Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=O)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29].C1C=CC=CC=1.Cl>N1C=CC=CC=1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[S:29])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOP(=O)(Cc1ccc(C(=O)N2CCCc3ccccc32)cc1)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOP(=O)(Cc1ccc(C(=S)N2CCCc3ccccc32)cc1)OCC
Temperature: 25 °C

Procedure:
0.77 Gram (2.0 mM) of 1-(4-diethoxyphosphinoylmethylbenzoyl)-1,2,3,4-tetrahydroquinoline and 1.0 g (4.6 mM) of phosphorus pentasulfide were suspended in a mixed solvent consisting of 20 ml of anhydrous benzene and 5 ml of anhydrous pyridine This suspension was heated and refluxed for 7 hours. After the reaction mixture was cooled to room temperature, the mixture was poured into 50 ml of ice-water, and the aqueous phase was acidified with 4N hydrochloric acid and then extracted with chloroform. The chloroform solution was dried over anhydrous sodium sulfate, and concentrated. Thus obtained residue was purified by means of a silica gel column chromatography (eluted with chloroform:ethyl acetate=1:1). The crude crystals were recrystallized from benzene-n-hexane to yield 0.23 g of 1-[(4-diethoxyphosphinoylmethylphenyl)thiocarbonyl]-1,2,3,4-tetrahydroquinoline as yellowish crystals. Melting point 96°-97° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:2]1.CCCCCC.C([Li])CCC.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24].CN(C)[CH:29]=[O:30].[Cl-].[NH4+]>O1CCCC1>[O:7]1[CH2:8][CH2:9][O:10][CH:6]1[C:3]1[CH:4]=[C:5]([CH:29]=[O:30])[S:1][C:2]=1[Si:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: c1cc(C2OCCO2)cs1
Reactant: C[Si](C)(C)Cl
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1sc(C=O)cc1C1OCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of 2-(thiophen-3-yl)-1,3-dioxolane (10.00 g, 64.02 mmol) in anhydrous tetrahydrofuran (50 ml) was cooled in a dry ice-methanol bath, and n-butyllithium hexane solution (1.59M, 44.3 ml, 70.4 mmol) was added dropwise while preventing the reaction mixture from exceeding −55° C. After stirring for 1 hr, chlorotrimethylsilane (8.94 ml, 70.4 mmol) was added dropwise while preventing the reaction mixture from exceeding −60° C. After stirring at −78 to −60° C. for 30 min, the mixture was warmed to 0° C. over 30 min and stirred at 0° C. for 1 hr. The reaction mixture was cooled again in a dry ice-methanol bath, and n-butyllithium hexane solution (1.59M, 46.3 ml, 73.6 mmol) was added dropwise while preventing the reaction mixture from exceeding −60° C. After stirring at −78 to −60° C. for 1 hr, N,N-dimethylformamide (12.4 ml, 160 mmol) was added dropwise, and the mixture was further stirred for 1 hr. The mixture was warmed to 0° C. over 1 hr, and saturated aqueous ammonium chloride solution (100 ml) was added. The mixture was washed 3 times with ethyl acetate, and the combined organic layer was washed twice with 0.2M hydrochloric acid and once with saturated brine. To the organic layer were added anhydrous magnesium sulfate and activated carbon, and the mixture was stirred for 5 min and filtered. The filtrate was concentrated under reduced pressure to give 4-(1,3-dioxolan-2-yl)-5-(trimethylsilyl)thiophene-2-carbaldehyde (16.09 g, 62.76 mmol, yield 98.0%) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1Cl)[C:5]#[N:6].[C:11](=[S:16])(OCC)[S-:12].[K+].Cl>CN(C=O)C.O>[C:5]([C:4]1[CH:7]=[CH:8][C:9]2[S:12][C:11]([SH:16])=[N:1][C:2]=2[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(Cl)c(N)c1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2sc(S)nc2c1
Temperature: 115 °C
Yield: 76.1 %

Procedure:
A mixture of 3-amino-4-chloro benzonitrile (13, 0.50 g, 3.28 mmol) and potassium O-ethyl dithiocarbonate (1.05 g, 6.55 mmol) in DMF (15 mL) was heated overnight at 110-120° C. under N2. After cooling, the reaction mixture was diluted with water and acidified with 1N HCl. The precipitate was collected by filtration, washed with water, and dried under vacuum to yield 14 (0.48 g, 76%).
Reaction SMILES: [CH3:1][C:2]1[C:3](N=NC2C=CC=CC=2O)=[C:4]([OH:15])[CH:5]=[C:6]([CH3:14])[C:7]=1C1C=CC=CC=1.O.[NH2:26]N>CO.[Ni]>[CH3:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[C:6]([CH3:14])[C:7]=1[NH2:26]
Reactant: Cc1cc(O)c(N=Nc2ccccc2O)c(C)c1-c1ccccc1
Reactant: NN
Agent: [Ni]
Solvent: O
Solvent: CO
Product: Cc1cc(O)cc(C)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
3,5-Dimethyl-4-phenylazophenol (132.0 g, 0.583 mol) was dissolved in methanol (500 mL) and pure (100%) hydrazine hydrate (113 mL, 2.33 mol), and Raney nickel [50% slurry in water (Aldrich), (2.5 mL)] was added to give an exothermic reaction. The mixture was stirred for one hour at ambient temperature and then heated to gentle reflux for three hours. The solution was filtered hot and cooled to room temperature. The crystals which formed were collected by filtration and dried to afford 3,5-dimethyl-4-aminophenol (42.4 g, 60% yield) as a white solid; m.p. 180.5-182.5; 1H-NMR (DMF-d7). δ 2.10 (s, 6H, CH3), 5.32 (s, 2H, NH2), 5.32 (s, 1H, OH), 6.45 (s, 2H, aromatic).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[N:9][C:8](S(C)=O)=[N:7][C:6]=2[N:5]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH:18]=[CH:19][CH:20]=2)[C:4](=[O:26])[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[CH3:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([NH:38][C:37]3[CH:36]=[CH:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[CH:40][CH:39]=3)=[N:7][C:6]=2[N:5]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH:18]=[CH:19][CH:20]=2)[C:4](=[O:26])[CH:3]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(S(C)=O)nc32)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nc32)c1
Temperature: 100 °C
Yield: 19.3 %

Procedure:
A microwave tube was charged with N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b; 210 mg, 0.57 mmol), 4-(4-methylpiperazino)aniline (136 mg, 0.71 mmol) and DIEA (0.20 mL, 1.14 mmol) in tert-butanol (5.5 mL). The tube was sealed and the mixture was heated to 100° C. for 3 d. The mixture was concentrated and then the brown solid was suspended in Et2O and collected by filtration. The brown solid was washed with Et2O to afford 270 mg of crude material. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0-20% MeOH in DCM. This enriched product was repurified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The product containing fractions were combined and concentrated. A saturated solution of aqueous NaHCO3 was added and the mixture was extracted with 3:1 CHCl3/IPA (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to provide N-(3-(5-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (52 mg, 0.11 mmol, 18% yield) as a yellow solid. m/z (ESI, +ve ion) 496.1 (M+H)+. NMR (400 MHz, DMSO-d6) δ ppm 10.35 (1H, s), 8.82 (1H, s), 7.93 (1H, d, J=8.61 Hz), 7.57-7.56 (1H, m), 7.53 (1H, t, J=8.12 Hz), 7.17-7.19 (2H, m), 6.95-7.02 (1H, m), 6.53-6.56 (1H, m), 6.37-6.48 (1H, m), 6.31 (1H, d, J=0.39 Hz), 6.21-6.28 (1H, m), 5.72-5.80 (1H, m), 2.91-3.02 (4H, m), 2.46 (3H, s), 2.39-2.44 (4H, m) 2.21 (3H, s).
Reaction SMILES: C([O:3][C:4]([C@@:6]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[C:15]([O:14][C:12]([NH:11][C@:6]1([C:4]([OH:5])=[O:3])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature and quenched with 1N NaOH (15 mL) and water (20 mL). The resulting mixture was washed with ethyl acetate (20 mL), and the organic phase was extracted with 20 mL 0.5N NaOH. The combined aqueous phases were acidified with 1N HCl until pH 4 and extracted with ethyl acetate (3×40 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (2.62 g, 87%). 1H NMR: (DMSO-d6) δ 1.22-1.26 (m, 1H), 1.37 (s, 9H), 1.50-1.52 (m, 1H), 2.05 (q, J=9 Hz, 1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz, 1H), 5.64-5.71 (m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, 1H)); MS m/z 228 (M++H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42].C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:33][CH2:32][N:31]([C:41](=[O:43])[CH3:42])[CH2:30][CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CCNCC2)ns1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3cccnc3C)n2)CC1
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(piperidin-4-yl)-1,2,4-thiadiazol-5-amine (29.52 g, 61.81 mmol) and triethylamine (21.54 ml, 154.5 mmol) were dissolved in THF (300 mL). Acetic anhydride (6.310 g, 61.81 mmol) was added and the reaction was stirred for 90 minutes. Saturated sodium bicarbonate (200 mL) and water (400 mL) were added and the reaction mixture was extracted with dichloromethane and 10% methanol in dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in MeOH (˜75 mL) and let stand. The resultant solids were filtered and washed with cold methanol to give a first crop (22.3 g). The filtrate was concentrated and solids were redissolved in methanol (30 mL) and allowed to stand. The precipitated solids were filtered and washed to afford a second crop (4.3 g). The 2 crops were combined to afford 1-(4-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone (26.7 g, 51.38 mmol, 83.13% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5](SC)[N:4]=1.[S:13]([O-:16])([O-])=[O:14].[Na+].[Na+].O1CCC[CH2:20]1>CO>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([S:13]([CH3:20])(=[O:16])=[O:14])[N:6]=1
Reactant: C1CCOC1
Reactant: O=S([O-])[O-]
Reactant: COc1cc(OC)nc(SC)n1
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC)nc(S(C)(=O)=O)n1
Reaction time: 0.25 h

Procedure:
A stirred solution of 143.6 grams (0.772 mole) of 4,6-dimethoxy-2-methylthiopyrimidine in 460 mL of tetrahydrofuran was cooled to 10°-15° C., and a cloudy solution of 525.0 grams (0.849 mole) of 80% monoperoxyphthalio acid, magnesium salt hexahydrate in 600 mL of methanol was added at a rate to maintain the reaction mixture temperature below 15° C. Upon completion of the addition, which required one hour, the reaction mixture was cooled, and 500 mL of aqueous 1M sodium sulfite solution was added dropwise to destroy excess peroxides present in the reaction mixture. Upon completion of addition, the reaction mixture was stirred for 15 minutes and then was concentrated under reduced pressure to a residue. The residue was stirred in 2500 mL of ethyl acetate and 1500 mL of water. The layers were separated, and the aqueous layer was extracted with 450 mL of ethyl acetate. The ethyl acetate layers were combined and washed with one 500 mL portion of water, two 350 mL portions of aqueous 20% potassium carbonate, two 350 mL portions of water, and one 300 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 123.3 grams of 4,6-dimethoxy-2-methylsulfonylpyrimidine; m.p. 126°-127.5° C. The reaction was repeated several times.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[CH3:13][N:14]1[C:23]2[C:18](=[CH:19][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=[O:33]>>[NH2:12][C@H:7]1[C:6]2[CH:5]=[N:4][CH:3]=[C:2]([C:20]3[CH:19]=[C:18]4[C:23](=[CH:22][CH:21]=3)[N:14]([CH3:13])[C:15](=[O:33])[CH2:16][CH2:17]4)[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: N[C@@H]1CCCc2c(Br)cncc21
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4N)ccc21

Procedure:
In analogy to the procedure described for the preparation of intermediate A-2 [E], Suzuki reaction of (+)-(R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (intermediate B-3b) with 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) gave the title compound as light yellow amorphous solid. MS: 308.2 (M+H)+.
Reaction SMILES: O=[C:2]1[N:6](CC2C=CC=CC=2)[CH2:5][CH:4]([C:14]([OH:16])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>C(#N)C>[CH:29]1([NH:32][C:14]([CH:4]2[CH2:3][CH2:2][NH:6][CH2:5]2)=[O:16])[CH2:31][CH2:30]1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=C(NC1CC1)C1CCNC1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 16.4 g (75 mmole) of 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml of acetonitrile was added 13.8 g (85 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60° C. for one hour, cooled to room temperature and treated with 4.85 g (85 mmole) of cyclopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1 N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 18.3 g of 5-oxo-1-phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide, mp 94°-96° C.
Reaction SMILES: C1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)C=CC=CC=1.[CH2:14]([CH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)[CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:14]([C@H:19]1[CH2:20][CH2:21][C@H:22]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:11][CH2:12][CH2:7][CH2:8][CH2:9][CH2:10][O:13][C:10](=[O:13])[CH:9]=[CH2:8])=[CH:29][CH:30]=2)[CH2:23][CH2:24]1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCC1CCC(c2ccc(O)cc2)CC1
Reactant: Oc1ccc(-c2ccccc2)cc1
Product: C=CC(=O)OCCCCCCOc1ccc([C@H]2CC[C@H](CCCCC)CC2)cc1

Procedure:
With the exception of replacing the 4-phenylphenol from the synthesis example 1 with 4-(4-pentylcyclohexyl)phenol, 19.4 g of a monoacrylate containing a group (h): 1-pentyl-4-(4-(6-acryloyloxyhexyloxy)phenyl)trans-cyclohexane was obtained in the same manner as the synthesis example 1. Hereafter this monoacrylate is abbreviated as (A-3).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][C:9]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)=[C:10]([CH:11]=[O:12])[C:6]=2[C:5](=[O:25])[N:4]([CH2:26][CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[C:3]1=[O:36].[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([Mg]Br)=[CH:40][CH:39]=1>C1COCC1.C(Cl)Cl.O>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([CH:11]([OH:12])[C:10]2[C:6]3[C:5](=[O:25])[N:4]([CH2:26][CH2:27][CH2:28][O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[C:3](=[O:36])[N:2]([CH3:1])[C:7]=3[S:8][C:9]=2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:22])([F:23])[F:24])[CH:15]=2)=[CH:40][CH:39]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Oc3cccc(OC(F)(F)F)c3)sc21
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cccc(OC(F)(F)F)c3)sc21
Reaction time: 0.03 h
Yield: 49.3 %

Procedure:
To a solution of 1-methyl-2,4-dioxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoro methoxy)phenoxy)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (50 mg, 0.095 mmol) in THF (2 mL) was added (4-chlorophenyl)magnesium bromide (0.19 mL, 0.190 mmol). The reaction was stirred for 2 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography PE/EA (5:1 to 3:1) to give 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-(3-(trifluoromethoxy)phenoxy)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 49.5% yield) as a solid. LCMS: [M+-THP-OH] 539 and TR=2.159 min.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH2:14](Br)[CH:15]=[CH2:16].O>CN(C=O)C>[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH2:16][CH:15]=[CH2:14])=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)c1ccc(C=O)cc1
Temperature: 25 °C

Procedure:
3.3 g (0.11 mol) of sodium hydride (80% in oil) and 100 ml of DMF are introduced under a stream of nitrogen into a round-bottomed flask. 15 g (0.1 mol) of 4-formylbenzoic acid, dissolved in 200 ml of DMF are added dropwise and the mixture is stirred at room temperature until gaseous evolution has ceased. 9.5 ml (0.11 mol) of allyl bromide are then introduced and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. 19 g (100%) of allyl ester are collected in the form of a slightly yellow oil.
Reaction SMILES: [CH3:1][C:2](=[N:4][NH:5][C:6]([NH2:8])=[O:7])[CH3:3].[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][CH2:13]N>>[C:2](=[N:4][NH:5][C:6]([NH:8][CH2:13][CH2:12][CH2:11][N:10]([CH3:15])[CH3:9])=[O:7])([CH3:3])[CH3:1]
Reactant: CN(C)CCCN
Reactant: CC(C)=NNC(N)=O
Product: CC(C)=NNC(=O)NCCCN(C)C

Procedure:
Acetone semicarbazone (23 g) and 3-dimethylaminopropylamine (24.5 g) were heated to 175° C. over 40 minutes, then cooled and partitioned between t-butyl methyl ether and brine. The ether layer was concentrated to give 13.2 g waxy solid 2-isopropylidene-N-(3-dimethylaminopropyl)hydrazinecarboxamide (mp 49°-53° C.). Of this, 2.0 g was boiled 8 hr. in water maintained at a volume of 20 ml, then treated with 1.67 ml 12N HCl and concentrated in vacuo to give 2.5 g crude N-(3-dimethylaminopropyl)hydrazinecarboxamide dihydrochloride as a syrup. One fifth of the latter was reacted with 5-nitro-2-furaldehyde (0.282 g) in 6 ml 1:1 methanol-ethanol containing 0.16 ml pyridine at reflux for 30 minutes. The mixture was cooled and treated with 10 ml isopropanol to give 0.51 g of the title compound as a yellow solid, mp 200°-202° C. (dec.).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:35](O)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(Cl)Cl.N1(C2C=CN=CC=2)CCCC1>[C:1]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:18])[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CCCCCCCCO
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCCCOC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
13.2 parts by weight of 1-carbobenzoxypiperidine-4-carboxylic acid are dissolved in 150 parts by volume of methylene chloride, 8 parts by volume of n-octanol and 0.7 part by weight of 4-pyrrolidinopyridine are added, and the mixture is cooled to 0 to 5° C. 12.0 parts by weight of dicyclohexylcarbodiimide are added, and the mixture is stirred at 5° C. for 2 hours and at room temperature for 4 hours. The mixture is left to stand overnight, the precipitated dicyclohexylurea is filtered off with suction (11.3 parts by weight), the solvent is stripped off in vacuo, the residue is stirred with diisopropyl ether in order to remove residual dicyclohexylurea and filtered, and the solvent is stripped off. 21 parts by weight of an oily residue are obtained. The residue is chromatographed on 1070 parts by weight of silica gel using CH2Cl2 /5% of methanol. 9.8 parts by weight of the compound (A) are obtained as an oil. ##STR42## 4-decyloxyphenoxy(4-benzoyl) chloroformate =(B)
Reaction SMILES: [CH2:1]([O:3][C:4]([O:6][C:7]1[CH:17]=[CH:16][C:10](/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)[CH:20]=[O:21]>S(Cl)(Cl)=O>[CH2:1]([O:3][C:4]([O:6][C:7]1[CH:17]=[CH:16][C:10](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:20](=[O:21])[C:12]([CH3:13])=[CH2:11])=[O:14])=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)Oc1ccc(/C=C/C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: C=C(C)C(=O)OCCCCOC(=O)/C=C/c1ccc(OC(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5.2 g of 4-(E)-ethyloxycarbonyloxycinnamic acid in 20 ml of thionyl chloride and 0.05 ml of N,N-dimethylformamide was heated under reflux for 3 hours. Subsequently, excess thionyl chloride was distilled off. 3.3 g of 4-hydroxybutyl methacrylate were added dropwise to a solution of the resulting 4-(E)-ethyloxycarbonyloxycinnamoyl chloride in 15 ml of pyridine while stirring at 0° C. within 15 minutes. The reaction mixture was stirred at room temperature for a further 12 hours, then poured into water and extracted three times with 50 ml of ethyl acetate each time. The combined organic phases were dried over magnesium sulphate, filtered and subsequently concentrated. Chromatographic purification on silica gel with hexane/ethyl acetate (vol. 7:3) gave 3 g of 4-methacryloyloxybutyl (E)-3-(4-ethoxycarbonyloxyphenyl)acrylate, m.p. 54°-56° C.