Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:27](=[N:28][C:29]2[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=2[CH3:37])[CH:26]=[C:13]2[C:14]3[C:19]([CH2:20][CH2:21][N:12]2[C:11]1=[O:38])=[CH:18][C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3>O.Cl>[C:2]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:27](=[N:28][C:29]2[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=2[CH3:37])[CH:26]=[C:13]2[C:14]3[C:19]([CH2:20][CH2:21][N:12]2[C:11]1=[O:38])=[CH:18][C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)(=[O:1])[NH2:3]
Reactant: N#C[O-]
Reactant: COc1cc2c(cc1OC)-c1cc(=Nc3c(C)cc(C)cc3C)n(CCCCN)c(=O)n1CC2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3c(C)cc(C)cc3C)n(CCCCNC(N)=O)c(=O)n1CC2
Temperature: 80 °C
Yield: 64.1 %

Procedure:
Sodium cyanate (0.28 g, 4.32 mmol) in water (6 ml) was added dropwise to a stirred solution of 2 (1.0 g, 2.16 mmol) in water (30 ml) and 1N HCl (4.3 ml) at 80° C. After 2 h at 80° C. the mixture was cooled and extracted with dichloromethane (3×20 ml) and the extract dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica gel [dichloromethane/methanol (97:3)] to obtain the title compound (0.70 g, 64%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])OC2=O)[NH:3]1.Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][NH:29][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:8][CH2:7][C:4]1[NH:3][C:2](=[O:1])[NH:6][N:5]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NOCc1ccccc1
Reactant: O=c1[nH]nc(Cn2c(=O)oc(=O)c3ccccc32)[nH]1
Agent: Cl
Product: O=C(NOCc1ccccc1)c1ccccc1NCc1n[nH]c(=O)[nH]1

Procedure:
Starting materials: 1-(5-Oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (see preparation 7E) and O-benzyl-hydroxylamine hydrochloride (Aldrich).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:19])=[C:15]([CH2:17]Cl)[N:16]=2)[CH:7]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[O:26]=[CH:27][C:28]1[CH:36]=[CH:35][C:33]([OH:34])=[C:30]([O:31][CH3:32])[CH:29]=1.CN(C)C=O>O>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:19])=[C:15]([CH2:17][O:34][C:33]3[CH:35]=[CH:36][C:28]([CH:27]=[O:26])=[CH:29][C:30]=3[O:31][CH3:32])[N:16]=2)[CH:7]=1)(=[O:4])=[O:3]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1oc(-c2cccc(OS(C)(=O)=O)c2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1nc(-c2cccc(OS(C)(=O)=O)c2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
A mixture of 3-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)phenyl methanesulfonate (8.35 g), potassium carbonate (3.65 g), vanillin (4.02 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl methanesulfonate as colorless crystals (7.95 g, 72%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 136-137° C.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([S:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][C:5]=2[N:24]=1.C(ON=O)CC(C)C.C(Br)(Br)[Br:34]>>[Br:34][C:2]1[S:3][C:4]2[C:9]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([S:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][C:5]=2[N:24]=1
Reactant: BrC(Br)Br
Reactant: CC(C)(CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Agent: CC(C)CCON=O
Product: CC(C)(CO)Nc1nc(SCc2ccccc2)nc2nc(Br)sc12
Temperature: 60 °C

Procedure:
To a solution of the product from Example 121 (0.1 g) in bromoform (5 ml) was added isoamylnitrite (0. 13 ml,) and the mixture heated at 60° C. for 10 mins. The mixture was evaporated to dryness then purified (SiO2, ethyl acetate:dichloromethane 1:9 as eluant) to give the subtitle compound (0.043 g).
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:17][C:18]([CH3:22])([CH3:21])[CH:19]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[C:18]([C:22]1[N:16]=[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[C:2]2[C:3]=1[N:4]1[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]1)=[N:1]2)([CH3:21])([CH3:19])[CH3:17]
Reactant: CC(C)(C)C=O
Reactant: Nc1ccccc1-c1cn2ccccc2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)(C)c1nc2ccccc2c2nc3ccccn3c12

Procedure:
Preparation analogous to S. Sharma et al., J. Comb. Chem. 2007, 9, 783. A mixture of 20.9 g (100 mmol) of 2-imidazo[1,2-a]pyridin-2-ylphenylamine [127219-06-1], 42.1 g (500 mmol) of 2,2-dimethylpropanal [630-19-3] and 1.9 g (10 mmol) of p-toluenesulfonic acid hydrate in 500 ml of xylene is heated under reflux for 16 h, during which the water formed is removed by azeotropic distillation and a gentle stream of air is passed into the solution. After cooling, the solvent is removed in vacuo, the residue is taken up in 1000 ml of ethyl acetate, washed twice with 500 ml of water each time, once with 500 ml of saturated sodium chloride solution and dried over magnesium sulfate. After recrystallisation from ethanol twice, the solid is freed from low-boiling and non-volatile secondary components by sublimation (p about 1×10−5 mbar, T about 180° C.). Yield: 9.1 g (33 mmol), 33%, purity: about 99.5% (NMR).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.Cl.[Cl:19][C:20]1[N:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl.N1C=CC=CC=1>[Cl:19][C:20]1[N:25]=[CH:24][C:23]([S:26]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (587 mg, 2.5 mmol) in dichloromethane (4 ml) and pyridine (4 ml) was treated with a suspension of 6-chloro-3-pyridinesulfonyl chloride hydrochloride (D32) (700 mg, 3 mmol) in dichloromethane (4 ml). After stirring at room temperature for 15 minutes the mixture was evaporated and the residue co-evaporated with toluene (×2). The residue was then partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed in water, brine, dried and evaporated. The residue was triturated with ether/and dried to give the title product. MS (ES+) 411/413 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:14][C:13](=O)[N:12]([CH3:16])[C:11]2=O)=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:16][N:12]1[CH2:13][CH2:14][CH:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:11]1
Reactant: CN1C(=O)CC(c2c[nH]c3ccccc23)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccccc23)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 3-(1-H-indol-3-yl)-1-methyl-pyrrolidine-2,5-dione (1.4 g) in tetrahydrofuran is treated with LiAlH4 (12 mL, 1.0M solution, 2 equiv), stirred at 50° C. for 8 hr, cooled to room temperature, quenched with water and 15% aqueous NaOH and filtered. The filtrate is dried over MgSO4 and concentrated in vacuo to afford the title product as an oil, 1.1 g, identified by HPLC and mass spectral analyses.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[CH2:31][CH2:32][O:33]C(=O)C)=[C:5]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:4]=1)#[N:2].FC(F)(F)C(O)=O>>[OH:33][CH2:32][CH2:31][N:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[S:37]([CH3:40])(=[O:39])=[O:38])[C:18]2[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=2[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[CH:21]=2)[C:11]1=[O:30]
Reactant: CC(=O)OCCN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CCO

Procedure:
Acetic acid 2-[4-(4-cyano-2-methanesulfonyl-phenyl)-2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,4,5,6,7,8-hexahydro-2H-quinazolin-3-yl]-ethyl ester (step 1, 60.0 mg, 0.10 mmol) is stirred with trifluoroacetic acid (3.0 mL, 36.94 mmol) at 60° C. for 6 h and concentrated under reduced pressure. The residue is stirred over night with acetonitrile and water (→hydrolysis of trifluoroacetic acid ester) and then purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 31.3 mg; ESI mass spectrum [M+H]+=534; Retention time HPLC: 0.78 min (005_CA01).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:31])[N:24]([CH2:26][CH2:27][C:28](=[O:30])[CH3:29])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:32][Mg]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:31])[N:24]([CH2:26][CH2:27][C:28]([OH:30])([CH3:32])[CH3:29])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(=O)CCn1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)nc1C
Reactant: C[Mg]Br
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1CCC(C)(C)O

Procedure:
The title compound was prepared using the method of the previous Example starting from (S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamide and methylmagnesium bromide. The crude product was purified by flash chromatography on silica gel by using CH2Cl2-MeOH as a gradient eluent (100:1-98:2). The final purification was made by preparative HPLC to obtain the title compound. 1H NMR (400 MHz, CDCl3): 1.22 (3H, d), 1.30 (6H, s), 1.65 (1H, broad s), 1.88 (2H, m), 2.42 (3H, s), 4.02 (2H, m), 4.30 (1H, distorted dd), 4.38 (1H, distorted dd), 4.55 (1H, m), 6.60 (1H, d), 7.47 (1H, s), 7.50 (1H, d), 7.62 (1H, d), 7.65 (1H, d), 7.84 (1H, dd), 7.99 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]#[N:33]>CC(=O)CC>[NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:31][C:32]#[N:33])[CH:18]=2)[N:3]=1
Reactant: Cc1cccc(C(=O)n2nc(Nc3cccc(O)c3)nc2N)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1cccc(C(=O)n2nc(Nc3cccc(OCC#N)c3)nc2N)c1
Temperature: 75 °C
Reaction time: 20 h

Procedure:
Alternatively, to a solution of 5-amino-3-[3-(hydroxy)phenylamino]-1-(3-(methyl)phenyl)carbonyl-1H-1,2,4-triazole (Ia-7) (0.84 g, 2.7 mmol) in 2-butanone (9 mL) was added K2CO3 (0.41 g, 3.0 mmol) and BrCH2CN (0.36 g, 3.0 mmol). After stirring the mixture at 75° C. for 20 h, the 2-butanone was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL), washed with water (50 mL), brine (30 mL), dried (Na2SO4) and concentrated to afford the crude product. Recrystallization from CH3CN afforded 5-amino-3-[3-(cyanomethoxy)phenylamino]-1-(3-(methyl)phenyl)carbonyl-1H-1,2,4-triazole (Ia-9) (0.12 g, 13%) as a white solid: Rf 0.22 (1:1 hexanes/ethyl acetate); mp (DSC) 220.0-224.4° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.05 (s, 1H), 7.91 (d, J=7.1 Hz, 1H), 7.83 (s, 2H), 7.50-7.39 (m, 3H), 7.20 (t, J=8.1 Hz, 1H), 7.12-7.09 (m, 1H), 6.56 (dd, J=7.9, 2.2 Hz, 1H), 5.04 (s, 2H), 2.43 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.6, 157.9, 157.2, 156.9, 142.3, 137.2, 133.0, 132.6, 130.8, 129.5, 127.8, 127.4, 116.5, 111.1, 105.2, 104.0, 53.3, 20.8; IR (ATR) 3449, 3367, 2325, 1684 cm−1; APCI MS m/z 349 [C18H16N6O2+H]+; HPLC (Method A) 96.8% (AUC), tR=12.81 min.
Reaction SMILES: [Br:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:21](O)([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[C:21]([O:5][C:4](=[O:6])[CH2:3][CH:2]([Br:1])[CH3:7])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(Br)CC(=O)O
Reactant: CC(C)(C)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CC(Br)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-{2-[4-(2,6-Dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-butyric acid tert-butyl ester was obtained according to a similar manner. The required 3-bromobutyric acid tert-butyl ester was prepared as follows: To a solution of 3-bromobutyric acid (5.0 mL; 47.0 mmol) in tetrahydrofuran (50 mL) was added dropwise trifluoroacetic anhydride (13.7 mL; 98.7 mmol) at −40° C. After 1 hour at −40° C. tert-butyl alcohol (20 mL) was added. The resulting mixture was allowed to warm to RT and stirred overnight. Subsequently, the reaction mixture was concentrated in vacuo. The residue was treated with 2M aqueous NaOH solution and extracted with Et2O. The organic layer was dried (Na2SO4), and concentrated in vacuo to afford 3-bromobutyric acid tert-butyl ester (6.05 g), which was used as such.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:9]([CH3:11])=[CH:10][C:3]=12.C([Li])(CC)C.C1CCCCC1.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:7]([C:33]([O:34][CH2:35][CH3:36])=[O:37])=[CH:6][N:5]=[C:4]2[N:8]([Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:19]([CH3:21])[CH3:20])[C:9]([CH3:11])=[CH:10][C:3]=12
Reactant: CCOC(=O)Cl
Reactant: Cc1cc2c(Cl)ccnc2n1[Si](C(C)C)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2c(cc(C)n2[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Temperature: -78 °C

Procedure:
A solution of 4-chloro-2-methyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (525 mg) in tetrahydrofuran (10 ml) was cooled to −78° C. under nitrogen atmosphere, and to the reaction mixture was added 0.99M sec-butyllithium/cyclohexane solution (4.1 ml) dropwise. After the mixture was stirred at −78° C., ethyl chlorocarbonate (389 μl) was added dropwise. The reaction solution was stirred at −78° C. for 30 minutes, saturated aqueous ammonium chloride (20 ml) was added, and the temperature was returned to ambient temperature. The reaction solution was transferred into a separating funnel and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane) to obtain ethyl 4-chloro-2-methyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (645 mg) as a colorless viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[S:13][CH2:12][CH2:11][CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:19](Cl)(=[O:21])[CH3:20]>C1COCC1>[C:19]([C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[S:9][CH2:10][CH2:11][CH2:12][S:13]1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: Clc1cccc(C2SCCCS2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)C1(c2cccc(Cl)c2)SCCCS1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The crude 2-(3-chlorophenyl)-1,3-dithiane is dissolved in anhydrous THF (400 mL). After chilling to −78° C., a solution of n-butyl lithium (2.5 Molar, 42 mL) is added slowly by syringe. The solution is stirred for 30 minutes at −78° C., followed by the addition of acetyl chloride. The mixture is warmed to room temperature, quenched by the addition of a saturated aqueous solution of NH4Cl, washed with water, brine, and dried (Na2SO4). After removing the dessicant, the filtrate was concentrated in vacuo to provide the desired product.
Reaction SMILES: CO.[NH2:3][C:4]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:10][CH:9]=1)=[O:7].[BH4-].[Na+]>C(OC(=O)C)C>[NH2:3][C:4]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:5]=1[CH:6]([OH:7])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)c2cc(Cl)ccc2N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(C(O)c2cc(Cl)ccc2N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a methanol (10 ml) solution of 2-amino-4′-tert-butoxycarbonylaminomethyl-5-chlorobenzophenone (0.9 g) was added sodium borohydride (0.28 g). The mixture was stirred for 30 minutes at room temperature, to which was added acetic acid ethyl ester (100 ml). The mixture was washed with water and dried over anhydrous Na2SO4. The solvent was then distilled off, and the residue was purified by means of a silica gel column chromatography to give the object 2-amino-5-chloro-α-(4-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.85 g) as a colorless oily product.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]([CH3:28])[CH2:26][OH:27]>>[OH:27][CH2:26][CH:25]([NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)[CH3:28]
Reactant: CC(N)CO
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC(C)CO)cn1
Yield: 89 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (150 mg, 0.5 mmol) was converted, using rac-2-amino-1-propanol instead of methylamine, to the title compound (158 mg, 89%) which was obtained as a white solid. MS: m/e=368.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH:7]([CH3:9])[CH3:8])=[C:5]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[O:4][N:3]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:1][C:2]1[C:6]([CH:7]([CH3:9])[CH3:8])=[C:5]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[O:4][N:3]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC(C)c1c(O)noc1-c1cccs1
Product: CC(C)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1cccs1
Yield: 85.5 %

Procedure:
3-Hydroxy-4-isopropyl-5-(2-thienyl)isoxazole (209 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (193 mg) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (301 mg, 86%) as colorless crystals.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)#[N:6].[CH2:16]([O:22][C:23]1[CH:24]=[C:25]([CH3:29])[CH:26]=[CH:27][CH:28]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH3:29][C:25]1[CH:24]=[C:23]([O:22][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:28]=[CH:27][C:26]=1[C:10]([C:9]1[CH:8]=[C:7]([CH:15]=[CH:14][CH:13]=1)[C:5]#[N:6])=[O:12]
Reactant: CCCCCCOc1cccc(C)c1
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCOc1ccc(C(=O)c2cccc(C#N)c2)c(C)c1
Temperature: 0 °C
Yield: 32 %

Procedure:
Anhydrous aluminium chloride (38.35 g) is added to a solution of the acid chloride prepared from 3-cyanobenzoic acid (36.3 g) as described in Example 26 and nitrobenzene (200 ml). A solution of 3-n-hexyloxytoluene (39.5 g) in nitrobenzene (50 ml) is added and the resulting mixture heated to 110°-120° C. for 3 hours. The reaction mixture is cooled and poured into a mixture of ice water (1,000 ml) and concentrated hydrochloric acid (100 ml). The mixture is extracted with ether (3×300 ml) and the combined extracts concentrated and the nitrobenzene removed by steam distillation. The resulting residue is dissolved in ether, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on silica gel (hexanes:ether; 70:30) to yield 3-(2-methyl-4-n-hexyloxybenzoyl)benzonitrile (21.1 g) as a dark brown oil and 3-(2-hydroxy-4-methylbenzoyl)benzonitrile, which is recrystallized from ethanol to give 5.78 g as a yellow solid (m.p. 126°-128°C.). The 3-(2-methyl-4-n-hexyloxybenzoyl)benzonitrile thereby obtained is heated under reflux in a mixture of acetic acid (160 g) and a solution of 75% sulfuric acid (160 g) for 1 hour. The cooled mixture is then poured into ice water (500 ml) and extracted with ether (3×200 ml). The extract is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is chromatographed on silica gel (hexanes:ether:acetic acid; 50:50:1). The main fraction is collected and concentrated in vacuo. The residual yellow solid is crystallized from heptane to yield 3-(4-n-hexyloxy-2-methylbenzoyl)benzoic acid (9.62 g) as yellow needles m.p. 136°-138° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:8]([CH3:10])=[O:9])[C:4]([O:6][CH3:7])=[O:5].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:11]([O:1][N:2]=[C:3]([C:8]([CH3:10])=[O:9])[C:4]([O:6][CH3:7])=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C(=NO)C(C)=O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(=NOCc1ccccc1)C(C)=O
Yield: 77.2 %

Procedure:
To a solution of 15.0 g (103 mmol) of methyl 2-hydroxyiminoacetoacetate in 200 ml of acetone, 14.4 g (113 mmol) of benzyl chloride and 21.4 g (155 mmol) of potassium carbonate were added and the mixture was heated under reflux for 15 hours. The reaction mixture was combined with 200 ml of water and extracted three times with 200 ml of diethylether. After washing with water and a saturated aqueous sodium chloride followed by drying over with anhydrous magnesium sulfate, the solvent was distilled off. The residue thus obtained was purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 18.7 g (yield: 77%) of methyl 2-benzyloxyiminoacetoacetate as a colorless crystal.
Reaction SMILES: [Na].[C:2]([O:11]C)(=O)[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[SH:5].Cl.Cl[CH2:15][C:16](=[NH:20])[O:17][CH2:18]C>CO>[OH:11][C:2]1[C:3]2[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=2[S:5][C:15]=1[C:16](=[NH:20])[O:17][CH3:18]
Reactant: COC(=O)c1ccccc1S
Reactant: CCOC(=N)CCl
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=N)c1sc2ccccc2c1O

Procedure:
A solution of 23 g (1 mol) of sodium in 1 l of anhydrous methanol is mixed with 84 g (0.5 mol) of methyl thiosalicylate while stirring. This is then mixed with 79 g (0.5 mol) of ethyl chloro-acetimidate hydrochloride and heated under reflux for 10 hours. The sodium chloride precipitate is filtered off and the desired product isolated by evaporation (yield: 73 g. m.p. 201° C).