Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[C:31]1([CH2:37][CH2:38][N:39]([CH2:44][CH:45]2[CH2:47][O:46]2)[S:40]([CH3:43])(=[O:42])=[O:41])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C>[C:31]1([CH2:37][CH2:38][N:39]([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:44][CH:45]([OH:46])[CH2:47][N:16]2[CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:18][CH2:17]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)N(CCc1ccccc1)CC1CO1
Reactant: CCOC(=O)CN1CCNCCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1
Solvent: CCO
Product: CCOC(=O)CN1CCN(CC(=O)OCC)CCN(CC(O)CN(CCc2ccccc2)S(C)(=O)=O)CCN(CC(=O)OCC)CC1

Procedure:
200 ml of absolute ethanol is poured over 8.61 g (20 mmol) of N,N',N"-tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 36 25 417 A1) in a bomb tube. After 5.11 g (20 mmol) of N-(2-phenylethyl)-N-[(2-oxiranyl)-methyl]-methanesulfonic acid amide is added (Example 2f), the bomb tube is closed, flushed with nitrogen, and the resulting reaction mixture is heated for 16 hours to 90° C. After the reaction (TLC control) is completed, the solvent is evaporated in a vacuum and the yellowish, oily residue is chromatographed on silica gel (Eluent: chloroform/methanol; methanol: 0-80%).
Reaction SMILES: P(=O)(O)(O)O.[CH3:6][C:7]([CH3:11])=[CH:8]C=O.C(O)C.[CH:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])OCC>CCOCC>[CH2:23]([O:22][CH:15]([O:19][CH2:20][CH3:21])[CH:6]=[C:7]([CH3:11])[CH3:8])[CH3:24]
Reactant: CC(C)=CC=O
Reactant: CCOC(OCC)OCC
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(C=C(C)C)OCC
Yield: 65 %

Procedure:
Bull. Soc. Fr. 1965, 1007-1014 discloses the use of phosphoric acid. 3-Methyl-2-butenal is stirred with ethanol, triethyl orthoformate and phosphoric acid at room temperature for 40 hours. The reaction mixture is then taken up in ether, washed with 0.5 N aqueous ammonia and dried over sodium sulfate. Subsequent distillation affords 3-methyl-2-butenal diethyl acetal in a yield of 65%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[CH:5].N1C=CN=C1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>CN(C=O)C.O>[Si:11]([O:1][CH2:2][CH2:3][C:4]#[CH:5])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: C#CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCO[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 89.1 %

Procedure:
A solution of 1-hydroxybut-3-yne (2.0 g, 0.028 mol) and imidazole (2.9 g, 0.043 mol) in DMF (5 ml) was treated with t-butyldimethylsilyl chloride (6.4 g, 0.043 mol). After 24 hr. at RT, the reaction was diluted with water and extracted with diethyl ether. The organic extracts were washed with water, dried, evaporated, and the volatile organics were removed by vacuum to afford the title compound as an oil (4.6 g, 89%). 1H NMR (400 MHz, CDCl3): δ 3.67 (t, J=7.1 Hz, 2H), 2.32 (m, 2H), 1.88 (s, 1H), 0.82 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=O.[C:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>CCCCCC.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14](/[CH:15]=[CH:23]/[C:22]([C:25]2[CH:26]=[CH:27][C:28]([S:31]([N:34]([CH3:35])[CH3:36])(=[O:33])=[O:32])=[CH:29][CH:30]=2)=[O:24])[CH:17]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)N(C)C)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)N(C)C)cc1
Yield: 12 %

Procedure:
The title compound was prepared in an analogous manner as Ex-1 using 5-(1H-indol-2-yl)-2,4-dimethoxybenzaldehye (Ex-32B) and 4-acetyl-N,N-dimethylbenzenesulfonamide (Ex-31A), 12% yield after silica gel column chromatography (hexane/EtOAc, 2:1), yellow solid, mp 158–162° C. 1H-NMR (300 MHz, CDCl3) δ 9.39 (br, 1H), 8.15 (m, 2H), 8.08 (d, J=9 Hz, 2H), 7.91 (d, J=9Hz, 2H), 7.64 (d, J=7 Hz, 1H), 7.57 (d, J=15 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.09–7.21 (m, 2H), 6.87 (d, J=2Hz, 1H), 6.60 (s, 1H), 4.10 (s, 3H), 4.01 (s, 3H), 2.76 (s, 6H). HRMS (ESI) Calcd. for C27H26N2O5S: 491.1641 (M+H)+; Found: 491.1638.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12](=O)[NH:13][N:14]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:12]1[N:13]=[N:14][C:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[CH:10][CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2ccc(=O)[nH]n2)c(C)c1
Product: Cc1ccc(-c2ccc(Cl)nn2)c(C)c1

Procedure:
6-(2,4-dimethylphenyl)pyridazin-3(2H)-one (example 13c) was heated with POCl3 (5.15 ml, 55 mmol) at 85° C. for 4 hours. Following cooling and treating with crushed ice a white solid obtained and was collected to give 1.36 g of the 3-chloro-6-(2,4-dimethylphenyl)pyridazine. 1H NMR (300 MHz, dMSO): δ 2.29 (s, 3H), 2.34 (s, 3H), 7.16-7.19 (m, 2H), 7.35-7.37 (d, 1H), 7.93-8.00 (dd, 2H); (M+H, 313).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([C:17]4[CH:18]=[C:19]([NH2:24])[C:20]([NH2:23])=[CH:21][CH:22]=4)[CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH:25](O)=O>O>[NH:9]1[C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]4[NH:23][CH:25]=[N:24][C:19]=4[CH:18]=3)=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1
Reactant: O=CO
Reactant: Nc1ccc(-c2nc3ccc(-c4ccc(N)c(N)c4)cc3[nH]2)cc1
Solvent: O
Product: Nc1ccc(-c2nc3cc(-c4ccc5[nH]cnc5c4)ccc3[nH]2)cc1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 5.8 %

Procedure:
4-(2-(4-Aminophenyl)-1H-benzo[d]imidazol-6-yl)benzene-1,2-diamine (200 mg, 0.64 mmol) and formic acid (0.24 mL, 6.35 mmol) were dissolved in H2O (2 mL) and the mixture heated to 160° C. for 20 min under microwave irradiation. On cooling, a precipitate formed, which was filtered off and washed with water. The filtrate was basified with K2CO3 and stirred for 30 min by which time a precipitate had formed. The mixture was filtered and the precipitate washed with water and dried under suction. The crude product was purified by column chromatography (EtOAc to 85:15 EtOAc-MeOH) to afford the product as a white solid (12 mg, 6%).
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][S:3][S:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(OCC)(=O)C>[CH3:16][S:17]([O:8][CH2:1][CH2:2][S:3][S:4][CH2:5][CH2:6][O:7][S:17]([CH3:16])(=[O:19])=[O:18])(=[O:19])=[O:18]
Reactant: OCCSSCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCSSCCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
10 g of 2,2′-dithiodiethanol and 14.44 g of triethylamine (TEA) are diluted in 100 mL of ethyl acetate (EtOAc). At 0° C., 16.35 g of methanesulfonyl chloride diluted in 35 mL of EtOAc are added dropwise to the reaction medium with rapid stirring. 7.22 g of TEA are introduced and stirring is continued at room temperature for 4 hours 30 minutes. 8.2 g of methanesulfonyl chloride are added dropwise at 15° C. and stirring is continued at room temperature for 17 hours. The precipitate is filtered off and washed with three times 50 mL of EtOAc. The organic phases are extracted with 100 mL of ice-water, 100 mL of water, three times 50 mL of saturated sodium hydrogen carbonate solution (NaHCO3), twice 20 mL of saturated sodium chloride solution (NaCl), and then dried over anhydrous sodium sulfate (Na2SO4). The EtOAc is evaporated off, and 17.49 g of a clear pale yellow oil are collected and stored at −25° C. The analyses indicate that the product is in accordance and pure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1Cl.[NH2:11][CH2:12][C:13]1[CH:14]=[C:15]([Br:19])[CH:16]=[N:17][CH:18]=1.CO>C(COC)OC>[Br:19][C:15]1[CH:14]=[C:13]([CH2:12][NH:11][C:7]2[NH:6][C:5]([CH3:9])=[N:4][C:3](=[O:10])[C:2]=2[Cl:1])[CH:18]=[N:17][CH:16]=1
Reactant: NCc1cncc(Br)c1
Reactant: Cc1nc(O)c(Cl)c(Cl)n1
Solvent: CO
Solvent: COCCOC
Product: Cc1nc(=O)c(Cl)c(NCc2cncc(Br)c2)[nH]1

Procedure:
A stirred mixture of 5,6-dichloro-2-methyl-4-pyrimidinol (1.20 g, 6.70 mmol) and 5-aminomethyl-3-bromopyridine (3.65 g, 19.5 mmol) in dimethoxyethane (25 mL) was heated at reflux for 14 hours. The mixture was then concentrated in vacuo and diluted with water. The precipitate was isolated by filtration with aqueous rinse, recrystallized twice from ethyl acetate, and then recrystallized a third time, but from methanol, to provide the title compound as a pure product (1.07 g, 3.25 mmol, 48%): mp 274°-275° C.; Rf 0.59 (20% MeOH in EtOAc); 1H NMR (DMSO-D6, 400 MHz)δ11.9 (br s, 1H), 8.57 (d, J=2 Hz, 1H), 8.49 (s, 1H), 7.93 (s, 1H), 7.46 (t, J=6 Hz, 1H), 4.56 (d, J=6.1 Hz, 2H), 2.18 (s, 3H); IR (KBr) 3300 (NH), 2790-3000 (CH), 1660, 1615, 2590 (C=C, C=N); mass spectrum m/e 329.8 (M+, 70%), 292.9 (M+ -Cl, 32%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:21][S:20][C:16]1[CH:15]=[C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CSc1cccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1cccc(C2=CCNCC2)c1

Procedure:
4-Hydroxy-4-(3-methylsulfanyl-phenyl)-piperidin-1-carboxylic acid tert-butyl ester (3.97 g) was dissolved in CH2Cl2 (500 ml) and trifluoroacetic acid (80 ml) was added in one portion. The mixture was refluxed for one hour and then washed with two portions of 10%-Na2CO3, dried (MgSO4), filtered and evaporated to dryness. Yield 2.07 g. MS m/z (relative intensity, 70 eV) 205 (M+, 73), 158 (44), 129 (95), 128 (80), 82 (bp).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH3:38])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH2:39].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[F:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH3:38])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH:39][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COCC#Cc1cc(F)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC#Cc1cc(F)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
4-Chloro-6-methoxy-7-(3-morpholin-4ylpropoxy)quinazoline (201 mg, 0.60 mmol) and 5-fluoro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (140 mg, 0.63 mmol) in DMF (3 ml) were cooled in an ice-water bath then treated dropwise, under an atmosphere of nitrogen, with a solution of sodium bis(trimethylsilyl)amide (1.0 M in THF, 1.25 ml). The resulting mixture was stirred at ice temperature for a further 90 minutes before quenching in dilute aqueous ammonium chloride solution and extracting with dichloromethane (containing a small percentage of methanol). The extract was washed with saturated brine, dried over magnesium sulphate and evaporated to an orange oil. The residue was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (245 mg, 78%) as a colourless solid; NMR Spectrum: (DMSOd6) 1.97 (quintet, 2), 2.40 (m, 4H), 2.47 (t, 2H), 3.36 (s, 3H), 3.59 (m, 4H), 3.95 (s, 3H), 4.20 (t, 2H), 4.37 (s, 2H), 6.16 (s, 2H), 6.91 (d, 1H), 7.19 (s, 1H), 7.81 (s, 1H), 8.36 (s, 1H), 9.52 (s, 1H); Mass Spectrum: M+H+ 525.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][C:14](OC)=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:14](=[O:15])[CH2:13][O:12][CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: COCC(=O)OC
Product: COCC(=O)NC(C)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
At room temperature, a solution of 20.06 g (0.129 mol) of racemic 1-(4-chloro-phenyl)-ethylamine in 20 g (0.19 mol) of methyl methoxyacetate is mixed with stirring with 1 g of Novozym 435® (=immobilized lipase from Candida antarctica; 7300 U/g). Stirring is continued at room temperature for one hour and the reaction is then terminated by filtering off the enzyme. The conversion is 43.9%. In the filtrate that remains, the (S)-enantiomer of 1-(4-chloro-phenyl)-ethylamine has an ee value of 61%, while the (R)-enantiomer of N-[l-(4-chlorophenyl)-ethyl]-methoxyacetamide obtained has an ee value of 98.4%.
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:30]([C:32]1[C:33](=[C:48]([C:51]#[N:52])[C:49]#[N:50])[O:34][C:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:38]([F:41])([F:40])[F:39])[C:36]=1[CH3:37])#[N:31]>C(O)C.O1CCCC1>[CH2:26]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=[CH:37][C:36]3[C:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:38]([F:41])([F:39])[F:40])[O:34][C:33](=[C:48]([C:51]#[N:52])[C:49]#[N:50])[C:32]=3[C:30]#[N:31])=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=O)cc2C)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)cc2C)c(OC)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
In 9 ml of ethanol and 3 ml of tetrahydrofuran were dissolved 400 mg (1.02 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl) vinyl]-2,5-dimethylbenzaldehyde and 360 mg (1.14 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred at 70° C. for 2 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography to give 441 mg of a black powder (yield: 62.8%; mp: 177-179° C.)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].O[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(P(CCCC)CCCC)CCC.N(C(N(C)C)=O)=NC(N(C)C)=O>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: OC1CCNCC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc2cccc(OC3CCNCC3)c2c1C
Temperature: 60 °C
Yield: 17.4 %

Procedure:
A mixture of 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (100 mg), 4-hydroxypiperidine (46 mg), tributylphosphine (170 μl) and 1,1′-azobis(N,N-dimethylformamide) (120 mg) in benzene (2 ml) was heated at 60° C. for one hour. The suspension was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was separated by silica gel column chromatography developed by dichloromethane-methanol to give 3-methyl-4-(piperidin-4-yloxy)-benzofuran-2-carboxylic acid ethyl ester (24 mg) as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.Cl.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1nc2cccc(-c3ccsc3)n2n1
Agent: Cl
Product: O=C(Nc1nc2cccc(-c3ccsc3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 2, but starting from 5-(3-thienyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A1), 82 mg; 0.38 mmol; 1.5 eq.) and nicotinoyl chloride hydrochloride (55 mg; 0.3 mmol; 1.2 eq.) as a beige solid (21 mg, 26%). HPLC, Rt: 2.15 min. (purity 97.3%). LC/MS, M+(ESI): 322.0, M−(ESI): 320.0.
Reaction SMILES: [CH:1]1([PH:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH3:12].C([Li])CCC.CC1C=CC(S(O[CH:29]2[CH2:34][CH2:33][CH:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:30]2)(=O)=O)=CC=1>>[CH:7]1([P:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:38]2[CH2:37][CH2:36][CH:35]([C:32]3[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=3)[CH2:40][CH2:39]2)[CH2:8][CH2:9][CH2:10][CH2:11]1.[BH3:12]
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(c3ccccc3)CC2)cc1
Reactant: C1CCC(PC2CCCC2)C1
Agent: B
Agent: [Li]CCCC
Product: c1ccc(C2CCC(P(C3CCCC3)C3CCCC3)CC2)cc1

Procedure:
The product is made similarly to its analog in Example 1 from dicyclopentyl-phosphine-borane (10.6 g; 57.5 mmol.), n-butyl lithium (39.5 mL of 1.6 M solution; 63.3 mmol.) and 4-phenylcyclohexyl 4-methylbenzenesulfonate (22.8 g; 68.9 mmol.). Yield 14.5 g (74%). 31P{1H} NMR (δ, C6D6, ppm): 33.22 and 33.83 (broad); 1H NMR (δ, C6D6, ppm): 0.944 (m, 3H, BH3), 1.2-2.2 (m, 27H, cyclopentyl+cyclohexyl), 2.82 (m, 1H, PhCH), 7.0-7.25 (m, 5H, Ph).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]([O:11][C:12]([N:14]1[C:23]2[C:18](=[N:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[C@H:17]([NH:26][CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[CH2:16][C@@H:15]1[CH2:42][CH3:43])=[O:13])([CH3:10])[CH3:9].N1C=CC=CC=1>ClCCl>[CH:8]([O:11][C:12]([N:14]1[C:23]2[C:18](=[N:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[C@H:17]([N:26]([C:1](=[O:3])[CH3:2])[CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[CH2:16][C@@H:15]1[CH2:42][CH3:43])=[O:13])([CH3:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@H]1C[C@@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nc(OC)ccc2N1C(=O)OC(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2nc(OC)ccc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.6 %

Procedure:
Add acetic anhydride (0.023 mL, 1.205 mmol) to a solution of (+/−)-cis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (125 mg, 0.241 mmol) and pyridine (0.097 mL, 1.205 mmol) in dichloromethane (2 mL), and stir at room temperature for 14 h. Remove the solvent under reduced pressure and purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (105 mg, 78%). 1H NMR (CDCl3, 300 MHz): δ 0.66-0.72 (m, 3H), 1.20-1.29 (m, 7H), 1.33-1.69 (m, 3H), 2.01-2.21 (m, 3H), 2.26-2.33 (m, 1H), 3.82, 3.86 (s, 3H), 4.22-4.28 (m, 1H), 4.81-5.01 (m, 2H), 6.59, 6.65 (d, J=8.7 Hz, 1H), 7.61-7.73 (m, 4H). MS (ES+): 562 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21])[C:6]1=[O:22])[CH2:2][CH2:3][CH3:4].[NH2:23][OH:24]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[NH:21])[NH:23][OH:24])[C:6]1=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCn1c(=O)n(CCCCC#N)c(=O)c2[nH]c(Cl)nc21
Solvent: CCO
Product: CCCCn1c(=O)n(CCCCC(=N)NO)c(=O)c2[nH]c(Cl)nc21
Temperature: 80 °C
Yield: 63.6 %

Procedure:
5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanenitrile (8.5 g, 26 mmol) was dissolved in EtOH (100 ml). Hydroxylamine (50% in water; 2.6 ml, 39 mmol) was added and the mixture heated at 80° C. for 48 h under nitrogen. The reaction mixture was concentrated in vacuo, the resultant solid washed with methanol and dried to give the title compound as a solid (5.9 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.C[Al](C)C.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH:19]1[C:24](O)=[O:25].Cl>C(Cl)Cl>[Cl:1][C:2]1[C:8]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:7][C:5]([NH:6][C:24]([CH:19]2[CH2:20][O:21][CH2:22][CH2:23][NH:18]2)=[O:25])=[C:4]([F:13])[CH:3]=1
Reactant: O=C(O)C1COCCN1
Reactant: CC(C)Oc1cc(N)c(F)cc1Cl
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)Oc1cc(NC(=O)C2COCCN2)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a stirring solution of 4-chloro-2-fluoro-5-(1-methylethoxy)aniline (15.52 g, 76.26 mmol) in CH2Cl2 (100 mL), under nitrogen at 0° C. (ice-bath) was added dropwise trimethylaluminum (114.4 mL, 228.78 mmol). The mixture was then stirred overnight at room temperature. 3-Morpholinecarboxylic acid (10.0 g, 76.20 mmol) was added portionwise at room temperature. The resultant reaction mixture was stirred at room temperature for 2 days. 6N HCl was added dropwise to the reaction mixture at 0° C. (ice-bath). The solid formed was filtered off and suspended in water (100 mL). The suspension was basicified with 50% aqueous NaOH to pH 13. 400 mL of CH2Cl2 was added. The organic layer was separated, dried over MgSO4 and the solvent was removed under vacuum to give the title compound of Step B as a white solid (10.5 g), m.p. 99°-101° C. 1H NMR: δ9.30 (br s,1H), 8.17 (d,1H), 7.14 (d,1H), 4.53 (q,1H), 3.96-3.61 (m,5H), 3.00-3.01 (m,2H), 1.37 (d,6H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[OH:17].[O:18]=O>C(Cl)(Cl)Cl>[CH3:16][C:12]1[C:13](=[O:18])[C:14]([CH3:15])=[C:9]([CH3:8])[C:10](=[O:17])[CH:11]=1
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: O=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1=CC(=O)C(C)=C(C)C1=O

Procedure:
3.96 g of cobalt di-(salcylal)-3,3'-diimino -di-n-propylamine (0.1 mole) and 1.01 g of triethylamine (0.01 mole) were dissolved in 100 ml of chloroform and oxygen gas (100 ml/min) was then bubbled into the resulting solution for 5 seconds at a temperature of 10°C to form an oxygen complex. To this was added a solution of 13.6 g of 2,3,5-trimethylphenol (0.1 mole) in 100 ml of chloroform in three portions and oxygen gas (250 ml/min) was again introduced into the solution for a period of 8 hours to complete the reaction. After completion of the reaction, chloroform was distilled off and the residue was steam distilled by introducing steam thereinto. The distillate was extracted with ether and the ether was then distilled off to give 15.0 g of pseudocumoquinone (0.1 mole) having a melting point of 32°C, that is, the yield was quantitative.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:15]1[C:24]2[C:19]3=[C:20]([CH2:25][CH2:26][C:27](=[O:28])[N:18]3[CH2:17][CH2:16]1)[CH:21]=[CH:22][CH:23]=2>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][C:12]([C:22]2[CH:23]=[C:24]3[C:19]4=[C:20]([CH2:25][CH2:26][C:27](=[O:28])[N:18]4[CH2:17][CH2:16][CH2:15]3)[CH:21]=2)=[O:14])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=C1CCc2cccc3c2N1CCC3
Reactant: CC(=O)N1CCC(CCC(=O)O)CC1
Product: CC(=O)N1CCC(CCC(=O)c2cc3c4c(c2)CCC(=O)N4CCC3)CC1

Procedure:
Using 3-(1-acetyl-4-piperidinyl)propanoic acid (13.8 g) and 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one (10.8 g) according to the same method as that of Reference Example 172, the title compound was obtained as colorless crystals (15.5 g) having a melting point of 130 to 131° C.