Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.Br[C:40]1[C:41]2[CH:51]=[CH:50][CH:49]=[CH:48][C:42]=2[S:43][C:44]=1[C:45](=[O:47])[CH3:46]>>[CH3:1][N:2]([CH3:38])[CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[N:15][C:14]([C:40]4[C:41]5[CH:51]=[CH:50][CH:49]=[CH:48][C:42]=5[S:43][C:44]=4[C:45](=[O:47])[CH3:46])=[N:13][C:12]=3[CH:11]=2)[CH2:7][CH2:8]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Reactant: CC(=O)c1sc2ccccc2c1Br
Product: CC(=O)c1sc2ccccc2c1-c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1

Procedure:
Following General Procedure G for Stille coupling, N,N-dimethyl-1-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-amine and 1-(3-bromobenzo[b]thiophen-2-yl)ethanone were reacted to give 208. LCMS m/z: 536.7 (MH+)
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=[N:17][C:10]=2[N:9]([CH3:27])[C:8]1=[O:28])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=[N:17][C:10]=2[N:9]([CH3:27])[C:8]1=[O:28]
Reactant: CC(C)CCc1c(OC(C)C)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CCc1c(OC(C)C)cnc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
To a solution of 3-(5-isopentyl-6-isopropoxy-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (48 mg, 0.123 mmol) in THF (1 mL) and water (1 mL) was added LiOH.H2O (10.3 mg, 0.246 mmol). The reaction was stirred at RT for 15 min then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-5-isopentyl-6-isopropoxy-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (22.6 mg, 50.5% yield) as a white solid. 1H NMR (CDCl3) δ: 8.24 (s, 1H), 4.61-4.56 (m, 1H), 4.32-4.13 (m, 2H), 3.68 (s, 3H), 3.55 (d, J=5.3 Hz, 2H), 3.32 (dd, J=17.2, 9.1 Hz, 3H), 2.02-1.84 (m, 2H), 1.71 (dd, J=13.2, 6.6 Hz, 1H), 1.39 (d, J=6.0 Hz, 6H), 0.99 (d, J=6.6 Hz, 6H). LCMS: MH+ 364 and TR=3.032 min.
Reaction SMILES: [CH2:1](OC1C=CC(CC(NC2C=C(OC)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)=O)=CC=1)[C:2]1C=CC=CC=1.[CH2:39]([O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][NH:55][C:56]2[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([O:74][CH3:75])[CH:70]=3)[CH2:65]2)=[CH:49][CH:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([O:46][C:47]1[CH:48]=[CH:49][C:50]([CH2:53][CH2:54][N:55]([CH2:1][CH3:2])[C:56]2[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([O:74][CH3:75])[CH:70]=3)[CH2:65]2)=[CH:51][CH:52]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NC(=O)Cc1ccc(OCc3ccccc3)cc1)C2
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(OCc3ccccc3)cc1)C2
Product: CCN(CCc1ccc(OCc2ccccc2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from 2-(4-benzyloxyphenyl)-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide according to an analogous synthetic method to Example 337, [2-(4-benzyloxyphenyl)ethyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (1.3 g) was used according to an analogous synthetic method to Example 36 to provide [2-(4-benzyloxyphenyl)ethyl]ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (1.2 g). The total amount of this compound was used according to an analogous synthetic method to Example 22 to provide the title compound (920 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].Cl[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[H-].[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[CH3:7][N:6]([CH3:8])[C:4](=[O:5])[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[NH:1][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1ccncc1Cl
Reactant: CN(C)C(=O)c1ccccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccncc1Nc1ccccc1C(=O)N(C)C
Temperature: 100 °C
Yield: 26 %

Procedure:
To a mixture of 2-amino-N,N-dimethylbenzamide (1.3 g, 6.77 mmol), 3-chloro-4-methylpyridine (0.745 mL, 6.77 mmol), Palladium acetate (0.150 g) and BINAP (0.60 g) in 1,4-dioxane (10 mL) was added NaH (0.677 g, 16.93 mmol) and the resulting mixture was heated at 100° C. for 2 hours. The solvent was removed under reduced pressure. The residue obtained was taken into dichloromethane (50 mL) and filtered through celite. The filtrate was washed with water (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified using flash column chromatography (SiO2) to provide 0.450 g of the desired product as a dark oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([CH:17]=[O:18])=[C:15]([S:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:14]=[C:13]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[C-]#N.[Na+].[CH3:37][OH:38].C(Cl)Cl>[O-2].[Mn+2].C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:38][CH3:37])=[O:18])=[C:15]([S:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[N:14]=[C:13]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CO
Reactant: COc1ccc(Sc2nc(-c3ccccc3)n(Cc3cc4c(cc3Cl)OCO4)c2C=O)cc1
Agent: [Mn+2]
Agent: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1c(Sc2ccc(OC)cc2)nc(-c2ccccc2)n1Cc1cc2c(cc1Cl)OCO2

Procedure:
The operation is carried out as in Example 9 starting with 2 g of the product of Example 20 using 10 g of manganese oxide, 1 g of sodium cyanide, 200 ml of methanol, 40 ml of methylene chloride and 600 ul of acetic acid, in this way 1.64 g of expected product is obtained (M.p.=161° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:10]([CH2:17][OH:18])=[N:9]2)=[CH:4][CH:3]=1>[O-2].[Mn+4].[O-2].C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:10]([CH:17]=[O:18])=[N:9]2)=[CH:6][CH:7]=1
Reactant: OCc1nn(-c2ccc(Br)cc2)c2c1CCCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=Cc1nn(-c2ccc(Br)cc2)c2c1CCCC2
Yield: 66.8 %

Procedure:
A toluene (150 ml) solution of the compound of Example 77 (3.0 g) was treated with activated manganese (IV) oxide (9.0 g) and azeotropically distilled during 30 minutes. The hot suspension was filtered and the filtrate evaporated to yield pure title compound (1.99 g). A repeat reaction provided 2.0 g. Crystallization of the combined product from acetonitrile gave 3.80 g, m.p. 120°-121° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.Cl[CH2:16]CCl.S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)c2ccccc12
Reactant: ClCCCl
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(Cl)c2ccccc12
Yield: 96 %

Procedure:
The synthesis method of Example 7-(1) was applied. The compound (1.93g) obtained in (2) above, 1,2-dichloroethane (50 ml), methanol (25 ml) and concentrated sulfuric acid (1.8 ml) were used as reagents to give 1.99 g of a red-brown solid (yield 96%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH:13]([CH3:16])[CH2:14]O)[CH2:9][CH2:8]1.P(Br)(Br)[Br:18].O>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH:13]([CH3:16])[CH2:14][Br:18])[CH2:9][CH2:8]1
Reactant: BrP(Br)Br
Reactant: CC(CO)N1CCN(c2ccccn2)CC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(CBr)N1CCN(c2ccccn2)CC1
Temperature: 60 °C

Procedure:
The alcohol prepared in Part (b) hereinabove, (30 grams; 0.136 moles), diluted with 40 ml of chloroform is added dropwise to 15 cc of phosphorus tribromide. The mixture is warmed to about 60° C. for 2 hours. The mixture is then cooled to below 0° C. and the excess of the reagent is decomposed with water. The mixture is made alkaline, the organic phase is separated and the aqueous phase extracted with chloroform. The total organic phase is combined, dried and allowed to evaporate, giving as a residue a yellow solid material, which after recrystallization gives Compound (c) with m.p. 50°-51° C. from n-hexane; Rf=0.54 (from ethyl acetate); IR (nujol) νmax: 1600, 1490, 1445, 1320, 1260, 785 cm-1 ; Br (Schoeninger)--Calculated %: 28.1--Found %: 27.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[C-:25]#[N:26].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:25]#[N:26])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C

Procedure:
N-[(4-chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide of Example No. 5 (0.19 g), Pd(PPh3)4 (0.10 g), and KCN (0.06 g) are heated at 60° C. in 60 mL freshly distilled tetrahydrofuran. The reaction is cooled to room temperature. The solid in the reaction mixture is filtered. Thin layer chromatography shows the desired product in the filtrate and the solid. Both are dissolved in a MeOH:CH2Cl2 mixture and adsorbed onto silica. The residue is chromatographed eluting with 3% MeOH:CH2Cl2 (1 L), followed by 4% MeOH:CH2Cl2 (1 L), and 5% MeOH:CH2Cl2 (1 L). The product-containing fractions are evaporated to give an off-white solid (0.08 g).
Reaction SMILES: [Na].[C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=[O:5].[CH:13]12[CH:21]=[CH:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][CH2:15][CH:14]2[C:22](Cl)=[O:23]>>[C:4]([O:6][C:22]([CH:14]1[CH2:15][CH2:16][CH:17]2[CH:18]=[CH:19][CH:13]1[CH2:21][CH2:20]2)=[O:23])(=[O:5])[CH2:3][C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: O=C(Cl)C1CCC2C=CC1CC2
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Agent: [Na]
Product: CC(C)(C)OC(=O)CC(=O)OC(=O)C1CCC2C=CC1CC2
Yield: 80.9 %

Procedure:
To a solution of sodium salt of mono-tert-butyl malonate (20.4 g) prepared according to the same procedure as in Example 4, bicyclo[3,2,2]non-8-ene-2-carbonyl chloride (18.5 g) obtained in Preparation Example 3 is slowly added, and the reaction mixture is reacted at −20° C. in a nitrogen atmosphere for 1 hour, and further reacted at 55° C. for 8 hours. Then, the mixture is worked up as in the procedure of Example 1, to obtain 25 g of the pure title compound (purity: 99%, yield: 82%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:25])=O>ClCCl>[C:1]([Cl:25])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1
Reaction time: 1 h

Procedure:
3.80 g (9 mmoles) of 4-[3-(1-adamantyl)-4)-methoxybenzolythio]benzoic acid, 40 ml of dichloromethane, 1.8 ml (9 mmoles) of dicyclohexylamine are introduced into a round bottomed flask and are stirred for one hour. To the solution thus produced, are added 720 82 l (9.9 mmoles) of thionyl chloride and this is stirred at ambient temperature for two hours. This is then evaporated to dryness, taken up in 500 ml of ethyl ether, followed by filtering the dicyclohexylammonium chloride and then by evaporating the solvent. By this means are obtained 3.97 g (100% ) of crude 4-[3-(1-adamantyl)-4)-methoxybenzolythio]benzoic acid chloride which is used directly for the later synthesis.
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[C:20]([F:27])=[CH:19][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:7]1=[O:18].CCN(C(C)C)C(C)C.Cl[C:38]1[N:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][N:39]=1>CS(C)=O.O.CCOC(C)=O>[F:2][C:3]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[C:20]([F:27])=[CH:19][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:38]3[N:43]=[CH:42][C:41]([CH2:44][CH3:45])=[CH:40][N:39]=3)[CH2:14][CH2:13]2)[C:7]1=[O:18]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1cc(F)c(OC2CCCN(C3CCNCC3)C2=O)cc1F
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(N3CCCC(Oc4cc(F)c(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 120 °C
Yield: 20.2 %

Procedure:
To a solution of 3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1,4′-bipiperidin-2-one HCl salt (64 mg, 0.15 mmol) and DIEA (0.080 mL, 0.45 mmol) in DMSO (2 mL) was added 2-chloro-5-ethylpyrimidine (26 mg, 0.18 mmol). The reaction was heated at 120° C. overnight. The reaction was cooled to ambient temperature and diluted with water (2 mL) and EtOAc (5 mL). The organic layer was separated and the aqueous washed with EtOAc. The combined organic layers were dried with MgSO4 and concentrated. The crude residue was purified by reverse phase HPLC (5 to 95% acetonitrile in water with 0.1% TFA). The combined fractions were concentrated to remove CH3CN and the pH adjusted to neutral by the addition of NaHCO3. The aqueous layer was extracted with EtOAc. The combined organic layers were dried with MgSO4 and concentrated to give 3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1′-(5-ethylpyrimidine-2-yl)-1,4′-bipiperidine-2-one (15 mg, 20%) as an off white solid. Mass spectrum (apci) m/z=495.2 (M+H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]1[O:10][CH:8]1[CH3:9].CN(CCO)C.C1(C=CC(O)=CC=1)O>>[C:1]([O:6][CH2:7][CH:8]([OH:10])[CH3:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC1CO1
Reactant: C=C(C)C(=O)O
Agent: CN(C)CCO
Agent: Oc1ccc(O)cc1
Product: C=C(C)C(=O)OCC(C)O
Reaction time: 8 h

Procedure:
2-hydroxypropyl methacrylate was prepared in the same apparatus and under the same reaction conditions as described in Example 5 by reacting, hourly, a mixture of 930 g methacrylic acid, 830 g proplyene oxide, 28.8 g N,N-dimethylaminoethanol, 9.3 g i-amyl nitrite and 0.93 g hydroquinone at a temperature of 100° C. After 8 hours of continuous operation, the reactor was free of polymer.
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19](OC)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:41][C@H:42]1[CH2:47][CH2:46][C@H:45]([NH2:48])[CH2:44][CH2:43]1>ClCCl>[NH2:41][C@H:42]1[CH2:47][CH2:46][C@H:45]([NH:48][C:19]([C:17]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[C@H:23]3[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]3)=[C:10]([NH:9][CH2:8][CH:7]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:18]=2)=[O:20])[CH2:44][CH2:43]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)N[C@H]4CC[C@H](N)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 105 °C

Procedure:
A mixture of methyl 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxylate (Preparation 9) (0.35 g, 0.64 mmol) and trans-1,4-diaminocyclohexane (0.6 g, 6.14 mmol) was heated at 105° C. for 3 hours. The mixture was dissolved in a little dichloromethane and purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:concentrated aqueous ammonia (80:20:1.2, by volume) changing to dichloromethane:methanol:concentrated aqueous ammonia (88:12:2, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (0.32 g, 79%).
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].[C:5]([C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15](Cl)=[CH:14][CH:13]=1)([OH:7])=[O:6].N>[NH2-].[Na+]>[C:5]([C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:2]([CH3:3])[C:1]#[N:4])=[CH:14][CH:13]=1)([OH:7])=[O:6]
Reactant: O=C(O)c1ccccc1CCc1ccc(Cl)cc1
Reactant: CCC#N
Agent: N
Agent: [NH2-]
Agent: [Na+]
Product: CC(C#N)c1ccc(CCc2ccccc2C(=O)O)cc1
Yield: 43.9 %

Procedure:
Propionitrile (286.5 g.) is added over the course of 40 minutes and with vigorous stirring to a suspension of sodamide (248 g.) [prepared from sodium (139.5 g.) and liquid ammonia (4 litres)] and then 4-(2-carboxyphenethyl)chlorobenzene (117 g.) is added over the course of 10 minutes. The ammonia is allowed to evaporate during a period of 16 hours. The brown residue is taken up in anaesthetic grade diethyl ether (1 litre) and then in water (2 litres) with care. The alkaline aqueous solution is decanted, extracted with diethyl ether (2 × 400 cc.) and then acidified by adding sulphuric acid (d = 1.36; 350 cc.) whilst cooling. The oil which separates out is extracted with methylene chloride (2 × 500 cc.). The organic extracts are dried over anhydrous sodium sulphate (100 g.) and concentrated to dryness under reduced pressure (20 mm.Hg) at 60°C. The residual oil is dissolved in hot disopropyl ether (120 cc.); on cooling, a product crystallises and is filtered off. 2-[4-(2-Carboxyphenethyl)phenyl]propionitrile (55 g.), melting at 73°C., is thus obtained; after three recrystallisations from ethyl acetate, the product melts at 129°C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:19][C:18]3[CH:17]=[N:16][N:15]([CH3:20])[C:14]=3[NH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1)=[O:28].[N:36]1([CH2:42][CH2:43][NH2:44])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:19][C:18]3[CH:17]=[N:16][N:15]([CH3:20])[C:14]=3[NH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH:44][CH2:43][CH2:42][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH2:31][CH2:30]1)=[O:28]
Reactant: NCCN1CCOCC1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(NCCN2CCOCC2)CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A solution of 1-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperidin-4-one (Compound number 701) (2.36 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) was added to a solution of 2-morpholin-4-yl-ethylamine (0.65 mg, 0.005 mmol) in 1,2-dichloroethane (0.05 ml) and the mixture was heated at 50° C. for 3 h then stirred at room temperature for 2 days. A solution of sodium tri-acetoxyborohydride (1.59 mg, 0.0075 mmol) in DMF (0.05 ml) was added and the mixture was stirred for 20 h at room temperature. Solvents were removed in vacuo to yield the title compound. MS: (ESI)+: [M+H]+=586.6
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[C:4]([C:15]2(O)[CH2:20][CH2:19][N:18]([CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH2:17][CH2:16]2)[CH:3]=1.O>OS(O)(=O)=O.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:15]2[CH2:20][CH2:19][N:18]([CH2:21]/[CH:22]=[CH:23]/[C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[CH2:17][CH:16]=2)[CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C1(O)CCN(C/C=C/c2ccc(Cl)cc2)CC1
Agent: O=S(=O)(O)O
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Cl)cc1C1=CCN(C/C=C/c2ccc(Cl)cc2)CC1

Procedure:
A suspension of N-(4-chloro-2-{1-[(E)-3-(4-chloro-phenyl)-allyl]-4-hydroxy-piperidin-4-yl}-phenyl)-2,2-dimethyl-propionamide (1.00 g) in 3N H2SO4 (7.5 ml) and DMSO (3 ml) was heated to reflux temperature for 48 hours. Then, water was added and the mixture extracted three times with CH2Cl2, the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (CH2Cl2:MeOH 95:5) to afford 4-chloro-2-{1-[(E)-3-(4-chloro-phenyl)-allyl]-1,2,3,6-tetrahydro-pyridin-4-yl}-phenylamine (0.205 g; viscous oil; Retention Time HPLC 2.15 min; MS (ES+) 359 (M+H+) and 4-(2-amino-5-chloro-phenyl)-1-[(E)-3-(4-chloro-phenyl)-allyl]-piperidin-4-ol (0.182 g; M.p. 168-170° C.; Retention Time HPLC 1.95 min; MS (ES+) 377 (M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[NH:11][C:10](=O)[NH:9][C:6]2=[N:7][CH:8]=1.P(Cl)(Cl)([Cl:17])=O>[Cl-].C[N+](C)(C)C>[Cl:17][C:10]1[NH:9][C:6]2=[N:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=[C:5]2[N:11]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)cnc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Product: FC(F)(F)c1cnc2[nH]c(Cl)nc2c1

Procedure:
Heat a solution of 6-trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one. (0.6 g, 2.95 mmol) and tetramethylammonium chloride (0.3 g) to 110° C. in phosphorus oxychloride (10 mL) for 10 hours. After cooling, remove the excess POCl3 in vacuo, and then neutralize with saturated NaHCO3, extract with EtOAc. Dry over Na2SO4, concentrate under vacuum to obtain 2-chloro-6-trifluoromethyl-3-H-imidazo[4,5-b]pyridine.