Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:14]O)=[CH:12][N:13]=2)=[CH:5][CH:4]=1.CCN(CC)CC.CS([Cl:29])(=O)=O.CCCCCCC.CCOC(C)=O>C(Cl)Cl>[Cl:29][CH2:14][C:11]1[S:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)=[N:13][CH:12]=1
Reactant: OCc1cnc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2ncc(CCl)s2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
To an ice-cooled solution of [2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (1.556 g, 6.0 mmol) and Et3N (1.67 ml, 12.0 mmol) in CH2Cl2 (14 ml) was slowly added methanesulfonyl chloride (0.75 ml, 9.6 mmol). After 2 h at 0° C. more Et3N (0.17 ml, 1.2 mmol) and methanesulfonyl chloride (0.07 ml, 0.96 mmol) were added. The reaction was kept for 16 h at 0° C. and 4 h at RT until the reaction was completed by TLC (n-heptane/EtOAc 4:1). The reaction was then partitioned between Et2O (3×)/aqueous saturated NaHCO3. The organic phases were washed once with aqueous 10% KHSO4. and aqueous 10% NaCl, dried over Na2SO4 and evaporated to give 1.58 g (95%) of 5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole as a light yellow solid, MS: 277 (M, 1Cl), MP: 55-57° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C@@H:29]([OH:31])[CH3:30].N.O>CS(C)=O.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C@@H:29]([OH:31])[CH3:30])(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: C[C@H](O)c1ccccc1Br
Agent: [Cu]I
Agent: N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](O)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reaction time: 2 h
Yield: 29.5 %

Procedure:
A mixture of sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (340 mg, 1.1 mmol), (1S)-1-(2-bromophenyl)ethanol (205 mg, 1.0 mmol) and copper(I) iodide (0.95 g, 4.99 mmol) in dimethyl sulfoxide (10 mL) was degassed and the flask placed in an oil bath at 110° C. The reaction mixture was stirred at this temperature for 2 hours. The cooled reaction mixture was poured into concentrated ammonia/water (1:1; 100 mL) and extracted with diethyl ether (4×50 mL). The extracts were washed with water then brine, combined, dried (MgSO4) and evaporated. The residue was purified by two flash columns, the first eluting with 5-10% diethyl ether/dichloromethane and the second eluting with 40-60% diethyl ether/isohexane, to give the title compound (120 mg, 29%). 1H NMR (500 MHz, CDCl3) δ 8.55 (1H, s), 8.17 (1H, d, J=8.0 Hz), 8.05 (1H, d, J=8.6 Hz), 8.02 (1H, s), 7.97 (1H, d, J=8.7 Hz), 7.84 (1H, dd, J=1.5, 8.5 Hz), 7.76 (2H, d, J=8.4 Hz), 7.69-7.63 (3H, m), 7.49 (1H, t, J=7.2 Hz), 7.19 (2H, t, 8.6 Hz), 5.68-5.62 (1H, m), 2.49 (1H, d, J=3.1 Hz), 1.35 (3H, d, J=6.3 Hz); m/z (ES+) 389 [(M-OH)+].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>CC(O)=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][N:26]3[CH2:27][CH2:28][CH:23]([C:19]4[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=4)[CH2:24][CH2:25]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Solvent: CC(=O)O
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R, without HOAc, using 1H-indole-5-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 376.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][N:24]=[C:25]4[CH2:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12])#[N:2]>Cl.O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][N:24]=[C:25]4[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([F:13])([F:14])[F:12])#[N:2]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OCC(F)(F)F)c(C#N)c4)n3)cccc12
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(-c2nc(-c3cccc4c(CCC(=O)O)nccc34)no2)ccc1OCC(F)(F)F
Yield: 85.3 %

Procedure:
1,1-Dimethylethyl 3-[5-(5-{3-cyano-4-[(2,2,2-trifluoroethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]propanoate (D49; 164 mg, 0.313 mmol) was stirred in 4M HCl in dioxane (3 ml) at room temperature for 2.5 hrs. The solvent was removed under vacuum and the residue was triturated under diethyl ether. Filtration provided a solid that was dried in a vacuum oven to give the title compound as a white solid (125 mg).
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:10])[O:7][CH2:8][CH3:9])C.[F:11][C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])=[CH:19][CH:18]=1>C1COCC1>[CH2:8]([O:7][C:6]([CH:25]1[CH2:26][CH2:27][N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:14]3[CH:29]=[CH:30][CH:31]=[C:12]([F:11])[CH:13]=3)=[CH:18][CH:19]=2)[C:24]1=[O:28])=[O:10])[CH3:9]
Reactant: CCOC(=O)OCC
Reactant: O=C1CCCN1c1ccc(OCc2cccc(F)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O
Reaction time: 5 h
Yield: 52 %

Procedure:
370 mg (15.4 mmol) sodium hydride is suspended in 20 ml THF and 911 mg (7.7 mmol) diethylcarbonate is added. The suspension is heated to reflux temperature. A solution of 2.0 g (7.0 mmol) 1-[4-(3-Fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one in 10 ml THF is slowly added into the boiling solution. The mixture is boiled for another 5 hours, then hydrolysed with cold water and washed successively with water, saturated sodium hydrogencarbonate solution, water and saturated sodium chloride solution. Chromatography (silica gel, dichloromethane/ethyl acetate) yields 1.3 g (52%) of a yellowish semisolid. MS: m/e=358.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:21])=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1
Reactant: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Product: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 61 %

Procedure:
As described for example 67, 6-((1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (55 mg, 0.17 mmol), was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (42 mg, 61%) which was obtained as a white foam. MS: m/e=412.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Br:17][C:18]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[C:14]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:20]([C:19]3[CH:23]=[C:24]([CH:25]=[CH:26][C:18]=3[Br:17])[C:27]#[N:28])=[O:21])[CH2:10][CH2:9]2)=[C:2]([F:1])[CH:3]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: N#Cc1ccc(Br)c(C(=O)O)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C#N)ccc3Br)CC2)c(F)c1
Yield: 49 %

Procedure:
Title compound was prepared according to procedure described in example K/step 2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-bromo-5-cyano-benzoic acid, (49% yield, white solid, MS (m/e): 430 (M+, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1.[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30]>>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[C:3]1[C:2]([NH:1][C:33]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:34])=[N:20][C:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:9]=[CH:10][C:5]=2[CH:4]=1
Reactant: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CC(C)N=C=O
Product: CCN(CC)CCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)NC(C)C)nc2n1

Procedure:
The procedure of Example 21 was followed to react 0.30 g of 7-amino-6-(2,6-dichlorophenyl)-2-(3-diethylamino-propylamino)-pyrido[2,3-d]pyrimidine from Example 20 and 0.077 mL of isopropyl isocyanate. The product was purified by medium pressure chromatography on silica gel eluting with 90:10:1 EtOAc:MeOH:TEA to afford the title compound, mp 88-100° C.; CIMS (1% ammonia in methane): m/z (relative intensity) 504 (MH+, 3), 506 (MH+ +2, 2), 86 (100)
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[C:15]([NH:16][C:17]3[C:18]4[C:25]([CH3:26])=[C:24]([C:27]([OH:29])=O)[S:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.N.C[N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[C:15]([NH:16][C:17]3[C:18]4[C:25]([CH3:26])=[C:24]([C:27]([NH2:32])=[O:29])[S:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1
Reactant: CO[C@H]1CC[C@H](Oc2ncccc2Nc2ncnc3sc(C(=O)O)c(C)c23)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@H](Oc2ncccc2Nc2ncnc3sc(C(N)=O)c(C)c23)CC1

Procedure:
Prepared analogously to 1.4 from 0.005 g 4-[2-(trans-4-methoxy-cyclohexyloxy)pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia (0.5 M in THF) in DMF using TBTU instead of HATU.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=O.[CH:9]([NH2:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:22][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN1CCN(C)C1=O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN1CCN(C)C1=NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3.79 grams (0.027 mole) of boron trifluoride etherate in 3 milliliters of anhydrous ether under dry argon, is added as rapidly as possible while maintaining control of the reaction, 1.8 gram (0.02 mole) of epichlorohydrin in 7 milliliters of dry ether. After about 3 hours, the crystals of triethyloxonium fluoborate which are formed are separated and washed with fresh dry ether under dry argon. The crystals are then dissolved in dry methylene chloride (5 ml.) and a solution of 2.28 grams (0.02 mole) of 1,3-dimethyl-2-imidazolidinone in 25 milliliters of dry methylene chloride is added. After stirring at room temperature for about 3 hours, 3.66 gram (0.02 mole) of benzhydrylamine in 5 milliliters of methylene chloride is added. The resulting mixture is allowed to stir overnight at room temperature. Treatment of the reaction mixture with excess cold (0° C.) 20% NaOH, shaking, and separation of the organic layer gives a solution of the free base. This solution is dried over anhydrous potassium carbonate, filtered and the solvent is vaporized in vacuo to afford the 1,3-dimethyl-2-diphenylmethyliminoimidazolidine product.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][OH:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][O:6][N:27]1[C:31](=[O:32])[C:30]2[C:29](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]1=[O:37]
Reactant: CSCCCO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 65.4 %

Procedure:
3-Methylsulfanyl-propan-1-ol (4.133 g, 38.92 mmol) was dissolved in THF (anhydrous, 100 mL). To this solution, triphenylphosphine (10.2 g, 38.92 mmol) and N-hydroxyphthalimide (6.4 mg, 38.92 mmol) were added and dissolved with stirring. Diisopropyl azodicarboxylate (8.5 mL, 42.812 mmol) was added dropwise thereto with cooling the reaction vessel in an ice-bath under nitrogen atmosphere. The reaction mixture was warmed to room temperature, and stirred for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and triturated with diethyl ether:hexane (1:1, about 100 ml) to precipitate triphenylphosphine oxide as a white solid, which was filtered off. The filtrate was concentrated under reduced pressure to give a yellow oily residue. The resultant yellow oil was purified by silica gel flash chromatography (BW300, Fuji Silysia Chemical, 20% ethyl acetate/hexane as an eluent) to give 2-(3-methylsulfanyl-propoxy)-isoindole-1,3-dione (6.4 g, 65%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([CH:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18](OC)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO.[OH-].[Na+]>C1(C)C=CC=CC=1.ClCCl>[C:22]1([CH:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:18][OH:19])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)C(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: OCC(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 92.4 %

Procedure:
To a 500 mL three-opening flask was slowly added a solution of diisobutylaluminum hydride in toluene (282 mL, 1 mol/L) at −30° C. After stirring, to the resulting mixture was slowly added a solution of methyl 2,2-diphenylacetate (21 g, 92.8 mmol) in dichloromethane dropwisely. After the completion of dropwise addition, the reaction was conducted at 25° C. for 12 hours. After the completion of reaction monitored by TLC, to the resulting mixture was slowly added methanol (10 mL), dichloromethane (100 mL) and an aqueous sodium hydroxide solution (100 mL, 1 mol/L) at −20° C. After the completion of reaction, to the reaction solution was added dichloromethane for extraction. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce 2,2-diphenyl ethanol (17 g) in a yield of 92.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]2[NH:15][CH:16]=[C:17]([CH:21]([C:23]3[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=3)O)[C:18](=[O:20])[N:19]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.C(O)=O.N.N.ClCCl>O>[CH3:1][O:2][C:3]1[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]2[NH:15][CH:16]=[C:17]([CH2:21][C:23]3[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[C:18](=[O:20])[N:19]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1CCCCNc1nc(=O)c(C(O)c2ccc(C)nc2)c[nH]1
Agent: N
Solvent: O=CO
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccnc1CCCCNc1nc(=O)c(Cc2ccc(C)nc2)c[nH]1
Yield: 42.2 %

Procedure:
2-[[4-(3-Methoxy-2-pyridyl)butyl]amino]-5-[(6-methyl-3-pyridyl)hydroxymethyl]-4-(1H)-pyrimidinone (0.99 g, 0.0025 mol), triethylamine (0.57 g, 0.0055 mol) and 98% formic acid (0.75 g, 0.015 mol) were stirred at reflux temperature for 41/2 hours. The reaction mixture was cooled, diluted with water (3 ml) and basified with ammonia solution (specific gravity 0.880) to pH 8.5. The aqueous solution was extracted into dichloromethane (2×5 ml); the organic layers were combined, dried over sodium carbonate, filtered and evaporated under reduced pressure to afford a foam. This foam was subjected to medium pressure liquid chromatography (Kieselgel 60, 230-400 Mesh) with methanolic ammonia: dichloromethane (10: 90). The relevant fractions were combined and evaporated under reduced pressure to afford the title compound (0.40 g). Crystallisation form ethanolic HCl afforded 2-[[4-(3-methoxy-2-pyridyl)butyl]amino]-5-[(6-methyl-3-pyridyl)methyl]-4-(1H)-pyrimidinone trihydrochloride as a crystalline solid m.p. 213° C.; nmr of the free base δ(CDCl3) 1.7 (4H, m), 2.5 (3H, s), 2.75 (2H, m), 3.3 (2H, m), 3.6 (2H, s), 3.8 (3H, s), 7.1 (3H, m), 7.4 (1H, s), 7.45 (1H, dd), 8.0 (1H, dd), 8.4 (1H, dd) ppm.
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH:14]2[CH:10]([CH:11]([CH3:25])[N:12]([CH3:24])[CH:13]2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu][C:28]#[N:29]>CN(C=O)C>[CH2:1]([N:8]1[C:9](=[O:26])[CH:10]2[CH:11]([CH3:25])[N:12]([CH3:24])[CH:13]([C:17]3[CH:22]=[CH:21][C:20]([C:28]#[N:29])=[CH:19][CH:18]=3)[CH:14]2[C:15]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1C2C(=O)N(Cc3ccccc3)C(=O)C2C(c2ccc(Br)cc2)N1C
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CC1C2C(=O)N(Cc3ccccc3)C(=O)C2C(c2ccc(C#N)cc2)N1C
Yield: 84.9 %

Procedure:
400 mg (0.96 mmol) of (3aRS,4SR,6RS,6aSR)-2-benzyl-4-(4-bromo-phenyl)-5,6-dimethyl-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione and 360 mg (4.02 mmol) of copper(I) cyanide were suspended in 25 ml of DMF and heated under reflux and under argon for 18 hours. After cooling about 15 ml of DMF were removed, then 30 ml of dichloromethane and 20 ml of concentrated aqueous ammonia solution were added. The mixture was stirred vigorously for a few hours. The blue aqueous phase was separated and the organic phase was washed twice with ammonia solution and once with water. The solvent was removed and the residue was purified chromatographically (hexane/ethyl acetate 2:1+1% triethylamine). 293 mg of (1RS,3SR,3aRS,6aSR)-4-(5-benzyl-2,3-dimethyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl)-benzonitrile (85%) were isolated as colourless crystals. M.p.: 188°-190° C. (ethyl acetate). FAB-MS: 719 ([2M+H]+, 3); 512 (3); 360 ([M+H]+, 100); 344 (41); 289 (15); 107 (37); 91 (56).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:25][C:26]3[CH:33]=[CH:32][CH:31]=[C:28]([CH3:29])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Cc1cccc(CCl)c1
Product: Cc1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c1

Procedure:
The title compound (0.004 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.1 g) using 3-methylbenzyl chloride (0.6 mL) in place of benzyl chloride. MS (ESI): exact mass calculated for C21H22ClN3, 351.15; found, m/z 352.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.31-7.26 (m, 2H), 7.26-7.21 (m, 2H), 6.99 (t, J=7.5 Hz, 1H), 6.88 (d, J=7.1 Hz, 1H), 6.76 (s, 1H), 6.67 (d, J=7.1 Hz, 1H), 5.13 (s, 2H), 2.79-2.73 (m, 4H), 2.69-2.65 (m, 2H), 2.63-2.60 (m, 2H), 2.09 (s, 3H).
Reaction SMILES: C1(=O)[N:5]([CH:6]2[CH2:9][N:8]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:7]2=[O:22])C(=O)C2=CC=CC=C12.CN(C)CCCN.CO.C(Cl)(Cl)Cl>C(OCC)(=O)C>[NH2:5][CH:6]1[CH2:9][N:8]([CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:7]1=[O:22]
Reactant: COC(=O)CC(c1ccccc1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: CN(C)CCCN
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CC(c1ccccc1)N1CC(N)C1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 82.6 %

Procedure:
3-Phthalimido-1-(2-methoxycarbonyl-1-phenylethyl)-2-azetidinone (1.90 g.) and N,N-dimethyl-1,3-propanediamine (1.14 g.) were added to a mixture of methanol (20 ml.) and chloroform (5 ml.), whereafter the mixture was stirred at ambient temperature for 17 hours. The reaction mixture was evaporated to dryness under reduced pressure to give a residue, which was dissolved in ethyl acetate (20 ml.). The solution was extracted with three portions of an aqueous solution consisting of 1 N hydrochloric acid (5.3 ml.) and water (11.3 ml.), and then the combined extract was washed with ethyl acetate. The aqueous solution was adjusted to pH 8 with sodium bicarbonate under ice-cooling and then extracted with three 10 ml. portions of chloroform. The extracts were washed with water and then dried over magnesium sulfate. The solvent was removed by distillation from the solution under reduced pressure to give oily 3-amino-1-(2-methoxycarbonyl-1-phenylethyl)-2-azetidinone (1.030 g.).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=[CH:29][C:28]=1[N+:37]([O-])=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[Pt]>[Si:1]([O:8][CH2:9][C@@H:10]([NH:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=[CH:29][C:28]=1[NH2:37])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:16][CH:17]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@H](Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)Nc1c(N)cnc2ccccc12
Reaction time: 20 h
Yield: 98.1 %

Procedure:
N-[(1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-(4-{[tert-butyl(dimethyl)silyl]oxy}benzyl)ethyl]-3-nitroquinolin-4-amine (25.24 g, 44.45 mmol) was dissolved in 300 mL of toluene and the solution was placed in a pressure bottle. Platinum on carbon (5%, 1.47 g) was then added and the reaction mixture was shaken under H2 at 35 PSI (2.4×105 Pa). After 20 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with toluene and acetonitrile and the combined filtrates were concentrated under reduced pressure to give N4-[(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(4-{[tert-butyl(dimethyl)silyl]oxy}benzyl)ethyl]quinoline-3,4-diamine (23.46 g) as an orange foam.
Reaction SMILES: BrC1[CH:3]=[N:4]C=C(C=1)C(O)=O.Br[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH:24]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].CC(C)C(N)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[Zn+2].[C-]#N.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].[Zn]>[C:3]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH:24]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])#[N:4]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)c1cncc(Br)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)C(N)=O
Product: CC(C)(C)OC(=O)c1cncc(C#N)c1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
Instead of the starting material of Reference Example 56, that is, the compound S55, the 5-bromonicotinic acid was used for the similar procedure as in Reference Example 56. To the obtained tert-butyl 5-bromonicotinate (22.4 g), dimethylacetoamide (112 ml), tris(dibenzylideneacetone)dipalladium (1.59 g), zinc cyanide (6.1 g), diphenylphosphinoferrocene (1.92 g), and zinc powder (0.68 g) were added and the mixture was stirred under argon atmosphere at 120° C. for 1.5 hours. The reaction solution was filtered by sellite, which was then washed with ethyl acetate, and the filtrate was washed with saturated saline. The organic layer was dried over with anhydrous sodium sulfate, then concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain tert-butyl 5-cyanonicotinate (13.1 g).