3 min run).
Reaction SMILES: CSC(SC)=[C:4]([C:7]#N)[C:5]#[N:6].CS[C:13](SC)=[C:14]([C:23]#[N:24])[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]>C(O)C>[O:16]1[C:15]2[CH:14]=[CH:13][CH:7]=[CH:4][C:5]=2[NH:6][C:13]1=[C:14]([C:23]#[N:24])[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: CSC(SC)=C(C#N)C(=O)N1CCOCC1
Solvent: CCO
Product: N#CC(C(=O)N1CCOCC1)=C1Nc2ccccc2O1

Procedure:
The procedure described in Example 1 is repeated using, instead of 3,3-bis(methylthio)-2-cyanoacrylonitrile, an equivalent amount of 3,3-bis(methylthio)-2-cyanoacrylic acid morpholide and holding the mixture under reflux for 24 hours to obtain 2-benzoxazolinylidene-cyanoacetic acid morpholide of melting point 217°-219° C. (from ethanol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][C:21]1[C:22](B(O)O)=[CH:23][S:24][CH:25]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:22]1[C:21]([CH3:20])=[CH:25][S:24][CH:23]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: Cc1cscc1B(O)O
Product: COc1ccc2c(-c3cscc3C)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-methyl-3-thiopheneboronic acid to give [6-methoxy-1-(4-methyl-thiophen-3-yl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33](=[N:35][OH:36])[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:48](OCC)(=[O:54])[C:49]([O:51][CH2:52][CH3:53])=[O:50].[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)[C:10]=1[C:33]1[CH2:34][C:48]([OH:54])([C:49]([O:51][CH2:52][CH3:53])=[O:50])[O:36][N:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=NO)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(O)CC(c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)=NO1
Reaction time: 1 h
Yield: 21 %

Procedure:
To a stirred solution of 1-[2,4-bis(benzyloxy)-6-(4-nitrophenoxy)phenyl]-N-hydroxyethanimine (10 g, 44 mmol) was added drop wise 2 M n-ButLi in hexane (45 mL, 44 mmol) at −78° C. and the stirring was continued for 1 hour at −78° C. then for ½ hour at room temperature. After recooling at −78° C., a solution of diethyl oxalate (3.22 g, 22 mmol) in THF (50 mL) was cannuled into the cloudy solution. The mixture was warmed at rt over 16 hours before the addition of a NH4Cl saturated solution (100 mL). The organic and aqueous layers were separated and the latter was diluted with ethyl acetate and thoroughly washed with brine. After drying over Na2SO4, the solvent was removed and the residue was chromatographed on silica gel eluting with ethyl acetate/hexane 7/5, to provide the title compound (2.7 g, yield 17%).
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH2:11][CH:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].Cl.[NH2:26][OH:27].C(=O)(O)[O-].[Na+]>C(O)(C)C>[OH:27][N:26]=[C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH2:9][CH:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11]2)=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])[NH2:2]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C#N)c(C(F)(F)F)c2)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)c(C(F)(F)F)c2)C1
Reaction time: 16 h
Yield: 87.7 %

Procedure:
A solution of tert-butyl 1-(4-cyano-3-(trifluoromethyl)benzyl)azetidine-3-carboxylate (0.268 g, 0.787 mmol), hydroxylamine hydrochloride (0.109 g, 1.57 mmol), and sodium bicarbonate (0.265 g, 3.15 mmol) in isopropanol (2.2 mL) was stirred at 90° C. for 6.0 hrs. HPLC and LCMS indicated that the reaction was 69% complete. Additional hydroxylamine hydrochloride (0.109 g), sodium bicarbonate (0.265 g), and isopropanol (2.2 mL) were added, and heating was continued for 16 hrs. The isopropanol was removed under reduced pressure, and the reaction mixture was diluted with ethyl acetate and washed with water (2×), washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)-3-(trifluoromethyl)benzyl)azetidine-3-carboxylate (0.258 g, 0.690 mmol, 88% yield) of a colorless, viscous oil. The compound had an HPLC ret. time=0.880 min.−Column: PHENOMENEX® S5 4.6×30 mm (2 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=374.10.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.BrN1C(=[O:16])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Ca+2]>ClC(Cl)(Cl)Cl.O>[OH:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: Cc1ccc(C#N)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccc(CO)cn1
Temperature: 25 °C

Procedure:
The compound of Example 4A (13 g, 110 mmol) is dissolved in 400 ml tetrachloro-methane, and 29.4 g (165 mmol) N-bromosuccinimide and 0.4 g (1.6 mmol) dibenzoylperoxide are added. The reaction mixture is refluxed for three hours, cooled down to room temperature and filtered. The solution is washed with aqueous sodium thiosulfate, dried over magnesium sulfate, and the solvent is removed in vacuo. The residue is dissolved in 200 ml dioxane and 200 ml water, calciumcarbonate (44 g, 440 mmol) is added, and the mixture is stirred at reflux for 2 hours. After cooling down to room temperature, the mixture is filtered, and dichloromethane is added. After phase separation, the organic phase is dried over magnesium sulfate, and the solvent is removed in vacuo. The product is purified by chromatography (silica, eluent cyclohexane/ethyl acetate 2:1).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=O.[CH3:12][CH:13]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][PH:15](=[O:17])[OH:16]>C1(C)C(C)=CC=CC=1>[O:3]=[C:1]1[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([P:15]([CH2:14][CH:13]([CH3:12])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:16])[OH:17])[O:7]1
Reactant: CC(C[PH](=O)O)CC(C)(C)C
Reactant: O=Cc1ccccc1C(=O)O
Solvent: Cc1ccccc1C
Product: CC(CC(C)(C)C)CP(=O)(O)C1OC(=O)c2ccccc21
Yield: 55.4 %

Procedure:
A mixture of 15 grams (0.1 moles) of 2-carboxybenzaldehyde and 17.82 grams of 2,4,4-trimethylpentyl phosphinic acid in 100 mL of xylene is heated to reflux and 1.8 mL of water is collected by azeotropic distillation using a Dean-Stark receiver. The xylene solvent is removed in vacuo and the residue is crystallized with a mixture of 50 mL of ethyl acetate and 100 mL heptane to yield 17.2 grams (56% yield) (3-oxo-1,3-dihydro-isobenzofuran-1-yl)-(2,4,4-trimethylpentyl)-phosphinic acid as an off-white powder, mp 117-121° C.
Reaction SMILES: [C:1]([C:3]1[N:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1)#[N:2].C(N(CC)CC)C.[SH2:17]>C(O)C>[CH3:9][N:4]1[C:5]([CH3:8])=[CH:6][CH:7]=[C:3]1[C:1](=[S:17])[NH2:2]
Reactant: Cc1ccc(C#N)n1C
Reactant: S
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(C(N)=S)n1C

Procedure:
5 g of 2cyano-1,5-dimethylpyrrol are dissolved in 40 ml of ethanol and treated with 10 ml of triethylamine. 50 ml of an ethanolic H2S solution (3.8 g/100 ml) are added and the mixture is heated for ca. 15 hours in an autoclave at 70°. The reaction mixture is cooled and the solvent is evaporated off to obtain ca. a quarter of its volume. 1,5-dimethylpyrrol-2-carbothioamide crystallizes upon cooling at 0° in the form of a light yellow precipitate.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)=[O:5])[CH3:2]>CCOC(C)=O.CO.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH:7]1[CH2:16][CH2:15][C:10]2([O:11][CH2:12][CH2:13][O:14]2)[CH2:9][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C=C1CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 8-ethoxycarbonylmethylidene-1,4-dioxaspiro[4.5]decane (crude, 172.9 g) 10% Pd—C (53.2% wet, 6.5 g) in EtOAc/MeOH (1250 mL and 400 mL) is stirred under H2 atmosphere at room temperature for 4 hours. The reaction mixture is filtered, and the filtrate is concentrated in vacuo to afford crude 8-ethoxycarbonylmethyl-1,4-dioxaspiro[4.5]decane. The crude product is used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:22][CH:21]=2)[CH:4]=[C:5]2[N:10]3[C@H:11]4[CH2:16][CH2:15][CH2:14][C@H:12]4[N:13]=[C:9]3[N:8]([CH3:17])[C:7](=[O:18])[C:6]=12.[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:17][N:8]1[C:7](=[O:18])[C:6]2=[C:2]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:3]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:24][CH:25]=3)[CH:4]=[C:5]2[N:10]2[C@H:11]3[CH2:16][CH2:15][CH2:14][C@H:12]3[N:13]=[C:9]12
Reactant: CN1C(=O)c2c(cn(Cc3ccc(-c4ccccn4)cc3)c2Cl)N2C1=N[C@@H]1CCC[C@@H]12
Reactant: Nc1ccccc1
Product: CN1C(=O)c2c(cn(Cc3ccc(-c4ccccn4)cc3)c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 150 °C

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-2-((4-Pyridin-2yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (5.6 mg, 0.013 mmol) is placed in a Biotage microwave tube, and then aniline (0.2 mL) is added. The mixture is heated at 150° C. for an hour. The mixture is purified by a semi-preparative HPLC to give product. MS (ESI) m/z 489.3 [M+H]+.
Reaction SMILES: [N:1]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][C@@H:3]2[CH2:6][NH:7][CH2:8][C@H:2]12.[H-].[Na+].I[CH2:26][CH3:27]>C1COCC1.O>[CH2:26]([N:7]1[CH2:6][C@@H:3]2[C@@H:2]([N:1]([C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=4)=[CH:13][CH:14]=3)[CH2:5][CH2:4]2)[CH2:8]1)[CH3:27]
Reactant: N#Cc1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1C[C@H]2CCN(c3ccc(-c4ccc(C#N)cc4)cc3)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
The product of Example 1E (22 mg, 0.076 mmole) was dissolved in 2.5 ml anhydrous THF under nitrogen. Sodium hydride (95%, 4 mg, 0.167 mmole) was added and the mixture was stirred at room temperature for 1 hour. Iodoethane (18 μl, 0.225 mmole) was added and the mixture was stirred at room temperature over night. The mixture was diluted with water and extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluting with a mixture of 0.2% ammonium hydroxide and 2% methanol in dichloromethane) to provide the title compound (11 mg, 46%). 1H NMR (CDCl3) δ ppm 7.64 (d, J=1.36 Hz, 4H) 7.50 (d, J=8.82 Hz, 2H) 6.65 (d, J=8.82 Hz, 2H) 4.14-4.23 (m, 1H) 3.47-3.60 (m, 1H) 3.27-3.39 (m, 1H) 2.92-3.04 (m, 1H) 2.70-2.81 (m, 1H) 2.38-2.67 (m, 5H) 2.11-2.25 (m, 1H) 1.89-2.03 (m, 1H) 1.08 (t, J=7.12 Hz, 3H); MS (M+H)+=318.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:17])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:6]=2.[O:18]1CCOCC1>O>[F:1][C:2]1[C:3]([CH:17]=[O:18])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:6]=2
Reactant: C1COCCO1
Reactant: COCCOc1ccc2cc(F)c(C)nc2c1
Solvent: O
Product: COCCOc1ccc2cc(F)c(C=O)nc2c1
Yield: 97 %

Procedure:
A solution of 3-fluoro-7-(2-methoxyethoxy)-2-methylquinoline (0.234 g, 0.995 mmol) and SeO2 (0.132 g, 1.19 mmol) in dioxane (10 mL) and water (0.1 mL) was stirred at 102° C. (bath) for 5 hours. The solid was removed by filtration. The filtrated was concentrated under reduced pressure. The residue obtained was purified by flash chromatography (1:1 hexane/ethyl acetate) to give 3-fluoro-7-(2-methoxyethoxy)quinoline-2-carbaldehyde (0.24 g, 0.963 mmol, 97% yield) as a solid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)[O:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.O.NN>C(O)C>[NH2:3][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)[O:20][CH:21]1[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: COc1cc(C#CCCCN2C(=O)c3ccccc3C2=O)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(C#CCCCN)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl 4-(3-(5-(1,3-dioxoisoindolin-2-yl)pent-1-ynyl)-5-methoxyphenoxy)piperidine-1-carboxylate (0.500 g, 0.97 mmol) and hydrazine monohydrate (0.094 mL, 1.94 mmol) were taken up into ethanol (5 mL) and the resulting mixture was stirred at 80° C. for 2.5 hours. The resulting mixture was filtered and the solvent was removed in vacuo to yield tert-butyl 4-(3-(5-aminopent-1-ynyl)-5-methoxyphenoxy)piperidine-1-carboxylate. MH+ 388.2