Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[Mg].Br[CH2:5][C@@H:6]([CH3:16])[CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1>O1CCCC1>[CH3:16][C@H:6]([CH2:5][CH2:8][CH2:7][CH:6]([CH3:16])[CH3:5])[CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1
Reactant: C[C@H](CBr)CCOC1CCCCO1
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)CCOC1CCCCO1
Reaction time: 0.08 h

Procedure:
4.7 g (0.202 mol) of magnesium shavings in a 3-necked flask under an argon atmosphere and provided with a calcium chloride tube are activated by addition of 2.0 ml of methyl iodide. After 5 minutes, the methyl iodide is removed and the magnesium washed several times with absolute tetrahydrofuran. To the activated magnesium is added dropwise a solution of 44 g (0.175 mol) of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran in 50 ml of absolute tetrahydrofuran at such a rate that the solvent just boils. Where the Grignard reaction does not start itself, it is warmed to 85° with the oil bath. After completed addition of 2-[(S)--4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran, the mixture is stirred at 85° for so long (0-15 min.) until only traces of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran are still present in accordance with gas-chromatographical analysis. The solution obtained is cooled to -78° and treated dropwise with 21.2 g (0.0875 mol) of 3-methyl-1-butanol--p-toluenesulphonate followed by 3.6 ml of a 0.1 molar solution of Li2CuCl4 in absolute tetrahydrofuran. This reaction mixture is stirred at -78° during 10 min. then at 0° for 2 hours and subsequently at room temperature for a further 14 hours. For the working up of the 2-[(R)-3,7-dimethyloctanoxy]-tetrahydro-2H-pyran obtained the mixture is poured on to ice and brought to pH 5-6 with 2-N sulphuric acid. By three-fold extraction with ether and removal of the solvent on the rotary evaporator there is obtained a mixture of (R)-3,7--dimethyl-1-octanol and 2[(R)-3,7-dimethyloctanoxy]-tetrahydro--2H-pyran. This mixture is treated portionwise in 100 ml of methanol at 0° with a total of 100 ml of 7-N aqueous hydrochloric acid. After 2-hours stirring at room temperature, the mixture is neutralised with dilute aqueous caustic soda and extracted with ether. After chromatography on silicagel, deactivated with 0.5% ammonia, with pentane/ether (4:1), there are obtained 10.6 g (76% based on 3-methyl-1-butanol-p-toluenesulphonate employed) of pure (R)-3,7-dimethyl-1-octanol. B.p. 58°-59°/0.05 Torr; [α]D20 =+4.0 (c=1.03, CHCl3).
Reaction SMILES: [CH:1]1([CH2:5][CH:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])[CH:12]=[N:11]2)[C:7](O)=[O:8])[CH2:4][CH2:3][CH2:2]1.[C:26]([Si:30]([CH3:41])([CH3:40])[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([Si:30]([CH3:41])([CH3:40])[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[CH:37][C:36]([NH:39][C:7](=[O:8])[CH:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][C:18]3[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=3[F:24])[CH:12]=[N:11]2)[CH2:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[N:35]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: O=C(O)C(CC1CCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(CC2CCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 40 %

Procedure:
Using the method described in Example 49, 3-cyclobutyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 29) and 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (Intermediate 3) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclobutyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as an off-white solid (342.2 mg, 40%); ES+-HRMS m/e calcd for C28H37N5O4SiF2 [M+H+] 574.2656 found 574.2656. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.07 (s, 6H) 0.80 (s, 9H) 1.49-1.67 (m, 1H) 1.68-2.02 (m, 5H) 2.03-2.30 (m, 3H) 3.86 (t, J=5.2 Hz, 2H) 4.06 (t, J=5.2 Hz, 2H) 5.28-5.38 (m, 1H) 6.01 (d, J=2.7 Hz, 1H) 6.36 (d, J=2.1 Hz, 1H) 7.33-7.43 (m, 2H) 7.43-7.51 (m, 1H) 7.53 (d, J=2.1 Hz, 1H) 8.26 (d, J=2.7 Hz, 1H) 10.78 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH2:2]1.[C:17]([O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[CH:30]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:17]([O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[CH:9]=[CH:10][N:11]=[CH:12]4)[CH2:2]2)[CH:30]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1cc(N[C@@H]2CCNC2)c2ccncc2c1
Reactant: O=Cc1cccc(OCCOC(=O)c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCCOc1cccc(CN2CC[C@@H](Nc3cccc4cnccc34)C2)c1)c1ccccc1
Temperature: 22.5 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a 100 mL round-bottomed flask with a magnetic stir bar were added (R)-N-(pyrrolidin-3-yl)isoquinolin-5-amine scuccinic acid salt (2.00 g, 6.04 mmol, from Example 5), tetrahydrofuran (30 mL), and 2-(3-formylphenoxy)ethyl benzoate (1.63 g, 6.04 mmol). The mixture was stirred at 20 to 25° C. for 15 minutes. To the mixture was added sodium triacetoxyborohydride (1.92 g, 9.05 mmol). The mixture was stirred at 20 to 25° C. for 20 hours. The reaction was quenched with 20 mL of 15% Na2CO3 (final pH ˜10). Tetrahydrofuran was removed by distillation under vacuum. The residue was extracted with 30 mL of methyl tert-butyl ether. The organic layer was washed with 30 mL of water (twice) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-12% methanol/dichloromethane) to give (R)-2-(3-((3-(isoquinolin-5-ylamino)pyrrolidin-1-yl)methyl)phenoxy)ethyl benzoate as a oil (2.57 g, 91% yield).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:7]([OH:8])[C@@H:6]([CH2:9][OH:10])[O:5][C@H:4]1[N:11]1[C:21]2[N:20]=[C:18]([NH2:19])[NH:17][C:15](=[O:16])[C:14]=2[N:13]=[CH:12]1.C[Si](Cl)(C)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29].[NH4+].[OH-]>N1C=CC=CC=1.O>[C:27]([NH:19][C:18]1[NH:17][C:15](=[O:16])[C:14]2[N:13]=[CH:12][N:11]([C:21]=2[N:20]=1)[C@@H:4]1[O:5][C@H:6]([CH2:9][OH:10])[C@@H:7]([OH:8])[C@H:3]1[O:2][CH3:1])(=[O:31])[CH:28]([CH3:30])[CH3:29]
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Reactant: CC(C)C(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Reaction time: 0.33 h

Procedure:
2'-O-methylguanosine (3.5 g) in pyridine (100 ml) was treated with trimethylsilyl chloride (9 ml, 6 eq) and isobutyryl chloride (6.2 ml) at RT for 4 hr. The reaction mixture was cooled in an ice bath, H2O (20) was added and stirring continued for an additional 20 min. NH4OH (20 ml) was added and after stirring for 30 min the reaction mixture was evaporated. The residue was triturated with H2O, filtered and the filtrate evaporated and purified by silica gel chromatography as per the procedure of Example 4 to yield the product as an off white solid (1.5 g). 1H NMR (DMSO-d6) δ 1.1 [d, 6, CH(CH3)2 ], 2.77 [m, 1, CH(CH3)2 ], 3.33-3.6 (m, 5, OCH3, H-5'), 3.93 (m, 1, H-4'), 4.22 (m, 1), 4.3 (m, 1), 5.1 (t, 1, 5'-OH), 5.28 (d, 1, 3'-OH), 5.9 (d, 1, H-1'), 8.28 (s, 1, H-8) and 11.9 (br s, 1, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([I:26])=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[C:31]1=[O:38].Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:35]([CH:32]2[CH2:33][CH2:34][N:30]([CH3:29])[C:31]2=[O:38])=[O:36])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[N:9]=[C:10]([I:26])[C:11]=12
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: CN1CCC(C(=O)O)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(I)c3c(Oc4ccc(NC(=O)C5CCN(C)C5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A 100 mL round-bottomed flask was charged with 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (300.0 mg, 0.6119 mmol), 1-methyl-2-oxopyrrolidine-3-carboxylic acid (87.59 mg, 0.6119 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (351.9 mg, 1.836 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (248.0 mg, 1.836 mmol), N-ethyl-N-isopropylpropan-2-amine (395.4 mg, 3.060 mmol) and THF (50 mL). The reaction mixture was stirred at ambient temperature overnight, and then partitioned between EtOAc and H2O. The phases were separated, and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (0.360 g, 95.6%). LRMS (APCI pos): m/e 616 (M+1). 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.31 (d, 1H), 7.79 (dd, 1H), 7.36 (d, 2H), 7.29 (m, 1H), 7.20 (t, 1H), 6.83 (m, 2H), 6.20 (d, 1H), 5.61 (s, 2H), 3.78 (s, 3H), 3.42-3.50 (m, 3H), 2.94 (s, 3H), 2.50-2.61 (m, 1H), 2.35-2.48 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]2=[O:13].Cl.[N:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.C(O)(=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:22]([NH:21][C:18]1[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=1)[C:6]2=[O:13]
Reactant: NNc1ccncc1
Reactant: COc1ccc2c(c1)C(=O)OC2=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)C(=O)N(Nc1ccncc1)C2=O
Yield: 33.9 %

Procedure:
A mixture of 5-methoxyisobenzofuran-1,3-dione (33.0 g), 4-pyridinylhydrazine hydrochloride (25.7 g) and glacial acetic acid (100 ml) was heated overnight, under reflux, under nitrogen, with stirring. Water (100 ml) was added, and the mixture was evaporated and dried in vacuo. The residue was triturated with acetone, the acetone decanted, and the residue was triturated with methanol to give 16.1 g of 5-methoxy-2-(4-pyridinylamino)isoindol-1,3-dione. To a mixture of lithium aluminum hydride (6.00 g) and dry tetrahydrofuran (150 ml) at ambient temperature, under nitrogen, 5-methoxy-2-(4-pyridinylamino)isoindol-1,3-dione hydrochloride (16.1 g) was added in portions, with stirring. The reaction mixture was stirred at room temperature, under nitrogen, 4 hrs, and sodium sulfate decahydrate was added in portions. The mixture was filtered through a bed of celite, the filter cake was washed thoroughly with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel, eluting with 7% methanol-dichloromethane followed by 185:14:1 dichloromethane:methanol:ammomium hydroxide. The appropriate fractions were collected and concentrated. The residue was crystallized from ethanol to give 5.8 (46%) of product, mp 166-167° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]([Cl:16])=[CH2:15])[C:7]=12.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]([Cl:16])=[CH2:15])[C:7]=12)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: C=C(Cl)Cn1c(C)c(C)c2cnnc(Cl)c21
Product: C=C(Cl)Cn1c(C)c(C)c2cnnc(OCc3ccccc3)c21
Yield: 10.9 %

Procedure:
The title compound was prepared as a white powder in 10.9% yield in a similar procedure to that described in Example 1 by using 7-chloro-1-(2-chloro-2-propenyl)-2,3-dimethylpyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH2:38]O)[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[F-:58].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH2:38][F:58])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: [F-]
Reactant: OC[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O[C@]1(CF)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of the compound from Example 138, Step A (63 mg, 0.1 mmol) in anhydrous dichloromethane (5 mL) under argon, were added 4-dimethylaminopyridine (DMAP) (2 mg, 0.015 mmol) and triethylamine (62 μL, 0.45 mmol). The solution was cooled in an ice bath and p-toluenesulfonyl chloride (30 mg, 0.15 mmol) was added. The reaction was stirred at room temperature overnight, washed with NaHCO3 (2×10 mL), water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated to a pink solid in vacuo. The solid was dissolved in anhydrous THF (5 mL) and cooled in an icebath. Tetrabutylammonium fluoride (1M solution in THF, 1 mL, 1 mmol) was added and the mixture stirred at room temperature for 4 h. The solvent was removed in vacuo, the residue taken up in dichloromethane, and washed with NaHCO3 (2×10 mL), water (10 mL) and brine (10 mL). The dichloromethane layer was dried over anhydrous Na2SO4, concentrated in vacuo, and purified by flash chromatography (SiO2, 2:1 hexanes/EtOAc) to afford the title compound (20 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12].C(OC)(=O)[CH2:15][C:16](OC)=[O:17].C[O-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:15][C:16](=[O:17])[CH:12]=[C:11]([OH:13])[CH2:10]1
Reactant: CC(=O)/C=C/c1ccc(F)cc1Br
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1C=C(O)CC(c2ccc(F)cc2Br)C1

Procedure:
To a 500 mL recovery flask was added (E)-4-(2-bromo-4-fluorophenyl)but-3-en-2-one (1B, 11.9 g, 49.0 mmol, 1.0 eq.) and MeOH (200 mL). Dimethyl malonate (1C, 6.47 g, 49.0 mmol, 1.0 eq.) was added, followed by NaOMe (30% wt in MeOH, 9.6 mL, 51.4 mmol, 1.05 eq.). The reaction mixture was refluxed overnight upon which it was concentrated to a brownish-red solid. The residue was taken up in 1N NaOH (150 mL) and refluxed for 1 h, during which the reaction color proceeded from cloudy-brown, to clear brown, to clear solution with brown precipitate. Concentrated HCl was carefully added until the mixture was acidic by pH paper. The reaction mixture was diluted with EtOAc (200 mL) and washed with saturated aqueous NaCl. The aqueous phase was extracted with EtOAc (1×75 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give a foamy orange solid that was carried on to the next step without further purification (14.3 g, 100%). ESI-MS: m/z 285.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[C:9]([O:16][CH3:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.CN(C)C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH:13]([O:12][C:10]1[C:9]([O:16][CH3:17])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:1][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[CH:11]=1)([CH3:14])[CH3:15]
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)c1cc(OC)c(OC(C)C)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c(OC(C)C)cc1NCc1ccc(OC)cc1
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A mixture of methyl 2-amino-4-isopropoxy-5-methoxybenzoate (12.67 g), 4-methoxybenzaldehyde (7.90 g), N,N-dimethylformamide (150 ml) and acetic acid (3 ml) was stirred for 8 hours. After stirring, the sodium triacetoxyborohydride (13.4 g) was added thereto. The reaction mixture was stirred for 1 night. To the reaction mixture was added 4-methoxybenzaldehyde (1.98 g) and sodium triacetoxyborohydride (3.35 g) and stirred for 1 day. The reaction mixture was concentrated under reduced pressure until the amount was concentrated to a half, adjusted to pH 8˜9 by adding 5% sodium carbonate. Water was added thereto, the precipitated solid was collected by filtration, washed with water and dried to obtain the target compound (18.9 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1(O)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[NH:12][C:11]1=[O:21])[CH3:2].N1C=CC=CC=1.O=S(Cl)[Cl:31]>C(Cl)Cl>[Cl:31][C:10]1([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[NH:12][C:11]1=[O:21]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccccc1C1(O)C(=O)Nc2ccc(OC)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ccccc1C1(Cl)C(=O)Nc2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
5 g (16.7 mmol) of the intermediate from Step A and 2.6 g (33.4 mmol) pyridine were dissolved in 50 mL CH2Cl2 and at 0° C. 3 g (25.1 mmol) SOCl2 were added slowly. Then the reaction mixture was stirred for 30 min. at 0° C. The reaction mixture was poured into an ice/water mixture and the organic phase was separated, washed with H2O, dried over magnesium sulfate and finally the solvent was removed in vacuo. The resulting residue was suspended in ether. The solid residue was separated and dried to give 3.2 g of the intermediate, which was used without further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH:33][CH2:34][CH2:35][CH3:36])[CH3:32]>>[CH2:31]([N:33]([CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH2:34][CH2:35][CH3:36])[CH3:32]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Reactant: CCCNCC
Product: CCCN(CC)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1

Procedure:
The product from Example 23D and ethyl(propyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.84 (m, 1H), 7.74 (d, J=8.1, 2H), 7.58 (m, 2H), 7.53 (d, J=8.1 Hz, 2H), 6.82 (s, 1H), 3.32-3.8 (m, 14H), 3.20 (m, 2H), 1.80 (m, 2H), 1.38 (t, J=7.5 Hz, 3H), 1.05 (t, J=7.5 Hz, 3H); MS (DCI) m/z 421 (M+H)+;
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH:15]([CH2:18][NH2:19])[O:14][C:13]=2[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[CH:31][C:32](=[O:36])[O:33]2)=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][CH:15]([CH2:18][NH:19][CH2:22][CH2:23][CH2:24][O:25][C:26]4[CH:27]=[CH:28][C:29]5[CH:30]=[CH:31][C:32](=[O:36])[O:33][C:34]=5[CH:35]=4)[O:14][C:13]=3[CH:20]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1COc2ccc(OCc3ccccc3)cc2O1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccc2ccc(OCCCNCC3COc4ccc(OCc5ccccc5)cc4O3)cc2o1
Yield: 25.7 %

Procedure:
2,3-Dihydro-7-benzyloxy-1,4-benzodioxin-2-methanamine (1.47 g, 5.42 mmole), 7-(3-chloropropoxy)coumarin (1.30 g, 5.45 mmole), diisopropylethylamine (4.0 ml, 23 mmole) and sodium iodide (4.17 g, 28 mmole) were combined in 150 ml of DMF and heated at 80°-100° C. for 2 days under a nitrogen atmosphere. The solvent was then removed and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on silica gel using first dichloromethane, then 0.5% methanol/dichloromethane, and finally 1% methanol/dichloromethane as eluant. The fractions containing material with Rf=0.26 on silica gel tlc (2.5% methanol/chloroform) were combined and concentrated in vacuum and the residue crystallized from 50 ml of isopropanol with the addition of 4.0 ml of 4N isopropanolic HCl to give 0.66 g of title compound as an off-white solid, monohydrochloride, m.p. 179°-181° C.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]3[N:12]([CH:27]([CH3:29])[CH3:28])[C:13](=[O:26])[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:15](=[O:16])[C:9]3=[CH:8][N:7]=2)[CH:5]=[CH:4]N=C1.[CH2:30]([N:32]([CH2:43][CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:42]=CC(N)=[CH:38][CH:37]=1)[CH3:31].C1(=O)OC(=O)CC1.CN(C)C=O>C(Cl)(Cl)Cl>[CH2:43]([N:32]([CH2:30][CH3:31])[CH2:33][CH2:34][O:35][C:36]1[CH:42]=[CH:4][C:5]([NH:1][C:6]2[N:11]=[C:10]3[N:12]([CH:27]([CH3:28])[CH3:29])[C:13](=[O:26])[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:15](=[O:16])[C:9]3=[CH:8][N:7]=2)=[CH:38][CH:37]=1)[CH3:44]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: COc1ccc(Cn2c(=O)c3cnc(-n4ccnc4)nc3n(C(C)C)c2=O)cc1
Agent: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(=O)n(Cc4ccc(OC)cc4)c(=O)n(C(C)C)c3n2)cc1
Temperature: 180 °C
Yield: 62.2 %

Procedure:
A mixture of 700 mg (1.78 mmol) of 7-(imidazol-1-yl)-1-isopropyl-3-(4-methoxybenzyl)-1H-pyrimido[4,5-d]pyrimidine-2,4-dione and 1.1 g (5.35 mmol) of 4-(2-diethylaminoethoxy)aniline is heated at 180° C. for 4 hours, then cooled. To the reaction mixture is added 357 mg (3.6 mmol) of succinic anhydride, 1 mL of chloroform, and 3 mL of dimethylformamide. The reaction mixture is heated at 50° C. for 2 hours, cooled, and diluted with chloroform. The mixture is washed with a saturated solution of sodium bicarbonate and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated. The residue is chromatographed on silica eluting with 5:95 methanol/chloroform to give a yellow solid which is crystallized from methanol/water to give 590 mg (61%) of the title compound: mp 139-141° C.
Reaction SMILES: [C:1]1([CH:7]2[O:11][CH:10]([CH2:12][CH2:13][OH:14])[C:9](=[C:15]=[C:16]=C=C)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:20]([O:23][CH2:24]C)(=[O:22])C>CO.Cl[Pd]Cl>[C:1]1([CH:7]2[O:11][CH:10]3[CH2:12][CH2:13][O:14][C:9]3([C:15](=[CH2:16])[C:20]([O:23][CH3:24])=[O:22])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Reactant: C=C=C=C=C1CC(c2ccccc2)OC1CCO
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CO
Product: C=C(C(=O)OC)C12CC(c3ccccc3)OC1CCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(5-phenyl-3-vinylidenevinylidene-tetrahydrofuran-2-yl)ethanol (39 mg, 0.18 mmol) was dissolved in 2 mL of methanol, and then was filled with CO gas (1 atm), followed by addition of PdCl2 (2.4 mg, 0.014 mmol) and CuCl2 (73 mg, 0.54 mmol). The solution was stirred for 4 hours at room temperature. When the reaction was completed, H2O was added and the solution was stirred for 5 minutes. The mixture was diluted with ethyl acetate, washed with H2O and NaCl. Organic layer was separated and dried with anhydride MgSO4. Solvent was removed under reduced pressure, and the remnant was purified through silica gel tube chromatography (EtOAc:n-Hexane=1:25, v/v), thus providing products (47 mg, 95%).