Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[CH:27][C:26]=1[C:36]([NH:38][CH3:39])=O)#[N:24]>C1(C)C=CC=CC=1>[C:23]([C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[CH:27][C:26]=1[C:36](=[S:10])[NH:38][CH3:39])#[N:24]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)c1cnn(-c2ccccc2)c1C#N
Solvent: Cc1ccccc1
Product: CNC(=S)c1cnn(-c2ccccc2)c1C#N
Yield: 7.8 %

Procedure:
Eight grams of Lawesson's Reagent was added to a stirring solution of 3 g of 5-cyano-1-phenyl-N-methyl-1H-pyrazole-4-carboxamide in 75 ml of toluene. The reaction mixture was refluxed for approximately 1 hour and the solution was evaporated to dryness. The residue was dissolved in methylene chloride and filtered. The filtrate was concentrated under reduced pressure and the residue was chromatographed employing high pressure liquid chromatography and methylene chloride as the eluent. Fractions containing the second spot were combined and the solvent was evaporated therefrom. The residue was recrystallized from toluene to provide 250 mg of 5-cyano-N-methyl-1-phenyl-1H-pyrazole-4-thiocarboxamide, MP=215°-217° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1.[H-].[Na+].Cl[CH2:20][C:21](=O)[CH3:22]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:10][C:11](=[O:16])[C:12]2[C:21]([CH3:22])=[CH:20][O:15][C:13]=2[CH2:14]1
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1C1CC(=O)c2c(C)coc2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(2-methoxyphenyl)cyclohexane-1,3-dione (mp144-145° C.; 1.09 g) in DMF (15 ml) was added 60% sodium hydride (0.22 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added chloroacetone (0.45 ml), and the mixture was stirred at 150° C. overnight (14 hours). The reaction solution was cooled and concentrated under reduced pressure. To the residue was added ice-water, and the mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(2-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.20 g).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.CI.[C:12](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:12])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)s1
Yield: 79.2 %

Procedure:
A solution of 5-bromothiophene-2-carboxylic acid (5.0 g, 24 mmol), methyl iodide (5.1 g, 30 mmol), and potassium carbonate (6.7 g, 48 mmol) in DMF (50 mL) was stirred at room temperature for 64 h. The reaction was quenched with water and the aqueous layer was extracted multiple times with ethyl acetate. The combined organic layers were washed with aqueous lithium chloride and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica, ethyl acetate/hexanes gradient) to afford the desired product (4.2 g, 79%): 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J=4.0 Hz, 1H), 7.07 (d, J=4.0 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]1[N:57]=[CH:56][N:55]=[C:54]([NH2:58])[CH:53]=1>CN(C=O)C>[CH3:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]1[N:57]=[CH:56][N:55]=[C:54]([NH:58][C:8]([CH:5]2[CH2:4][CH2:3][C:2](=[O:1])[NH:7][CH2:6]2)=[O:10])[CH:53]=1
Reactant: COc1ccccc1-c1cc(N)ncn1
Reactant: O=C1CCC(C(=O)O)CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(NC(=O)C2CCC(=O)NC2)ncn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-oxo-piperidine-3-carboxylic acid (XLIX) (0.22 g, 1.5 mmol) in dry DMF (10 ml) was added HBTU (1.13 g, 2.98 mmol) and DIPEA (0.40 ml, 2.3 mmol) under ice cooled condition, and then it was allowed to stir at room temperature for 45 minutes. To this reaction mixture was added 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (0.30 g, 1.5 mmol) in dry DMF dropwise at ice bath temperature. The reaction mixture was then heated for 4 hours at 120° C. After completion of the reaction, it was cooled and DMF was evaporated completely. The residue was dissolved in ethyl acetate (30 ml), washed with water (2×15 ml) and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Final purification was achieved by flash column chromatography using silica gel (10% methanol/dichloromethane) to give 6-oxo-piperidine-3-carboxylic acid [6-(2-methoxy-phenyl)-pyrimidin-4-yl]amide. Yield: 78.2 mg, 17%.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:30]=[CH:29][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1.O[CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[O:35]1[CH2:36][CH2:37][CH:32]([O:13][C:14]2[CH:30]=[CH:29][C:17]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:19])=[CH:16][CH:15]=2)[CH2:33][CH2:34]1
Reactant: OC1CCOCC1
Reactant: O=C(c1ccc(O)cc1)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(OC2CCOCC2)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
Diethyl azodicarboxylate (1.47 g, 8.4 mmol) was slowly added dropwise to a solution of 4-(4-hydroxybenzoyl)-nitrobenzene (1.7 g, 7 mmol) (prepared as described in Example 1, steps), 4-hydroxytetrahydropyran (0.78 g, 7.7 mmol) and triphenylphosphine (2.2 g, 8.4 mmol) in dry tetrahydrofuran (20 mL) while stirring at room temperature under inert atmosphere. The reaction mixture was stirred for an additional hour then quenched with water (1 mL) and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (Na2SO4), and concentrated in vacuo. The crude product was chromatographed on silica gel (25% ethyl acetate/hexanes) and crystallized from hexanes to give 4-(4-tetrahydropyran-4-yloxybenzoyl)-nitrobenzene (1.4 g, 61%) as a white solid, m.p. 105–106° C.; Analysis for C18H17NO5: Calc.: C, 66.05; H, 5.23; N, 4.28; Found: C, 65.95; H, 5.14; N, 4.38. MS m/e (%): 283 (M+; 100).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:8]2[C:6]3[N:7]=[C:2]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(CSc2ncnc3c(N4CCS(=O)CC4)nc(Cl)nc23)cc1
Reactant: C1CNCCN1
Product: COc1ccc(CSc2ncnc3c(N4CCS(=O)CC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(4-methoxybenzyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 217°-219° C.) and piperazine.
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9]C)=O)[CH:3]=1.[NH3:11]>CO>[I:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([NH2:11])=[O:9])[CH:3]=1
Reactant: N
Reactant: COC(=O)c1cc(I)[nH]n1
Solvent: CO
Product: NC(=O)c1cc(I)[nH]n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 5-iodo-1H-pyrazole-3-carboxylate (compound 260.3, 900 mg, 3.57 mmol) in methanol (5 mL). Ammonia (25% aq.) (15 mL) was added and the resulting solution was stirred overnight at 60° C., then cooled and concentrated under reduced pressure to obtain the title compound as a white solid (0.8 g, 95%).
Reaction SMILES: Br[CH2:2][Cl:3].C[O:5][C:6]([CH:8]1[CH:13]=[CH:12][C:11]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:10]=2[O:9]1)=O.[Li]CCCC.CCCCCC>C1COCC1.O.C(O)(=O)C>[Cl:3][CH2:2][C:6]([CH:8]1[CH:13]=[CH:12][C:11]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:10]=2[O:9]1)=[O:5]
Reactant: ClCBr
Reactant: COC(=O)C1C=Cc2cc(F)ccc2O1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCl)C1C=Cc2cc(F)ccc2O1
Yield: 98.6 %

Procedure:
1.2 g of bromochloromethane (9.2 mmol) were added at room temperature to a solution of 1.0 g of crude 6-Fluoro-1-benzopyran-2-carboxylic acid methyl ester (4.7 mmol) in 15 ml of THF. The solution was then cooled to −80/−85° C. and 4.6 ml of 2.5 M n-BuLi in hexane (9.2 mmol) were slowly added to maintain the internal temperature between −75° C. and −80° C. The reaction progress was monitored by TLC. The solution was then acidified by the addition of 1 ml glacial acetic acid in 2 ml THF between −70° C. and −80° C. 5 ml of water were then added at 0° C. and the aqueous layer was then removed after decantation. The organic layer was concentrated under reduced pressure to give the title compound (1.05 g) as a yellow oil (titration by NMR: ≈80% w/w).
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([N:20]3[CH2:25][CH2:24][CH2:23][C:22](=O)[CH2:21]3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC(O)=O.[BH3-]C#N.[Na+]>CO.O>[CH2:27]([NH:34][CH:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:19]2[C:14]3[CH:13]=[CH:12][N:11]([S:1]([C:4]4[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=4)(=[O:3])=[O:2])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:21]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N4CCCC(=O)C4)ncnc32)cc1
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N4CCCC(NCc5ccccc5)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-one (75 mg, 0.2 mmol) and benzylamine (25 μL, 0.22 mmol) in MeOH (3 mL) was added AcOH (20 μL, 0.4 mmol) and NaBH3CN (32 mg, 0.5 mmol). The solution was stirred at rt for 16 hr after which time the solvent was removed in vacuo to afford a residue which was diluted with water and extracted with EtOAc. The organic phase was separated, washed with aq. NaHCO3 and water, dried (Na2SO4) and concentrated in vacuo to afford a residue which was purified by column chromatography (silica gel, gradient EtOAc in hexanes). EIMS (m/z): calcd. for C25H27N5O2S (M++1) 462.2. found 462.2.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1.[CH2:25]=O.[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:17]=[C:16]([CH2:18][N:19]([CH3:25])[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1
Reactant: Cc1cc(CNCCC(C)C)ccc1Oc1ccc(C(N)=O)cn1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CN(C)CCC(C)C)ccc1Oc1ccc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A solution of Example 227 (1.0 equiv) in MeOH (0.2 M solution) was treated with formaldehyde (5 equiv) and stirred at room temperature (r.t.) for 2 hours. Sodium Borohydride was added and stirred at r.t. overnight. The solvent was removed under vacuum and crude residue was purified by silica gel chromatography using the appropriate eluent (typically mixtures CHCl3/EtOH 7%/NH4OH 0.7%) to afford the title compound as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1.[CH3:14]O>>[OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1
Reactant: CO
Reactant: O=C(O)C1CCC(OCCO)CC1
Product: COC(=O)C1CCC(OCCO)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The crude product from Example 1A is dissolved in 40 ml of methanol, and 200 mg of Dowex 50 WX8-100 ion exchanger (washed beforehand 7× with in each case 20 ml of 2 M hydrochloric acid and then 7× with in each case 20 ml of methanol) are added. The mixture is stirred at +64° C. for 20 h. After cooling to RT, the ion exchanger is filtered off and the filtrate is concentrated on a rotary evaporator. The crude product is directly used in the next reaction without further purification.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.[OH-].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:12][CH2:13][CH2:14][CH2:15][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: ClCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: ClCCCn1ncc2ccccc21
Temperature: 60 °C
Yield: 59.1 %

Procedure:
1H-benzopyrazole (11.8 g, 0.10 mol) was dissolved into 200 ml of 20% wt. sodium hydroxide, 3-chlorobromopropane (31.2 g, 0.20 mol) and tetrabutyl ammonium bromide (1.0 g) were added, and mixed for 5 min. The mixture was heated to 60° C., stirred to react for 2 hours. Then the reaction solution was cooled down to ambient temperature, 100 ml of dichloromethane was added for extraction and liquid separation. To the aqueous phase, 100 of dichloromethane was added for extraction. Organic phases were mixed, washed with 100 ml of saturated saline. Liquid was separated, and organic phase was evaporated to dryness to produce oily product. Oily products were separated and purified by chromatography with neutral Al2O3 to produce 11.5 g of 1-(3-chloropropyl)-1H-benzopyrazole, with a yield of 59.3%.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][O-:15].[Na+].[H-].[Na+]>CO>[Cl:13][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([CH3:12])=[CH:11][C:2]([O:15][CH3:14])=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1cc(Cl)nc2cc(Cl)ccc12
Reactant: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)c2ccc(Cl)cc2n1

Procedure:
2-Chloroquinoline 14 (7.0 g; 32.8 mmol) was added to a solution of sodium methoxide in methanol generated from 1.08 g (36.1 mmol) of 80% sodium hydride in 80 ml of methanol. The resulting mixture was refluxed overnight. It was filtered while still hot to remove undissolved matter. The product crystallized from the methanol upon cooling to deliver 6.1 g (70%) of 15 as a white solid. 1H NMR (CDCl3): δ 2.62 (s, 3H); 4.10 (s, 3H); 6.78 (s, 1H); 7.38 (d, 1H); 7.81 (d, 1H); 7.93 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH2:16][CH3:17])[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.B(O)(O)[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1.C(N(CC)C(C)C)(C)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:16]([C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[N:5]=1)[CH3:17]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCCC(C(=O)OC)c1c(Cl)nc(N2CCCCC2)nc1CC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(CC)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Yield: 38.4 %

Procedure:
methyl 2-(4-chloro-6-ethyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.190 g; 0.559 mmol), p-tolylboronic acid (114 mg; 0.839 mmol), tetrakis(triphenylphosphine) palladium(0) (64.6 mg; 0.056 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-Diisopropylethylamine (0.344 mL; 2.236 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 30 min. The reaction mixture was partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 85 mg (35%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]2[C:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][CH:9]=[C:8]2[CH3:15])[O:4][N:3]=1.[H][H]>C(O)C.[Pt]=O>[CH3:15][C:8]1[CH:7]([C:5](=[O:4])[CH:6]=[C:2]([NH2:3])[CH3:1])[C:12]([CH3:13])([CH3:14])[CH2:11][CH2:10][CH:9]=1
Reactant: [H][H]
Reactant: CC1=CCCC(C)(C)C1c1cc(C)no1
Agent: O=[Pt]
Solvent: CCO
Product: CC(N)=CC(=O)C1C(C)=CCCC1(C)C
Yield: 90 %

Procedure:
4.10 g (0.020 mole) of 3-methyl-5-[2,6,6-trimethylcyclohex-2-en-1-yl]-isoxazole were dissolved in 5 ml of anhydrous ethanol and the solution was added to 0.173 g of a mixture of 83.6 % of platinum oxide in 30 ml of ethanol, the said mixture having previously been subjected to a hydrogenation. The solution was then subjected to a hydrogenation at room temperature and at atmospheric pressure and, after absorption of one equivalent of hydrogen, filtered through a "Celite" carrier. After having been concentrated under reduced pressure the residual solution was subjected to chromatography on a magnesium silicate column by elution with a mixture of chloroform/hexane (25/75) to yield 3.73 g (yield: 90 %) of 2,6,6-trimethyl-1-[3-amino-but- 2-en-1-oyl]-cyclohex-2-ene.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[C:15]1([C:21]2([NH2:24])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[CH3:14][S:13][C:4]1[N:3]=[C:2]([NH:24][C:21]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:23][CH2:22]2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: NC1(c2ccccc2)CC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(SC)nc1NC1(c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 104.2 %

Procedure:
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (550 mg, 2.36 mmol) and 1-phenylcyclopropanamine (420 mg, 3.16 mmol) in CH3CN (6 mL) at room temperature was added DIEA (0.5 mL, 2.60 mmol). The mixture was stirred at room temperature for 3 h and 50° C. for 3 h. The mixture was diluted with EtOAc, washed with 1N HCl, Sat. NaHCO3, brine, dried and concentrated to give ethyl 2-(methylthio)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxylate (810 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[CH:18]=[C:17]([C:19]3([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)[CH:16]=[CH:15][C:13]=2[N:14]=1)[CH:5]=O.Cl.[NH:29]1[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][N:29]2[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[CH:18]=[C:17]([C:19]3([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][CH2:21]3)[CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)C1CNC1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)cc3s2)c(F)c1
Agent: Cl
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)cc4s3)c(F)c2)C1

Procedure:
Reaction of 3-fluoro-4-(6-(1-phenylcyclopropyl)benzo[d]thiazol-2-yl)benzaldehyde (0.050 g, 0.13 mmol) and methyl azetidine-3-carboxylate hydrochloride (0.030 g, 0.20 mmol) according to Reference R and general procedure for reductive amination afforded methyl 1-((3-fluoro-4-(6-(1-phenylcyclopropyl)benzo[d]thiazol-2-yl)phenyl)methyl)azetidine-3-carboxylate. MS (ESI) m/z: Calculated: 472.2; Observed: 473.1 (M++1).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH:18]([CH3:20])[CH3:19])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([F:23])[CH:25]=2)[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH:18]([CH3:19])[CH3:20]
Reactant: CCOP(=O)(Cc1cc(OC)c(C(C)C)c(OC)c1)OCC
Reactant: O=Cc1cccc(F)c1
Product: COc1cc(C=Cc2cccc(F)c2)cc(OC)c1C(C)C

Procedure:
This material was prepared from diethyl(3,5-dimethoxy-4-i-propylbenzyl)phosphonate and 3-fluorobenzaldehyde in the same way as described in example 21.
Reaction SMILES: [CH:1]1([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.CN(C)P(N(C)C)(N(C)C)=O.C([N-]C(C)C)(C)C.[Li+].Br[CH2:35][CH2:36][Cl:37]>C1COCC1>[Cl:37][CH2:36][CH2:35][C:4]1([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2][CH:1]([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: ClCCBr
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1CCC(CCCl)(C(=O)OC)CC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
To the above described mixture of crude dimethyl cyclohexane-1,4-dicarboxylate (100 g, 0.5 mol) and hexamethylphosphoramide (360 mL, 2 mol) in anhydrous THF (800 mL) was added the freshly prepared lithium diisopropylamide solution (preparation described above) over 30 min at −40° C. After stirring for 1 h at this temperature, 1-bromo-2-chloroethane (42 mL, 0.5 mol) was added over 1. The mixture was stirred for 3 h at −78° C. and then stirred overnight at room temperature. The reaction was quenched by the addition of aqueous hydrochloric acid solution (3 N, 420 mL). The solvent was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (200 mL×3). The combined extracts were washed with brine (2×300 mL) and dried over sodium sulfate. Concentration gave the title compound (116 g, yield 88%) which was used in the next step without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 3.72 (s, 3H), 3.65 (s. 3H), 3.46-3.42 (m, 2H), 2.33-2.21 (m, 3H), 2.05-1.85 (m, 4H), 1.58-1.42 (m, 2H), 1.25-1.15 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[I:11]N1C(=O)CCC1=O>C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: Clc1ncnc2[nH]cc(I)c12

Procedure:
The tricyclic nucleoside 6.7 was synthesized starting from 4-chloro-1H-pyrrolo[2,3-d]pyrimidine 2.1. The nucleobase 2.1 was treated with N-iodosuccinimide in THF at room temperature for 4 hr to provide 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 6.1. Then 6.1 was converted to the corresponding sodium salt with sodium hydride in acetonitrile and reacted with bromo-sugar 2.4 ((i) Helv. Chim. Acta. 1995, 78, 486; (ii) WO 02/057287, 2002), to give nucleoside 6.2. which was directly converted to 4-amino-5-iodo-7-[3,5-bis-O-(2,4-dichlorophenylmethyl)-2-C-methyl-β-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine 6.3. A Stille coupling reaction between nucleoside 6.3 and Z-3-tributylstannylacrylate provided compound 6.4. The cyclization of compound 6.4 was accomplished by heating in DBU/dioxane overnight to afford the protected tricyclic nucleoside 6.5, which was then treated with boron trichloride in CH2Cl2 to produce nucleoside 6.6.