Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:33])[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:20]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:20]=[C:19]([CH3:33])[CH:24]=[CH:23][CH:22]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(C)c3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[O:4][N:3]=1.[NH2:16][C@H:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[NH:22]C(=O)OC(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[ClH:61].O1CCOCC1>CN(C=O)C.CO>[ClH:61].[NH2:16][C@H:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[NH:22][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[C:5]1[O:4][N:3]=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1noc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2N)n1

Procedure:
A mixture of 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (CAS number 475105-77-2; 0.84 g, 4.12 mmol), tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 0.75 g, 3.74 mmol), HATU (2.14 g, 5.62 mmol) and triethylamine (1.57 ml, 11.23 mmol) was stirred in dry DMF (12.5 ml) at room temperature for 17 hours. The reaction mixture was partitioned between ethyl acetate and water, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol). The resulting cream solid was recrystalised from ethyl acetate, to which was then added methanol (10 ml) and HCl in 1,4-dioxane (4M, 4.68 ml, 18.72 mmol) and the reaction was stirred at room temperature for 17 hours. The reaction was concentrated in vacuo and azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:10]1(=[O:16])[O:15][CH:13]([CH3:14])[CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[C:11]1[CH2:12][CH:13]([CH3:14])[O:15][C:10]1=[O:16]
Reactant: CC1CCC(=O)O1
Reactant: O=Cc1ccccc1O
Solvent: Cc1ccccc1
Product: CC1CC(=Cc2ccccc2O)C(=O)O1
Yield: 66.9 %

Procedure:
Salicylaldehyde (15.2 g) and γ-valerolactone (25 g) were dissolved in toluene (150 ml). By the reactions as in the same manner as in Example 307, the title compound (17 g) was obtained, melting point 112–114° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH2:16]1[O:19][CH:17]1[CH3:18].C(N(CC)CC)C>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:16][CH:17]([OH:19])[CH3:18])=[CH:8][CH:7]=1
Reactant: Oc1ccc(Oc2cccc(F)c2)cc1
Reactant: CC1CO1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(O)COc1ccc(Oc2cccc(F)c2)cc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A mixture of 6.13 g of p-(m-fluorophenoxy)phenol, 2.79 g of propylene oxide and 0.12 g of triethylamine is stirred at 90° C. for 18 hours. The cooled mixture is subsequently diluted with 100 ml of diethyl ether and washed successively twice with 50 ml of 2N hydrochloric acid each time, three times with 50 ml of 2N sodium hydroxide each time, with 50 ml of water and with 50 ml of saturated sodium chloride solution. After drying over anhydrous sodium sulfate and evaporation there is obtained 1-[p-(m-fluorophenoxy)phenoxy]-2-propanol of melting point 37°-39° C.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:28](=[O:29])[C:18]3=[CH:19][NH:20][C:21]4[C:22]([F:27])=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]3=[N:16]2)=[CH:11][CH:10]=1)([O-])=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:6][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:28](=[O:29])[C:18]3=[CH:19][NH:20][C:21]4[C:22]([F:27])=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]3=[N:16]2)=[CH:11][CH:10]=1
Reactant: O=c1c2c[nH]c3c(F)cccc3c-2nn1-c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Nc1ccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)cc1
Temperature: 80 °C
Yield: 104.7 %

Procedure:
Tin (II) chloride dihydrate (12.5 g, 0.055 mol) was added in one portion to a stirred solution of 2-(4-nitrophenyl)-6-fluoro-2,5-dihydro-pyrazolo[4,3-c]quinolin-3-one (intermediate 1) (3.59 g, 0.011 mol) in ethyl alcohol (110 ml) at room temperature. The mixture was then heated to 80° C. for 8 h, cooled to room temperature and filtered to leave a yellow solid. The solid was suspended in a biphasic solution of ethyl acetate (1L), a saturated solution of Rochelles salt (500 ml) and a saturated solution of sodium bicarbonate (500 ml) and stirred at room temperature for 2 h. The mixture was filtered and the remaining solid was washed with water and dried under vacuum to afford the title compound (3.39 g, 99%) as a bright yellow solid, LCMS m/z 295.30 [M+H]+ @ RT 0.84 min.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([OH:17])=O)[CH:8]=2)[CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(C)=CC=CC=1.O>[OH:1][C:2]1[C:11]([C:12]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:17])[CH:8]=2)[CH:3]=1
Reactant: O=C(O)c1ccc2cc(O)c(C(=O)O)cc2c1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccc1)c1ccc2cc(O)c(C(=O)Nc3ccccc3)cc2c1
Temperature: 90 °C
Yield: 45.8 %

Procedure:
2-Hydroxy-3,6-dihydroxycarbonylnaphthalene (4.64 g) and aniline (4.10 g) were dispersed in xylene (92.8 g), followed by heating to 90° C. Phosphorous trichloride (2.4 g) was added dropwise at 90 to 100° C., and then the mixture was reacted at 140° C. for 3 hours. After the completion of the reaction, water (92.8 g) was added and the reaction solution was neutralized with sodium carbonate at 90° C. The solution was filtered at room temperature and washed in turn with xylene (46.4 g) and water (46.4 g). The resultant crystal was subjected to reflux washing using acetone (80 g) and then filtered. This operation was repeated three times, followed by drying to obtain 3.5 g of 2-hydroxy-3,6-diphenylaminocarbonylnaphthalene as a white powdered crystal (melting point: 314-317° C.).
Reaction SMILES: Cl.[CH:2]1([C:5]2[CH:6]=[C:7]([CH3:17])[C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.[CH:18]([C@@H:21]1[CH2:25][O:24][C:23](=[O:26])[N:22]1[C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)([CH3:20])[CH3:19]>>[CH:2]1([C:5]2[CH:6]=[C:7]([CH3:17])[C:8]([N:11]3[CH2:12][CH2:13][N:14]([C:31]([C:30]4[CH:29]=[CH:28][C:27]([N:22]5[C@H:21]([CH:18]([CH3:19])[CH3:20])[CH2:25][O:24][C:23]5=[O:26])=[CH:35][CH:34]=4)=[O:32])[CH2:15][CH2:16]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C(C)C)cc2)CC1
Yield: 42.5 %

Procedure:
By reaction and treatment in the same manner as in Example 29 and using 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (381 mg) described in Preparation Example 49 and (R)-4-(4-isopropyl-2-oxooxazolidin-3-yl)benzoic acid (374 mg) described in Preparation Example 18, the title compound (286 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:24]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[I:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1cc(OCc2ccccc2)ccn1Cc1cccc(F)c1
Solvent: CC#N
Product: O=c1c(I)c(OCc2ccccc2)ccn1Cc1cccc(F)c1
Temperature: 65 °C
Yield: 90.6 %

Procedure:
A mixture of 4-(benzyloxy)-1-(3-fluorobenzyl)pyridin-2(1H)-one (4.83 g, 15.6 mmol) in anhydrous acetonitrile (55 mL) and N-iodosuccinimide (NIS, 3.86 g, 17.1 mmol) was heated at 65° C. under nitrogen for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (silica gel) using ethyl acetate/hexane (1:1 v:v). The appropriate fractions were collected according to ES MS (M+H 436) and washed with Na2SO3 to remove the color impurities. The fractions were concentrated under reduced pressure and dried in vacuo to afford the desired product (6.15 g, 90%) as a light yellow solid. 1H-NMR (CD3OD, 400 MHz) δ7.73 (d, 1H, J=7.6 Hz), 7.47 (d, 2H, J=7.2 Hz), 7.39 (m, 4H), 7.08 (m, 3H), 6.39 (d, 1H, J=8.0 Hz), 5.29 (s, 2H), 5.19 (s, 2H); ES-HRMS m/z 436.0210 (M+H calculated for C19H16NO2FI requires 436.0196).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][CH:10]=O.Br[Si](C)(C)C.[NH2:18][C:19]1[N:24]=[C:23]([OH:25])[CH:22]=[C:21]([NH:26][CH3:27])[N:20]=1>O.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.C(#N)C>[NH2:18][C:19]1[NH:24][C:23](=[O:25])[C:22]2[C:9]([C:2]3[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=3[CH3:12])=[CH:10][N:26]([CH3:27])[C:21]=2[N:20]=1
Reactant: CNc1cc(O)nc(N)n1
Reactant: Cc1cc(C)c(CC=O)c(C)c1
Agent: C[Si](C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CS(C)=O
Product: Cc1cc(C)c(-c2cn(C)c3nc(N)[nH]c(=O)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of dimethylsulfoxide (468 mg, 6.00 mmol) and acetonitrile (8 ml) was added to a mixture of mesitylacetoaldehyde (904 mg, 5.57 mmol), bromotrimethylsilane (919 mg, 6.00 mmol) and acetonitrile (8 ml) at 0° C. After stirring at room temperature for 0.5 hour, the mixture was diluted with water (70 ml) and extracted with ethyl acetate (100 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. A mixture of the residue, 2-amino-6-(methylamino)pyrimidin-4-ol (1.69 g, 6.00 mmol), potassium carbonate (50 mg) and dimethylsulfoxide (3 ml) was heated at 100° C. for 1 hour. After cooling, the mixture was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extracts were combined, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (1:1) to give 1.07 g (68%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:15][C:14](=[O:16])[C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.C(N(CC)CC)C.Cl.ClCC[N:29]1[CH2:36][CH:35]2[CH2:37][CH:31]([CH2:32][CH2:33][CH2:34]2)[CH2:30]1>>[CH:31]12[CH2:37][CH:35]([CH2:34][CH2:33][CH2:32]1)[CH2:36][N:29]([CH:12]1[NH:11][CH2:10][C:9]3[C:14](=[O:16])[O:15][C:5]4[CH:4]=[C:3]([CH3:17])[C:2]([Cl:1])=[CH:7][C:6]=4[C:8]=3[CH2:13]1)[CH2:30]2
Reactant: Cc1cc2oc(=O)c3c(c2cc1Cl)CCNC3
Reactant: ClCCN1CC2CCCC(C2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc2oc(=O)c3c(c2cc1Cl)CC(N1CC2CCCC(C2)C1)NC3
Yield: 64.4 %

Procedure:
Prepared by the method described for Example 13 from 9-chloro-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (1.2 g, 0.005 moles), triethylamine (1.4 ml, 0.010 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.3.1]nonane hydrochloride (1.1 g, 0.005 moles). Recrystallization from methanol gave the product (1.2 g), mp 147°-149° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12](OC)=[C:13]([C:16]#[N:17])[C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[OH:20][CH2:21][CH2:22][NH:23][NH2:24].C(N(CC)CC)C.O>C(O)C>[NH2:17][C:16]1[N:23]([CH2:22][CH2:21][OH:20])[N:24]=[C:12]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[C:13]=1[C:14]#[N:15]
Reactant: NNCCO
Reactant: CCOc1cc(C(OC)=C(C#N)C#N)ccc1OC
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1cc(-c2nn(CCO)c(N)c2C#N)ccc1OC
Temperature: 25 °C

Procedure:
2-((3-ethoxy-4-methoxyphenyl)(methoxy)methylene)malononitrile (200 mg, 0.78 mmol), 2-hydroxyethylhydrazine (0.056 mL, 0.78 mmol), and triethylamine (0.10 mL, 0.78 mmol) were combined in ethanol (5 mL) and heated to reflux for 90 minutes. The reaction was then cooled to RT, water was added and the aqueous phase was extracted three times with EtOAc, CH2Cl2, and CHCl3. The organic phase was concentrated and carried onto the next step without further characterization. ESI-MS (M+H)+ m/z calcd 303.1, found 303.0.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]C2)=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:32][CH2:31][C@H:30]([C:33](O)=[O:34])[CH2:29]2)[N:23]=1.C(OC(N1CC(C(O)=O)C1)=O)C1C=CC=CC=1>>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:32][CH2:31][C@H:30]([C:33]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][C@@H:7]4[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9]4)=[CH:20][CH:21]=3)=[O:34])[CH2:29]2)[N:23]=1
Reactant: O=C(O)[C@H]1CCN(c2cccnn2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Agent: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(NC(=O)[C@H]3CCN(c4cccnn4)C3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1A, substituting (R)-tert-butyl 3-(4-aminophenoxy)pyrrolidine-1-carboxylate for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and (S)-1-(pyridazin-3-yl)pyrrolidine-3-carboxylic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([CH3:29])[CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:33][CH2:34]1
Reactant: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f53) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH2:20])[N:3]=1.[H-].[Na+].I[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[O:13][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])=[C:4]([NH2:20])[N:3]=1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CCCCCCCCCCCCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.4 %

Procedure:
2,6-Diamino-9-(β-D-ribofuranosyl)purine (50 g, 180 mmol) and sodium hydride (7 g) in DMF (1 L) were heated to boiling for 2 hr. Iodooctadecane (100 g) was added at 150° C. and the reaction mixture allowed to cool to RT. The reaction mixture was stirred for 11 days at RT. The solvent was evaporated and the residue purified by silica gel chromatography. The product was eluted with 5% MeOH/CH2Cl2. The appropriate fractions were evaporated to yield the product (11 g). 1H NMR (DMSO-d6) 67 0.84 (t, 3, CH2); 1.22 (m, 32, O—CH2—CH2—(CH2)16); 1.86 (m, 2, O—CH2CH2); 3.25 (m, 2, O—CH2); 3.93 (d, 1, 4′H), 4.25 (m, 1, 3′H); 4.38 (t, 1, 2′H); 5.08 (d, 1, 3′-OH); 5.48 (t, 1, 5′-OH); 5.75 (s, 2, 6-NH2); 5.84 (d, 1, 1′-H); 6.8 (s, 2, 2-NH2); and 7.95 (s, 1, 8-H).
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[C@@H:3]1[C@H:5]([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=2)[O:4]1.[CH2:18]([Li])CCC.CI>>[CH3:1][Si:2]([CH3:17])([CH3:16])[C@@H:3]1[C@:5]([CH3:18])([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=2)[O:4]1
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)[C@H]1O[C@H]1c1ccc2ccccc2c1
Solvent: CI
Product: C[C@@]1(c2ccc3ccccc3c2)O[C@@H]1[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
Trimethyl[(2R,3S)-3-(naphthalene-2-yl) oxirane-2-yl]silane (9.8 μg, 0.40 mmol) was dissolved in THF anhydride (1.6 mL) in a nitrogen atmosphere and the resultant solution was cooled down to −78° C. Thereinto, n-butyl lithium (2.69 molL−1 in 180.3 μL, 0.48 mmol of hexane solution) was dropped and the resultant reaction mixture was stirred at −78° C. for 90 minutes. Thereto, methyl iodide (99.8 μL, 1.60 mmol) was added and the resultant reaction mixture was stirred at −78° C. for 15 minutes. Thereafter, the reaction mixture was returned to the room temperature and was further stirred for 1 hour. The reaction was quenched with water and the resultant mixture was extracted with ethyl acetate. The organic phase was washed with water and saline and was dried over Na2SO4. The obtained crude product was purified by silica gel column chromatography (n-pentane/diethyl ether=0/0) to produce trimethyl [(2R,3S)-3-methyl-3-(naphthalene-2-yl) oxirane-2-yl]silane in a yield of 71%. Trimethyl[(2R,3S)-3-methyl-3-(naphthalene-2-yl) oxirane-2-yl]silane
Reaction SMILES: Cl[CH2:2][S:3]([NH:6][C:7]1[C:28]([OH:29])=[CH:27][C:10]2[C@H:11]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:12]([OH:17])[C:13]([CH3:16])([CH3:15])[O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4].[OH-].[Na+].[Cl-].[NH4+]>CO>[CH3:15][C:13]1([CH3:16])[C@H:12]([OH:17])[C@@H:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:9](=[CH:8][C:7]3[NH:6][S:3](=[O:5])(=[O:4])[CH2:2][O:29][C:28]=3[CH:27]=2)[O:14]1
Reactant: CC1(C)Oc2cc(NS(=O)(=O)CCl)c(O)cc2[C@H](NCCc2ccccc2)[C@H]1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Oc2cc3c(cc2[C@H](NCCc2ccccc2)[C@H]1O)OCS(=O)(=O)N3
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
To a solution of 1-Chloro-N-{(3R*,4S*)-3,6-dihydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-7-yl} methanesulfonamide (220 mg, 0.50 mmol) in methanol (2.2 mL), 1 mol/L sodium hydroxide aqeuous solution (1.00 mL, 1.00 mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours. Then, the temperature was raised to 50° C., and the mixture was further stirred for 2 hours. Upon the completion of the reaction, the solution was cooled on standing, neutralized with saturated aqueous ammonium chloride solution, extracted 4 times with chloroform, and dried over anhydrous sodium sulfate. The solvent was distilled off and the aimed product was obtained (yield: 37%).
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=4)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:14]2=[O:42])[CH2:9][CH2:8]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([N:15]2[CH2:16][C:17]3[C:18](=[N:19][C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=4)=[N:21][CH:22]=3)[N:13]([C@H:10]3[CH2:11][CH2:12][C@H:7]([OH:6])[CH2:8][CH2:9]3)[C:14]2=[O:42])=[CH:35][CH:36]=1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccc(OC)c(OC)c4)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(N2Cc3cnc(Nc4ccc(OC)c(OC)c4)nc3N([C@H]3CC[C@H](O)CC3)C2=O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(4-methoxy-phenyl)-7-(3,4-dimethoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (90 mg, 0.24 mmol) (from Example 19b supra) in dichloromethane (5 mL) was added trifluoroacetic acid (2.0 mL) (Aldrich) at 0° C. The mixture was stirred at 0° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate to give crude product which was recrystallized from ethyl acetate-hexanes to give 3-(4-methoxy-phenyl)-1-(trans-4-hydroxy-cyclohexyl)-7-(3,4-dimethoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 41 mg, 59%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:5]([N:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9](O)=[O:10])=[O:6]>O1CCCC1>[CH3:1][N:2]1[C:3]2[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=2[C:5](=[O:6])[N:7]2[CH2:14][CH2:13][CH2:12][CH:8]2[C:9]1=[O:10]
Reactant: CNc1ccccc1C(=O)N1CCC[C@H]1C(=O)O
Solvent: C1CCOC1
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 24.8 g of (-)-1-(N-methylanthraniloyl)proline and 18.0 g. of N,N'-carbonyldiimidazole in 300 ml. of dry tetrahydrofuran is stirred for 2 hours at room temperature and then heated at reflux temperature for 3 hours. The reaction mixture is concentrated to remove the solvent and the residue is extracted into benzene. The benzene solution is washed twice with water and concentrated to recover the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH2:10]Cl)=[CH2:9])[N:3]=1.[Br-:12].[K+].CC(=O)CC.CN(C)C=O>O>[Br:12][CH2:10][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=1)=[CH2:9]
Reactant: C=C(CCl)c1cccc(Cl)n1
Reactant: [Br-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=C(CBr)c1cccc(Cl)n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 64.7 %

Procedure:
A mixture of 1.0 g of 2-chloro-6-(1-chloromethylvinyl) pyridine, 2.0 g of potassium bromide, 5 ml of 2-butanone and 5 ml of N,N-dimethylformamide was stirred at 100° C. for 12 hours. After the reaction mixture was cooled to room temperature, water was added thereto to extract the mixture with ethyl acetate. The extract was subsequently washed with an aqueous solution of 10% sodium thiosulfate, water, saturated saline solution in that order, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane - ethyl acetate 25:1) to obtain 0.80 g of the objective compound.