Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(F)C=C(F)C=1C(NC1C=CC=C([C:13]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])N=1)=O.C[N:29]1[CH2:34][CH2:33]C(C(O)=O)[CH2:31][CH2:30]1.S(Cl)(Cl)=O.C(NCC)C>>[CH2:30]([N:29]([CH2:34][CH3:33])[C:13]([CH:15]1[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]1)=[O:14])[CH3:31]
Reactant: CN1CCC(C(=O)O)CC1
Reactant: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Solvent: CCNCC
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)C1CCN(C)CC1

Procedure:
The present invention relates to a process for preparing 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or salt thereof, further comprising the step of: reacting 1-methylpiperidine-4-carboxylic acid with thionyl chloride and diethyl amine to yield N,N-diethyl-1-methylpiperidine-4-carboxamide.
Reaction SMILES: [F:1][C:2]1[C:18]([F:19])=[CH:17][C:5]2[N:6]([OH:16])[C:7]([C:9]3[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=3)=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:22]I>C1COCC1>[F:1][C:2]1[C:18]([F:19])=[CH:17][C:5]2[N:6]([O:16][CH3:22])[C:7]([C:9]3[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CI
Reactant: On1c(-c2cncc(F)c2)nc2cc(F)c(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COn1c(-c2cncc(F)c2)nc2cc(F)c(F)cc21
Reaction time: 1 h

Procedure:
To a solution of 5,6-difluoro-2-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-1-ol 0.15 g, 0.0003 mol) in THF (3.5 ml) was added NaH (0.045 g, 0.0011 mol) at room temperature. After stirring for 5 min at room temperature MeI (0.04 mL, 0.00059 mol) was added in one shot and further stirred for another 1 hr. After the consumption of the starting material (by TLC) the reaction mixture was washed with H2O and extracted with EtOAc (2×30 mL). The organic phase was dried and concentrated under vacuum. The crude was washed with Hexanes and further purified by chromatography (5-40% EtOAc/Hexanes) to give the desired compound 372 as a white solid. 1H NMR (400 MHz, DMSO-d6), δ: 9.28 (s, 1H), 8.62 (s, 1H), 8.24 (s, 1H), 7.58 (s, 1H), 7.32 (s, 1H), 4.06 (s, 3H). MS (M+1): 280, Purity 99.67%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([CH2:14][Cl:15])[C@H:11]2[O:16][C@@](OC)(C)[C@](OC)(C)[O:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:13][C@H:12]([CH2:14][Cl:15])[C@@H:11]([OH:16])[C@H:10]([OH:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(C)O[C@@H]2[C@@H](CCl)CN(Cc3ccccc3)C[C@H]2O[C@]1(C)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O[C@@H]1[C@@H](CCl)CN(Cc2ccccc2)C[C@H]1O

Procedure:
To a solution of (2S,3S,4aR,8S,8aR)-6-benzyl-8-(chloromethyl)-2,3-dimethoxy-2,3-dimethyloctahydro-[1,4]dioxino[2,3-c]pyridine (2) (2.2 g, 5.9 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (0.35 mol, 26 mL). Reaction mixture was heated at reflux for about 1 hour at which point reaction was judged complete by TLC. Excess solvent and TFA were evaporated in vacuo and the residue was chromatographed using silica gel (2-8% MeOH in CHCl3). Fractions were combined and evaporated to give (1.3 g, 87%) as the title compound. Product was characterized via HPLC/MS (MH+=255) and judged to be >95% pure.
Reaction SMILES: FS(C(C(C([O:13][C:14]([C:17]([O:23][C:24]([C:27]([O:33][C:34]([C:37]([C:40]([F:43])([F:42])[F:41])([F:39])[F:38])([F:36])[F:35])([C:29]([F:32])([F:31])[F:30])[F:28])([F:26])[F:25])([C:19]([F:22])([F:21])[F:20])[F:18])(F)[F:15])=O)(F)F)(F)F)(=O)=O.[F-].[Na+]>>[C:40]([C:37]([C:34]([O:33][C:27]([C:24]([O:23][C:17]([C:14]([F:15])=[O:13])([C:19]([F:21])([F:22])[F:20])[F:18])([F:25])[F:26])([C:29]([F:32])([F:31])[F:30])[F:28])([F:36])[F:35])([F:39])[F:38])([F:43])([F:42])[F:41]
Reactant: O=C(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)C(F)(F)S(=O)(=O)F
Agent: [F-]
Agent: [Na+]
Product: O=C(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Temperature: 140 °C

Procedure:
FSO2CF2CF2COOCF2CF(CF3)OCF2CF(CF3)OCF2CF2CF3 (3.6 g) obtained in Example 2-5 was charged into a flask together with NaF powder (0.02 g) and heated at 140° C. for 10 hours in an oil bath with vigorous stirring. At the upper portion of the flask, a reflux condenser having the temperature maintained at 20° C. was installed. After cooling, a liquid sample (3.4 g) was recovered. As a result of the analysis by GC-MS, CF3CF2CF2OCF(CF3)CF2OCF(CF3)COF and the title compound were confirmed as the main products. The NMR yield of the title compound was 70.9%, and the yield of CF3CF2CF2OCF(CF3)CF2OCF(CF3)COF was 72.0%.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[CH3:43][C:31]1[N:30]([CH2:29][C:26]2[CH:27]=[CH:28][C:23]([C:18]3[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:24][CH:25]=2)[C:38]2[C:33]([C:32]=1[CH3:42])=[CH:34][C:35]([C:39](=[O:40])[NH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1])=[CH:36][CH:37]=2
Reactant: Cc1ccccc1CN
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1ccccc1CNC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 2-methylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[S:3]([N:6]1[C:10](SC2C=CC=CC=2)=[CH:9][N:8]=[C:7]1[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])(=[O:5])=[O:4].CC(C[AlH]CC(C)C)C.CO.[C@H](O)(C([O-])=O)[C@@H](O)[C:39]([O-])=[O:40].[Na+].[K+]>CCOCC>[CH3:25][N:2]([CH3:1])[S:3]([N:6]1[C:10]([CH:39]=[O:40])=[CH:9][N:8]=[C:7]1[Si:18]([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:19])[CH3:20])(=[O:5])=[O:4]
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reactant: CN(C)S(=O)(=O)n1c(Sc2ccccc2)cnc1[Si](C)(C)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CN(C)S(=O)(=O)n1c(C=O)cnc1[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
A solution of cyclohexenone (1) (2.88 g, 30 mmol) in hexanes at −78° C. was treated with DIBAL (30 mL, 1.0 M in cyclohexane). After 25 m, MeOH (7 mL) was added and the mixture was warmed to rt. A saturated solution of Rochelle's salt was added followed by dilution with ether (100 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated under vacuum. The product was purified by chromatography on SiO2 with 20% EtOAc:Hx to give a clear colorless alcohol 2, 2.0 g (68%).
Reaction SMILES: [Mg].Br[C:3]1[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=2[S:6][CH:7]=1.[F:12][C:13]([F:30])([F:29])[CH:14]1[CH2:16][N:15]1[S:17]([C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28])(=[O:19])=[O:18]>C1COCC1.[Cu]I>[S:6]1[CH:7]=[C:3]([CH2:16][CH:14]([NH:15][S:17]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])(=[O:19])=[O:18])[C:13]([F:29])([F:12])[F:30])[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][C:5]1=2
Reactant: Cc1cc(C)c(S(=O)(=O)N2CC2C(F)(F)F)c(C)c1
Reactant: Brc1csc2ccccc12
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)NC(Cc2csc3ccccc23)C(F)(F)F)c(C)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
A mixture of 9 mg (2.20 mmol) of magnesium powder, 79 mg (0.37 mmol) of 3-bromobenzo[b]thiophene, 8 mg (0.04 mmol) of copper (I) iodide, and 50 mg (0.17 mmol) of 2-trifluoromethyl-1-(2,4,6-trimethylbenzenesulfonyl)aziridine in 1 mL of THF was warmed at 80° C. in a sealed tube. After 30 minutes, the reaction was quenched with 7 mL of saturated aqueous ammonium chloride solution and extracted with three 7 mL portions of ethyl acetate. The combined organic layers were washed with two 5 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was chromatographed on silica gel using dichloromethane-hexanes (1:1) to load the sample and then eluting with dichloromethane-hexanes (1:1, then 75:25). The material from the column was triturated with ether-hexanes to afford 17 mg (23%) of the title compound as a white solid which is consistent with the desired product. MS: m/z 428.51 (M+1).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](OC(=O)C)(=O)[CH3:12]>>[CH3:11][C:12]1[O:9][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: Cc1nc2ccccc2c(=O)o1

Procedure:
Anthranilic acid (274.3 g) and acetic anhydride (1.1 L) were combined then heated at reflux for 3.5 hours. The reaction mixture was concentrated under vacuum. The residue was combined with methanol (550 mL) then concentrated under vacuum to provide 2-methyl-4-oxo-3,1-benzoxazine as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[N:39]=[C:38](Cl)[CH:37]=[CH:36][N:35]=1>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([C:36]2[CH:37]=[CH:38][N:39]=[C:34]([Cl:33])[N:35]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ccnc(Cl)n2)cc1
Yield: 31.7 %

Procedure:
Using an analogous procedure to that described in Method 4, N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13, 3.9 g, 8.9 mmol) was reacted with 2,4-dichloropyrimidine (3.06 g, 20.5 mmol). The crude residue was purified by flash chromatography on silica, eluting with ethyl acetate/isohexane (1:1) to give the title compound (1.2 g, 32%); NMR Spectrum: (DMSO-d6) 1.45 (s, 9H), 7.23 (m, 2H), 7.57 (t, 2H), 8.15 (d, 2H), 8.29 (d, 1H), 8.38 (d, 2H), 8.73 (s, 1H), 8.91 (d, 1H), 10.00 (s, 1H); Mass Spectrum: M−H− 423.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][C:13]1[S:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[N+:17]=1[CH3:18].[Cl:23][C:24]([Cl:35])([Cl:34])[C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:18][N:17]1[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[S:14][C:13]1=[CH:12][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([C:24]([Cl:23])([Cl:34])[Cl:35])=[CH:26][CH:27]=1
Reactant: Cc1sc2ccccc2[n+]1C
Reactant: O=C(Cl)c1ccc(C(Cl)(Cl)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1C(=CC(=O)c2ccc(C(Cl)(Cl)Cl)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-dimethylbenzothiazolinium-p-toluene sulphonate (10 g) was slurried in dry toluene (50 ml) and cooled to 5 degC. A solution of 4-trichloromethylbenzoyl chloride (8.9 g) in dry toluene (10 ml) was added dropwise to the stirred slurry over a period of 30 minutes, maintaining the temperature at 10-15 degC. A solution of triethylamine (7 ml) in dry toluene (10 ml) was then added dropwise over a period of 30 minutes, the temperature again being maintained at 10-15 degC. The reaction mixture was stirred for two hours at room temperature. The solid product was filtered off, reslurried in methanol and recrystallised from a 3/1 chloroform/methanol solution.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[N:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1>CCCCCC.C1COCC1>[OH:7][CH:8]=[CH:9][CH2:35][C:32]1[CH:31]=[CH:30][N:29]=[CH:34][CH:33]=1
Reactant: OCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccncc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC=CCc1ccncc1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
n-Butyllithium (25 ml of a 1.6M solution in hexane, 40 mmol) was added dropwise to a stirred suspension of 2-hydroxyethyltriphenylphosphonium bromide (7.74 g, 20 mmol) in THF (50 ml) at −70° C. and the mixture allowed to warm to −30° C. and stirred for 2 hours. 4-Pyridinecarboxaldehyde (2.16 g, 20 mmol) was added to the resulting red solution, and the mixture stirred for 1 hour at −30° C. and then cooled to −70° C. n-Butyllithium (12.5 ml of a 1.6M solution in hexane, 20 mmol) was added and the reaction mixture stirred at −70° C. for 1 hour. The mixture was quenched with isopropanol and allowed to warm to ambient temperature. Saturated aqueous ammonium chloride solution was added, the organic layer separated and the aqueous layer extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine and dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate to give 4-(3-hydroxyprop-2-en-1-yl)pyridine MS-ESI: 136 [MH]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:19])[CH2:10]P(=O)(OCC)OCC)[CH:6]=[CH:7][CH:8]=1.O1CCCC1.[H-].[Na+].O=[C:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:19])[CH2:10][C:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH:29]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(CC(=O)c1cccc(OC)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CC=C(CC(=O)c2cccc(OC)c2)CC1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a stirred mixture of 41 parts of diethyl [2-(3-methoxyphenyl)-2-oxoethyl]phosphonate and 180 parts of tetrahydrofuran are added portionwise 5 parts of sodium hydride dispersion 61% while cooling at about 15° C. Upon completion, stirring is continued for 30 minutes at room temperature. Then there are added dropwise 21 parts of ethyl 4-oxo-1-piperidinecarboxylate at about 20° C. Stirring is continued for 4 hours at 60° C. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is distilled, yielding 30 parts (83%) of ethyl 2,3-dihydro-4-[2-(3-methoxyphenyl)-2-oxoethyl]-1(6H)-pyridinecarboxylate; bp. 200°-210° C. at 1 mm. pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[N:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH:21]([C:18]1[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=1)[C:6]2=[CH2:7]
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Reactant: O=Cc1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C1c2cc(OC)c(OC)cc2C(=O)C1c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
##STR6## 19.2 g of 5,6-dimethoxyindanone, 15 g of pyridine-4-aldehyde and 19 g of p-toluenesulphonic acid were heated to boiling under reflux in a water separator for 5 h in 250 ml of toluene. The resulting precipitate was filtered off with suction after cooling and stirred at room temperature for 30 min in 10% strength sodium carbonate solution. The resulting pale-yellow precipitate was filtered off with suction, washed with water and dried in air. Yield: 24.4 g (87%).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH2:12][CH2:11][C:10]2=[O:17].[N+:18]([O-])([OH:20])=[O:19]>O>[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=1)[O:13][CH2:12][CH2:11][C:10]2=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCOc2ccc(F)cc21
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCOc2c1cc(F)cc2[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (5 mL) was cooled to −15° C., treated with 6-fluoro-2,3-dihydro-4H-chromen-4-one (1.0 g, 6.0 mmol), treated with a mixture of 70% nitric acid (1.8 mL) and concentrated sulfuric acid (2.8 mL), stirred at 0° C. for 2 hours and poured into water. The resulting solid was collected by filtration, washed with water and dried under vacuum. Purification of the residue on silica gel eluting with 1:1 ethyl acetate:hexanes provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C2CCCN2)cc1
Product: COc1ccc(C2CCCN2S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound, white solid, m.p. 122° C. and MS: m/e=332 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-methoxy-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.[Mg].[C:11](=[O:13])=[O:12].Cl>O1CCCC1>[CH2:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:11]([OH:13])=[O:12])[CH3:9]
Reactant: CCc1cccc(Br)c1
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1cccc(C(=O)O)c1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution (45 mL) of 1-bromo-3-ethylbenzene (5.1 g, 28 mmol) in tetrahydrofuran was added dropwise to a mixture (5.0 mL) of magnesium turnings (0.74 g, 31 mmol) and tetrahydrofuran under an argon atmosphere, and the mixture was stirred as it was for 30 min. The reaction mixture was added to the crushed dry ice and the mixture was stirred as it was for 1 h. 1N Hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried, filtrated and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=5:1) to give the title compound (3.87 g, yield 93%). oil.
Reaction SMILES: [C:1]1([P:7](Cl)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:38])[CH:30]=[CH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:20][CH2:19]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C1COCC1>[C:1]1([P:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:38])[CH:30]=[CH:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[CH2:20][CH2:19]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(C=Cc1cccnc1)NCCCCC1CCNCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCC1CCN(P(=O)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1.06 ml (5.55 mmol) diphenylphosphinic acid chloride are dissolved in 20 ml abs. THF and cooled to ca. 0° C. under moisture exclusion. 2.0 g (5.55 mmol) N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride (substance 14 as a dihydrochloride) and 2.3 ml (16.6 mmol) TEA are suspended in 90 ml abs. THF and added dropwise under ice cooling. The mixture is stirred for four days at RT without further cooling. Subsequently the solvent is removed under vacuum and the residue is taken up in 70 ml 10% sodium hydroxide solution and extracted twice, each with 100 ml CHCl3. The combined organic phases are washed with saturated NaCl solution, dried over sodium sulfate and the solvent is removed under vacuum. The residue is pre-purified over silica gel with CHCl3/CH3OH (90/10), subsequently further purified by flash-chromatography with CHCl3/CH3OH (90/10) and crystallized from 30 ml acetic acid ethyl ester. Colorless crystals remain with a MP of 154–155° C.; yield: 1.04 g (30%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[N+:16]([C:19]1[C:20](O)=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)([O-:18])=[O:17].C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:3][C:20]1[C:19]([N+:16]([O-:18])=[O:17])=[CH:24][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:22][N:21]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Temperature: 100 °C
Yield: 55 %

Procedure:
To a solution of phosphoryl chloride (2.0 mL, 21.2 mmol) and quinoline (1.30 mL, 10.8 mmol) was added solid powder 3-nitro-5-(trifluoromethyl)pyridin-2-ol (4.00 g, 18.3 mmol) (95% purity). The resulting dark brown thick suspension was heated to reflux for 4 h and gradually turned into a very cloudy dark brown solution. After cooling to 100° C., water (11 mL) was slowly added to the mixture which was further cooled to room temperature and neutralized carefully with Na2CO3. The resulting solution was extracted with EtOAc three times. The extracts were combined, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc/hexanes 30:70) to afford 2.28 g of desired product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].Br[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[O:11]([CH2:10][CH2:9][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCOc1ccccc1
Reactant: O=Cc1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cccn1CCOc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.5 %

Procedure:
To a solution of 1H-pyrrole-2-carbaldehyde (0.45 g, 4.8 mmol) and 1-(2-bromoethoxy)benzene (1.1 g, 5.3 mmol) in DMF (20 mL) was added K2CO3 (3.3 g, 24 mmol). After stirring 16 hr at room temperature, the mixture was diluted with ethyl acetate (200 mL) and washed with H2O (2×100 mL) then brine (100 mL). The organic layer was dried (MgSO4), filtered and then concentrated to provide 1.1 g (˜100%) of crude 1-(2-phenoxyethyl)-1H-pyrrole-2-carbaldehyde as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[N:15][C:6]2[N:7]=[CH:8][C:9](=[O:14])[N:10]([CH2:11][CH:12]=C)[C:5]=2[CH:4]=1.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:16]=[N:15][C:6]2[N:7]=[CH:8][C:9](=[O:14])[N:10]([CH2:11][CH:12]=[O:18])[C:5]=2[CH:4]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)cnc2ncc(OC)cc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cnc2ncc(=O)n(CC=O)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7-(Methyloxy)-1-(2-propen-1-yl)pyrido[2,3-b]pyrazin-2(1H)-one (846 mg, 3.900 mmol) was dissolved in 1,4-dioxane (20 ml) and water (10 ml). Sodium periodate (20.09 g, 9.75 mmol) was added, followed by osmium tetroxide (0.83 ml of 4% aqueous solution). The mixture stirred at rt for 4 h, and then extracted with 20% MeOH/DCM (3×200 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give [7-(methyloxy)-2-oxopyrido[2,3-b]pyrazin-1(2H)-yl]acetaldehyde (existing mostly as the methyl hemiacetal) as an impure brown solid (969 mg, 113%).
Reaction SMILES: [O:1]1[C:9]2[CH:10]=[CH:11][C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20]1.[BH3-]C#N.[Na+].Cl>CO>[CH:19]1([N:4]2[CH2:3][CH2:2][O:1][C:9]3[CH:10]=[CH:11][C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=3[O:7][CH2:6][CH2:5]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CCCC1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OCCNCCO2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc2c(c1)OCCN(C1CCCC1)CCO2

Procedure:
To methanol add N-(3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonin-9-yl)methanesulfonamide, cyclopentanone, and NaBH3CN. Adjust the pH to six with concentrated HCl. Monitor the progress of the reaction by thin-layer chromatography. Upon completion add concentrated HCl until gas evolution ceases. Partition the reaction mixture between EtOAc and water. Add 1N aqueous NaOH until the solution is basic. Separate and dry the organic layer over Na2SO4. Filter the drying agent and remove the solvent in vacuo to obtain the title compound.