Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:11](=O)(=[O:14])([OH:13])[OH:12].[CH2:16]=[O:17]>O>[CH2:16]=[O:17].[C:9]1([S:11]([OH:14])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc2ccccc2c1
Reactant: O=S(=O)(O)O
Agent: C=O
Solvent: O
Product: O=S(=O)(O)c1cccc2ccccc12
Temperature: 160 °C

Procedure:
A charge of 64 g (0.5 mole) of naphthalene was heated to 160° C. and 75 g (0.75-0.765 mole) of 98-100% strength sulfuric acid was added. The reaction mixture was maintained for 2 hours at 160° C. under constant stirring, was then cooled to 100° C. and 20 g of water added. Then 40 g of 37% by weight formaldehyde solution and 80 g of water were added and the reaction mixture maintained at 100° C. for 4 hours to obtain a naphthalene sulfonic acid formaldehyde condensate solution. The condensate solution was added to a milk of lime mixture containing 37 g of lime and 56 g water, to which was then added 166 g of crystalline aluminum sulfate dissolved in 300 grams of water. Calcium sulfate was filtered off and a 20% by weight solution of the aluminum salt of the naphthalene sulfonic acid formaldehyde condensate obtained.
Reaction SMILES: [CH3:1][CH:2]=[C:3](N1CCOCC1)[CH2:4][CH3:5].[CH:12]([CH:14]=[CH2:15])=[O:13]>O1CCOCC1.Cl>[CH3:15][C:14]1[C:12](=[O:13])[CH:2]([CH3:1])[CH2:3][CH2:4][CH:5]=1
Reactant: C=CC=O
Reactant: CC=C(CC)N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1=CCCC(C)C1=O
Reaction time: 8 h

Procedure:
26.1 g (0.168 mole) of N-(3-pent-2-enyl)-morpholine is slowly added dropwise to a solution, cooled to 0°, of 16.8 g (0.3 mole) of freshly distilled acrolein in 150 ml of dioxane, with the temperature rising to 5° C. After completion of the addition, stirring is maintained for half an hour with ice-cooling, and the mixture is then allowed to stand overnight. The solvent is afterwards evaporated off and the oil obtained as residue is dissolved in 120 ml of 20% aqueous hydrochloric acid. On stirring of the acidified solution at room temperature, there precipitates an oil which, after one to two days' stirring, is taken up in ether. The aqueous phase is extracted a further five times with ether. The combined ether phases are dried over magnesium sulphate and the ether is distilled off. There is obtained 18.5 g of crude 2,6-dimethyl-cyclohex-2-en-1-one in the form of oil, which yields, after distillation in a water-jet vacuum, 15.0 g of 2,6-dimethyl-cyclohex-2-en-1-one (72% of theory); b.p. 62°-63° C./ 10 Torr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([CH2:17][NH:18]C(OC(C)(C)C)=O)[CH:14]=[CH:13][C:12]=2[Cl:26])=[CH:5][C:4]=1[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=1)=[O:29]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([CH2:17][NH2:18])[CH:14]=[CH:13][C:12]=2[Cl:26])=[CH:5][C:4]=1[C:28]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([Br:37])=[CH:35][CH:36]=1)=[O:29]
Reactant: COc1ccc(NC(=O)c2cc(CNC(=O)OC(C)(C)C)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)c2cc(CN)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 2.66 g N-[4-methoxy-3-(4-bromophenyl)aminocarbonyl-phenyl]-2-chloro-5-(tert.butoxycarbonylamino)methyl-benzamide (4.51 mmol) 25 mL 4M HCl in dioxane and 50 mL dioxane was stirred for 2 h at rt and 60 min at 50° C. and concentrated i.vac. to furnish the subtitle compound. Yield: (quantitative). MS [M+H]+=488 (Br/Cl-isotope pattern).
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7](=[O:30])[C@H:8]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[N:9]([CH2:12][C:13]([NH:15][CH:16]([CH3:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:33]([N:40]=[C:41]=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:33]([NH:40][C:41](=[O:42])[NH:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7](=[O:30])[C@H:8]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[N:9]([CH2:12][C:13]([NH:15][CH:16]([CH3:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:14])[C:10](=[O:11])[C:4]=2[CH:3]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(CC(=O)O)NC(=O)CN1C(=O)c2cc(N)ccc2NC(=O)[C@@H]1Cc1ccc(O)cc1
Reactant: O=C=NCc1ccccc1
Solvent: CN(C)C=O
Product: CC(CC(=O)O)NC(=O)CN1C(=O)c2cc(NC(=O)NCc3ccccc3)ccc2NC(=O)[C@@H]1Cc1ccc(O)cc1
Temperature: 45 °C

Procedure:
To a solution of 3-(R,S)-{2-[7-Amino-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-butyric acid (0.2 mmol, 88mg). in DMF (6 ml) was added benzylisocyanate (158 μl 1.2 mmol). The mixture was shaken at 45° C. over night and then was evaporated to dryness. The crude product was purified by RP-HPLC to give 3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-butyric acid: MS (ISN) 572 (M−H)−.
Reaction SMILES: CCCCCC.Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH2:12][CH2:11]2.C([O:19][B:20](OCC)[O:21]CC)C.[Cl-].[NH4+]>O1CCCC1>[CH2:13]1[C:14]2[C:10](=[CH:9][C:8]([B:20]([OH:21])[OH:19])=[CH:16][CH:15]=2)[CH2:11][CH2:12]1
Reactant: Brc1ccc2c(c1)CCC2
Reactant: CCOB(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)CCC2
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butylithium in hexane (13.2 mL of 1.6 M, 21 mmol) is added to a stirred solution of 5-bromo-indane (1.06 g 4 mmol) in dry tetrahydrofuran (30 mL) at −75° C. under an argon atmosphere. The mixture is stirred for 30 min at −65° C., then treated with triethylborate (3.07 g, 21 mmol) and stirred for 60 min at −50° C. The resulting mixture is allowed to warm to 0° C. and then treated with a saturated aqueous solution of ammonium chloride (60 mL) and extracted with ethyl acetate (2×80 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 50% ethyl acetate in hexaen) and recrystallised from ethyl acetate-hexane to give indan-5-boronic acid as a colourless crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:3]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:21]3[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:3]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C=O)n2C
Reactant: CC(C)(O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(CN1CCC(C(C)(C)O)CC1)n2C
Reaction time: 17 h
Yield: 83.7 %

Procedure:
A mixture of 2-chloro-9-methyl-6-((S)-3-methylmorpholin-4-yl)-9H-purine-8-carbaldehyde (450 mg, 1.52 mmol), 2-piperidin-4-ylpropan-2-ol (239 mg, 1.67 mmol) and 4 Å powdered molecular sieves (450 mg) in DCE (10 mL) was stirred for 6 h before the addition of sodium triacetoxyborohydride (644 mg, 3.04 mmol). The resulting mixture was allowed to stir for 17 h then filtered through Celite®, washing with MeOH. The resulting filtrate was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-4%) affording the title compound as a cream solid (538 mg, 84%). LCMS (method H): RT 2.02 min [M+H]+ 423.3
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]=[C:9]=[S:10])=[C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[CH:4][CH:3]=1.[NH3:17]>>[CH3:1][C:2]1[C:7]([NH:8][C:9]([NH2:17])=[S:10])=[C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: Cc1cccc(N2CCOCC2)c1N=C=S
Product: Cc1cccc(N2CCOCC2)c1NC(N)=S

Procedure:
Reaction of 6-methyl-2-morpholinophenyl isothiocyanate (8.8 g) with 33% alcoholic ammonia solution (60 ml) at room temperature for 5 hours gave 1-(6-methyl-2-morpholinophenyl)thiourea (9 g) as a pale yellow solid, m.p. 199° C. which was recrystallised from a 1:1 mixture of ethylacetate and hexane.
Reaction SMILES: [CH2:1]1[CH:7]2[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][CH2:3][NH:2]1.[CH2:15](Br)[CH3:16].O>CN(C=O)C>[CH2:15]([N:2]1[CH2:3][CH2:4][CH2:5][N:6]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH2:8][CH:7]2[CH2:1]1)[CH3:16]
Reactant: CCBr
Reactant: c1ccc2c(c1)CC1CNCCCN21
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCCN2c3ccccc3CC2C1
Reaction time: 10 h

Procedure:
1.88 g of 2,3,4,5,11,11a-hexahydro-1H-1,4-diazepino-[1,2-a]indole in 20 ml of DMF are stirred for one hour at 20° with 1.48 g of K tert.-butylate, 1.1 g of ethyl bromide are added and the solution is stirred for a further 10 hours. 200 ml of water are then added and the mixture is extracted several times with ethyl acetate. After drying and evaporating the organic phase, 2-ethyl-2,3,4,5,11,11a-hexahydro-1H-1,4-diazepino[1,2-a]indole is obtained. Hydrochloride, m.p. 204°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH3:14])[N:13]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cccc(I)c1-c1nnn[nH]1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nnc(-c2c(F)cccc2I)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(2-fluoro-6-iodophenyl)-1H-tetrazole (23.48 g, 80.97 mmol), potassium carbonate (16.79 g, 0.121 mol), and iodomethane (16.09 g, 0.113 mol) in 25 mL DMF was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water, and the organic extract was washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0-10% ethyl acetate in hexanes to provide 5-(2-fluoro-6-iodophenyl)-2-methyl-2H-tetrazole that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 305.06 for M+H+.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:8]2[CH:21]=[C:22]([Cl:24])[CH:23]=[C:7]2[C:6]=1[OH:25])=[O:4].[NH2:26][CH2:27][C:28]([O-:30])=[O:29].[Na+]>>[Cl:24][C:22]1[CH:23]=[C:7]2[C:6]([OH:25])=[C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[N:8]2[CH:21]=1
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(OC)cc2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)c3cc(Cl)cn32)cc1

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 6-chloro-4-hydroxy-2-oxo-1-(4-methoxy-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 406 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4=CC=CC=C4C3=O)[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cccc(-c2nccn2CCCCCCN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc(-c2nccn2CCCCCCN)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(6-methyl-2-pyridyl)-1-(6-(phthalimido)hexyl)imidazole (4.2 g) in 50 mL EtOH was added 1.5 mL hydrazine hydrate. The resulting solution was stirred at 80° C. overnight. The solution was cooled to room temperature and suction filtered to remove the precipitate. The filtrate was evaporated to give the crude product, which was purified by a silica gel column using 5% conc. NH3H2O/CH3CN as the eluent. Yield: about 2.5 g.
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH2:10]([O:12][C:13](=[O:31])[C:14]([CH3:30])([CH3:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:10]([O:12][C:13](=[O:31])[C:14]([CH3:30])([CH3:29])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[N:6]1[CH2:7][CH2:8][C:9]2[O:1][CH:2]=[CH:3][C:4]=2[CH2:5]1)[CH3:11]
Reactant: CCOC(=O)C(C)(C)CCCCCC(Br)c1ccccc1Cl
Reactant: c1cc2c(o1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2occc2C1
Temperature: 60 °C
Yield: 30.6 %

Procedure:
4,5,6,7-Tetrahydrofuro[3,2-c]pyridine (0.47 g, 3.82 mmol), 8-bromo-8-(2-chlorophenyl)-2,2-dimethyloctanoic acid ethyl ester (1.47 g, 3.78 mmol) in DMF (36 mL), and potassium carbonate (0.77 g, 5.58 mmol) were combined under an argon atmosphere at room temperature. The mixture was heated to 60° C. for 3 days under argon atmosphere, monitored by TLC. The DMF was evaporated under reduced pressure and the residue was dissolved in diethyl ether (120 mL), washed with water (3×30 mL), brine (30 mL), and dried over Na2SO4. The crude oil was purified by column chromatography (silica gel, ethyl acetate/heptane 1/9) to afford pure 8-(2-chlorophenyl)-8-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid ethyl ester (Compound Ip, 0.50 g, 30.3% yield) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 7.48 (d, 1H, J=7.5 Hz), 7.36 (d, 1H, J=7.8 Hz), 7.32-7.15 (m, 3H), 6.17 (s, 1H), 4.20 (dd, 1H, J=9.0, 4.8 Hz), 4.08 (q, 2H, J=7.2 Hz), 3.62 (d, 1H, J=13.5 Hz), 3.11 (d, 1H, J=13.5 Hz), 2.88-2.58 (m, 4H), 1.95-1.70 (m, 2H), 1.45-1.40 (m, 2H), 1.30-1.0 (m, 15H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 178.01, 149.01, 140.94, 139.50, 135.00, 129.57, 129.04, 128.03, 126.85, 115.92, 108.90, 63.43, 60.36, 47.65, 47.54, 42.36, 40.91, 33.27, 30.57, 25.67, 25.41, 25.06, 24.73, 14.55. HRMS (HR, DART-TOF): Calculated for (M+H)+: 432.2300. found 432.2316.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[H-].[Na+].[CH3:24]I>>[CH:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[S:5][C:6]([C:7]([OH:9])=[O:8])=[C:2]([O:1][CH3:24])[N:3]=2)=[CH:13][CH:14]=1)([CH3:21])[CH3:20]
Reactant: CI
Reactant: CCOC(=O)c1sc(-c2ccc(OC(C)C)cc2)nc1O
Agent: [H-]
Agent: [Na+]
Product: COc1nc(-c2ccc(OC(C)C)cc2)sc1C(=O)O
Yield: 72 %

Procedure:
Ethyl 4-hydroxy-2-(4-isopropoxyphenyl)-5-thiazolecarboxylate prepared in Example 22 was methylated with sodium hydride and methyl iodide and hydrolyzed by a conventional process to give 2-(4-isopropoxyphenyl)-4-methoxy-5-thiazolecarboxylic acid (yield: 72%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.Cl[C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH:16][C:18]4[CH:26]=[C:25]5[C:21]([CH2:22][C:23](=[O:27])[NH:24]5)=[CH:20][CH:19]=4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2nccn3nc(N)nc23)cn1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Product: Cn1cc(-c2nccn3nc(Nc4ccc5c(c4)NC(=O)C5)nc23)cn1

Procedure:
8-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, synthesized as described earlier, is coupled with 6-chloro-oxindol according to general procedure 2.
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.S(Cl)(Cl)=O>N1C=CC=CC=1>[F:23][C:21]([F:22])([F:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2C(F)(F)F)CC1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC=C(c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 29021.7 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-[2-(trifluoromethyl)phenyl]piperidine-1-carboxylate (0.75 g, 2.2 mmol) in pyridine (15 mL) cooled in an ice bath was slowly added thionyl chloride (0.79 mL, 11 mmol) and the mixture was warmed to room temperature and stirred overnight (17 h). The reaction was quenched with ice water. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated. Purification by flash chromatography on silica gel (0-40% B over 25 min. Bottle A=hexanes, Bottle B=EtOAc) gave 209 g of the desired product as a solid. MS calculated for C17H20F3NO2: (M+H) 328; found 228.0 (M-Boc+H).
Reaction SMILES: CN(C)C=O.[OH:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:23][O:22][C:20]([CH2:19][O:6][N:7]1[C:8](=[O:17])[C:9]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:10]2[C:11]1=[O:12])=[O:21]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 50 ml of dry N,N-dimethylformamide are added 10 g of N-hydroxyphthalimide and 9.38 g of methyl bromoacetate, followed by addition of 8.5 g of potassium carbonate. The mixture is stirred at room temperature for 2 days and, then, poured into 400 ml of water. The resulting crystalline precipitate is recovered by filtration, washed with water, hexane and ether in this order to give colorless needles of N-methoxycarbonylmethoxyphthalimide, m.p. 137°-142° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na].[CH2:20]([OH:23])[CH2:21][CH3:22]>>[NH2:1][C:2]1[N:10]=[C:9]([O:23][CH2:20][CH2:21][CH3:22])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCO
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na]
Product: CCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reaction time: 3 h
Yield: 74 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) and sodium propylate (316 mg, 3.85 mmol) were dissolved in 1-propanol (20 ml) and then the solution was refluxed on heating under stirring for 3 hours. The reaction mixture was evaporated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate and evaporated in vacuo to dryness. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (162 mg, yield 74%).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=[N:17][C:10]=2[N:9]([CH3:30])[C:8]1=[O:31])=O.O[Li].O>C1COCC1.O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:31])[N:9]([CH3:30])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][CH:19]([CH3:20])[CH3:21])=[CH:28][CH:27]=1
Reactant: CC(C)Oc1cnc2c(c1Cc1ccc(Cl)cc1)c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1cnc2c(c1Cc1ccc(Cl)cc1)c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-isopropoxy-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (55 mg, 0.13 mmol) in THF (6 mL) and water (6 mL) was added LiOH.H2O (10.9 mg, 0.26 mmol). The reaction was stirred at RT for 15 min then diluted with water (20 mL) and extracted with EA (3×15 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-6-isopropoxy-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (20 mg, 37% yield) as a white solid. 1H NMR (CDCl3) δ: 8.33 (s, 1H), 7.18 (s, 4H), 4.73 (s, 2H),), 4.68-4.68 (m, 1H), 4.28-4.15 (m, 2H), 3.69 (s, 3H), 3.52 (dd, J=11.8, 6.2 Hz, 2H), 3.16 (t, J=7.0 Hz, 1H), 1.97-1.82 (m, 2H), 1.34 (d, J=6.0 Hz, 6H). LCMS: MH+ 418 and TR=2.915 min.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[CH:7]12[CH2:13][CH:10]([CH:11]=[CH:12]1)[CH:9]([C:14](Cl)=[O:15])[CH:8]2[C:17](Cl)=[O:18]>O1CCCC1>[C:2]([O:4][C:17]([CH:8]1[CH:9]([C:14]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:15])[CH:10]2[CH2:13][CH:7]1[CH:12]=[CH:11]2)=[O:18])([CH3:5])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C(Cl)C1C2C=CC(C2)C1C(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1C2C=CC(C2)C1C(=O)OC(C)(C)C

Procedure:
Potassium tert-butoxide (34 g; 0.3 mol) was dissolved in 250 ml of anhydrous tetrahydrofuran (THF) in a round-bottom flask. 5-norbornene-2,3-dicarbonyl chloride (22 g; 0.1 mol) then was slowly added thereto at room temperature, and the reactant was reacted at a temperature of 45° C. for about 12 hours.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([I:12])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH3:20]>C(O)C.C(OCC)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([I:12])=[C:9]([O:11][CH2:19][CH3:20])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(I)c(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CCOc1cc(C(C)(C)C)ccc1I
Temperature: 25 °C
Yield: 99 %

Procedure:
The mixture of 5-tert-butyl-2-iodo-phenol (132.7 g, 480.6 mmol), potassium carbonate (265.7 g, 1923 mmol) and ethyl iodide (76.9 mL, 961.3 mmol) in ethanol (1.125 mL) was heated at reflux overnight. Upon cooling to room temperature, the reaction mixture was diluted with diethyl ether. The white solids were filtered off, and the filtrate was concentrated in vacuo to give 4-tert-butyl-2-ethoxy-1-iodo-benzene (144.7 g) as pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13].[Br:14]Br.O>CC(O)=O>[Br:14][C:6]1[CH:7]=[C:2]([F:1])[C:3]([O:12][CH3:13])=[CH:4][C:5]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: COc1cc(CC(=O)O)ccc1F
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(CC(=O)O)c(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 4-fluoro-3-methoxyphenylacetic acid (5.0 g, 27.1 mmol) in AcOH (20 ml) was added bromine (1.5 ml, 29.8 mmol). The mixture was stirred at room temperature for three hours. Water was added and the precipitate was isolated by filtration. The white solid was washed with water and dried to give (2-bromo-4-fluoro-5-methoxy-phenyl)-acetic acid (6.21 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[CH:15][C:16]#[N:17])[CH2:9][C:10](OCC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>>[NH2:17][C:16]1[N:21]([CH:18]2[CH2:20][CH2:19]2)[C:10](=[O:11])[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:15]=1
Reactant: CCOC(=O)CC(=CC#N)c1cccc(Cl)c1
Reactant: NC1CC1
Product: Nc1cc(-c2cccc(Cl)c2)cc(=O)n1C1CC1

Procedure:
Starting compounds: ethyl 3-(3-chlorophenyl)-4-cyano-3-butenoate and cyclopropylamine
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][O:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][N:8]=[CH:7][N:6]=1>C1COCC1.[Ni]>[F:14][C:2]([F:1])([CH3:13])[CH2:3][O:4][C:5]1[C:10]([CH2:11][NH2:12])=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: CC(F)(F)COc1ncncc1C#N
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(F)(F)COc1ncncc1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
To a solution of 4-(2,2-difluoropropoxyl)pyrimidine-5-carbonitrile (1.7 g, 8.54 mmol) in THF (30 mL) was added Raney nickel (500 mg, crude). The resulting mixture was stirred at room temperature overnight under hydrogen atmosphere. The reaction was filtered and the filtrated was concentrated in vacuo and purified by silica gel column chromatography (5% MeOH in DCM) to afford the desired product (650 mg, 3.20 mmol, 37% yield) as a yellow solid. MS (ESI) m/z 204.1 [M+H]+.