Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=2[F:17])=[C:4]([Cl:18])[N:3]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:18][C:4]1[C:5]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=2[F:17])=[C:6]([Cl:8])[N:7]=[C:2]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[N:3]=1
Reactant: Fc1cc(F)c(-c2c(Cl)nc(Cl)nc2Cl)c(F)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cc(F)c(-c2c(Cl)nc(-n3ccnc3)nc2Cl)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
A mixture of the above 2,4,6-trichloro-5-(2,4,6-trifluorophenyl)pyrimidine (104 mg), imidazole (23 mg, 0.33 mmol), and potassium carbonate (92 mg, 0.66 mmol) in 2 mL of N,N-dimethylformamide is stirred at room temperature for 3 h. The mixture is partitioned between ethyl acetate and saturated sodium chloride. The organic layer is washed with saturated sodium chloride (×4), dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of hexanes to 50% ethyl acetate in hexanes. Concentration provides 4,6-dichloro-2-(1H-imidazol-1-yl)-5-(2,4,6-trifluorophenyl)pyrimidine as a tan solid (71 mg, mp 72-74° C.). MS: m/z 345.2 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[Cl:35])=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[ClH:34].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[Cl:35])=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3cc(Cl)ccc3Cl)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2cc(Cl)ccc2Cl)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 163 %

Procedure:
Compound 66-4 (740 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (500 mg) as a white powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][C:5]#[C:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=2[F:24])[CH:8]=1)[CH3:2].C1(C)C=CC=CC=1.C(O)C.Cl.[C:38]1([CH2:44][C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCOCC1.C1(C)C=CC=CC=1>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][C:5]#[C:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:48]([NH:47][C:45](=[O:46])[CH2:44][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[S:49])=[CH:19][C:18]=2[F:24])[CH:8]=1)[CH3:26]
Reactant: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: C1COCCO1
Product: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
To a stirred solution of 4-(2-(3-(diethylamino)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine (369 mg, 1.00 mmol) in 1:1 toluene/ethanol (5 mL) was added a solution of 4N HCl (0.375 mL, 1.50 mmol) in dioxane. Then 2-phenylethanoyl isothiocyanate (886 mg, 5.00 mmol; prepared according to J. Org. Chem. 1964, 29, 1115-1119) was added as a solution in toluene (1 mL) all at once. After stirring for 30 minutes at room temperature, the reaction mixture was concentrated. The residue was triturated with EtOAc (5 mL), and the resulting suspension was stirred for 1 hour to break up large chunks. The yellow suspension was filtered. The yellow solid was partitioned between EtOAc (15 mL) and a saturated aqueous solution of NaHCO3 (20 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (2×15 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. The crude was purified on a Biotage Horizon system using a reverse phase C18 column (M25 size). The following gradient was utilized [solvent A=water, solvent B=CH3CN]: 15-30% B (100 mL), 30-70% B (300 mL), 70-95% B (100 mL), 95-100% B (100 mL), collecting in 96×9 mL tubes. Residual water/CH3CN was azeotroped with absolute EtOH (3×20 mL). The product was obtained as a white powder (170 mg, 31%). 1H NMR (400 MHz, CDCl3) δ 12.51 (br s, 1H), 8.59 (br s, 1H), 8.51 (d, J=6 Hz, 1H), 7.94 (m, 1H), 7.59 (s, 1H), 7.41 (m, 4H), 7.32 (m 2H), 7.26 (m, 1H, overlaps chloroform), 6.54 (d, J=6 Hz, 1H), 3.76 (s, 2H), 3.74 (s, 2H), 2.67 (q, J=7 Hz, 4H), 1.15 (t, J=7 Hz, 6H). LRMS (APCI neg) m/e 545 (M−1). HPLC: 100% purity (220 nm).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][N:21]([CH3:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][NH2:34])[CH2:27]1>>[CH3:35][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][NH:34][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:27]1
Reactant: CN(C)CCCCC1CCCN(CCN)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Product: CN(C)CCCCC1CCCN(CCNC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Yield: 53 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[3-[4-(dimethylamino)butyl]-piperidin-l-yl]ethanamine in a yield of 53% of theory. Colourless crystals, m.p. 119°-120° C.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7](OCC)=[O:8])[CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C>C1C=CC=CC=1>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
To a stirred solution of 1-tert-butyl 4-ethyl 1,4-piperidinedicarboxylate (Preparation 49, 12.8 g, 0.05 mol) in benzene (300 ml) under nitrogen was added slowly diisobutyl aluminium hydride (1 M solution, 100 ml, 0.1 mol). The reaction mixture was stirred at room temperature for 3 h before quenching by the addition of water (100 ml) followed by addition of hydrochloric acid (1 M) to adjust to pH 4. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated to give an oil. The crude oil was purified by flash chromatography on silica gel eluting with ethyl acetate:dichloromethane (6:4) to give the title compound as an oil (5.0 g, 46%).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1.[O:12]=[C:13]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:14]1>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[OH:12][C:13]1([CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]2=[O:3])[CH2:14][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:16]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Reactant: C[Si](C)(C)OC1=CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C1CCCCC1C1(O)CN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 5 h
Yield: 92.4 %

Procedure:
A solution of 1-(trimethylsiloxy)cyclohexene (200 mg, 1.17 mmol) and benzyl 3-oxoazetidine-1-carboxylate (289 mg, 1.41 mmol), prepared using procedures similar to those described in Reference 3, in tetrahydrofuran (3.90 mL) was cooled to −78° C. for 10 minutes followed by the addition of titanium tetrachloride (0.13 mL, 1.17 mmol). The reaction mixture stirred for an additional 5 hours at −78° C. The mixture was quenched with aqueous sodium bicarbonate and the aqueous layer was extracted with ether (2×). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified on silica gel chromatography column (3:2 hexanes/ethyl acetate) to afford benzyl 3-hydroxy-3-(2-oxocyclohexyl)azetidine-1-carboxylate (328 mg, 37%). 1H NMR (CDCl3): 7.28-7.34 (m, 5H), 5.08 (s, 2H), 4.02 (d, 1H), 3.89 (d, 1H), 3.87 (s, 1H), 3.55 (s, 1H), 2.71 (q, 1H), 2.29-2.43 (m, 2H), 2.11 (s, 2H), 1.95 (s, 1H), 1.66 (d, 3H); MS (EI) for C17H21NO4: 303 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH3:18])=[CH:13][CH:12]=1)=[O:10].NO.[OH-].[K+].CO>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:17]([CH3:18])[C:14]2[CH:13]=[CH:12][C:11]([S:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])=[O:10])=[CH:16][CH:15]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)CCCCCS(=O)c1ccc(N(C)Cc2ccc(Cl)cc2)cc1
Agent: NO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1ccc(Cl)cc1)c1ccc(S(=O)CCCCCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of the 6-(4-((4-chlorobenzyl)-methylamino)-benzenesulfinyl)-hexanoic acid methyl ester (1.6 g, 4.0 mmol) in distilled THF (25 mL) containing 50% aqueous hydroxylamine (2.6 mL, 40 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 8 mL, 8 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (25 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (2×50 mL) and the combined extracts were washed with brine (100 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The solid residue was recrystallised from acetone/40-60° C. petroleum ether to give the title compound (867 mg, 53%) as a white powder, mp 109-111° C.
Reaction SMILES: [Br:1][C:2]1[C:15](=[O:16])[NH:14][C:5]2[N:6]=[C:7]([NH:11][CH2:12][CH3:13])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][OH:23]>CN(C=O)C>[Br:1][C:2]1[C:15](=[O:16])[N:14]([CH2:20][CH2:21][CH2:22][OH:23])[C:5]2[N:6]=[C:7]([NH:11][CH2:12][CH3:13])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1
Reactant: CCNc1nc(C)c2cc(Br)c(=O)[nH]c2n1
Reactant: OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNc1nc(C)c2cc(Br)c(=O)n(CCCO)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
To a solution of 6-bromo-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.35 mmol) in DMF (2 mL), prepared using procedures analogous to those described in Example 14, was added NaH (30 mg, 60%, 0.7 mmol). The mixture was stirred for 30 min at room temperature and was warmed to 70° C. 3-Bromopropanol (48 mg, 0.35 mmol) was then added. The stirring was continued for 12 h. Standard workup and purification by column chromatography gave 33 mg (27% yield) of 6-bromo-2-(ethylamino)-8-(3-hydroxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 5.42 (br s, 1H), 4.59 (br s, 2H), 3.50-3.47 (m, 5H), 2.55 (s, 3H), 2.02 (br s, 2H), 1.28 (t, 3H); MS (EI) for C13H17BrN4O2: 341 (MH+).
Reaction SMILES: [C:1]([N:3]=[C:4]([S-:6])[S-:5])#[N:2].[K+:7].[K+].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.CO>O>[C:1]([N:3]=[C:4]([S-:6])[S:5][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=1)#[N:2].[K+:7]
Reactant: ClCc1ccc(Cl)cc1
Reactant: N#CN=C([S-])[S-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#CN=C([S-])SCc1ccc(Cl)cc1
Reaction time: 5 h

Procedure:
A mixture of 80 g of dipotassium N-cyano-dithioimidocarbonate, 64.9 g of p-chlorobenzyl chloride, 400 ml of methanol and 400 ml of water was stirred for 5 hours and the solvents were evaporated. The residue was crystallized from ethanol to obtain monopotassium S-p-chlorobenzyl N-cyano-dithioimidocarbonate with a melting point of 250° C (dec).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:33][CH2:32][CH2:31][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:30])[CH2:21][S:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:33][CH2:32][CH2:31][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:30])[CH2:21][S:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)CS(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: O=C(CS(=O)c1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 79.4 %

Procedure:
(2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-[1-hydroxy-2-(phenylsulfinyl)ethyl]pyrrolidine (850 mg) was subjected to DMSO-DCC oxidation as in Example 1-D) to give 672 mg of (2S)-1-(N-benzyloxycarbonyl-L-prolyl)-2-[(phenylsulfinyl)acetyl]-pyrrolidine (See Table 1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1CCNCC1
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Brc1cccc(CN2CCCCC2)n1
Reaction time: 20 h

Procedure:
To a stirred solution of 6-bromo-2-pyridine carboxaldehyde (5.05 g, 27 mmol) in anhydrous CH2Cl2 (200 mL) at RT, under N2, piperidine (2.95 mL, 29 mmol) was added, followed by NaBH(OAc)3 (11.51 g, 54 mmol) and AcOH (6.2 mL, 108 mmol) 30 min later. After 20 h, a 2M solution of Na2CO3(aq) (20 mL) was added. The mixture was vigorously stirred for an additional 30 min, washed successively with a saturated solution of NaHCO3(aq) until the pH of the aqueous layer reached 7 (2×100 mL), H2O (100 mL) and brine (100 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound as a yellow oil. This was used crude in the next step. MS m/z: 255 (M+H), 257 (M+3).
Reaction SMILES: [H-].[Na+].CI.CN(C=O)C.[C:10]([O:14][C:15](=[O:32])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)=[CH:19][CH:18]=1)(C)(C)C>O.C(OCC)(=O)C>[CH3:10][O:14][C:15](=[O:32])[NH:16][C:17]1[CH:18]=[CH:19][C:20]([B:23]2[O:24][C:25]([CH3:30])([CH3:31])[C:26]([CH3:29])([CH3:28])[O:27]2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
60% Sodium hydride (0.55 g) and methyl iodide (1.2 mL) were added to a DMF (6.0 mL) solution of t-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (2.0 g), and the mixture was stirred for 18 hours at room temperature. Ethyl acetate and water were added to the reaction mixture, and the organic layer was isolated. The extract was washed sequentially with water and brine, and dried over anhydrous sodium sulfate. Then, the desiccant was filtered out, whereafter the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the precipitated solid was collected by filtration to obtain t-butyl=methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (white solid) (1.46 g, 70%).
Reaction SMILES: Cl.O1[C:6]2([CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[O:5]CC1>C1COCC1>[N:15]1[CH:16]=[CH:17][C:12]([CH:9]2[CH2:8][CH2:7][C:6](=[O:5])[CH2:11][CH2:10]2)=[CH:13][CH:14]=1
Reactant: c1cc(C2CCC3(CC2)OCCO3)ccn1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(c2ccncc2)CC1
Reaction time: 3 h
Yield: 69 %

Procedure:
2 M HCl (13.6 ml) was added to a solution of 4-(1,4-dioxaspiro[4.5]decan-8-yl)pyridine (3.0 g, 13.6 mmol, 1 eq) in THF (136 ml), and stirring was carried out for 3 h at RT. The solvent was removed under reduced pressure. The residue was diluted with water (50 ml) and rendered basic with solid sodium hydrogen carbonate. Then extraction with ethyl acetate (2×100 ml) was carried out. The combined organic phases were washed with water (80 ml), dried over sodium sulfate and concentrated under reduced pressure. The desired product was used in the next step without being purified further. Yield: 69% (1.65 g, 9.42 mmol).
Reaction SMILES: [C:1]([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:4][OH:5])#[N:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:20][S:21]([O:5][CH2:4][C:3]([C:1]#[N:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)(=[O:23])=[O:22]
Reactant: N#CC(CO)(c1ccc(Cl)cc1)c1ccccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CS(=O)(=O)OCC(C#N)(c1ccc(Cl)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-cyano-2-(2-chlorophenyl)-2-(4-chlorophenyl)ethanol (18 g., 0.06 mole) and methane sulfonyl chloride (7.8 g., 0.07 mole) in 200 ml. of benzene is added dropwise at 10° C., 7.5 g. (0.08 mole) of triethylamine. The reaction mixture is stirred at room temperature for 30 minutes and then heated on a steam bath for another 30 minutes. The precipitate formed is filtered and the filtrate is washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 22 g. of product; mp 124°-7° C., which is identified by nmr.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][N:37]([CH3:43])[CH2:38][CH2:39][CH2:40][NH:41][CH3:42]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:41]([CH2:40][CH2:39][CH2:38][N:37]([CH3:43])[CH3:36])[CH3:42])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: CNCCCN(C)C
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(N(C)CCCN(C)C)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 72.5 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (20 mg, 0.04 mmol) in DCM (5 mL) was added N,N,N′-trimethyl-1,3-propanediamine (0.029 mL, 0.20 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (16 mg, 72%). LC-MS m/z 552 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 3H), 1.66 (m, 4H), 2.03 (m, 2H), 2.19 (s, 6H), 2.32 (s, 3H), 2.98 (s, 3H), 3.37 (m, 4H), 4.15 (s, 2H), 7.17 (t, 2H), 7.45 (d, 1H), 7.53 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=[O:5])[CH3:2].[Li+].[CH3:24]C([N-]C(C)C)C.CI>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH3:24])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCN(CC2COc3ccccc3O2)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCCN(CC2COc3ccccc3O2)C1
Reaction time: 1 h

Procedure:
To a solution of 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine-3-carboxylic acid ethyl ester (10.05 g, 32.90 mmol) in dry THF (100 ml) at −78° C. was slowly added LDA (20.1 ml, 1.8 M). The reaction mixture was stirred at this temperature for 1 h. Methyl iodide (2.25 ml, 36.21 mmol) was then added, the cooling bath removed and stirring was continued for 10 h. After addition of water, the reaction mixture was extracted with EtOAc (3×25 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (EtOAc/heptane, 70:30).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[CH2:3][OH:4].[C:15]1([CH:21]2[CH2:23][CH:22]2[C:24](O)=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[OH:4][CH2:3][CH:2]([NH:1][C:24]([CH:22]1[CH2:23][CH:21]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:25])[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1
Reactant: O=C(O)C1CC1c1ccccc1
Reactant: N[C@@H](CO)c1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(CO)c1ccc2ccccc2c1)C1CC1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.5 %

Procedure:
A mixture of (R)-2-amino-2-naphthalen-2-yl-ethanol (0.2 mmol), 2-phenyl-cyclopropanecarboxylic acid (0.2 mmol), EDAC.HCl (0.4 mmol), DMAP (0.2 mmol), and triethylamine (0.6 mmol) in dichloromethane (2 mL) was stirred at room temperature for 12 h. The reaction mixture was purified by flash chromatography eluting with 50% hexanes in ethyl acetate to give the desired product (52 mg) as a solid.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:37])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=3)[N:14]=1)[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10](=[O:30])[C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:8]2)=[O:4].[NH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:23]([N:11]1[C:12]2[C:7](=[C:6]([OH:37])[C:5]([C:3]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:4])=[N:14][C:13]=2[C:15]2[CH:20]=[N:19][C:18]([S:21][CH3:22])=[N:17][CH:16]=2)[CH:8]=[C:9]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:10]1=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cnc(SC)nc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CSc1ncc(-c2nc(C(=O)NCCC(=O)O)c(O)c3cc(-c4ccccc4)c(=O)n(Cc4ccccc4)c23)cn1
Temperature: 25 °C
Yield: 42.1 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-(2-methylsulfanyl-pyrimidin-5-yl)-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (34 mg, 0.067 mmol), β-alanine (594 mg, 6.7 mmol) and NaOMe solution (10.7 mL, 5.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 16 mg of the title compound as an off-white solid. MS: (+) m/z 568.33 (M+1).