Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36].C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
7-[[4-[(1-t-Butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile obtained in Reference Example 2 (150 mg) was dissolved in 1 ml of pyridine, 211 mg of ethanesulfonyl chloride was added to the solution, and the mixture was stirred at 0° C. for 20 minutes and then at room temperature for 3 hours. Ethyl acetate was added to the reaction solution. The mixture was washed with 10% citric acid aqueous solution and brine in that order, dried over anhydrous sodium sulfate, and then evaporated. The resulting residue was purified by silica gel column chromatography using hexane:ethyl acetate (75:25) as the eluent to give 176 mg of N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]ethanesulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:24]([OH:26])=[CH:23][CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:30]([O:35][CH3:36])(=[O:34])[C@H:31]([CH3:33])O>>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:31]([CH3:33])[C:30]([O:35][CH3:36])=[O:34])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COC(=O)[C@H](C)O
Reactant: Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Product: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Yield: 69 %

Procedure:
4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-ol was reacted with (S)-methyl lactate as described in Example 5, starting material to give methyl (2R)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (760 mg, 69%); Mass spectrum 472.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([Sn](C)(C)C)[CH:15]=[C:14]([NH2:23])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[C:27]2[CH:33]=[N:32][N:31]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:28]2=[N:29][CH:30]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH3:43][C:40]1[CH:41]=[CH:42][C:37]([S:34]([N:31]2[C:28]3=[N:29][CH:30]=[C:25]([C:16]4[CH:15]=[C:14]([NH2:23])[C:13]5[CH:12]=[N:11][N:10]([S:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)(=[O:9])=[O:8])[C:18]=5[CH:17]=4)[CH:26]=[C:27]3[CH:33]=[N:32]2)(=[O:36])=[O:35])=[CH:38][CH:39]=1
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3cc(Br)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ncc3cc(-c4cc(N)c5cnn(S(=O)(=O)c6ccccc6)c5c4)cnc32)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
1-(Phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (775 mg), Pd(PPh3)4 (212 mg) and 5-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrazolo[3,4-b]pyridine (775 mg) were introduced into a microwave vial and DMF (10 ml) was added. The mixture was heated in the microwave at 120° C. for 4 h. The solvent was removed in vacuo and the crude residue was placed on a high vacuum line overnight. The resulting brown oil was purified by FlashMaster II. The crude material was dissolved in chloroform and added to the top of 2×100 g silica SPE cartridges that were subsequently eluted with 0-100% ethyl acetate:cyclohexane over 60 min. The product-containing fractions were combined and the solvent was removed in vacuo. The residue was dried on a high vacuum line to give the title product, 371 mg as a cream solid.
Reaction SMILES: [CH:1](=O)[CH3:2].[NH2:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[BH3-]C#N.[Na+].[CH3:24][C:25](O)=O>CC#N.O>[CH2:24]([N:4]([CH2:1][CH3:2])[C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCc1cccc(N)c1
Reactant: CC=O
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCN(CC)c1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77 %

Procedure:
Acetaldehyde (0.52 ml, 0.4 g, 9.08 mmol, 5 eq) was added to a stirred solution of tert-butyl 3-aminobenzylcarbamate (derived from 3-(aminomethyl)aniline (TCI America)) in 11 ml CH3CN/H2O (10:1) at 0° C. After 5 min NaBH3CN (0.3 g, 4.54 mmol, 2.5 eq) was added. The reaction was adjusted to pH {tilde over ( )} 7 with HOAc and stirred at 0° C. for 5 min. The ice-bath was removed and the reaction was stirred at room temperature for 45 min. The solvent was removed in vacuo. The residue was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (×2). The combined organics were washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo. Purification via flash chromatography yielded 0.3875 g (1.4 mmol, 77% yield) of tert-butyl 3-(diethylamino)benzylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5].Cl.[NH2:23][OH:24].C([O-])(=O)C.[Na+]>CO.O>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([CH:20]=[N:23][OH:24])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5]
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC2(O)CCCCCC2)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(NCC1(O)CCCCCC1)c1cc(C=NO)ccc1Cl
Yield: 45.9 %

Procedure:
A solution of 2-chloro-5-formyl-N-(1-hydroxy-cycloheptylmethyl)-benzamide (290 mg, 0.94 mmol), hydroxylamine hydrochloride (78 mg, 1.13 mmol) and sodium acetate (223 mg, 2.72 mmol) in methanol (5 mL) and water (5 mL) was stirred at room temperature for 3 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, and brine, dried over sodium sulfate, filtered and adsorbed onto silica gel. The residue was purified by chromatography (1:1 ethyl acetate-hexane) to afford the title compound (140 mg).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16]>>[ClH:10].[NH2:5][CH2:4][C:3]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=1[N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16]
Reactant: N#Cc1cc(Cl)ccc1Br
Reactant: O=C1NCCN1
Product: Cl
Product: NCc1cc(Cl)ccc1N1CCNC1=O

Procedure:
(Step 1) Using 2-bromo-5-chlorobenzonitrile and imidazolidin-2-one, and in the same manner as in the Example 35, Steps 1 to 3, 1-[2-(aminomethyl)-4-chlorophenyl]imidazolidin-2-one hydrochloride was obtained.
Reaction SMILES: [CH3:1][C:2]1(OC)O[C:5]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[N:21]=[N:22][N:23]([CH3:25])[N:24]=3)=[CH:15][C:14]=2[CH3:26])(OC)[CH:4]=[CH:3]1.CO.C(O)(=O)C.O.[NH2:36][NH2:37]>O>[CH3:1][C:2]1[N:36]=[N:37][C:5]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[N:21]=[N:22][N:23]([CH3:25])[N:24]=3)=[CH:15][C:14]=2[CH3:26])=[CH:4][CH:3]=1
Reactant: COC1(C)C=CC(CCCOc2c(C)cc(-c3nnn(C)n3)cc2C)(OC)O1
Reactant: NN
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1ccc(CCCOc2c(C)cc(-c3nnn(C)n3)cc2C)nn1
Temperature: 25 °C
Yield: 29 %

Procedure:
Under nitrogen with stirring 5-methyl-2-[3-[2,6-dimethyl-4(2-methyl-tetrazol-5-yl)-phenoxy]-propyl]-2,5-dimethoxy-2,5dihydrofuran (820 mg, 1.8 mmol), 0.8 mL of methanol, and 1.5 mL of 1% aqueous acetic acid solution were combined at room temperature, refluxed for 10 min, and then cooled to room temperature. To the above solution was added hydrazine hydrate (0.26 mL) over a 2 min period, and the mixture was allowed to reflux for 1 h, and cooled to room temperature. The mixture was diluted with water, the aqueous layer was extracted with methylene chloride, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to afford 180 mg (29%) of 3-methyl-6-[3-[2,6-dimethyl-4-(2-methyl-tetrazol-5-yl)-phenoxy]-propyl]-pyridazine (Formula I; R1, R2 =3,5-dimethyl, R3 =6-methyl, R4 =hydrogen, R5 =2-methyltetrazol-5-yl), m.p. 114°-115° C.
Reaction SMILES: [OH-].[Na+].Cl.Cl.[CH3:5][NH:6][NH:7][CH3:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[S:18])=[CH:12][CH:11]=1>O.C(O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:6]([CH3:5])[NH:7][CH3:8])=[S:18])=[CH:12][CH:11]=1
Reactant: CNNC
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNN(C)C(=S)Nc1ccc(Cl)cc1
Temperature: 50 °C
Yield: 38.9 %

Procedure:
To a stirred solution of sodium hydroxide (6.1 g, 0.15 mole) in 40 ml of water and 250 ml of ethanol was added N,N'-dimethylhydrazine dihydrochloride (10 g, 0.076 mole). The reaction mixture was warmed to 50° C., and 4-chlorophenylisothiocyanate (12.8 g, 0.076 mole) was added in small portions. Upon complete addition, the reaction mixture was heated under reflux for two hours and then allowed to cool. The cooled reaction mixture was filtered and the filtrate concentrated under reduced pressure to remove most of the solvent. The concentrate was taken up in 200 ml of toluene. The toluene was removed under reduced pressure. This procedure was repeated with two additional 200 ml portions of toluene to remove the remaining ethanol and water traces by azeotropic distillation. The brown residual oil was recrystallized twice from ethanol to give N-(4-chlorophenyl)-1,2-dimethylhydrazinecarbothioamide (6.8 g, mp 103°-104° C.). The nmr spectrum of the product was consistent with the assigned structure.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:19])([CH3:18])[C:12]=2[CH:20]=1.[CH:21]1([C:27]2[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([C:27]2[CH:28]=[CH:29][C:30]([S:33][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]3[CH:9]=[CH:10][C:11]4[NH:16][C:15](=[O:17])[O:14][C:13]([CH3:19])([CH3:18])[C:12]=4[CH:20]=3)=[CH:31][CH:32]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Sc1ccc(C2CCCCC2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCBr)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCCSc3ccc(C4CCCCC4)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(5-bromopentoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-cyclohexyl-thiophenol.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[N:17][N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][C:19]=12.[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>CN(C)C=O.O>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[N:17][N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([O:28][S:35]([C:32]3[CH:33]=[CH:34][C:29]([CH3:39])=[CH:30][CH:31]=3)(=[O:37])=[O:36])=[N:20][C:19]=12
Reactant: O=c1[nH]c2c(-c3ccccc3F)nnn2c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Oc2nc3c(-c4ccccc4F)nnn3c3ccccc23)cc1
Reaction time: 18 h
Yield: 102.1 %

Procedure:
Triethylamine (5.6 ml, 40 mmol) was added to a stirred solution of 3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-α]quinazolin-5(4H)-one (5.47 g, 19.5 mmol) and p-toluenesulfonyl chloride (3.82 g, 20 mmol) in dry N,N-dimethylformamide (100 ml) at room temperature under nitrogen. The brown suspension was stirred for 18 h then diluted with water (800 ml). The yellow precipitate was collected, washed sequentially with water and diethyl ether, then dried in vacuo to give 3-(2-fluorophenyl)-5-(4-methylbenzenesulfonyloxy)-[1,2,3]triazolo[1,5-α]quinazoline (8.65 g, 100%). δH (400 MHz; CDCl3) 2.42 (3H, s), 7.23 (2H, d, J=8), 7.28-7.34 (2H, m), 7.47-7.50 (1H, m), 7.76 (1H, dd, J=8 and 8), 7.87 (1H, ddd, J=7, 7 and 2), 8.04-8.08 (3H, m), 8.30 (1H, dd, J=8 and 1), 8.70 (1H, d, J=8); m/z (ES+) 435 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][CH:3]=1.[CH3:9][C@H:10]1[O:15][C@@H:14]([CH3:16])[CH2:13][NH:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:12]2[CH2:11][C@H:10]([CH3:9])[O:15][C@H:14]([CH3:16])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Fc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H]1CN(c2ccc(Br)cc2)C[C@H](C)O1
Temperature: 150 °C
Reaction time: 25 h

Procedure:
A mixture of 1-bromo-4-fluorobenzene (10 g), cis-2,6-dimethylmorpholine (7.74 ml) and potassium carbonate (15.8 g) in dimethylsulfoxide (50 ml) was stirred for 25 hours at 150° C. The reaction mixture was cooled and poured into water (500 ml), and stirred for 10 minutes. The reaction mixture was extracted with ethyl acetate (100 ml×2), washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give a crude yellow oil (680 mg). The crude oil was purified by silica gel chromatography (1:0-10:1 hexane-ethyl acetate) to give 4-(4-bromophenyl)-cis-2,6-dimethylmorpholine (360 mg).
Reaction SMILES: [OH-:1].[CH2:2](Br)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10]S(C)=[O:12]>CO>[CH2:10]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:2]([OH:12])(=[O:1])[C:3]([CH3:8])=[CH2:4]
Reactant: CS(C)=O
Reactant: BrCc1ccccc1
Reactant: [OH-]
Solvent: CO
Product: C=C(C)C(=O)O
Product: C=Cc1ccccc1
Yield: 50 %

Procedure:
Then, into a 500 ml four necked flask, 30.0 g of the above polymer and 50 ml of methanol were added and dissolved, and then 4.2 of potassim hydroxide was added, stirred and dissolved. Then, 16.2 g of benzyl bromide and 100 ml of dimethyl sulfoxide were added thereto, and the mixture was stirred at 80° C. for 2 hours. The reaction solution was dropwise added to a methanol/1.5% hydrochloric acid aqueous solution (volume ratio of 1/1). A white powder was recovered and vacuum-dried to obtain a partial benzyl ester of a styrene/methacrylic acid copolymer (esterification rate: 50% to methacrylic acid, as determined by potentiometric titration). The obtained amount was 32.5 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=O)=[N:3][CH:2]=1.O.[NH2:19][NH2:20]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[NH:20][N:19]=2)=[N:3][CH:2]=1
Reactant: NN
Reactant: O=C1c2ccccc2C(=O)C1c1ccncn1
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(Cc2ccncn2)c2ccccc12

Procedure:
1.20 g (5.35 mmol) 2-pyrimidin-4-yl-indan-1,3-dione in 30 ml ethanol is spiked with 345 μl (6.96 mmol) hydrazine hydrate and heated for 5 h to 100° C. After cooling, the product is filtered off and washed with ethanol: m.p.: 204-206° C.; Anal. calc. (C13H10N4O.0.5 H2O ) C 63.15%, H 4.48%, N 22.66%; found C 63.3%, H 4.5%, N 22.7%; FAB MS (M+H)+=239.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[OH:20])[O:13][C:12](=[O:21])[C:11]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3][CH2:2]1.[C:28](=O)([O-])[O-].[K+].[K+].[I-].[K+].S(OC)(OC)(=O)=O>C(C(C)=O)C(C)C>[CH3:28][O:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:10]([O:9][CH2:8][CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[C:11]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:12](=[O:21])[O:13]2
Reactant: O=C([O-])[O-]
Reactant: O=c1oc2cccc(O)c2c(OCCN2CCOCC2)c1-c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: COS(=O)(=O)OC
Product: COc1cccc2oc(=O)c(-c3ccccc3)c(OCCN3CCOCC3)c12
Yield: 25.2 %

Procedure:
18.4 g. (0.05 mol) of 4-(2'-morpholinoethoxy)-5-hydroxy-3-phenyl coumarin (Example 30), 9.7 g. (0.07 mol) of potassium carbonate, 0.5 g. of potassium iodide and 250 ml. of methyl isobutyl ketone are brought over one hour to 80° C. The temperature is then brought to 60° C. and 7.6 g. (0.06 mol) of freshly distilled dimethyl sulphate are added dropwise in 20 minutes. Refluxing takes place for 8 hours and, after cooling, filtering is carried out. The filtrate is evaporated under vacuum and then, after washing with sodium bicarbonate and then water, and extraction with chloroform, there are obtained, after evaporation, 4.8 g. of an oil which cannot be crystallised. Yield 25.2% (theoretical yield 19.1 g.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH2:8]([O:10][CH:11]([O:20][CH2:21][CH3:22])[C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:9].C(OCC)C>N1CCCCC1.C1C=CC=CC=1>[C:2]1([CH:6]=[C:13]([C:12]([CH:11]([O:10][CH2:8][CH3:9])[O:20][CH2:21][CH3:22])=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccs1
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Solvent: CCOCC
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1cccs1)C(=O)C(OCC)OCC

Procedure:
A solution of thiophene-2-carbaldehyde (2.2430 g), ethyl 4,4-diethoxyacetoacetate (4.3648 g) and piperidine (4 drops) in benzene (20 ml) was refluxed under azeotropic dehydration for 4.5 hours. After cooling, to the resultant solution was added diethyl ether, and the solution was washed with water and dried. The solvent was removed from the reaction mixture to give oily ethyl 2-(2-thenylidene)-4,4-diethoxyacetoacetate. The mixture of the compound obtained above and ethyl 3-aminocrotonate (2.6 g) was heated in an oil bath (about 100° C.) for 7.5 hours. The resultant mixture was dissolved in diethyl ether, washed with water and dried. The solvent was removed to give brown oil (9.0 g). The oil was purified by column chromatography on silica gel with an eluent (benzene: ethyl acetate=20:1) to give diethyl 2-methyl-4-(2-thienyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate. The product was recrystallized from n-hexane to give yellowish crystals (2.2056 g), m.p. 77° to 77.5° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.[OH-].[Na+]>O>[O:20]1[CH:18]([CH2:16][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:19]1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)CC2CO2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., 100 g (506.9 millimoles) of dibenzyl-amine (dissolved in 300 ml of methylene chloride) is added dropwise to a thoroughly stirred suspension of 234.51 g (2.53 mol) of epichlorohydrin and 200 ml of 32% sodium hydroxide solution. The mixture is stirred for 2 hours at 0° C. and then 3 hours at room temperature. The mixture is diluted with 31 of water and extracted 3 times with 500 ml of methylene chloride. The organic phases are combined, dried over magnesium sulfate, and evaporated under vacuum. The remaining oil is flash-chromatographed on silica gel (mobile phase: methylene chloride/hexane/acetone: 20/10/3).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:20][CH3:21])=[O:5]
Reactant: CCO
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C(F)(F)F)cc1Br
Temperature: 0 °C
Yield: 100 %

Procedure:
238 g (0.885 mol) of 2-bromo-4-(trifluoromethyl)benzoic acid, 1000 ml of absolute ethanol and 100 ml of concentrated sulfuric acid are introduced successively into a 2-liter round-bottomed flask. The reaction mixture is brought to reflux for 6 hours and then poured, after cooling, onto 2.5 liters of ice-cold water; the oil formed is extracted with ethyl acetate. The organic phase is successively washed with water, with 1N sodium hydroxide solution and then again with water. After drying over magnesium sulfate, the solvent is evaporated to provide 263 g (yield: 100%) of ethyl 2-bromo-4-(trifluoromethyl)benzoate in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH2:24][OH:25])[C:10]=3[O:9][C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)=[CH:4][CH:3]=1.BrCCCO[CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1.[C:46]([O-:49])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:4]4[CH2:3][CH2:2][CH2:34][CH2:46][O:49]4)[C:12](=[O:21])[N:11]([CH2:22][CH2:23][CH2:24][O:25][CH:42]4[CH2:43][CH2:44][CH2:45][CH2:40][O:41]4)[C:10]=3[O:9][C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)=[CH:33][CH:34]=1
Reactant: BrCCCOC1CCCCO1
Reactant: O=C([O-])[O-]
Reactant: O=c1c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)oc2n(CCCO)c(=O)n1CCCO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)oc2n(CCCOC2CCCCO2)c(=O)n1CCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 128.6 %

Procedure:
To a solution of 5-(4-chlorobenzyl)-6-(3-chlorophenyl)-1,3-bis(3-hydroxypropyl)furo[2,3-d]-pyrimidine-2,4(1H,3H)-dione (Compound 27, Step 7, 77.4 mg, 0.2 mmol) in DMF (4 mL) was added 2-(3-bromo propoxy)tetrahydro-2H-pyran (88.8 mg, 0.4 mmol) and K2CO3 (55.2 mg, 0.24 mmol). The reaction was stirred at RT for 2 h then diluted with EA (10 mL) and water (3 mL). The organic layer was washed with brine (3 mL), dried over Na2SO4 and concentrated to give 5-(4-chlorobenzyl)-6-(3-chlorophenyl)-1,3-bis(3-(tetrahydro-2H-pyran-2-yloxy)propyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione (86.4 mg, 64% yield) as a yellow solid. LCMS: MH+ 671 and TR=2.435 min. Used without further purification.