Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:15][N:16]3[CH2:20][CH:19]([CH:21]=[C:22]([F:24])[F:23])[CH2:18][C:17]3=[O:25])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1.[CH3:26][O-:27].[Na+].O>CO.CCOC(C)=O.O(C(C)C)C(C)C>[F:23][C:22]([F:24])=[CH:21][CH:19]1[CH2:20][N:16]([CH2:15][C:8]2[N:6]3[N:7]=[C:2]([O:27][CH3:26])[CH:3]=[CH:4][C:5]3=[N:10][C:9]=2[C:11]([F:14])([F:13])[F:12])[C:17](=[O:25])[CH2:18]1
Reactant: O=C1CC(C=C(F)F)CN1Cc1c(C(F)(F)F)nc2ccc(Cl)nn12
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: CO
Product: COc1ccc2nc(C(F)(F)F)c(CN3CC(C=C(F)F)CC3=O)n2n1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A solution of {[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluoro-vinyl)-pyrrolidin-2-one 33 (500 mg, 1.31 mmol, 1 eq) and sodium methoxide (142 mg, 2.63 mmol, 2 eq) in methanol (5 ml) is heated in microwave apparatus (300 W, T 150° C.) until complete conversion (0.5 h). After cooling to room temperature, water (10 ml) is added and the methanol is removed under reduced pressure. Subsequent extraction with dichloromethane (2×20 ml), drying of cumulated organic layers over MgSO4, filtration and solvent evaporation under reduced pressure affords the crude reaction mixture which is recristallized in AcOEt/iPr2O to yield 0.46 g of 4-(2,2-difluorovinyl)-1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one 42.
Reaction SMILES: O1CCCCC1[N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[C:16]1[C:17]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([NH:29]C(=O)C)=[N:27][CH:28]=2)=[N:18][CH:19]=[CH:20][CH:21]=1>Cl>[N:11]1[C:12]([C:16]2[C:17]([NH:22][C:23]3[CH:28]=[N:27][C:26]([NH2:29])=[CH:25][CH:24]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:13]2[C:8]([NH:7][CH:15]=[N:14]2)=[N:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)cn1
Agent: Cl
Product: Nc1ccc(Nc2ncccc2-c2ncnc3[nH]cnc23)cn1

Procedure:
A solution of N-(5-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)pyridin-2-yl)acetamide (18.8 mg, 44 μmol) in 5N aqueous HCl (1 mL) was heated at 95° C. for 1 h, after which time LCMS indicated conversion to desired product. The solution was made slightly alkaline with 5N aqueous NaOH (about pH 8) and the resulting precipitate was collected by filtration, washing with water, and dried to give N3-(3-(9H-purin-6-yl)pyridin-2-yl)pyridine-3,6-diamine (6.0 mg, 45% yield) as a dark solid. 1H NMR (d6-DMSO, 400 MHz) δ 12.17 (bs, 1H), 9.74 (d, 1H), 8.98 (s, 1H), 8.55 (s, 1H), 8.21 (m, 2H), 7.77 (dd, 1H), 6.89 (dd, 1H), 6.49 (d, 1H), 5.65 (bs, 3H); m/z (API-ES) 305, (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17](=[O:18])[N:16]([CH3:19])[CH:15]=[C:14]([Br:20])[N:13]=2)=[CH:7][CH:6]=1)C.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Br:20][C:14]1[N:13]=[C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][OH:3])=[CH:6][CH:7]=2)[C:17](=[O:18])[N:16]([CH3:19])[CH:15]=1
Reactant: CCOC(=O)c1ccc(Nc2nc(Br)cn(C)c2=O)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cn1cc(Br)nc(Nc2ccc(CO)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
A slurry of 4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-benzoic acid ethyl ester (1) (7.75 g; 22.02 mmol) in CH2Cl2 (200 mL) was cooled to −78° C. under N2. A solution of DIBAL-H (100 mL; 1.0 M in CH2Cl2) was added dropwise over 30 min. to the stirring slurry, and the reaction allowed to warm gradually to rt over 30 min. The reaction stirred for 1 hr at rt, and was monitored by LC-MS until only product was observed. The reaction was cooled to 0° C. in an ice bath and was quenched by slow addition of 1.0 N NaOH (75 mL). The reaction bilayer was extracted with EtOAc (5×100 mL) and the EtOAc layers were pooled, washed with brine and dried over solid Na2SO4. After filtering off the solids, the filtrate was evaporated down to an orange-red oil, which was then redissolved in 3 mL CH2Cl2 and triturated slowly with diethyl ether (20 mL) to provide 5-bromo-3-(4-hydroxymethyl-phenylamino)-1-methyl-1H-pyrazin-2-one (2) as a light orange solid (3.1 g). MS 311.25 & 313.20 (M+H)
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][NH:20]1>CN(C=O)C>[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][N:20]1[C:10]1[CH:11]=[C:12]2[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: c1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4ccccc4C3)cc21
Yield: 44.7 %

Procedure:
177 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 250 mg of isoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 110 mg of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Br:10])[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])=[CH:6][C:3]=1[CH:4]=O.[CH3:22][NH:23][NH2:24]>C1COCC1>[Br:1][C:2]1[CH:9]=[C:8]([Br:10])[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])=[CH:6][C:3]=1[CH:4]=[N:24][NH:23][CH3:22]
Reactant: CNN
Reactant: O=Cc1cc(Oc2ccc([N+](=O)[O-])cc2F)c(Br)cc1Br
Solvent: C1CCOC1
Product: CNN=Cc1cc(Oc2ccc([N+](=O)[O-])cc2F)c(Br)cc1Br
Yield: 76.5 %

Procedure:
2,4-Dibromo-5-(2-fluoro-4-nitrophenoxy)benzaldehyde (13.0 g, 31.0 mmol) is refluxed with methylhydrazine (4.3 g, 93 mmol) in THF (130 mL) for 2 hours. The reaction is quenched with water (150 mL) and extracted with MTBE (2×150 mL). The organic layer is washed with saturated sodium chloride aqueous solution (2×150 mL), dried with anhydrous sodium sulfate, and concentrated to obtain a solid. The crude solid is recrystallized in EtOAc/hexane to obtain 1-(2,4-dibromo-5-(2-fluoro-4-nitrophenoxy)benzylidene)-2-methylhydrazine as a yellow solid (10.6 g, 76.7% yield). MS (m/z): 447.9 (M+H).
Reaction SMILES: [F:1][CH:2]=[C:3]([CH2:16]Br)[CH2:4][N:5]1C(=O)C2=CC=CC=C2C1=O.[H-].[Na+].O.NN.[ClH:23].[CH:24]([OH:27])([CH3:26])[CH3:25]>CN(C)C=O.[Cl-].[Na+].O.C(O)C.CCOCC>[ClH:23].[CH:24]([O:27][CH2:16]/[C:3](=[CH:2]\[F:1])/[CH2:4][NH2:5])([CH3:26])[CH3:25]
Reactant: O=C1c2ccccc2C(=O)N1CC(=CF)CBr
Reactant: CC(C)O
Agent: Cl
Agent: NN
Agent: [Cl-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)OC/C(=C\F)CN
Reaction time: 3 h

Procedure:
Solid 1-fluoro-2-bromomethyl-3-phthalimidopropene (0.60 g) is added to a previously prepared mixture of isopropanol (0.12 g) and sodium hydride dispersion (96 mg of 55-60% oil dispersion) in dimethylformamide (10 ml) at room temperature. Stirring is continued for 3 hours, then brine as added and the product is isolated by ether extraction. This product is treated with hydrazine hydrate (0.13 g) in ethanol (20 ml) under reflux for 3 hours. Dilute aqueous hydrochloric acid is added and the resulting mixture is washed with ethyl acetate, then the aqueous layer is concentrated to about 5 ml. The residual solution is treated with di-tert-butyl dicarbonate (0.44 g), sodium chloride (1 g) and chloroform (20 ml) then sufficient sodium bicarbonate is added to adjust the pH of the aqueous layer to about 8. The mixture is refluxed for 11/2 hours then the crude N-Boc derivative can be isolated by extractive work-up. Purification is achieved by silica chromatography using ether/petroleum ether as eluent. Cleavage of the Boc protecting group (anhydrous hydrogen chloride in ether) affords (Z)-2-isopropoxymethyl-3fluoroallylamine as its hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3=[CH:19][CH:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C1C=CC2N(O)N=[N:32]C=2C=1.[Cl-].[NH4+].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3=[CH:19][CH:20]=[CH:21][C:22]([C:23]([NH2:32])=[O:25])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NC(=O)c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12

Procedure:
5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carboxylic acid (20 mg) was reacted in NMP (0.4 ml) with HOBt.H2O (40 mg), ammonium chloride (40 mg), DIEA (100 ul) and EDCI (50 mg) at 70° C. for 1 hour. Water was added and the precipitate filtered and dried. After trituration in methanol and filtration, 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carboxamide was isolated as a solid (8 mg). LCMS (ES): >95% pure, m/z 349 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:21])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[CH:4]=1.[CH2:24]([OH:26])[CH3:25].C1COCC1.[BH4-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([O:21][C:24](=[O:26])[CH3:25])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[CH:4]=1
Reactant: CCO
Reactant: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@H]1CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]1CC2
Temperature: 80 °C

Procedure:
A solution of 60 mg. of rac.-1,3-dimethoxy-8α-estra-1,3,5(10)-trien-17-one in 3 ml. of ethanol and 1.0 ml. of THF is gradually combined at room temperature with 60 mg. of NaBH4 and agitated for 30 minutes under N2 and at room temperature. The reaction mixture is neutralized with glacial acetic acid, concentrated, taken up in ether, washed neutral with saturated NaCl solution, dried, and evaporated. The residue is dissolved in 1 ml. of pyridine, the solution is mixed with 0.5 ml. of acetic anhydride and maintained for 1 hour at 80° C. under N2. After cooling, the mixture is introduced into ice water; the precipitate is filtered off and taken up in ether. The ether solution is washed neutral with saturated NaCl solution, dried, and evaporated. Recrystallization from methanol over carbon yields 42 mg. of product, m.p. 131°-134° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][OH:14])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:15]([N:19]([CH3:28])[C:20](N1C=C[N+](C)=C1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[H-].[Na+]>C1COCC1.CN(C=O)C>[C:15]([N:19]([CH3:28])[C:20](=[O:21])[O:14][CH2:13][CH2:12][NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([Br:1])=[CH:3][N:4]=2)[N:7]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CN(C(=O)n1cc[n+](C)c1)C(C)(C)C
Reactant: OCCNc1ccc2ncc(Br)n2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C(=O)OCCNc1ccc2ncc(Br)n2n1)C(C)(C)C
Reaction time: 24 h
Yield: 31 %

Procedure:
To a solution of 2-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)ethanol (0.35 g, 1.5 mmol) and 1-(tert-butyl(methyl)carbamoyl)-3-methyl-1H-imidazol-3-ium (0.30 g, 1.5 mmol) in THF/DMF (6.0 mL/3.0 mL) was added NaH (0.15 g, 60% in mineral oil, 2.5 mmol). The reaction was stirred for 24 h and then quenched with water, extracted with ether, concentrated and purified by ISCO column chromatography give 2-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)ethyl tert-butyl(methyl)carbamate as product (0.17 g, 31% yield). LRMS (ESI) m/e 372.0 [(M+H)+, calcd for C14H21BrN5O2 371.2].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)C=O.C(OC1C=CC(OB(O)O)=CC=1)C1C=CC=CC=1.[Br:36]C1C=CC(O)=CC=1.C(Cl)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:11]([O:10][C:9]1[CH:8]=[CH:7][C:4]([Br:36])=[CH:3][CH:2]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=Cc1ccc(OCC2CCCCC2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: OB(O)Oc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Solvent: ClCc1ccccc1
Product: Brc1ccc(OCc2ccccc2)cc1

Procedure:
The intermediate 32 (1.76 g), 4-benzyloxyphenyl boric acid [6.75 g, 4-benzyloxy bromobenzene was prepared according to a process described in the process c-1 in example 1 from 4-bromophenol (Tokyo Chemical Ind. Co., Ltd.) and benzyl chloride (Tokyo Chemical Ind. Co., Ltd.), and the product was prepared according to a method described in the reference Y Satoh et al. SYNTHESIS page 1146, 1994], anhydrous potassium carbonate (4.09 g) and tetrakis (triphenylphosphine)palladium (0)(342 mg) were reacted according to the method described in the process i in example 23 to obtain the compound in the title (2.30 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].CC1C=CC(S(O[CH2:33][C@H:34]2[CH2:38][CH2:37][CH2:36][O:35]2)(=O)=O)=CC=1.BrCC1CCCCO1>>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:33][C@H:34]1[CH2:38][CH2:37][CH2:36][O:35]1)[C:11]3=[O:19]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Reactant: COc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Product: COc1cc2c(cc1C)C1(CO2)C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 6-methoxy-5-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (72%) as a colorless solid: mp 151-153° C.; 1H NMR (300 MHz, CDCl3) δ7.27 (dd, J=7.7, 7.7 Hz, 1H), 7.15-6.98 (m, 3H), 6.48 (s, 1H), 6.44 (s, 1H), 4.90 (d, J=8.9 Hz, 1H), 4.65 (dd, J=8.9, 2.3 Hz, 1H), 4.32-4.21 (m, 1H), 3.99-3.61 (m, 4H), 3.78 (s, 3H), 2.10-1.63 (m, 4H), 1.99 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.3 (2), 160.3, 159.1, 142.9 (2), 132.6 (2), 128.7 (2), 124.2 (2), 123.7 (2), 119.5 (2), 119.2 (2), 109.5 (2), 93.7, 80.4 (2), 77.0 (2), 68.2 (2), 57.9, 55.5, 44.6 (2), 29.1 (2), 25.6 (2), 15.9 (2); MS (ES+) m/z 366.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[O:22]1[C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=[N:23]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH:21][C:27]([C:26]2[O:22][N:23]=[CH:24][CH:25]=2)=[O:28])=[CH:17][CH:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Reactant: O=C(Cl)c1ccno1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)c2ccno2)nn1
Yield: 77 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (280 mg, 1 mmol) was converted, using isoxazole-5-carbonyl chloride instead of methoxyacetyl chloride, to the title compound (290 mg, 77%) which was obtained as a white solid. MS: m/e=378.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[N:5][CH:6]=[N:7]2.[I:13]Cl>Cl>[Cl:1][C:2]1[CH:11]=[C:10]([I:13])[C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[N:5][CH:6]=[N:7]2
Reactant: Oc1ccc(Cl)c2cncnc12
Reactant: ClI
Agent: Cl
Product: Oc1c(I)cc(Cl)c2cncnc12

Procedure:
5-Chloro-8-hydroxy-quinazoline (10 mmol) was added to a stirred solution of ICl (12 mmol) in concentrated HCl (10 mL).8 After 5 min, the precipitate was isolated via filtration, washed successively with H2O, saturated sodium thiosulfate and H2O, and dried. This provided 5-chloro-8-hydroxy-7-iodo-quinazoline (A53) as a solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[C:30](=[O:31])[O:29][C:28]([CH3:33])([CH3:32])[O:27][C:26]=2[CH:34]=1.O.[BH4-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:21][C:22]3[CH:23]=[CH:24][C:25]4[C:30](=[O:31])[O:29][C:28]([CH3:32])([CH3:33])[O:27][C:26]=4[CH:34]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: CC1(C)OC(=O)c2ccc(N)cc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A solution of 4-[(4-butylphenyl)ethynyl]benzaldehyde (2.0 g, 7.63 mmol, intermediate which may be obtained according to methods disclosed in EP03103780.7) and 7-amino-2,2-dimethyl-4H-1,3-benzodioxine-4-one (1.47 g, 7.63 mmol) in toluene (30 mL) was heated at reflux for 96 hrs with azeotropic removal of water. The reaction mixture was concentrated off under reduced pressure. MeOH (15 mL) and THF (15 mL) were then added, and the resulting mixture chilled at 0° C. Sodium borohydride (375 mg, 9.9 mmol) was added portionwise and the mixture was stirred for 1 hr at 0° C., then 3 hrs at room temperature. The reaction mixture was diluted with EtOAc (60 mL) and washed with an aqueous solution of NaOH (3×15 mL, 1N). The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. Et2O (100 mL) was added and the resulting white precipitate was filtered off to give 2.2 g (66%) of the title compound as a white solid. HPLC, Rt: 5.62 min (purity: 93.6%). LC/MS, M−(ESI): 438.3, M+(ESI): 440.2. 1H NMR (CDCl3) δ: 7.71 (d, J=8.6 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.29 (d, J=7.9 Hz, 2H), 7.14 (d, J=7.9 Hz, 2H), 6.32 (m, 1H), 6.01 (m, 1H), 4.38 (s, 2H), 2.61 (t, J=7.5 Hz, 2H), 1.60 (s, 6H), 1.65-1.50 (m, 2H), 1.42-1.28 (m, 2H), 0.91 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](O)[N:3]=1.O=P(Cl)(Cl)[Cl:12]>>[Cl:12][C:4]1[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)nc(O)n1
Product: Cc1cc(C)nc(Cl)n1

Procedure:
To a 50 ml single neck round-bottomed flask was added 4,6-dimethylpyrimidin-2-ol (5.0 g, 0.04 mol) followed by POCl3 (15.0 ml, 0.097 mol). The resulting suspension was heated to reflux overnight. Heating was stopped. After cooling, the mixture was concentrated, poured into crushed ice and extracted with diethyl ether (100 ml×2). The organic layer was washed with 10% NaHCO3 solution, dried over Na2SO4 and evaporated to get a pale yellow solid. Yield: 3.3 g (58%) 1H NMR (400 MHz, CDCl3): δ 2.48 (s, 6H), 6.97 (s, 1H). LCMS: (ES+) m/z=143.6 (M+H)+
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:17]1[CH:21]=[C:20]([CH:22]=[O:23])[S:19][C:18]=1[CH:24]=[O:25]>C1COCC1>[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[C:17]1[CH:21]=[C:20]([CH2:22][OH:23])[S:19][C:18]=1[CH2:24][OH:25]
Reactant: O=Cc1cc(-c2ccc3ccccc3c2)c(C=O)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(-c2ccc3ccccc3c2)c(CO)s1

Procedure:
About 0.022 mole of lithium aluminum hydride may be stirred into about 50 milliliters of anhydrous THF to make a slurry under an inert atmosphere, and cooled in an ice bath. About 0.01 mole of 3-(naphth-2-yl)-2,5-diformylthiophene may be dissolved in about 10 milliliters of anhydrous THF and added to the slurry with stirring. The reaction may be stirred and allowed to rise to room temperature, and then refluxed for about 2 hours. The reaction mixture may be cooled, carefully quenched with about 50 milliliters of water and washed with about 0.1 M sodium hydroxide. The organic layer may be dried, and the solvent may be removed to leave a residue. The residue may be purified via silica gel chromatography to give (3-(naphthalen-2-yl)thiophene-2,5-diyl)dimethanol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([CH:25](O)[CH2:26][CH2:27][CH:28]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[OH:29])[CH:10]=[C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:25]2[CH2:26][CH2:27][C@H:28]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[O:29]2)[CH:10]=[C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(OCc2ccccc2)cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCO
Reaction time: 1 h

Procedure:
A solution of 1-[3-(2-hydroxyethylsulfonyl)-4-n-propoxy-5-benzyloxyphenyl]-4-(3,4,5-trimethoxyphenyl)butan-1,4-diol (from previous experiment) in chloroform (20 mL) was treated with 10% trifluroacetic acid (20 mL). The reaction was monitored by TLC. After 1 h, anhydrous sodium carbonate was added, and the solid was filtered off and washed with chloroform. The solvent was evaporated and the residue was passed through a flash column of silica gel (hexane-ethyl acetate; 2:1, v/v). The cis- and trans-isomers were then separated by HPLC (hexane-ethyl acetate; 1:1, v/v). Rf 0.33 (hexane-ethyl acetate; 1:1, v/v); NMR (CDCl3) δ 0.98 (t, J=7.5 Hz, CH2CH2CH3), 1.83 (m, CH2CH2CH3), 2.85 (t, J=6.5 Hz, OH), 3.67 (q, SO2CH2), 3.98 (q, SO2CH2CH2), 4.17 (t, CH2CH2CH3), 5.18 (s, CH2C6H5), 6.63 (s, 2 H, C5ArH).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH2:23])[CH:16]=1.[Cl:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29].C([O-])(O)=O.[Na+]>>[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH:23][C:28](=[NH:29])[C:27]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:26]=2[Cl:25])[CH:16]=1
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: COC(=O)c1ccc(OC)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1ccc(OC)c(NC(=N)c2ccc(F)cc2Cl)c1
Temperature: 160 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Anhydrous p-toluene sulfonic acid (41.99 g, 220.76 mmol) was melted at 120° C. and 3-amino-4-methoxy benzoic acid methyl ester (20 g, 110.38 mmol) obtained in step 1 of Preparation Example 1 and 2-chloro-4-fluorobenzonitrile (25.76 g, 165.57 mol) were added thereto and stirred at 160° C. for 8 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding NaHCO3 thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (26.70 g, 79.47 mmol) in a yield of 72%.