Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C@@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH3:11][C@H:12]1[NH:13][CH2:14][CH2:15][N:16]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:17]1
Reactant: C[C@@H]1CNCCN1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2ccccc2[N+](=O)[O-])CCN1
Yield: 470 %

Procedure:
To a solution of 2-bromo-nitrobenzene (0.4 g, 2.0 mmol) in 1,4-dioxane (10 mL) was added (R)-(+)-2-methylpiperazine (0.25 g, 0.25 mmol) and powdered K2CO3 (7.5 mmol, 0.8 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was cooled, it was filtered through a sintered glass funnel and the solvent was evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield (R)-(+)-3-methyl-1-(2-nitrophenyl)-piperazine as an orange-red oil (0.26 g, 78%).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[CH:24]=[CH:25][C:26](=[O:28])[CH3:27]>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[CH:24]1[CH2:3][C:2](=[O:1])[CH2:27][C:26](=[O:28])[CH2:25]1
Reactant: CC[O-]
Reactant: CC(=O)C=Cc1cc(Cl)ccc1Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC(=O)OCC
Product: O=C1CC(=O)CC(c2cc(Cl)ccc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (6.2 g) were added at room temperature ethanol (150 ml) and diethyl malonate (14.6 g), and then added little by little 4-(2,5-dichlorophenyl)-3-buten-2-one (19.0 g). The mixture was stirred at room temperature for 30 minutes, refluxed for 2 hours and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated, and to the residue was added 2M sodium hydroxide (50 ml). The mixture was refluxed for 2 hours and cooled, and to the mixture was added 2.5M sulfuric acid (50 ml) for 15 minutes. The mixture was refluxed for 1.5 hours and cooled, and precipitated crystals were filtered and washed with water and toluene to give 5-(2,5-dichlorophenyl)cyclohexane-1,3-dione (9.9 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O>>[CH2:8]([C:4]1[CH:3]=[C:2]([C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:9]
Reactant: CCc1cccc(Br)c1
Reactant: OB(O)c1cccs1
Product: CCc1cccc(-c2cccs2)c1

Procedure:
1-Bromo-3-ethylbenzene and thiophene-2-boronic acid were treated in a manner similar to Reference Example 20-(1) to give 2-(3-ethylphenyl)thiophene as a pale yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[CH3:51][O:52][C:53]1[CH:54]=[C:55]([CH:58]=[CH:59][C:60]=1[O:61][CH3:62])CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][C:58]2[CH:55]=[CH:54][C:53]([O:52][CH3:51])=[C:60]([O:61][CH3:62])[CH:59]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(CO)cc1OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(=O)Nc2cc(C)c(Oc3ccnc4cc(OC)c(OC)cc34)cc2C)cc1OC
Temperature: 25 °C
Yield: 71.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (89 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (124 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3,4-dimethoxybenzyl alcohol (72 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (102 mg, yield 67%).
Reaction SMILES: CO[C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=O)[CH:6]=1.C(O)(=O)C.[C:18]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-:34](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:8][CH2:7][CH2:6][CH:5]([CH3:10])[CH3:4].[BH2:34][N+:27]1([CH2:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][CH2:3][OH:13])[CH:6]=2)[CH2:26][CH2:25][CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:29][CH2:28]1
Reactant: COC(=O)Cc1cccc(C=O)c1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: B[N+]1(Cc2cccc(CCO)c2)CCC(c2ccccc2)CC1
Product: CCCC(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(3-Formyl-phenyl)-acetic acid methyl ester (0.64 g), acetic acid (0.18 mL) and 4-phenyl-piperidine (0.48 mL) were combined in dichloromethane (10 mL). After 1 hour, sodium triacetoxyborohydride (0.95 g) was added and the reaction stirred overnight. After 24 hours, the solvent was evaporated. The resultant residue was loaded onto a conditioned SCX cartridge (10 g, Varian) and washed with methanol (50 mL), then eluted with methanolic ammonia solution (2M, 50 mL). The elution fraction was evaporated and the residue was dissolved in ethanol (10 mL). Calcium chloride anhydrous (0.67 g) was added followed by sodium borohydride (0.45 g) and the resulting mixture stirred overnight. An aqueous potassium carbonate solution (2M, 50 mL) was added and the ethanol evaporated. The aqueous was extracted with ethyl acetate (3×50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (sodium sulfate) and evaporated. The residue was redissolved in tetrahydrofuran (10 mL) and cooled to 0° C., under nitrogen. Borane-methyl sulfide complex (2M solution in tetrahydrofuran, 2.25 mL) was added and the resulting mixture stirred for 5 min. The tetrahydrofuran was evaporated and the residue purified on silica, eluting with diethyl ether: iso-hexane [1:1 to 1:0] to give subtitle product, as an oil 193 mg.
Reaction SMILES: O=O.[C:3]([OH:6])(=[S:5])[CH3:4].C(O[CH:11]1[NH:14][C:13](=[O:15])[CH2:12]1)(=O)C.[H][H]>>[C:3]([S:5][CH:11]1[NH:14][C:13](=[O:15])[CH2:12]1)(=[O:6])[CH3:4]
Reactant: CC(=O)OC1CC(=O)N1
Reactant: CC(O)=S
Reactant: [H][H]
Agent: O=O
Product: CC(=O)SC1CC(=O)N1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a cold (0°-5° C.) oxygen-free 1 N NaOH solution (27.5 ml.) was added thioacetic acid (2.09 g., 27.5 mmole) at such a rate that the temperature was maintained between 0°-5° C. The resulting solution was added dropwise (over 20 min.) to a cold (0.5° C.) oxygen-free aqueous solution (11 ml.) of 4-acetoxy-2-azetidinone (3.23 g., 25 mmole) [prepared in Liebigs Ann. Chem., 539 (1974)]. The reaction mixture was stirred under a nitrogen atmosphere for 0.5 hr. at 0°-5° C. and for 2-2.5 hr. at 23°-25° C. before being extracted with chloroform (4×25 ml.). The organic extracts were combined, washed with water (10 ml.), dried over anhydrous Na2SO4 and concentrated to a yellow syrup, 3.3 g., 91% yield. The title product was found to be identical to the sample prepared by Clauss in Liebigs Ann. Chem., 539 (1974). δ (ppm, CDCl3), 7.2 (1H, NH), 5.23 (1H, dd, Jcis =2.8, Jtrans =5.0, H-H), 3.55 (1H, ddd, Jgem =15.2, JHNH =2.0, H-3 trans), 2.95 (1H, ddd, Jgem =15.2, Jcis =2.8, JHNHSl, H-3 cis) and 2.36 (3H, s, methyl).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:27]=[CH:26][C:11]([C:12]([NH:14][C:15]3[C:16]4[CH:22]=[C:21]([C:23](O)=[O:24])[S:20][C:17]=4[NH:18][N:19]=3)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.C(OC(Cl)=O)C.[CH3:43][C:44]([NH2:52])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH3:45]>CN(C)C=O.ClCCl>[CH3:43][C:44]([NH:52][C:23]([C:21]1[S:20][C:17]2[NH:18][N:19]=[C:15]([NH:14][C:12](=[O:13])[C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:27][CH:26]=3)[C:16]=2[CH:22]=1)=[O:24])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH3:45]
Reactant: CC(C)(N)c1ccccc1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4sc(C(=O)O)cc34)cc2)CC1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4sc(C(=O)NC(C)(C)c5ccccc5)cc34)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.9 %

Procedure:
To an ice-cooled suspension of 3-([4-(4-methylpiperazin-1-yl)benzoyl]amino}-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (113 mg, 0.27 mmol) and N,N′-diisopropylethylamine (2.1 mmol, 0.38 mL) in 3 mL of N,N-dimethylformamide were added, dropwise, 0.154 mL of ethylchloroformate (1.6 mmol). After 20 minutes, 1-methyl-1-phenyl-ethylamine (0.302 mL, 2.1 mmol) was added to the obtained solution and the reaction mixture was allowed to warm to room temperature. After 16 hours, the reaction mixture was diluted with dichloromethane and washed with an aqueous solution of sodium bicarbonate. After solvent evaporation the residue was taken up with methyl alcohol (9 mL) and triethylamine (1 mL) and stirred at 40° C. for 2 hours. The reaction mixture was then evaporated to dryness to give an oil, which was purified by flash chromatography over silica gel, using dichloromethane/methanol/ammonia 7N solution in methyl alcohol (93:6:1) as eluent, to afford the title compound as a white solid (61 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:23])=O>ClCCl.CN(C)C=O>[Cl:23][C:13]([C:12]1[CH:16]=[CH:17][C:9]([CH2:8][C:7]2[CH:18]=[CH:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1)=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Nitrobenzyl)-benzoic acid (1.03 g, 4 mmol) was dissolved in dichloromethane (40 mL). Oxalyl chloride (0.42 mL, 1.2 eq) was added to the mixture, followed by 1 drop of N,N-dimethylformamide. The mixture was stirred for 1 hour at room temperature and the solvents evaporated to give 4-(4-chlorocarbonylbenzyl)-nitrobenzene (1.10 9) as a pale yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10].C(N(CC)CC)C.CCCCCCCCCCCC>[Pd]>[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C=CC(=O)OC
Agent: [Pd]
Solvent: CCCCCCCCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1ccccc1
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
Starbon®-Pd(10% wt) was prepared according to example 39 and was tested in the Heck reaction of iodobenzene and methyl acrylate (see Reaction Scheme 7). Iodobenzene (8 mmol, 0.85 mL), methyl acrylate (8 mmol, 0.70 mL), triethylamine (5 mmol) and the Starbon-Pd catalyst (0.050 g) were mixed together in a microwave tube and placed in a Microwave reactor under stirring at 70° C. for 5 min. The microwave power employed in the reaction was 300 W. Dodecane (1 mmol) was employed as internal standard and results were analysed by GC. The Starbon-Pd material afforded complete (>99 mol %) conversion of the starting material with a selectivity higher than 80 mol % to the cross-coupled product, methyl cinnamate in 5 min.
Reaction SMILES: [CH2:1]([N:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=O)C1C=CC=CC=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28].C1([O:39]C(=O)OC2C=CC=CC=2)C=CC=CC=1.C(OCC)C>C1(C)C(O)=CC=CC=1>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([N:8]2[CH2:9][C:10](=[O:12])[N:23]([C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([OH:29])=[O:28])[C:1]2=[O:39])=[CH:18][CH:17]=1)([CH3:20])([CH3:21])[CH3:22]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)c1ccc(N(CC(=O)O)Cc2ccccc2)cc1
Agent: Cc1ccccc1O
Solvent: CCOCC
Product: CC(C)(C)c1ccc(N2CC(=O)N(c3cccc(C(=O)O)c3)C2=O)cc1

Procedure:
A solution of benzyl-N-(4-tert-butylphenyl)glycine (1.20 g, 4.04 mmol), 3-aminobenzoic acid (0.55 g, 4.01 mmol) and diphenylcarbonate (0.87 g, 4.06 mmol) in cresol (4 mL) was heated to reflux for 5 h. The mixture was cooled, poured into 20 mL diethyl ether, and filtered. The solid product as named in the title was dried under vacuum (1.10 g, 3.12 mmol, 78%). m.p. 256-258° C. 1H NMR (d6-DMSO, 300 MHz): δ 8.01 (1H, t, J=2 Hz), 7.98 (1H, dt, J=8, 2 Hz), 7.70-7.62 (2H, m), 7.60 (2H, d, J=8 Hz), 7.43 (2H, d, J=8 Hz), 4.60 (2H, s), 1.28 (9H, s). Mass spectrum (ES+): m/z 354 (23), 353 (100). Elemental analysis: calculated for C20H20N2O4 C, 68.07; H, 5.85; N, 7.61; observed C, 68.17, H, 5.72, N, 7.95.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[O:22][CH3:23])=[O:13].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[CH:11][C:12]([C:14]1[C:15]([O:22][CH3:23])=[CH:16][CH:17]=[CH:18][C:19]=1[O:20][CH3:21])=[O:13]
Reactant: COc1cccc(OC)c1C(C)=O
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(OC)c1C(=O)C=Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.5 %

Procedure:
(40) To a solution of 2,6-dichlorobenzaldehyde (485 mg, 2.77 mmol) and 2,6-dimethoxyacetophenone (500 mg, 2.77 mmol) in 4.1 ml of methanol was added 1.0 ml of 40% sodium hydroxide in water at 10° C. After stirring for 1.5 hours at room temperature, a solid appeared and was filtered. The precipitate was recrystallized from methanol to afford 481 mg (51.5%) of faint-yellow needles: mp 126.8-127.8° C. 1H NMR (250 MHz) δ 7.48-7.42 (d, 1 H), 7.37-7.31 (m, 3 H), 7.11-7.04 (d, 1 H), 6.63-6.60 (d, 2 H), 3.81 (s, 6 H); 13C NMR (62.7 MHz) 195.1, 158.0, 138.4, 136.5, 135.2, 132.6, 131.4, 130.0, 129.0, 117.9, 104.2, 56.1 ppm. Elemental Analysis. Calculated for C17H14Cl2O3: C, 60.55; H, 4.19. Found: C, 60.60; H, 4.18.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.O.CC[O:25][CH2:26][CH3:27].[C:28](OC(=O)C)(=O)[CH3:29]>>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:26](=[O:25])[CH:27]=[C:28]([CH3:29])[O:17][C:15]=3[CH3:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(=O)OC(C)=O
Reactant: CCOCC
Solvent: O
Product: Cc1cc(=O)c(-c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)c(C)o1
Reaction time: 0.5 h

Procedure:
A solution of 1-(4-(4-trifluoromethylphenoxy)phenyl)propan-2-one (54.5 g) in acetic anhydride (100 ml) was added, over 5 min, to a vigorously stirred mixture of polyphosphoric acid (200 g) and acetic anhydride (100 ml) at 80°. After stirring for 30 min the warm mixture was poured into water (1 liter). The solution was stirred for 30 min then extracted with toluene (3×500 ml). The combined extracts were washed with water then satd. aq. sodium bicarbonate, dried over magnesium sulphate and concentrated in vacuo to give an oil. Trituration with ether afforded the title compound as a yellow solid (18.20 g), m.p. 86°-7°, NMR δH (CDCl3) 6.95-7.8 (8H, m), 6.2 (1H, s), 2.3 (3H, s), 2.2 (3H, s).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.[C:27]([O:34]C([O-])=O)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O>ClC(Cl)C.CO.C(N(CC)CC)C>[C:30]([O:29][C:27]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)=[O:34])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCOC(=O)C=C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
51.0 g of ethyl (1-benzylpiperidin-4-ylidene)acetate was dissolved in 200 ml of dichloroethane. After adding 36.5 g of 1-chloroethyl chloroformate under ice-cooling, the resulting mixture was heated under reflux for 2 hours. After adding 100 ml of methanol, the resulting mixture was further heated under reflux for 40 minutes and then allowed to stand at room temperature overnight. Then 60 g of triethylamine was added to the reaction mixture under ice-cooling. Further, 300 ml of methanol was added thereto and the system was made homogeneous. Next, 47.2 g of tert-butyl dicarbonate was added and the resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium chloride and saturated sodium hydrogencarbonate and dried over anhydrous magnesium sulfate followed by filtration. After distilling off the solvent under reduced pressure, the crude crystals thus obtained were ground and washed with hexane to thereby give 15.2 g of the title compound. The filtrate was concentrated and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 37.8 g of the additional title compound as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:24][C:25]1[CH:29]=[CH:28][NH:27][C:26]=1[C:30](O)=[O:31].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Cl:24][C:25]1[CH:29]=[CH:28][NH:27][C:26]=1[C:30]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:23])=[O:31]
Reactant: O=C(O)c1[nH]ccc1Cl
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]ccc3Cl)c2F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (71.0 mg, 0.206 mmol), 3-chloro-1H-pyrrole-2-carboxylic acid (30.0 mg, 0.206 mmol) and diisopropylethyl amine (0.036 ml, 0.206 mmol) in DMF (3.0 ml) was added HATU (78 mg, 0.206 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and the solvent was removed. The crude material was purified via reverse phase HPLC to give 3-chloro-N-[(4-chloro-3-{[3-cyano-5-(trifluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-pyrrole-2-carboxamide (83 mg, 0.176 mmol, 85% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.78 (t, 1H), 8.11 (s, 1H), 7.95 (t, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.46-7.57 (m, 1H), 7.37 (t, 1H), 6.92 (t, 1H), 6.18 (t, 1H), 4.54 (d, 2H). LC-MS (ES+) m/z 472.12, [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].CI.[C:12]([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:12]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1cc(C)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of 2-chloro-5-methyl-phenol (93 g, 0.65 mol) in CH3CN (700 mL) was added CH3I (111 g, 0.78 mol) and K2CO3 (180 g, 1.3 mol). The mixture was stirred at 25° C. overnight. The solid was filtered off and the filtrate was evaporated under vacuum to give 1-chloro-2-methoxy-4-methyl-benzene (90 g, 89%). 1H NMR (300 MHz, CDCl3) δ 7.22 (d, J=7.8 Hz, 1H), 6.74-6.69 (m, 2H), 3.88 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:16])[NH:6][C:7]1[O:8][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:10][N:11]=1.[CH:19]([C:22]1[N:26]2[CH:27]=[C:28]([O:31][C@@H:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C@@H:35]([NH2:42])[CH2:34][CH2:33]3)[CH:29]=[CH:30][C:25]2=[N:24][N:23]=1)([CH3:21])[CH3:20].CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:12]([C:9]1[O:8][C:7]([NH:6][C:5]([NH:42][C@@H:35]2[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:32]([O:31][C:28]3[CH:29]=[CH:30][C:25]4[N:26]([C:22]([CH:19]([CH3:21])[CH3:20])=[N:23][N:24]=4)[CH:27]=3)[CH2:33][CH2:34]2)=[O:16])=[N:11][N:10]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)c1nnc2ccc(O[C@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1nnc(NC(=O)OCC(Cl)(Cl)Cl)o1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)c1nnc2ccc(O[C@H]3CC[C@H](NC(=O)Nc4nnc(C(C)(C)C)o4)c4ccccc43)cn12
Yield: 81.4 %

Procedure:
A solution of Intermediate 5d (83.1 mg, 0.263 mmol), Intermediate 5c (80.6 mg, 0.250 mmol), and DIPEA (54.4 μL, 0.313 mmol) in DMF (2 mL) was stirred at 125° C. for 45 min. After cooling, the mixture was concentrated in vacuo to give a brown oil. This was suspended in water (5 mL) and extracted with DCM (2×5 mL). The combined organics were passed through a hydrophobic frit and concentrated under vacuum to leave a brown oil. Purification by FCC, using 0-8% MeOH in EtOAc, followed by trituration (diethyl ether) afforded a buff solid (99.6 mg). Further purification by HPLC (10-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a flocculent white solid (25.9 mg, 21%). LCMS (Method 5): Rt 3.77 min, m/z 490 [MH+]. 1H NMR (400 MHz, CDCl3): 1.39 (9H, s), 1.52 (3H, d), 1.55 (3H, d), 2.00 (1H, m), 2.21-2.36 (2H, m), 2.43 (1H, m), 3.32 (1H, sept), 5.28-5.34 (2H, m), 7.12 (1H, dd), 7.30-7.38 (3H, m), 7.47-7.50 (2H, m), 7.73 (1H, d), 8.35 (1H, br s), 8.49 (1H, br d).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH:17](O)[CH3:18])[CH:8]=[N:7][C:6]=2[N:5]([CH3:20])[C:3]1=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.CN1C(=O)C2N(CCCCC=C)C=NC=2N(C)C1=O>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH3:18])[CH:8]=[N:7][C:6]=2[N:5]([CH3:20])[C:3]1=[O:4]
Reactant: CC(O)CCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Agent: C=CCCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CC=CCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C

Procedure:
7 g of 1,3-dimethyl-7-(5-hydroxyhexyl)-xanthine and 9.5 g of p-toluene sulphonic acid are refluxed in 100 ml of toluene for 12 hours with continuous separation of the water formed in the reaction. After cooling to room temperature, the reaction mixture is mixed with 100 ml of diethyl ether, washed with sodium bicarbonate solution and water until neutral and the organic phase dried over sodium sulphate is evaporated under reduced pressure. After column chromatography on silica gel with methylene chloride/acetone (1:1) as eluent and distillation under reduced pressure a product is obtained from the residue which still contains a few percent of isomeric 1,3-dimethyl-7-(hex-5-enyl)-xanthine (as shown by the n.m.r. spectrum). Yield: 4.3 g (65.5% of theory relative to the starting product used). Melting point: 58°-64° C.