Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([N:24]([CH2:39][C:40]1[CH:41]=[N:42][C:43](Br)=[CH:44][CH:45]=1)[C:25](=[O:38])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:47]1[CH2:51][CH2:50][CH2:49][C:48]1=[O:52].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I>[CH2:1]([C@H:8]([N:24]([CH2:39][C:40]1[CH:41]=[N:42][C:43]([N:47]2[CH2:51][CH2:50][CH2:49][C:48]2=[O:52])=[CH:44][CH:45]=1)[C:25](=[O:38])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN1
Reactant: O=C([C@H](Cc1ccccc1)N(Cc1ccc(Br)nc1)C(=O)C=Cc1ccc(C(F)(F)F)cc1)N1CCN(Cc2ccccc2)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C([C@H](Cc1ccccc1)N(Cc1ccc(N2CCCC2=O)nc1)C(=O)C=Cc1ccc(C(F)(F)F)cc1)N1CCN(Cc2ccccc2)CC1
Temperature: 120 °C
Yield: 41.3 %

Procedure:
In an inert atmosphere, N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(6-bromo-pyridin-3-ylmethyl)-3-(4-trifluoromethyl-phenyl)-acrylamide (70 mg, 0.101 mmol), 2-pyrrolidinon (10.3 mg, 0.121 mmol), potassium carbonate (27.9 mg, 0.202 mmol), copper(I)iodide (1 mg, 0.005 mmol) and N,N-dimethylenediamine (1 mg, 0.01 mmol) were dissolved in dioxane (1 mL). The reaction mixture was heated to 120° C. for 12 h, then filtered over a plug of silicagel with EtOAc, concentrated and purified by perp. HPLC to give 29 mg (52%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-[6-(2-oxo-pyrrolidin-1-yl)-pyridin-3-ylmethyl]-3-(4-trifluoromethyl-phenyl)-acrylamide. (LC-MS: tR=1.02 min; [M+H]+=688.46).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:11](=[CH:12][CH:13]=1)[CH:10]1[CH2:14][CH:6]2[CH2:7][CH2:8][NH:9]1.[BrH:15]>>[Br-:15].[OH:2][C:3]1[CH:4]=[C:5]2[C:11](=[CH:12][CH:13]=1)[CH:10]1[CH2:14][CH:6]2[CH2:7][CH2:8][NH2+:9]1
Reactant: COc1ccc2c(c1)C1CCNC2C1
Reactant: Br
Product: Oc1ccc2c(c1)C1CC[NH2+]C2C1
Product: [Br-]

Procedure:
A solution of 4-methoxy-9-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (0.50 g of oxalate salt) in hydrobromic acid (48% in water, 10 mL) is stirred at reflux temperature for 3 h. Then, the solution is concentrated under reduced pressure and the residue is azetropically dried using toluene and ethanol. The residue is washed with acetone and dried to give the product as a solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([C:23]#[C:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C.C(OC(=O)C)(=O)C.[CH3:45][S:46]([CH3:48])=O>>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([C:23]#[C:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:30])([F:31])[F:29])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[O:33][CH2:45][S:46][CH3:48])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CS(C)=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)C[C@@H]1O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CSCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
To a solution of (2) (1.84 g, 3.7 mmol) in dry DMSO (7 ml) was added acetic acid (3.2 ml) and acetic anhydride (10.2 ml). The mixture was stirred for 2 days at room temperature, before it was quenched with sat. aq. NaHCO3. EtOAc (50 ml) was added and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with sat. aq. NaHCO3 solution and dried (MgSO4). After removing the solvent under reduced pressure, the product (3) was purified by chromatography on silica (EtOAc:petroleum ether 8:2) yielding a clear sticky oil (1.83 g, 89%) 1H NMR (d6 DMSO): δ 0.00 (s, 6H, CH3), 0.79 (s, 9H, tBu), 1.96-2.06 (m, 1H, H-2′), 1.99 (s, 3H, SCH3), 2.20-2.26 (m, 1H, H-2′), 3.63-3.74 (m, 2H, H-5′), 3.92-3.95 (m, 1H, H-4′), 4.11-4.13 (m, 2H, CH2), 4.28-4.30 (m, 1H, H-3′), 4.59 (br s, 2H, CH2), 5.97 (t, J=6.9 Hz, 1H, H-1′), 7.85 (s, 1H, H-6), 9.95 (t, J=5.3 Hz, 1H, NH), 11.64 (s, 1H, NH). Mass (−ve electrospray) calcd for C22H32F3N3O6SSi 551.17, found 550.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.O=[C:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:17]2[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH2:8][CH2:7]1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
4-(3,4-Dichlorophenoxy)piperidine (Method B, 1.44 g), ethyl 4-oxocyclohexanecarboxylate (1.0 g) and acetic acid (0.34 ml) were combined in THF 10 ml and the solution was cooled in ice. Sodium triacetoxy borohydride (1.45 g) was added and the mixture was stirred overnight and allowed to come to ambient temperature. The reaction mixture was poured onto a stirred saturated aq solution of sodium bicarbonate. The mixture was extracted with ethyl acetate thrice, the organic phases were washed with brine, dried, filtered and evaporated. The residue was purified on an SCX cartridge (International Sorbent Technology Isolute® Flash SCX-2), washed with methanol and then product eluted with 0.7M ammonia in methanol. Further purification by chromatography (silica, 90:9:1 DCM:methanol:triethylamine) gave the subtitle compound (1.59 g; MS [M+H]+ (APCI+) 400/402) as a mixture of cis/trans isomers.
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[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.Cl.[Br:43][C:44]1[CH:45]=[C:46]([C@H:50]([NH2:52])[CH3:51])[CH:47]=[CH:48][CH:49]=1>C(Cl)(Cl)Cl>[Br:43][C:44]1[CH:45]=[C:46]([C@H:50]([NH:52][C:34]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[O:40])[CH3:51])[CH:47]=[CH:48][CH:49]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: C[C@@H](N)c1cccc(Br)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4cccc(Br)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 120.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.14 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (1R)-1-(3-bromophenyl)ethylamine hydrochloride (54 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (70 mg, yield 57%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=3[O:21][CH3:22])[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Cu][C:24]#[N:25].[CH3:26][N:27](C=O)C>>[C:26]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:24]#[N:25])=[CH:16][C:15]=3[O:21][CH3:22])[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1)#[N:27]
Reactant: CN(C)C=O
Reactant: N#C[Cu]
Reactant: COc1cc(Br)ccc1-c1ccnc(-c2ccc(Br)cc2)n1
Product: COc1cc(C#N)ccc1-c1ccnc(-c2ccc(C#N)cc2)n1
Reaction time: 1 h
Yield: 40 %

Procedure:
A suspension of the dibromo compound of Example 13 (8.4 g, 0.02 mole) and copper(I)cyanide (4.45, 0.05 mole) in 40 mL dry DMF is heated at reflux under nitrogen for 30 hr (TLC followed). The excess DMF is distilled under vacuum and the residue triturated with 100 mL water and stirred with 500 mL 10% sodium cyanide (aqueous) for 1 hr, filtered, washed with water and dried. The solid is subjected to soxlet extraction with acetone (24 hr) followed by chromatography over neutral aluminumoxide, elution with ether:CHCl3 (8:2) to chloroform, to yield a white crystalline solid. Recrystallized from CHCl3 :ether (1:4) yielded 2.5 g of a white solid (40%) having a mp 239-240° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([NH2:23])=O)[NH:6]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:33])[NH2:23])[NH:6]2
Reactant: CN(c1ccc(Cl)c2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CN(c1ccc(Cl)c2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
A mixture of 4-chloro-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.54 g), Lawesson's reagent (0.59 g) and tetrahydrofuran (20 ml) was stirred at 60° C. for 3 hr. The reaction mixture was concentrated, toluene was added, and the resulting crystals were filtrated, washed with toluene, and dried to give the title compound (0.51 g, yield 87%) as yellow crystals. melting point >248° C. (decomposition).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10](#[N:14])[CH2:11][C:12]#[N:13].[N+](=[CH:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])=[N-]>C(Cl)Cl>[C:20]1([C:18]2[O:19][C:12]([CH2:11][C:10]#[N:14])=[N:13][CH:17]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#CCC#N
Reactant: [N-]=[N+]=CC(=O)c1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: N#CCc1ncc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
BF3.Et2O (1.1 mL, 8.5 mmol) was added dropwise to a solution of malononitrile (2.26 g, 34.2 mmol) in dry CH2Cl2 (20 mL) at 0° C., followed by addition of 2-diazo-1-phenylethanone (0.5 g, 3.4 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 1 h and then quenched with aqueous 10% NaOH solution. The organic product was extracted with EtOAc and the combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 5-10% EtOAc in petroleum ether) to get 2-(5-phenyloxazol-2-yl)acetonitrile (200 mg, yield 32%) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 7.66-7.63 (m, 2H), 7.47-7.38 (m, 3H), 7.32 (s, 1H), 4.02 (s, 2H). MS (ESI) m/z: Calculated for C11H8N2O: 184.06. found: 185.2 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][C:7]1[C:8]([CH3:52])=[N:9][C:10]([CH3:51])=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:28]=[N:29][N:30]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:31]=2)=[CH:17][CH:16]=1.C(N(CC)CC)C.O>ClCCl>[C:1]([NH:5][CH2:6][C:7]1[C:8]([CH3:52])=[N:9][C:10]([CH3:51])=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:28]=[N:29][N:30]([C:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:31]=2)=[CH:19][CH:20]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CN)c(C)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCc1c(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)cc(C)nc1C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
(Example 49A): A solution of acetyl chloride (79 mg) in dichloromethane (1 ml) was added to a solution of 3-aminomethyl-2,6-dimethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (628 mg) and triethylamine (101 mg) in dichloromethane (15 ml). The solution was left to stand for 1 hour and then water (15 ml) was added. The organic phase was separated, washed with saturated sodium chloride solution (15 ml) and then dried (MgSO4). The solvent was removed by evaporatoion and the residue was purified by flash chromatography, eluting with methanol/dichloromethane (1:19 v/v) to give 3-acetamidomethyl-2,6-dimethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]pyridine (594 mg), as a foam; NMR (CDCl3): 1.8(s,3H), 2.5(s,3H), 2.6(s,3H), 4.45(d,2H), 5.0(s,2H), 5.6(br t, 1H), 6.6(s,1H), 6.9-7.0(m, 6H), 7.25-7.6 (complex m,16H), 7.95(dd,1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[C:15](=[O:17])=[O:16]>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:15]([OH:17])=[O:16]
Reactant: O=C=O
Reactant: Fc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 10.0 grams (0.076 mole) of 1,3,5-trifluorobenzene in 150 ml of anhydrous tetrahydrofuran, under an argon atmosphere, was cooled to -78° and 4.8 grams (0.076 mole) of n-butyllithium (as 48.7 ml of a 1.55 molar solution in hexane) was added dropwise during a 30-minute period. Upon completion of addition the reaction mixture was stirred at -78° for eight hours. A quantity of fresh, crushed dry ice, sufficient to cause the reaction mixture to become a thick slurry, was added to the reaction vessel. The reaction mixture was allowed to warm to ambient temperature as it was stirred for 26 hours. The tetrahydrofuran was removed from the reaction mixture under reduced pressure. The residue was washed into a separatory funnel with 100 ml of aqueous 2N sodium hydroxide and 200 ml of diethyl ether. The aqueous base layer was separated and the organic layer extracted with two 100 ml portions of aqueous 2N sodium hydroxide. The organic layer was discarded and the combined aqueous base layer and extracts were washed with 100 ml of diethyl ether, cooled, and acidified with concentrated hydrochloric acid. The mixture was saturated with sodium chloride and extracted with three portions of 150 ml each of diethyl ether. The combined ether extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a solid residue. The residue was recrystallized from toluene to give 10.2 grams of 2,4,6-trifluorobenzoic acid; mp 225°-227°.
Reaction SMILES: Cl/[C:2](/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]/[O-].[K+].Cl.O1CCOCC1.[Br:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=1>C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:24]=[CH:23][N:22]2[C:2]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:25]=[C:21]2[CH:20]=1
Reactant: CCOC(=O)/C(Cl)=C\[O-]
Reactant: Nc1cc(Br)ccn1
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2cc(Br)ccn12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.3 %

Procedure:
Potassium (E)-2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (4.4 g, 23 mmol; prepared as in Example 65, step B1) was suspended in toluene (40 mL) and a 4M solution of HCl in dioxane (2.0 mL, 8.1 mmol). The mixture was stirred at ambient temperature for 5 minutes. 4-Bromopyridin-2-amine (2.0 g, 12 mmol) was added to the mixture and heated to 40° C. for 22 hours. The mixture was cooled to ambient temperature and extracted with 2M HCl (3×75 mL). Solid K2CO3 was added to the combined aqueous extracts until CO2 evolution ceased. The aqueous phase was extracted with MTBE (2×50 mL), dried over MgSO4, filtered and concentrated to give the product (2.4 g). MS (ES+APCI) m/z=268.7 (M+H).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:21]=[CH:22][C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[S:23][C:13]=3[N:14]=2)=[CH:18][CH:19]=1
Reactant: NCCc1ccccc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-4-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-phenethylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)(=[O:3])[CH3:2]>C(O)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:8]=2[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cccc(Oc2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=O)OCc1ccc2c(c1)oc1ccccc12
Yield: 15.7 %

Procedure:
A mixture of 3-phenoxybenzyl acetate 50 (21.8 g, 90 mmol) (prepared by acetylation of commercial 3-phenoxybenzyl alcohol) and palladium acetate (40 g, 179 mmol) in acetic acid (300 mL) was refluxed for 6 h, cooled and filtered. The filtrate was evaporated to dryness and the residue treated with 100 mL of a mixture cyclohexane/ethyl acetate (6/1) and filtered. The filtrate was concentrated to give a colored oil which was purified by chromatography on silica gel (cyclohexane/ethyl acetate, 6/1) to afford pure dibenzofuran-3-yl-methyl acetate 51 (3.4 g) and a mixture of dibenzofuran-3-yl-methyl acetate 51 (Rf=0.6) and dibenzofuran-1-yl-methyl acetate 52 contaminated with compound 51 (Rf of compound 52=0.53) (8.4 g) as a white solid. 52 will be used without any further purification in the next step
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>C(Cl)Cl.O1CCOCC1>[N:11]1([C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1.[ClH:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2CCCN3)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1nc2c(c(N3CCNCC3)n1)CCCN2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(5,6,7,8-Tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.88 g, 2.75 mmol) in DCM (10 mL) was added HCl in dioxane (4M, 5 mL). The mixture was stirred at RT for 4 hours. The solvent was removed to give 4-Piperazin-1-yl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine as HCl salt (0.80 g, 99%). MS (APCI+) [M+H]+220.
Reaction SMILES: [CH:1]([CH:4]([CH2:10][CH2:11][C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7](=[O:9])[CH3:8])([CH3:3])[CH3:2].C>C(OCC)(=O)C.[Pd]>[CH:1]([CH:4]([CH2:5][CH2:6][C:7](=[O:9])[CH3:8])[CH2:10][CH2:11][C:12](=[O:14])[CH3:13])([CH3:3])[CH3:2]
Reactant: CC(=O)C=CC(CCC(C)=O)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)CCC(CCC(C)=O)C(C)C

Procedure:
1.96 g (10 mM) of 5-isopropyl-non-3-ene-2,8-dione, prepared according to the method described in paragraph (a) of example 2, in 20 ml of ethyl acetate were reduced by catalytic hydrogenation in the presence of 0.196 gof palladium at 10% over charcoal. After filtration and evaporation of the volatile portions, a residue was obtained which by fractional distillationgave 1.77 g (89%), of the desired dione; B.p. 80°/0.001 Torr;
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12]>C(OCC)C>[Cl:8][C:9]1[C:10]([C:11]([C:3]2[S:4][CH:5]=[CH:6][CH:7]=2)=[O:12])=[CH:14][CH:15]=[C:16]([CH3:18])[N:17]=1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: Brc1cccs1
Agent: [Mg]
Solvent: CCOCC
Product: Cc1ccc(C(=O)c2cccs2)c(Cl)n1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a diethyl ether suspension of magnesium was added dropwise 2-bromothiophene at room temperature, and the whole was reacted. After cooling to 0° C., the reaction mixture was added with 2-chloro-6-methylnicotinic acid and, after being warmed to room temperature, the whole was stirred for 12 hours. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain 2-chloro-6-methyl-3-(thiophene-2-carbonyl)pyridine. NMR1: 7.79 (1H, dd, J=5.0, 1.1 Hz), 7.78 (1H, d, J=7.7 Hz), 2.63 (3H, s).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1)[CH3:3].[I:12][CH3:13]>CC(C)=O>[I-:12].[OH:11][C:10]1[C:5]([CH2:4][N+:2]([CH3:13])([CH3:1])[CH3:3])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)Cc1ncccc1O
Reactant: CI
Solvent: CC(C)=O
Product: C[N+](C)(C)Cc1ncccc1O
Product: [I-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
To a solution of 2-[(dimethylamino)methyl]pyridin-3-ol (207 g, 1.37 mol) in acetone (2000 mL) was added dropwise iodomethane (778 g, 5.48 mol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The resulting crystals were collected by filtration to give the title compound (369 g, yield 92%).
Reaction SMILES: C(O)(=O)C.[C:5]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[OH:21])(=[NH:7])[NH2:6].C[O-].[Na+].[CH2:25]([O:32][C:33](=[CH:36]N(C)C)[CH:34]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH2:25]([O:32][C:33]1[CH:34]=[N:7][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[OH:21])=[N:6][CH:36]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)N)C(O)C1
Reactant: CN(C)C=C(C=O)OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(OCc3ccccc3)cn2)C(O)C1
Temperature: 25 °C
Yield: 27.5 %

Procedure:
A solution of 372 mg (1 mmol) of tert-butyl (3RS,4RS)-4-carbamimidoyl-3-hydroxy-piperidine-1-carboxylate acetate in 10 ml of methanol was treated with 1 ml of 1N sodium methylate solution and stirred at room temperature. Subsequently, 205 mg (1 mmol) of 2-benzyloxy-3-dimethylamino-acrolein (EPA 0 477 901) were added thereto and the solution was heated to reflux for 18 hours. For the working-up, the reaction mixture was evaporated under reduced pressure and the residue was taken up in 20 ml of methylene chloride and washed with 5 ml of water. The organic phase was separated, dried over sodium sulphate and finally evaporated under reduced pressure. For purification, the residue was chromatographed on silica gel using a 1:4 mixture of methylene chloride and ethyl acetate as the eluent. There were obtained 106 mg (27% of theory) of tert-butyl (3RS,4RS)-4-(5-benzyloxy-pyrimidin-2-yl)-3-hydroxy-piperidine-1-carboxylate as a colourless oil; MS: 386 (M+H)+.