Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]3[CH2:12][C@H:13]4[CH2:26][C@H:14]4[C:15]=3[N:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[N:17]=2)=[O:9])[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)Cl>[O:32]=[S:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]3[CH2:12][C@H:13]4[CH2:26][C@H:14]4[C:15]=3[N:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[N:17]=2)=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(NC1CCSCC1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(NC1CCS(=O)CC1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Reaction time: 1 h
Yield: 14.5 %

Procedure:
A solution of (1aR,5aR)-2-(2,4-difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (tetrahydro-thiopyran-4-yl)-amide (0.014 g, 0.037 mmol) in anhydrous DCM (0.5 mL) was cooled to 0° C. on an ice bath. 3-Chlorobenzoperoxoic acid (7.08 mg, 0.041 mmol) in DCM (0.5 mL) was added drop wise and the reaction was stirred for 1 hour. The reaction mixture was extracted with DCM/water and NaHCO3. The organic phase was concentrated and the residue was purified by HPLC to provide the title compound (2.1 mg) as a white solid. LCMS m/z=392.5 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].S(Cl)([Cl:13])=O>CN(C)C=O.C1C=CC=CC=1>[O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([Cl:13])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)CCCCC(=O)O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)CCCCC(=O)Cl

Procedure:
6-Oxo-heptanoic acid (20.1g; 0.14 mole), thionyl chloride (18.3g; 11.2 ml; 0.154 mole) and dry benzene (300 ml) together with dimethylformamide (three drops) were stirred at room temperature for 22 hours. The halogenating reagent and benzene were removed on the rotary evaporator. A further 100 ml of benzene was added and the solution was again evaporated under reduced pressure (to remove last traces of thionyl chloride). The quantitatively formed liquid acid chloride was used directly in step (b).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)=[O:4].OO.C([O-])(O)=[O:18].[Na+]>CC(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][C:11]([OH:18])=[CH:10]2)=[O:4]
Reactant: O=C([O-])O
Reactant: COC(=O)c1cccc2cccnc12
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cccc2cc(O)cnc12
Yield: 44 %

Procedure:
To a solution of the intermediate 8-Quinolinecarboxylic acid methyl ester (2.89 mmol) in AcOH (4 ml) was added 30% H2O2 (0.6 ml). The reaction mixture was heated at 85 degrees for 7.5 hr. The reaction mixture was treated with sat NaHCO3, and extracted six times with CHCl3. Organic layer was dried over anhydrous MgSO4, and concentrated. Crude residue was triturated with CHCl3/Toluene to provide compound 313 (256 mg, 44%, in 2 steps).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])=[CH:8][CH:7]=2)[CH2:3]1.Br[C:19]1[N:24]=[C:23]([N:25]([CH3:31])[CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])[CH:22]=[CH:21][CH:20]=1.CC([O-])(C)C.[Na+].O>O1CCOCC1.CN(C=O)C>[OH:29][C:27]([CH3:30])([CH3:28])[CH2:26][N:25]([CH3:31])[C:23]1[N:24]=[C:19]([O:1][CH:2]2[CH2:3][N:4]([C:6]3[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])=[CH:10][CH:11]=3)[CH2:5]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(N2CC(O)C2)cc1
Reactant: CN(CC(C)(C)O)c1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3cccc(N(C)CC(C)(C)O)n3)C2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
23 mg (0.10 mmol) (S)—N-{1-[4-(3-Hydroxy-azetidin-1-yl)-phenyl]ethyl}-acetamide (V.1) in 1,4-dioxane (2.0 mL) is added to 31 mg (0.12 mmol) 1-[(6-bromo-pyridin-2-yl)-methyl-amino]-2-methyl-propan-2-ol. 38 mg (0.40 mmol) NaOtBu is added followed by 7.4 mg (0.01 mmol) chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II). The mixture is stirred for 12 h at 50° C. 7.8 mg (0.01 mmol) chloro(2-dicyclohexylphosphino-2′,4′,6′-triisoporpyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) is added and the mixture is stirred for 12 h at 100° C. After cooling to room temperature water (0.5 mL) and DMF (2.0 mL) are added and the mixture is filtered and concentrated. The residue is purified by HPLC (acetonitrile/water (+0.1% NH4OH)) to yield the desired product.
Reaction SMILES: [C:1]([C:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:2].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29][Br:30])=[CH:26][CH:25]=1>>[Br-:30].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29][N+:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][C:3]([C:1]#[N:2])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:26][CH:25]=1
Reactant: N#CC(Cc1ccccn1)(c1ccccc1)c1ccccc1
Reactant: Clc1ccc(CCBr)cc1
Product: N#CC(Cc1cccc[n+]1CCc1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 115 °C
Yield: 14.7 %

Procedure:
A mixture of 2-(2-cyano-2,2-diphenylethyl)pyridine (1.70 g, 6 mmol) (see Preparation 5) and 4-chlorophenethyl bromide (1.10 g, 5 mmol) was heated at 115° C. for 26 hours, allowed to cool to room temperature and triturated with ethanol:ether=1:2 (15 ml). The resulting solid was collected, washed with ether, dried and recrystallised first from water and then from ether/2-propanol to give the title compound (0.37 g, 14%) as colourless crystals, m.p. 210°-211° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([S:22]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11]2)(=[O:23])=[O:24])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCCOc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCCOc3ccccc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid ethyl ester (4.2 g, 9.1 mmol) dissolved in THF:Methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (75%); off white powder; mp 195° C.; MS: 434.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([CH:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:60][C:58]1[S:57][C:47]2[C:48]([CH:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:49][CH:50]=[C:45]([O:44][CH3:43])[C:46]=2[N:59]=1)=[O:8]
Reactant: COc1cccc(C(=O)O)c1
Reactant: COc1cnc(C2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cccc(C(=O)Nc2nc3c(OC)cnc(C4CCOCC4)c3s2)c1

Procedure:
From 3-methoxybenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 400 (M+H+, 100).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][C@H:14]([C:16]2[N:21]=[C:20]3[CH:22]=[CH:23][N:24]([CH3:25])[C:19]3=[CH:18][C:17]=2[N:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH3:15])=[N:5][C:6](SC)=[N:7][C:8]=1[CH2:9][CH3:10])#[N:2].O[O:40][S:41]([O-:43])=O.[K+].[C:45](#N)C>O.CCOC(C)=O>[C:1]([C:3]1[C:4]([NH:13][C@H:14]([C:16]2[N:21]=[C:20]3[CH:22]=[CH:23][N:24]([CH3:25])[C:19]3=[CH:18][C:17]=2[N:26]2[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:30][CH2:31]2)[CH3:15])=[N:5][C:6]([S:41]([CH3:45])(=[O:43])=[O:40])=[N:7][C:8]=1[CH2:9][CH3:10])#[N:2]
Reactant: O=S([O-])OO
Reactant: CCc1nc(SC)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Reactant: CC#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nc(S(C)(=O)=O)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 20 mL round-bottom flask were added (S)-tert-butyl 4-(5-(1-((5-cyano-6-ethyl-2-(methylthio)pyrimidin-4-yl)amino)ethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)piperazine-1-carboxylate (78 mg, 0.145 mmol) in acetonitrile (1.5 mL) and water (1.5 mL) along with OXONE® (223 mg, 0.363 mmol) at 0° C. The reaction mixture was allowed to stir for 30 minutes at 0° C. and then for 3.5 hours at room temperature. LCMS indicated the reaction was mostly complete. The reaction mixture was diluted with EtOAc and washed with brine (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (ISCO 4 g, 30-100% EtOAc/hexane gradient) to give the title compound as a yellow oil. ESI-MS m/z [M+H]+ calc'd for C27H36N8O4S, 569. found 569.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:12]2)=O)=CC=1)([O-])=O.O1CCCC1.O.[Li+].[OH-]>CO>[OH:10][C@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH2:12]1
Reactant: COc1ccc(CCN2CC[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(CCN2CC[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-3-(4-Nitrobenzoyloxy)-1-(4-methoxyphenethyl)pyrrolidine (1.00 g, 2.70 mmol) was dissolved in methanol (20 ml), tetrahydrofuran (20 ml) and water (10 ml). 4 M-LiOH (3 ml) was added dropwise in the obtained solution, and they were stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and then the residue was distributed in water and ether. The organic layer was dried, and the solvent was evaporated under reduced pressure to obtain (S)-3-hydroxy-1-(4-methoxyphenethyl)pyrrolidine in the form of a light yellow oil (541 mg, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:18]=[CH:17][C:16](CO)=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:21]N1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(#N)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:18]=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(CO)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.6 %

Procedure:
To a solution of dl-N-t-butoxycarbonyl-p-hydroxymethylphenylglycine (3.0 g, 0.011 mole) and N-hydroxysuccinimide (1.25 g., 0.011 mole) in 10 ml dry tetrahydrofuran and 50 ml dry acetonitrile was added N,N'-dicyclohexylcarbodiimide (2.238 g., 0.011 mole). The mixture was stirred at room temperature overnight. The dicyclohexylurea was filtered off and the filtrate taken to dryness under reduced pressure. The resulting solid was triturated with ether and filtered to give the N-hydroxysuccinimide ester of N-t-butoxycarbonyl-p-hydroxyphenylglycine (3.4 g., 83 percent yield) m.p. 141°-148° dec.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([CH3:24])=[CH:4][N:3]=1.Cl.[CH3:26][N:27]1[C:35]([CH3:36])=[C:34]2[C:29]([CH:30]=[C:31]([NH2:37])[CH:32]=[CH:33]2)=[N:28]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:26][N:27]1[C:35]([CH3:36])=[C:34]2[C:29]([CH:30]=[C:31]([NH:37][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:10][CH:11]5[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:13][CH:12]5[CH2:23]4)[C:5]([CH3:24])=[CH:4][N:3]=3)[CH:32]=[CH:33]2)=[N:28]1
Reactant: Cc1cnc(Cl)nc1NC1CC2CN(C(=O)OC(C)(C)C)CC2C1
Reactant: Cc1c2ccc(N)cc2nn1C
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 150 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a suspension of tert-butyl 5-((2-chloro-5-methylpyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (421.5 mg, 1.19 mmol) and 2,3-dimethylindazol-6-amine hydrochloride (734.5 mg, 3.72 mmol) in n-BuOH (10 mL) was added DIPEA (795.2 mg, 6.09 mmol). The reaction mixture was stirred at 150° C. under microwave for 2 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as brown oil (570.5 mg, 100%).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[C:11]1[O:12][C:13]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:14]=2[N:15]=1>O1CCCC1>[CH3:20][C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:12][C:13]=2[CH:19]=1
Reactant: Cc1ccc2nc(Cl)oc2c1
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1nc2ccc(C)cc2o1
Yield: 92.1 %

Procedure:
0.73 g (7 mmol) ethyl hydroxyacetate is dissolved in 20 ml tetrahydrofurane and 0.36 g (9 mmol) 60% sodium hydride is added to it. After 20 minute stirring 1.0 g (6 mmol) 2-chloro-6-methyl-1,3-benzoxazole is added and the mixture is heated under reflux for 3 hours. The solvent is removed, the residue is dissolved in 15 ml water, extracted with 3×20 ml ethyl acetate. The united organic phase is dried over sodium sulfate and evaporated to obtain 1.3 g title compound as an oil. LC-MS[MH+]=236 (C12H13NO4 235.24)
Reaction SMILES: [Na].[CH3:2]O.[C:4]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])[CH3:5].C(OCC)=O.[CH3:18][NH:19][CH3:20]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:18][N:19]([CH3:2])[CH:20]=[CH:5][C:4]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CNC
Reactant: CO
Reactant: CC(=O)c1cccnc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC=O
Product: CN(C)C=CC(=O)c1cccnc1
Reaction time: 0.75 h

Procedure:
8 g (0.35 mol) of sodium are placed in 260 ml of toluene and at 100° made into a suspension using a vibromixer. After cooling to 0°, 17 ml (0.42 mol) of methanol are added dropwise, with cooling, and the mixture is then stirred for 45 minutes at 75°. At 25° and with ice-cooling, a solution of 38.5 ml (0.35 mol) of 3-acetylpyridine and 28 ml (0.35 mol) of ethyl formate in 300 ml of toluene are added dropwise in the course of 45 minutes. The yellow suspension is stirred for 16 hours at 25° and then 23.7 g (0.52 mol) of dimethylamine are added. After the addition of 100 ml of toluene, the mixture is stirred for 45 minutes at 25°, and then at 0° a solution of 20 ml of acetic acid in 150 ml of toluene is added dropwise in the course of 30 minutes and the mixture is then boiled at reflux for 1 hour. After cooling to 25°, the mixture is filtered and washed with 500 ml of toluene/hexane (1:1) and the filtrate is concentrated until crystallisation begins. Cooling to 0°, filtration and drying at 80° under HV yield 3-dimethylamino-1-(3-pyridyl)-2-propen-1one; m.p. 81°-82°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1)=[O:4].C(=O)([O-])O.[Na+].Cl[CH2:18][CH:19]=O>CO.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:18]=[CH:19][N:11]=[C:7]2[CH:6]=1)=[O:4]
Reactant: O=CCCl
Reactant: COC(=O)c1ccnc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccn2ccnc2c1
Yield: 38 %

Procedure:
A solution of crude 2-aminopyridin-4-ylcarboxylic acid methyl ester (13.0 g) in methanol (150 ml) was treated with sodium hydrogencarbonate (14.3 g, 0.171 mol) and chloroacetaldehyde (8 ml of a 45 wt % solution in water) then heated at reflux for 16 h. The reaction was cooled and pre-adsorbed directly on to silica gel. Purification by flash chromatography eluting with dichloromethane (+1% conc. ammonia) on a gradient of methanol (1%-4%) gave a solid which was triturated with 5% ether in isohexane to afford imidazo[1,2-α]pyridine-7-carboxylic acid methyl ester (8.0 g, 38% from pyridine N-oxide) as a tan solid. 1H NMR (400 MHz, CDCl3) δH 3.97 (3H, s), 7.37-7.43 (2H, m), 7.70 (1H, s), 7.80 (1H, s), 8.18 (1H, dd, J 1 and 7), 8.38 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][CH:16]([N:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.NC1C=CC(C2CCC(=O)CC2)=C2[C:31]=1[C:30](=[O:32])[N:29]([CH3:33])[CH2:28]2.C(N1CCNCC1)(=O)C>>[C:30]([N:29]1[CH2:33][CH2:21][N:19]([CH:16]2[CH2:17][CH2:18][CH:13]([C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[C:10]4[C:6]=3[CH2:7][N:8]([CH3:12])[C:9]4=[O:11])[CH2:14][CH2:15]2)[CH2:20][CH2:28]1)(=[O:32])[CH3:31]
Reactant: CN1Cc2c(C3CCC(=O)CC3)ccc(N)c2C1=O
Reactant: CN1Cc2c(C3CCC(N(C)C)CC3)ccc(N)c2C1=O
Agent: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C2CCC(c3ccc(N)c4c3CN(C)C4=O)CC2)CC1

Procedure:
The title product was prepared according to the procedure for Compound 233A using 7-amino-2-methyl-4-(4-oxocyclohexyl)-2,3-dihydro-1H-isoindol-1-one and 1-acetylpiperazine. 1H NMR (CDCl3, 400 MHz): δ=1.80-1.98 (m, 3 H), 2.01-2.14 (m, 6 H), 2.25 (d, J=19.20 Hz, 1 H), 2.42-2.62 (m, 5 H), 3.12-3.17 (m, 3 H), 3.45-3.70 (m, 4 H), 4.28-4.33 (m, 2 H), 5.10 (br. s., 2 H), 6.58 (d, J=8.08 Hz, 1 H), 7.17 (d, J=8.34 Hz, 1 H). MS (ES+): m/z 371.26 [MH+] (TOF, polar).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[O:18][CH2:17][O:16][C:5]=2[CH:6]=[C:7]([CH2:9][C@@H:10]2[CH2:15][O:14][C:12](=[O:13])[CH2:11]2)[CH:8]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH:24]=O.[H-].[Na+].CO.Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[O:18][CH2:17][O:16][C:5]=2[CH:6]=[C:7]([CH2:9][C@@H:10]2[CH2:15][O:14][C:12](=[O:13])/[C:11]/2=[CH:24]/[C:23]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:21]([O:20][CH3:19])[CH:22]=2)[CH:8]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COc1cc(C[C@@H]2COC(=O)C2)cc2c1OCO2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(/C=C2/C(=O)OC[C@H]2Cc2cc(OC)c3c(c2)OCO3)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 48 h
Yield: 47.6 %

Procedure:
A solution of (S)-3-[1-(5-methoxy-3,4-methylenedioxyphenyl)methyl]butanolide (25.0 g, 0.1 mol) and 3,4,5-trimethoxybenzaldehyde (31.0 g, 0.16 mol) in 400 ml of toluene was cooled to 0° C. under an argon stream, followed by the addition of 10.8 g of sodium hydride (60%, 0.27 mol) and 0.4 ml (0.01 mol) of methanol. After stirred at 0° C. for 15 minutes and further at room temperature for 48 hours, the reaction mixture was ice-cooled and added with 100 ml of 6N-HCl. After the removal of the water layer, the organic layer was washed successively with water, saturated NaHCO3 and saturated NaCl, and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography (silica gel: "MERCK #9385", 500 g, eluent: 1:2 mixed solvent of ethyl acetate and hexane), whereby 20.38 g of the title compound were obtained as colorless oil (yield: 48%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])[CH:2]=[CH2:3]>CCO.[Pd]>[OH:12][C:11]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: C=CCc1cc(C#N)ccc1O
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(C#N)ccc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.5 %

Procedure:
3-Allyl-4-hydroxybenzonitrile (20.0 g, 126 mmol) (Example 32) was dissolved in EtOH (320 mL) under argon. Pd/C (80 mg, 10%, Fluka) was added and the reaction mixture was stirred under a hydrogen atmosphere (1 atm) at rt for 20 h. The catalyst was filtered off, and then the reaction mixture was concentrated under reduced pressure, yielding 20.2 g (99%) of the title compound as a slightly greenish oil. 1H NMR (400 MHz, CDCl3): 0.95 (t, 3H), 1.63 (m, 2H), 2.56 (m, 2H), 6.86 (d, 1H), 7.30 (m, 2H).
Reaction SMILES: ClCCCO[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:12]=[CH:13]/[C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:12][CH2:13][CH2:14][O:15][C:9]2[CH:8]=[C:7](/[CH:12]=[CH:13]/[C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)[CH:6]=[CH:11][CH:10]=2)[CH2:26][CH2:25]1
Reactant: ClCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Reactant: CN1CCNCC1
Product: CN1CCN(CCCOc2cccc(/C=C/c3nc4ccccc4o3)c2)CC1

Procedure:
The title compound was prepared as described in Example 1 starting with (A) of Example 1 (2.0 g, 6.4 mmol) and using N-methylpiperazine in place of dibutylamine to produce 0.56 g (25% yield of the free base of the title compound which was converted to the HCl salt, mp 250°-252° C. IR: 1600 cm-1. MS: 378(MH+). 1H NMR (CDCl3): δ 7.82-7.00 (m, 10H), 4.13 (t, J=5.2 Hz, 2H), 3.31 (m, 13H), 2.41 (m, 2H).
Reaction SMILES: O.[OH-].[Na+].C([CH:6]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7]([OH:9])=[O:8])C.[N+]([O-])([O-])=O.[Nd+3:18].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[C:27]1(C)C=CC=C[CH:28]=1>>[CH2:27]([O:9][C:7](=[O:8])[CH2:6][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:28].[Nd:18]
Reactant: CCCCC(CC)C(=O)O
Reactant: Cc1ccccc1
Reactant: [Nd+3]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCC(=O)OCC
Product: [Nd]
Reaction time: 0.5 h

Procedure:
In a 10 liter Turbosphere® dryer reactor (available from PIERRE GUERIN S. A.) the following charges are made: water 1500 gr, caustic soda anhydrous 278 gr. The agitation is started and 1000 gr of ethyl hexanoic acid (MW=144) are fed over 10 minutes. At the clear solution, it is added 3600 gr of toluene and the mixture is brought to from about 30 to about 50° C. 1364 gr of an aqueous solution of neodymium nitrate (concentration 497 gr or Nd203 /1) is added over 30 minutes. The mixture is agitated during the 30 minutes then decanted. The aqueous layer is removed. The upper organic layer is washed once with 1200 gr of water and distilled under vacuum up to about 90° C. A bluish powder of neodymium ethylhexanoate is obtained (1400 gr).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[O:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([C:31]([F:34])([F:33])[F:32])=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClC(Cl)(F)C(Cl)(F)F>[F:1][C:2]([F:15])([F:14])[S:3]([O-:6])(=[O:5])=[O:4].[F:32][C:31]([F:34])([F:33])[SH:29]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[OH+:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]1=2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=S(c1ccccc1Oc1ccccc1)C(F)(F)F
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: FC(F)(F)[SH]1c2ccccc2[OH+]c2ccccc21
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 144 h
Yield: 26.1 %

Procedure:
Trifluoromethanesulfonic anhydride 176 microliters (1.05 mmol) was added to a solution of 300 mg (1.05 mmol) of 1-phenoxy-2-(trifluoromethylsulfinyl)benzene in 8 ml of 1,1,2-trichloro-1,2,2-trifluoroetane, and the mixture was stirred for 6 days at room temperature. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel thin-layer chromatography (acetonitrile:methylene chloride=1:3) to give 115 mg (26.2%) of S-(trifluoromethyl)dibenzo -1,4-oxathiinium trifluoromethanesulfonate as white crystals. The properties of the product are shown in Table 1.