Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:24])[CH2:10][CH2:11][CH2:12][C:13]([C:15]1[N:20]=[C:19](I)[C:18]([O:22][CH3:23])=[CH:17][CH:16]=1)=[O:14].[CH3:25][O:26][C:27](=[O:30])[CH:28]=[CH2:29]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:7][O:8][C:9](=[O:24])[CH2:10][CH2:11][CH2:12][C:13]([C:15]1[N:20]=[C:19](/[CH:29]=[CH:28]/[C:27]([O:26][CH3:25])=[O:30])[C:18]([O:22][CH3:23])=[CH:17][CH:16]=1)=[O:14]
Reactant: C=CC(=O)OC
Reactant: COC(=O)CCCC(=O)c1ccc(OC)c(I)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1nc(C(=O)CCCC(=O)OC)ccc1OC
Temperature: 100 °C
Reaction time: 5 h

Procedure:
244 mg of palladium acetate, 3.66 g of potassium carbonate and 3.4 g of tetrabutylammonium bromide are added to a solution of 3.87 g of 5-(2-iodo-3-methoxy-6-pyridyl)-5-oxopentanoic acid methyl ester and 1.87 ml of acrylic acid methyl ester in 10 ml of dimethylformamide, and the suspension is heated to 100° C. with stirring and under argon atmosphere for 5 hours. The solvent is removed in a vacuum, the residue is mixed with water, shaken out with ethyl acetate, the organic phase is dried on sodium sulfate and concentrated by evaporation. The crude product is chromatographed on silica gel with hexane/0-15% ethyl acetate. 1.89 g of 5-{3-methoxy-2-[2-methoxycarbonyl-(1E)-1-ethenyl-]-6-pyridyl}-5-oxopentanoic acid methyl ester of melting point 87°-89° C. is obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[C:14]([F:20])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([F:20])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc(OCCCCc2ccccc2)cc1F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(OCCCCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A solution of 4-(4-phenylbutoxy)-2-fluorobenzyl alcohol (1.38 g, 5.03 mmol) in dichloromethane (50 ml) was added with pyridinium chlorochromate (1.63 g, 7.54 mmol), stirring at room temperature for 1 h. After that the reaction mixture was filtered on celite, washing with dichloromethane. After drying and removing the solvent, the resulting crude was purified by chromatography through a silica gel column, eluting with dichloromethane, thereby recovering 1.02 g of the title compound (74% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([C:6](=[O:17])[NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:3]([OH:5])=[O:4].[F:19][C:20]([F:32])([F:31])C1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:1][C:2]([CH3:18])([C:6](=[O:17])[NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:20]([F:32])([F:31])[F:19])[CH:12]=1)(=[O:10])=[O:9])[C:3]([OH:5])=[O:4]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C(=O)O)C(=O)NS(=O)(=O)c1ccccc1
Product: CC(C)(C(=O)O)C(=O)NS(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
2,2-dimethyl-3-oxo-3-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)propanoic acid was prepared in the same manner as 2,2-dimethyl-3-oxo-3-[(phenylsulfonyl)amino]propanoic acid starting from 3-(trifluoromethyl)benzenesulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]>C(OCC)(=O)C.[Pd]>[NH2:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[CH:12]=1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N)cc1F

Procedure:
To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 6.4 mmol, Aldrich) and Na2Cr2O7 (2.74 g, 8.4 mmol) in 13.7 ml of HOAc was added slowly 6.83 ml of H2SO4. This mixture was slowly heated to 90° C. for 1 hour to give a greenish heterogeneous solution. The mixture was cooled to room temperature and diluted with ethyl acetate. The pH of the solution was adjusted to 4 with aqueous NaOH. The mixture was extracted with more ethyl acetate. The combined organic layers were washed with NaHCO3 (sat.), then brine and dried over Na2SO4. After filtration, the solution was concentrated to dryness which then was dissolved in 6 ml of SOCl2, and heated at 80° C. for 1 hour. The excess of SOCl2 was removed under reduced pressure and the residue was dissolved in 5 ml of CH2Cl2, 2 ml of EtOH and 2 ml of pyridine. The mixture was stirred at room temperature for 2 hours and concentrated to dryness. Ethyl 2-fluoro-4-nitrobenzoate was obtained as a white solid after column chromatography of the residue with ethyl acetate/hexane (1/9). This solid was then dissolved in 10 ml of ethyl acetate, and Pd/C (50 mg) was added. Hydrogenation converted ethyl 2-fluoro-4-nitrobenzoate into the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]OS(C)(=O)=O)=[CH:33][C:32]=2[CH3:46])=[C:28]([CH:47]([CH3:49])[CH3:48])[NH:27][N:26]=1)(=O)C.[NH2:50][C:51]([CH3:55])([CH3:54])[CH2:52][OH:53].[I-].[Na+]>C(#N)C.C(O)C>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:50][C:51]([CH3:55])([CH3:54])[CH2:52][OH:53])=[CH:33][C:32]=3[CH3:46])=[C:28]([CH:47]([CH3:48])[CH3:49])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOS(C)(=O)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)CO
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: Cc1cc(OCCCNC(C)(C)CO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (1 g) in dichloromethane (16 mL) were added triethylamine (0.29 mL) and methanesulfonyl chloride (0.15 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole (1.12 g). The obtained 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]-2-methylphenyl}methyl)-1H-pyrazole (0.2 g) was dissolved in a mixed solvent of acetonitrile (2 mL) and ethanol (2 mL). To the solution were added 2-amino-2-methyl-1-propanol (0.25 g) and a catalytic amount of sodium iodide, and the mixture was stirred at 60° C. for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.16 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (0.13 g).
Reaction SMILES: C(=O)([O-])O.[Na+].[O:6]=[C:7]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:32][CH2:33][CH3:34])=[CH:16][C:11]=2[O:10][C:9]([C:35]([O:37]CC)=[O:36])=[CH:8]1.C(O)C>O>[O:6]=[C:7]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:32][CH2:33][CH3:34])=[CH:16][C:11]=2[O:10][C:9]([C:35]([OH:37])=[O:36])=[CH:8]1
Reactant: CCCc1ccccc1OCCCCCCCOc1ccc2c(=O)cc(C(=O)OCC)oc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1ccccc1OCCCCCCCOc1ccc2c(=O)cc(C(=O)O)oc2c1

Procedure:
A solution of 2.15 parts of sodium hydrogen carbonate in 40 parts of water was added to a refluxing solution of 3.0 parts of ethyl 4-oxo-7-[7-(2-n-propyl phenoxy)heptyloxy]-4H-1-benzopyran-2-carboxylate in 50 parts of ethanol. More water was added to produce a clear solution which was refluxed for 2 hours. Acidification of the filtrate precipitated the acid as a semi-solid mass which was converted to a fine solid by persistent mechanical disruption of the gum cakes. The solid was filtered off, dried and crystallised from benzene/petrol (bp. 80°-100°) to furnish 2.8 parts of 4-oxo-7-[7-(2-n-propylphenoxy)heptyloxy]-4H-1-benzopyran-2-carboxylic acid as white microcrystals, mp. 149°-150° .
Reaction SMILES: [OH:1][CH2:2][C:3]1([OH:6])[CH2:5][CH2:4]1.[CH3:7][S:8](Cl)(=[O:10])=[O:9]>C(Cl)Cl>[CH3:7][S:8]([O:1][CH2:2][C:3]1([O:6][S:8]([CH3:7])(=[O:10])=[O:9])[CH2:5][CH2:4]1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(O)CC1
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(OS(C)(=O)=O)CC1
Temperature: -10 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
To a mixture of 1-(hydroxymethyl)cyclopropanol (100 mg, 1.14 mmol) and TEA (202 mg, 1.82 mmol, Shantou Xilong chemical factory) in 20 mL of dry CH2Cl2 under N2, was added MsCl (156 mg, 1.32 mmol, Shanghai Haiqu chemical Ltd.) dropwise via a syringe at −10° C. After stirring for 4 hrs at −10° C., the mixture was washed with ice-water and extracted with CH2Cl2 (30 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give the desired compound as pale yellow oil (139 mg, 50%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([OH:15])=O)[CH2:2][CH:3]=[CH2:4].C(Cl)(=O)C(Cl)=O.[NH:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH2:23].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([NH:23][NH:22][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:15])[CH2:2][CH:3]=[CH2:4]
Reactant: CC(C)(C)OC(=O)NN
Reactant: C=CCCOc1ccccc1CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCOc1ccccc1CC(=O)NNC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of 2-(2-(but-3-en-1-yloxy)phenyl)acetic acid (0.22 g, 1.06 mmol, 1 equiv) in DCM (11 mL) was added one drop DMF followed by oxalyl chloride (0.19 mL, 2.11 mmol, 2 equiv). Gas evolution observed. After 1 h, the reaction was concentrated in vacuo to provide the crude acid chloride. The acid chloride was taken up in DCM (5 mL) and added slowly to a solution of tert-butyl hydrazinecarboxylate (168 mg, 1.27 mmol, 1.2 equiv) and DIPEA (0.55 mL, 3.17 mmol, 3 equiv) in DCM (11 mL). After stirring 1 h, the reaction was diluted with DCM, washed with saturated aqueous NaHCO3, dried (MgSO4), and concentrated in vacuo. The crude product was purified via flash column chromatography (0-100% EtOAc/hexane) to provide the product (0.28 g, 83%) as a viscous tan oil. 1H NMR (400 MHz, CDCl3) δ 7.62 (br. s., 1H), 7.31-7.23 (m, 2H), 7.00-6.87 (m, 2H), 6.48-6.26 (m, 1H), 5.99-5.85 (m, 1H), 5.23 (dd, J=17.1, 1.5 Hz, 1H), 5.17 (d, J=10.3 Hz, 1H), 4.14-4.09 (m, 2H), 3.61 (s, 2H), 2.61 (q, J=6.4 Hz, 2H), 1.48-1.36 (m, 9H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[C:24]1(B(O)O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:32]4[C:33]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:29]=[CH:30][CH:31]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4cccc5ccccc45)c(C(=O)O)s3)c2cc1OC
Yield: 36.9 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 1-naphthaleneboronic acid (25.8 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-naphthalen-1-yl-thiazole-5-carboxylic acid (15.9 mg, 37%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.41 (br.s., 1 H); 8.85 (s, 1 H); 8.01-8.09 (m, 2H); 7.92 (dd, 1 H); 7.72 (dd, 1 H); 7.69 (s, 1H); 7.50-7.65 (m, 3H); 7.40 (s, 1 H); 3.84 (s, 3 H); 3.68 (s, 3 H). MS m/z 432 (M+1).
Reaction SMILES: [I:1]Cl.[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]2[N:11]=[CH:12][CH:13]=[C:6]2[N:5]=1>C(Cl)(Cl)Cl>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]2[N:11]=[CH:12][C:13]([I:1])=[C:6]2[N:5]=1
Reactant: Cc1cc(C)n2nccc2n1
Reactant: ClI
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)n2ncc(I)c2n1

Procedure:
A solution of ICl [5.0g (27 mmoles)] in CHCl3 (50 ml) was added to a stirred solution of 5,7-dimethyl pyrazolo[1,5-a]pyrimidine [2.96g (20 mmoles)] in CHCl3 (50 ml). Within a few minutes, the mixture became warm and crystals of the hydrochloride salt of the subject compound began to separate. The mixture was warmed on the steam bath for 2-3 minutes to complete the reaction, and then refrigerated overnight. The yellow hydrochloride salt was separated by filtration, washed with Et2O, and air dried. The yellow solid, which weighed 4.4g, was dissolved in water (100 ml) and this solution was made alkaline by the addition of NaOH solution (2.5N). The alkaline solution was extracted with CHCl3 3(25 ml), and the CHCl3 extracts were dried over Na2SO4. The CHCl3 extract was chromatographed on basic alumina, and the CHCl3 eluant evaporated to dryness. The residue was recrystallized from petroleum ether (30°-60°) to afford 2.02g (37%) of analytically pure product; mp 120°-2°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[O:16][CH2:15][CH:14]([NH:20]C(=O)OC(C)(C)C)[CH2:13]3)[CH:6]=[CH:5][N:4]=1)#[N:2]>Cl.O1CCOCC1>[NH2:20][CH:14]1[CH2:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([O:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:1]#[N:2])[CH:8]=3)[CH:11]=2)[O:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)NC1COc2ccc(Oc3ccnc(C#N)c3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(Oc2ccc3c(c2)CC(N)CO3)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
A solution of tert-butyl {6-[(2-cyanopyridin-4-yl)oxy]-3,4-dihydro-2-H-chromen-3-yl}carbamate in 2M HCl in dioxane (8 mL) was allowed to stir at rt overnight. The reaction mixture was concentrated and the residue was purified by column chromatography to give 4-[(3-amino-3,4-dihydro-2H-chromen-6-yl)oxy]pyridine-2-carbonitrile (0.17 g, 12%).
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:11][CH2:10][C@@H:9]([N:12]2[C:17]3=[N:18][C:19]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:13]2=[O:37])[CH2:8]1)(C)(C)C.O>FC(F)(F)C(O)=O.ClCCl>[OH:6][C@@H:7]1[CH2:11][CH2:10][C@@H:9]([N:12]2[C:17]3=[N:18][C:19]([NH:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:13]2=[O:37])[CH2:8]1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@@H]3CC[C@@H](O[Si](C)(C)C(C)(C)C)C3)C2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@@H]3CC[C@@H](O)C3)C2=O)cc1
Reaction time: 0.5 h

Procedure:
(−)-(1R,3R)-1-[3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentyl]-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (148 mg, 0.27 mmol) (from Example 27e supra) was dissolved at 0° C. in a 25% trifluoroacetic acid in dichloromethane solution (5 mL) that contained water (300 μL). After stirring for 30 minutes the reaction mixture was partitioned between ethyl acetate and 0.5 N aqueous sodium hydroxide. The pH of the aqueous layer was adjusted to 12 via the addition of solid sodium hydroxide. The organic layer was then collected, dried over sodium sulfate, filtered and concentrated to give the crude product. Purification by silica gel column chromatography using a 0–100% ethyl acetate in hexanes to 0–40% tetrahydrofuran in ethyl acetate gradient followed by a precipitation out of dichloromethane with excess pentane afforded (+)-(1R,3R)-1-(3-hydroxy-cyclopentyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid. (Yield 92 mg, 86%).
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([N:30]=[C:31]=[S:32])[CH3:29].ClCCl.C(OCC)(=O)C>C(O)C>[CH2:28]([NH:30][C:31]([NH:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:17]2[CH:26]=[CH:27][C:14]([C:12]3[N:13]=[C:9]([CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[NH:10][CH:11]=3)=[CH:15][CH:16]=2)=[CH:25][CH:24]=1)=[S:32])[CH3:29]
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Reactant: CCN=C=S
Solvent: ClCCl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCNC(=S)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Yield: 45 %

Procedure:
A mixture containing 4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (0.5 g, 1.40 mmol) and ethylisothiocyanate (0.162 g, 1.70 mmol) in 10 ml of ethanol is heated for four hours under reflux. 5 ml of dichloromethane and traces of ethyl acetate and ethanol are added to the residue obtained. The medium is stirred for thirty minutes, then filtered and the solid obtained is dried. A cream-coloured powder is obtained with a yield of 45%.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[S:4].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([CH3:18])=[N:15]2)=[CH:10][CH:9]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:6])[C:3](=[S:4])[O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([CH3:18])=[N:15]2)=[CH:10][CH:9]=1
Reactant: CN(C)C(=S)Cl
Reactant: Cc1ccc2ccc(O)cc2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc2ccc(OC(=S)N(C)C)cc2n1
Reaction time: 24 h
Yield: 147.9 %

Procedure:
Referring now to FIG. 22, under nitrogen, dimethylthio-carbamoyl chloride (1.35 g, 10.95 mmol) and DMAP (1.33 g, 10.95 mmol) were added to a suspension of 4 (300.0 mg, 0.628 mmol) in CH2Cl2 (6 mL). The dark brown solution was stirred for 24 h before it was diluted with chloroform and purified by column chromatography (4:6 to 1:1 EtOAc/hexane) to provide 16 (299 mg, 0.929 mmol, 64%) as an off-white solid: 1H NMR (CDCl3) δ 8.05, (1H, d, J=8.4 Hz), 7.78 (1H, d, J=8.8 Hz), 7.67 (1H, d, J=2.4 Hz), 7.29 (1H, dd, J=8.0, 2.8 Hz), 7.27, (1H, dd, J=8.4, 3.6 Hz), 3.48 (3H, s), 3.40 (3H, s), 2.73 (3H, s); 13C NMR (CDCl3) δ 187.6, 159.9, 154.7, 148.6, 136.2, 128.3, 124.8, 122.7, 122.1, 120.9, 43.5, 39.1, 25.6; FTIR (neat) 3379, 2940, 1624, 1603, 1531, 1504, 1393, 1283, 1206, 1169, 1130, 843, 748 cm−1; MS (ESI) m/z calculated for (C13H14N2OS+H)+ 247, found 247; HRMS (ESI) m/z calculated for (C13H14N2OS+H)+ 247.0905, found 201.0900.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: CCc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(4-fluorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH3:5][N:6]([C:8]([NH:10][C:11]([NH2:13])=[NH:12])=[NH:9])[CH3:7]>CC(C)=O>[CH3:5][N:6]([C:8]([NH:10][C:11]([NH2:13])=[NH:12])=[NH:9])[CH3:7].[C:1]([O-:4])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Agent: CN(C)C(=N)NC(=N)N
Solvent: CC(C)=O
Product: CC(=O)[O-]

Procedure:
20.00 g (1 equivalent) of metformin hydrochloride and 4.84 g (1 equivalent) of sodium hydroxide were stirred in 200 Ml of ethanol for 2 hours at room temperature, and then remaining solid was filtered and the filtrate was concentrated under reduced pressure. Then 300 Ml of acetone was added to the resulting solid and stirred. Insoluble material was filtered, and the filtrate was concentrated under reduced pressure to obtain 12.0 g of metformin free base. 500 Ml of acetone and 10 Ml (1.45 equivalents) of glacial acetic acid were added to the metformin free base, and then the mixture was stirred. The resulting crystal was filtered and washed with acetone, and then dried at 60° C. to obtain 13.6 g of metformin acetate (yield: 59.5%).
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])=[C:10]([CH3:21])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:22])=[N:7]2.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:30][CH3:31]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([C@H:12]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:13]([O:15][CH2:30][CH3:31])=[O:14])=[C:10]([CH3:21])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:22])=[N:7]2
Reactant: CCI
Reactant: Cc1ccc2c(Br)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetic acid (17 g, 46.6 mmol) in DMF (200 mL) was added Cs2CO3 (30.4 g, 93.2 mmol), followed with the addition of iodoethane (11 g, 69.9 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours, diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product. LCMS-ESI+: calc'd for C19H24BrNO3: 394.1 (M+H+); Found: 394.0 (M+H+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:29])([F:28])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:26][CH2:25][C:15]3([CH2:24][CH2:23][C:18]4([O:22][CH2:21][CH2:20][O:19]4)[CH2:17][CH2:16]3)[C:14]2=[O:27])=[CH:9][CH:8]=1)[OH:6].I[CH3:31]>CN(C=O)C>[F:29][C:4]([F:3])([F:28])[C@@H:5]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:26][CH2:25][C:15]3([CH2:16][CH2:17][C:18]4([O:22][CH2:21][CH2:20][O:19]4)[CH2:23][CH2:24]3)[C:14]2=[O:27])=[CH:11][CH:12]=1)[O:6][CH3:31]
Reactant: CI
Reactant: O=C1N(c2ccc([C@@H](O)C(F)(F)F)cc2)CCC12CCC1(CC2)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H](c1ccc(N2CCC3(CCC4(CC3)OCCO4)C2=O)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 91.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 311 mg) was combined with DMF (10 mL) under argon. The suspension was cooled down to 0° C. and a solution of 10-[(R)-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (1.50 g) in DMF (15 mL) was added dropwise over a period of 10 minutes. The mixture was stirred for 45 minutes at 0° C., then, iodomethane (663 mg) was added dropwise over a period of 10 minutes. The mixture was stirred at 0° C. for 15 minutes and then warmed up to RT for 1.5 hours. The reaction mixture was poured into ice/water and was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was once again evaporated with toluene (200 mL). The crude material was purified by flash chromatography (gradient of ethyl acetate in heptane) to give the title compound as a colorless solid (1.42 g). MS (ESI): 400.2 (MH+).