Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:29](=[O:30])[CH:28]=[C:21]2[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]2[C:19]1=[O:31].[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:29](=[O:30])[CH:28]=[C:21]4[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]4[C:19]3=[O:31])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: O=c1cc2n(c(=O)n1CCCCCl)CCCS2(=O)=O
Reactant: Sc1cccc2nccn12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc2n(c(=O)n1CCCCSc1cccc3nccn13)CCCS2(=O)=O
Reaction time: 0.5 h

Procedure:
To a suspension of 0.053 g (2.2 mmol) of 60% oily sodium hydride in 15 ml of N,N-dimethylformamide, 0.33 g (2.2 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 30 minutes. To this mixture, 0.61 g (2.0 mmol) of 7-(4-chlorobutyl)-1,1-dioxo-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 0.33 g (2.2 mmol) of sodium iodide were added, followed by stirring at 100° C. for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by recrystallization (solvent, chloroform/diethyl ether) to yield 0.442 g (52.6%, light green powder) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[F:24])[CH:12]=2)=[O:10])=[N:6][C:7]=1[CH3:8]
Reactant: Fc1ccccc1CBr
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ccccc3F)c3ccccc3c2=O)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
Compound 4i was prepared following the procedure outlined in Step 3 of Example 1. Briefly described here, 32 mg (0.12 mmol) of 3-(5,6-dimethyl-pyridine-2-carbonyl)-1H-quinolin-4-one 3d, 6 mg (0.14 mmol) of 60% sodium hydride and 26 mg (0.14 mmol) of 2-fluorobenzyl bromide were combined in 0.5 mL N,N-dimethylformamide and stirred at rt for 2 h. The product was purified using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 50 min. The HPLC fractions containing pure product were lyophilized to give 43 mg of a pale yellow solid 4i as trifluoroacetate salt: LC-MSD, m/z for C24H19FN2O2 [M+H]+=387.5, HPLC retention time: 1.8 min; 1H NMR (400 MHz, CDCl3): δ 2.5 (s, 3H), 2.8 (s, 3H), 5.7 (s, 2H), 7.1-7.2 (m, 3H), 7.3-7.4 (m, 1H), 7.5-7.6 (m, 1H), 7.6-7.7 (m, 1H), 7.7-7.8 (m, 1H), 8.1-8.2 (m, 1H), 8.5-8.6 (m, 1H), 9.05 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]2[O:12][CH2:13][CH2:14][NH:15][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5])C.O.[OH-].[Li+]>O1CCCC1>[O:12]1[CH2:13][CH2:14][NH:15][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:11]1=2
Reactant: CCOC(=O)c1cccc2c1OCCN2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc2c1OCCN2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of 3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid ethyl ester 2.1 g (10 mmol) of step 3 in a mixture of tetrahydrofuran 10 mL and distilled water 10 mL was added lithium hydroxide monohydrate 0.85 g (20 mmol), followed by stirring at room temperature for 8 hrs. After concentrating the reaction mixture in a vacuum, the reaction mixture was diluted with ethylacetate, washed with 1N HCl and a saturated NaCl solution, and dried over magnesium sulfate. The residue was concentrated in a vacuum and crystallized in ethylacetate/hexane to obtain 1.6 g of the title compound (yield 89%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]>C(OCC)(=O)C.O=[Pt]=O>[OH:10][CH:3]([C:2]([F:1])([F:11])[F:12])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(O)C(F)(F)F
Yield: 75.6 %

Procedure:
A solution of 19.31 g of ethyl trifluoroacetoacetate (Fairfield Chemical) in 50 ml of ethyl acetate was hydrogenated at atmospheres on a Parr shaker over (0.5 g) PtO2 as a catalyst. The volatiles were removed and the residue distilled under high vacuum to afford 14.75 g (76%) of the title compound as a low melting solid. bp=47°-49° C. at 0.1 mm of Hg, mp (uncorrected)=about 25° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:21])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.Br[CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].CCN(CC)CC>CCO>[OH:21][C@@H:13]([CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1)[CH2:14][N:15]1[CH2:16][CH2:17][N:18]([CH2:23][CH2:24][N:25]2[C:29](=[O:30])[C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[C:26]2=[O:35])[CH2:19][CH2:20]1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCN4C(=O)c5ccccc5C4=O)CC3)ccc2s1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol (500 mg, 1.63 mmol) in EtOH (25 mL) was added N-(2-bromoethyl) phthalimide (435 mg, 1.71 mmol) and Et3N (0.79 mL, 5.7 mmol). The reacting solution was shaken at 90° C. for 16 hours. Upon cooling, the solution was concentrated to an oil and purified via flash column chromatography (4:1 EtOAc/MeOH) to afford 2-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)benzo[c]azolidine-1,3-dione.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([NH:14][CH:15]([CH2:27][OH:28])[CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:13])([CH3:10])([CH3:9])[CH3:8].[Cl-].[NH4+]>C(N(CC)CC)C.C(Cl)Cl.CS(C)=O>[C:7]([O:11][C:12]([NH:14][CH:15]([CH:27]=[O:28])[CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:13])([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)(C)OC(=O)NC(CO)CC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C=O)CC(=O)OCc1ccccc1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
8 ml of a methylene chloride solution containing 0.81 g (6.4 mmol) of oxalyl chloride was cooled to −70° C., and 2 ml of a methylene chloride solution containing 0.65 g of DMSO was added dropwise over 10 minutes. The mixture was stirred at −60° C. for 10 minutes, and then, 5 ml of a methylene chloride solution containing 1.01 g (3.27 mmol) of benzyl 3-t-butoxycarbonylamino-4-hydroxybutanoate was added dropwise over 10 minutes. The mixture was stirred at −50° C. for one hour, and then, 3.3 ml of triethylamine was added dropwise. After completion of the dropwise addition, the temperature of the mixture was gradually raised and when the temperature reached to 0° C., a saturated aqueous ammonium chloride solution was added to the mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by the silica gel column chromatography method (n-hexane/ethyl acetate=7/3) to obtain 0.80 g (2.6 mmol) of benzyl 3-t-butoxycarbonylamino-3-formylpropionate as pale yellowish oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:20]CC4C=CC(OC)=CC=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH2:20])[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(CNc2cc3c(Nc4ccc(Cl)c(Br)c4)ncnc3cn2)cc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2c(Nc3ccc(Cl)c(Br)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 42 h
Yield: 99.8 %

Procedure:
To a stirred heterogeneous mixture of compound 214 (2.92 g, 6.20 mmol) and DCM (60 mL) was added trifluoroacetic acid (4.75 mL, 62.0 mmol), followed by anisole (1.36 mL, 12.4 mmol), and the mixture was stirred further at room temperature for 42 h. It was poured into petroleum ether (600 mL) and stirred at room temperature for ca. 20 min. Petroleum ether layer was decanted and discarded. The process was repeated with more petroleum ether (300 mL). To the solid left behind was added 5M NH3 (80 mL) at 0° C. and stirred at room temperature for 15 min. The solid was collected and washed successively with water (6×10 mL), petroleum ether-ethyl acetate=3:1 (3×20 mL), and dried to give N4-(3-bromo-4-chlorophenyl)pyrido[3,4-d]-pyrimidine-4,6-diamine (223) (2.17 g, 100%), mp 271-274° C.; 1H NMR δ [(CD3)2SO] 9.82 (s, 1H), 8.72 (s, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.42 (s, 1H), 7.97 (dd, J=8.8, 2.3 Hz, 1H, 7.62 (d, J=8.8 Hz, 1H), 7.14 (s, 1H), 6.30 (s, 2H). Anal. Calcd for C13H9BrClN5.0.6H2O: C, 43.20; H, 2.85; N, 19.38. Found C, 43.00; H, 2.95; N, 19.12.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[N:37]=[C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[S:39][CH:40]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[N:37]=[C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[S:39][CH:40]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCc1csc(-c2ccccn2)n1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2csc(-c3ccccn3)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 2-[4-(chloromethyl)-1,3-thiazol-2-yl]pyridine (0.72 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.80 g, 44%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:17]#N.Cl.C(=O)([O-])[OH:26].[Na+]>C(OCC)C.CCCCCC>[S:8]1[CH:9]=[CH:10][N:11]=[C:7]1[C:17]([C:16]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:14]([O:13][CH3:12])[CH:15]=1)=[O:26]
Reactant: Brc1nccs1
Reactant: COc1ccc(C#N)cc1OC
Reactant: O=C([O-])O
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(C(=O)c2nccs2)cc1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
A hexane solution of butyllithium (9.50 mM) was dissolved in dried diethyl ether (6.5 ml) and cooled to −78° C. A solution of 2-bromothiazole (1.03 g, 6.13 mM) in diethyl ether (0.5 ml) was dropped into this solution. The solution was stirred at that temperature for 30 minutes, then a solution of 3,4-dimethoxybenzonitrile (1.00 g, 6.13 mM) in diethyl ether (3.0 ml) was added and the resultant mixture stirred for a further 6 hours. 1N Hydrochloric acid (20 ml) was poured into the solution obtained, which was then warmed to room temperature and stirred for 30 minutes, then a saturated sodium hydrogencarbonate solution was added to neutralize the solution and extraction was performed with ethyl acetate. Next, the organic layer was washed with brine and dried over anhydrous magnesium sulfate, then the solvent was removed in vacuo to obtain a dark red solid residue. The residue was purified by flash chromatography (SiO2: eluted by gradient from 50% hexane/methylene chloride to 25% hexane/methylene chloride). The solvent was removed in vacuo and the resultant product was dried to obtain 3,4-dimethoxyphenyl 2-thiazolyl ketone 0.71 g (yield 46.5%) as a red solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([CH:9]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[N:14]=[CH:13][C:12]=2[O:11][CH2:10]1)=O.N>C(O)C>[CH3:24][O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]1[O:11][CH2:10][CH:9]([C:7]3[N:1]=[C:2]([NH2:4])[S:3][CH:6]=3)[CH2:22][C:21]2=1
Reactant: NC(N)=S
Reactant: COc1ccc2ncc3c(c2c1)CC(C(=O)CBr)CO3
Agent: N
Solvent: CCO
Product: COc1ccc2ncc3c(c2c1)CC(c1csc(N)n1)CO3
Yield: 7.7 %

Procedure:
Thiourea (190 mg, 2.5 mmol, 1.0 eq) is added at room temperature to a stirred solution of 2-bromo-1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-ethanone (850 mg, 2.5 mmol, 1.0 eq) in ethanol (200 mL) and the resulting suspension is heated to reflux for 15 minutes. Then pH of the reaction mixture is adjusted to 8-10 by the addition of a 30% aqueous ammonia solution. Solvent was removed to give the crude product that is purified by preparative HPLC to afford 4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-thiazol-2-ylamine as a white solid (60 mg, 13% yield).
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:5]1[CH:19]=[CH:18][C:8]2[N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH:10]=[N:11][C:7]=2[CH:6]=1)[CH3:4].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[NH:32][N:31]=[C:30]([CH:33]3[CH2:35][CH2:34]3)[CH:29]=2)[CH:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:33]1([C:30]2[NH:31][N:32]=[C:28]([NH:27][C:25]3[CH:24]=[CH:23][N:22]=[C:21]([N:2]([CH3:1])[CH:3]([C:5]4[CH:19]=[CH:18][C:8]5[N:9]([CH:12]6[CH2:17][CH2:16][CH2:15][CH2:14][O:13]6)[CH:10]=[N:11][C:7]=5[CH:6]=4)[CH3:4])[N:26]=3)[CH:29]=2)[CH2:35][CH2:34]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: CNC(C)c1ccc2c(c1)ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(c1ccc2c(c1)ncn2C1CCCCO1)N(C)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
A tube was charged with mixture of 84 (200 mg, 0.77 mmol), 53 (181 mg, 0.77 mmol) and DIPEA (200 mg, 1.5 mmol) in IPA (5 mL), sealed and stirred at 120° C. overnight. The reaction mixture was cooled to RT and concentrated under reduced pressure. The crude residue was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (5% to 15% MeOH) to afford 68 mg (19%) of (±)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-methyl-N2-(1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethyl)pyrimidine-2,4-diamine (86) as white solid: MS (ESI) m/z=459.2 (M+1).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23](=[O:24])[CH2:22][C:21]([CH3:25])=[N:20]2)[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+]>O>[Cl:12][C:13]1[CH:14]=[C:15]([N:19]2[C:23](=[O:24])[CH:22]=[C:21]([CH3:25])[N:20]2[CH3:1])[CH:16]=[CH:17][CH:18]=1
Reactant: CC1=NN(c2cccc(Cl)c2)C(=O)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(=O)n(-c2cccc(Cl)c2)n1C
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 52.7 %

Procedure:
90 g of p-toluenesulfonic acid was added to 50 g of 1-(3-chlorophenyl)-3-methyl-2-pyrazolin-5-one [Chemical Abstracts Registry Number (90-31-3)], and the resulting mixture was stirred on an oil bath at 150° C., for 2.5 hours. The reaction mixture was allowed to cool down to 100° C. or less. A solution prepared from 25 g of sodium hydroxide and 150 ml of water was added dropwise thereto. After adding thereto 350 ml of water, the mixture was extracted with chloroform. The chloroform phase was separated and then dried over anhydrous potassium carbonate. After insoluble materials were filtered off, the filtrate was concentrated to dryness to obtain 28.1 g of 1-(3-chlorophenyl)-2,3-dimethyl-3-pyrazolin-5-one. When recrystallization was carried out from ethyl acetate, crystals having a melting point of 98° to 100° C. were obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:21])[NH:5][C:6](=[O:20])[N:7]([CH:19]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][OH:14])[C@@:10](C(=O)C)([OH:11])[CH2:9]1)[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[P:37]([O-])([O-:44])([O:39]CCC#N)=[O:38].N.C(O)(C)C.O>N1C=CC=CC=1>[P:37]([O:14][CH2:13][C@H:12]1[O:15][C@@H:8]([N:7]2[CH:19]=[C:3]([CH2:1][CH3:2])[C:4](=[O:21])[NH:5][C:6]2=[O:20])[CH2:9][C@@H:10]1[OH:11])([OH:44])([OH:39])=[O:38]
Reactant: N#CCCOP(=O)([O-])[O-]
Reactant: CCc1cn([C@H]2C[C@@](O)(C(C)=O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: O
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)c(=O)[nH]c1=O
Yield: 29.7 %

Procedure:
A mixture of 0.3 g (0,001 mole) of 5-ethyl-3'-acetyl-2'-desoxyuridine, 1.2 g of dicyclohexylcarbodiimide and 2 ml of a pyridine solution of 0.002 mole of β-cyanoethyl phosphate were reacted to obtain 200 mg (62% yield) of 5-ethyl-2'-desoxyuridine-5'-monophosphate with an Rf=0.17 [1-7-2 ammonia-isopropanol-water mixture].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@H:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([OH:25])[CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:26]([N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:19]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O[C@H]1CCC[C@@H](N(Cc2ccccc2)Cc2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1CCC[C@@H](N(Cc2ccccc2)Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
Oxalyl chloride (3.81 mL, 43.6 mmol) was dissolved in dry DCM (150 mL) and cooled to −78° C. DMSO (6.75 mL, 95.0 mmol) in dry DCM (20 mL) was added dropwise to the reaction mixture and the reaction was stirred for 15 minutes at −78° C. Next, (1S,3R)-3-(dibenzylamino)-cyclohexanol (11.7 g, 39.6 mmol) in dry DCM (100 mL) was added dropwise using an addition funnel and the reaction was stirred at −78° C. for 15 minutes. TEA (27.6 mL, 198 mmol) was then added and the reaction was stirred at −78° C. for 1 h. The dry-ice bath was removed and the reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was washed with brine (5×500 mL), the organic layer was separated, dried over magnesium sulfate and concentrated to yield (R)-3-(dibenzylamino)cyclohexanone (10.2 g, 88%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.26-7.39 (m, 8H), 7.17-7.25 (m, 2H), 3.56-3.70 (m, 4H), 2.71-2.81 (m, 1H), 2.60-2.69 (m, 1H), 2.25-2.42 (m, 2H), 2.04-2.11 (m, 1H), 1.88-1.99 (m, 2H), 1.69-1.82 (m, 1H), 1.18-1.33 (m, 1H); MS (ESI) m/z 294.4 [M+1]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C@@H:6]2[CH2:8][C@:5]32[C@H:9]2[C@H:18]([CH2:19][CH2:20][C@:3]13[CH3:4])[C@@H:17]1[C:12]([CH2:13][C:14](=[O:21])[CH2:15][CH2:16]1)=[CH:11][CH2:10]2.C(=O)(O)[O-].[Na+].O>CC(C)=O.Cl>[OH:1][C@H:2]1[CH2:7][C@@H:6]2[CH2:8][C@:5]32[C@H:9]2[C@H:18]([CH2:19][CH2:20][C@:3]13[CH3:4])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]2
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4CC(=O)CC[C@@H]43)[C@@]13C[C@H]3C[C@@H]2O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@]13C[C@H]3C[C@@H]2O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution that consists of 2 g of 17β-hydroxy-14α,15α-methylenestr-5-en-3-one in 95 ml of acetone and 5 ml of 5% aqueous hydrochloric acid is stirred for 2.5 hours at room temperature. Then, 10 ml of saturated aqueous sodium bicarbonate solution and 200 ml of water are added in succession. This solution is concentrated by evaporation in a vacuum rotary evaporator, whereby crystallization is used. The crystals are filtered off, dried, dissolved in acetone and applied to a silica gel column (0.063-0.2 mm, Merck). Chromatography with cyclohexane ethyl acetate 7:3 (v/v) as an eluant yields 17β-hydroxy-14α,15α-methylenestr-4-en-3-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1.[C:13]1([CH3:25])[CH:18]=[CH:17][C:16]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH3:25][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=2)=[O:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: OCCc1ccc(B(O)O)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(B(O)O)cc2)cc1
Temperature: 0 °C

Procedure:
4-(2-Hydroxyethyl)phenylboronic acid (1.00 g, 6.02 mmol) was treated with pyridine (90 mL) and p-toluenesulfonylisocyanate (1.01 mL, 6.63 mmol) at room temperature for 2 hours. The mixture was poured into ice-2M HCl (200 mL) and extracted with ethyl acetate, and the organic fraction was dried (MgSO4). After removal of solvent, the residue was purified flash column chromatography on silica gel eluting with dichloromethane/methanol to give 2.20 g (quant.) of the title compound as white solids: MS (ESI) m/z 381 [M+NH4]+, 362 [M−H]−, 1H-NMR (DMSO-d6) δ 2.40 (3H, s), 2.81 (2H, t, J=6.6 Hz), 4.18 (2H, t, J=6.6 Hz), 7.13 (2H, d, J=7.7 Hz), 7.40 (2H, d, J=8.6 Hz), 7.67-7.75 (2H, m), 7.97 (1H, s), 11.95 (1H, br).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][C:6](Br)([CH2:17][CH2:18][CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22].C1CN2C(=NCCC2)C1.O.Cl>CS(C)=O.C(O)C>[CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH:7]=[C:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22]
Reactant: CCCC1(Br)Cc2c(c(C)c(C)c3oc(C(=O)O)cc23)C1=O
Agent: C1CN=C2CCCN2C1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CS(C)=O
Product: CCCC1=Cc2c(c(C)c(C)c3oc(C(=O)O)cc23)C1=O

Procedure:
A solution of 4,5-dimethyl-6-oxo-7-bromo-7-propyl-7,8-dihydro-6H-indeno[5,4-b]furan-2-carboxylic acid (1.2 g., 0.0033 mole) and 1,5-diazabicyclo [4.3.0]-5-nonene (0.8 ml.) in dimethylsulfoxide (8 ml.) is stirred at 25°C. for one hour then treated with water (30 ml.) hydrochloric acid (5 ml.) and ethanol (20 ml.) affording 4,5-dimethyl-6-oxo-7-propyl-6H-indeno[5,4-b]-furan-2-carboxylic acid as a red solid which melts at 242°C. after recrystallization from nitromethane.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:31])[C:8]2[CH:13]=[N:12][C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)=[N:10][C:9]=2[N:23]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:24]=1)=[O:5])C.[NH3:32]>CO>[CH:25]1([N:23]2[C:9]3[N:10]=[C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)[N:12]=[CH:13][C:8]=3[C:7](=[O:31])[C:6]([C:4]([NH2:32])=[O:5])=[CH:24]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: N
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCCn3ccnc3)ncc2c1=O
Solvent: CO
Product: NC(=O)c1cn(C2CCCCC2)c2nc(NCCCn3ccnc3)ncc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
8-Cyclohexyl-2-(3-imidazol-1-yl-propylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (4.5 mg, 0.011 mmol) was added to 1.0 mL of 7 N ammonia in methanol. The mixture was stirred in a sealed tube at room temperature overnight. The solvent was evaporated to leave a white solid of 8-cyclohexyl-2-(3-imidazol-1-yl-propylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (4.0 mg, 95%). 1H NMR (400 MHz, CDCl3/CD3OD (20:1 v/v)) δ (ppm): 9.18 (s), 8.74 (s), 7.15 (br, 1H), 7.02 (br, 1H), 6.92 (br, 1H), 5.02 (m, 1H), 4.06 (t, J=6.6 Hz, 2H), 3.43 (br, 2H), 2.17 (m, 2H), 2.00-1.30 (br, 10H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C20H25N7O2: 396.21 (M+H). Found: 396.2.