Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12]C(=O)C)[C@H:10]([O:16]C(=O)C)[C@@H:9]([O:20]C(=O)C)[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][N:45]4[CH2:50][C:49]5([CH2:55][CH2:54][N:53]([C:56](=[O:66])[CH2:57][NH:58][C:59](=[O:65])[NH:60][CH2:61][CH:62]([CH3:64])[CH3:63])[CH2:52][CH2:51]5)[CH2:48][CH2:47][CH2:46]4)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=O)C.CO.C[O-].[Na+]>O>[CH2:61]([NH:60][C:59]([NH:58][CH2:57][C:56]([N:53]1[CH2:54][CH2:55][C:49]2([CH2:48][CH2:47][CH2:46][N:45]([CH2:44][CH2:43][CH2:42][O:41][C:38]3[CH:37]=[CH:36][C:35]([CH2:34][C:26]4[C:27]5[C:32](=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])[N:24]([C@H:8]5[C@H:9]([OH:20])[C@@H:10]([OH:16])[C@H:11]([OH:12])[C@@H:6]([CH2:5][OH:4])[O:7]5)[CH:25]=4)=[CH:40][CH:39]=3)[CH2:50]2)[CH2:51][CH2:52]1)=[O:66])=[O:65])[CH:62]([CH3:64])[CH3:63]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(OCCCN4CCCC5(CCN(C(=O)CNC(=O)NCC(C)C)CC5)C4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cccc2c1c(Cc1ccc(OCCCN3CCCC4(CCN(C(=O)CNC(=O)NCC(C)C)CC4)C3)cc1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
Cool a mixture of [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-[3-[9-[2-(isobutylcarbamoylamino)acetyl]-4,9-diazaspiro[5.5]undecan-4-yl]propoxy]phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (74.28 mmoles; 68.20 g) and methanol (341.00 mL) in an ice-bath. Add sodium methoxide (111.43 mmoles; 6.02 g). Stir the mixture for 10 minutes. Pour the mixture into water (3.5 L), then filter the mixture. Wash the solid with water, dry on the sinter, and further dry in a vacuum oven at 60° C. to give the title compound (49.8 g, 89% yield) mass spectrum (m/z): 750.6 (M+1).
Reaction SMILES: O=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]>O>[C@@H:11]12[O:12][CH2:2][C@H:3]([O:4]1)[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@@H:9]2[OH:10]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Solvent: O
Product: O[C@@H]1[C@H](O)[C@@H]2OC[C@H](O2)[C@H]1O

Procedure:
Syrupy L-gulose was heated on a steam bath in water with strong acid resin (Dowex 50 W-X8, H+ form) for 64 h. The solution was then filtered, the resin washed with water, and the combined filtrate was passed onto a column packed with strong base resin (Amberlite IRA-900, OH- form). The column was washed with distilled water to elute the title compound which crystallized from ethanol. Recrystallized from ethanol it has mp 155.5°-156.5° C. The column was then immediately washed with aqueous acetic acid (M) to elute unreacted L-gulose which was recycled to provide further title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7](O)=[O:8].[CH:15]([NH2:17])=O>O>[CH3:13][O:12][C:11]1[CH:10]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:14]=[CH:15][NH:17][C:7]2=[O:8]
Reactant: NC=O
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Solvent: O
Product: COc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 190 °C
Reaction time: 3 h

Procedure:
A mixture of 4,5-dimethoxyanthranilic acid (19.7 g) and formamide (10 ml) was stirred and heated at 190° C. for 5 hours. The mixture was allowed to cool to approximately 80° C. and water (50 ml) was added. The mixture was stored at ambient temperature for 3 hours. The precipitate was isolated, washed with water and dried to give 6,7-dimethoxy-3,4-dihydroquinazolin-4-one (3.65 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.[F-].[K+]>O1CCOCC1>[Cl:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([C:11]([F:22])([F:21])[F:10])[CH:17]=1
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: Oc1ccc(-c2cccc(C(F)(F)F)c2)c(Cl)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
4-Bromo-3-chlorophenol (518 mg, 2.5 mmol), 3-(trifluoromethyl)phenylboronic acid (617 mg, 3.25 mmol), potassium fluoride (435 mg, 7.5 mmol) palladium acetate (28 mg, 0.125 mmol) and S_phos (102 mg, 0.25 mmol) were stirred in dioxane (10 mL) at 80° C. for 4 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). The EtOAc was dried over MgSO4 and evaporated. The residue was resubjected to the reaction conditions and was redissolved in dioxane (10 mL). 3-(trifluoromethyl)phenylboronic acid (380 mg, 2 mmol), potassium fluoride (348 mg, 6 mmol) palladium acetate (14 mg, 0.0625 mmol) and S_phos (51 mg, 0.125 mmol) were added and the reaction stirred at 80° C. for a further 4 hours. The reaction mixture was worked up as before and the crude product was chromatographed on silica eluting with a gradient of heptane:ethyl acetate 100:0 to 75:25. Fractions containing product were evaporated. The resulting material was chromatographed on silica eluting with a gradient of cyclohexane:triethylamine:isopropyl alcohol 95:5:0 to 95:5:10 to give the title compound (310 mg, 1.14 mmol, 45%) as a colourless gum.
Reaction SMILES: [CH2:1]([C:8]1([CH2:23][CH2:24]I)[C:20](=[O:21])[N:11]2[CH2:12][CH:13]=[CH:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[C:31]([OH:34])(=[S:33])[CH3:32]>CC(C)=O>[C:31]([S:33][CH2:24][CH2:23][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:20](=[O:21])[N:11]2[CH2:12][CH:13]=[CH:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[N:10]2[C:9]1=[O:22])(=[O:34])[CH3:32]
Reactant: COC(=O)C1C=CCN2C(=O)C(CCI)(Cc3ccccc3)C(=O)N12
Reactant: CC(O)=S
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1C=CCN2C(=O)C(CCSC(C)=O)(Cc3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
(b) A mixture of 0.5 g of methyl 2-benzyl-2,3,5,8-tetrahydro-2-(2-iodoethyl)-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate, 0.15 g of potassium acetate and 0.1 g of thioacetic acid in 40 ml of acetone was stirred at room temperature for 5 hours. The solvent was removed by evaporation and the residue was partitioned between dichloromethane and water. The organic phase was separated, dried over magnesium sulfate and evaporated to give 0.4 g (90%) of methyl 2-(2-acetylthioethyl)-2-benzyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (diastereomer A) in the form of a pale yellow oil.
Reaction SMILES: [NH2:1]/[C:2](=[N:12]\[OH:13])/[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:14][CH2:15]OC(C)=O.CC[O-].[Na+]>CCO>[CH3:14][C:15]1[O:13][N:12]=[C:2]([CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:8])[CH3:10])[N:1]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)NC/C(N)=N/O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(CNC(=O)OC(C)(C)C)no1
Yield: 93.8 %

Procedure:
To a stirred solution of (Z)-tert-butyl 2-amino-2-(hydroxyimino)ethylcarbamate (945 mg, 5 mmol) and EtOAc (2.0 mL, 20.0 mmol) in EtOH (100 mL) was added a solution of NaOEt in EtOH (13 mL, 50.0 mmol) and refluxed for 6 h. The reaction mixture was cooled and all the solvent was evaporated under reduced pressure. The residue was dissolved in water and the aqueous layer was extracted with EtOAc. The combined organic layers were dried on Na2SO4 and concentrated to provide 1.0 g of tert-butyl (5-methyl-1,2,4-oxadiazol-3-yl)methylcarbamate.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3([CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[O:15][C:14]3[C:23]([CH3:30])=[C:24]([CH3:29])[C:25]([OH:28])=[C:26]([CH3:27])[C:13]2=3)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1.O>CN(C)C=O>[CH:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[C:16]3([CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[O:15][C:14]3[C:23]([CH3:30])=[C:24]([CH3:29])[C:25]([O:28][CH2:37][C:36]4[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)=[C:26]([CH3:27])[C:13]2=3)=[CH:10][CH:11]=1)([CH3:5])[CH3:4]
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C2(CCN(C)CC2)O3)cc1
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 64.3 mmol, 1.61 mmol) was added to a solution of 3-(4-isopropylphenyl)-1′,4,6,7-tetramethylspiro[benzofuran-2(3H),4′-piperidine]-5-ol (509.0 mg, 1.34 mmol) in N,N-dimethylformamide (25 mL) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 4-methoxybenzyl chloride (244.0 mg, 1.56 mmol) and the mixture was stirred for further 30 minutes at room temperature. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Chromatorex NH DM1020, Fuji Silysia Chemical LTD) (hexane/ethyl acetate=1/1) to obtain the title compound (262 mg, yield 39%). This was amorphous.
Reaction SMILES: [CH3:1][N:2]1[CH:7]([CH3:8])[CH2:6][CH:5](O)[CH2:4][CH:3]1[CH3:10].S(Cl)([Cl:13])=O>C1C=CC=CC=1.O>[CH3:1][N:2]1[CH:7]([CH3:8])[CH2:6][CH:5]([Cl:13])[CH2:4][CH:3]1[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC1CC(O)CC(C)N1C
Solvent: O
Solvent: c1ccccc1
Product: CC1CC(Cl)CC(C)N1C
Temperature: 70 °C

Procedure:
The starting material, 1,2,6-trimethyl-4-piperidinol, may be prepared by the method disclosed in Archi Kem, Volume 27, pages 189-192 (1955). To a cooled (ice-bath) solution of 1,2,6-trimethyl-4-piperidinol (12.2 g, 85.3 mmol) in 120 mL of dry benzene is slowly add thionylchloride (17 mL, 233 mmole). The dark reaction mixture is warmed to 70° C. for 20 min. The reaction is cooled and then suspended in water followed by filtration. The filtrate is extracted once with diethylether. The aqueous layer is separated and the basified with 30% NaOH solution. The product is then extracted twice with CH2Cl2, washed once with brine, dried (Na2SO4), filtered and the solvent removed to produce a crude brown liquid which is distilled (2-4 mmHg, 62°-64° C.) to give the title compound (8.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[H-].[Na+].CN(C)C=O.[CH3:17][O:18][C:19](=[O:22])[CH2:20]Br>O>[CH3:17][O:18][C:19](=[O:22])[CH2:20][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9]
Reactant: COC(=O)CBr
Reactant: Cc1cc(Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-bromo-2-methylphenol (1.0 g, 5.35 mmol), sodium hydride (0.26 g, 6.42 mmol, 60% mineral oil), N,N-dimethylformamide (10 mL), and methyl-2-bromoacetate (0.56 mL, 5.88 mmol) is stirred at room temperature 18 hr. The mixture is diluted with water (50 mL) and the product extracted to ethyl acetate (3×50 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered, concentrated and purified via silica chromatography eluting with 8:2 hexanes:ethyl acetate to afford title compound as a colorless oil, 1.03 g, 74%. MS M+ 259. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].Cl[C:20]1[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=1>CO>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[C:14]([NH:16][C:20]3[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=3)[CH:13]=[CH:12][N:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: N#Cc1cnc(Cl)s1
Reactant: CC(=O)N1CCN(c2nccc(N)n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1CCN(c2nccc(Nc3ncc(C#N)s3)n2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-(4-acetylpiperazin-1-yl)pyrimidin-4-amine 4-4 (0.1 g, 0.45 mmol) was dissolved in dry TBF and then 1 equivalent of sodium hydride (0.036 g, 0.45 mmol) was added and this was stirred for 20 minutes at 25° C. then 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.065 g, 0.45 mmol) was added followed immediately by 1 more equivalent of sodium hydride. The reaction was then stirred at 100° C. for 3 hours. The reaction was cooled to 25° C. and methanol was added. This solution was loaded directly onto a silica column and eluted with DCM:MeOH:NH4OH (95:5:0.5). Fractions were combined and evaporated to yield the product, 4-5. Hi-Res MS: calc: 330.1132 found: 330.1137. 1H-NMR (DMSO): 8.33 ppm (s, 1H); 8.19 ppm (d, 1H); 6.34 ppm (d, 1H); 3.88 ppm (m, 2H); 3.80 ppm (m, 2H); 3.57 ppm (m, 4H); 2.07 ppm (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[O:23][CH2:22][CH2:21][O:20]2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CC>[CH2:21]1[O:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)([CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([C:4]3[N:3]=[C:2]([NH2:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=3)[CH2:31][CH2:32]2)[O:23][CH2:22]1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Fc1ccc(C2(CCCN3CCNCC3)OCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Product: Nc1nc(N2CCN(CCCC3(c4ccc(F)cc4)OCCO3)CC2)ccc1[N+](=O)[O-]

Procedure:
5.6 g 2-amino-6-chloro-3-nitropyridine, 10 g 1-(3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-propyl)piperazine, 5 g potassium carbonate and 100 ml n-propanol are refluxed 21/2 hours. After cooling the precipitate is filtered off. The filtrate is concentrated to ca. 10 ml and diluted with the same volume of diisopropyl ether. The resulting cristallisate is admixed with the above mentioned precipitate and partitioned between water and methylene chloride. The organic phase is filtered and evaporated to give the heading compound, m.p. 117°-118°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:18])=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pt]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Product: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(Cl)cc1N

Procedure:
The title compound was prepared from (5-azetidin-1-yl-4-chloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example C14) by hydrogenation with 5% Pt/C according to the general procedure J (method a). Obtained as a white solid (3.664 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[CH:14])[C:6]=2[CH:15]=1.[N:17]([O-])=O.[Na+].[OH-].[Na+]>Cl>[F:16][C:3]1[C:2]([NH:1][NH2:17])=[CH:15][C:6]2[N:7]([CH2:12][C:13]#[CH:14])[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: C#CCN1C(=O)COc2cc(F)c(N)cc21
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C#CCN1C(=O)COc2cc(F)c(NN)cc21
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A suspension of 6-amino-7-fluoro-4-propargyl-2H-1,4-benzoxazin-3(4H)-one (13.0 g) in conc. hydrochloric acid (70 g) was cooled to 0° to 5° C., and a saturated solution of sodium nitrite (5.1 g) was dropwise added thereto at 0° to 5° C., followed by stirring for 2 hours. The resultant mixture was cooled to -30° C., and a solution of anhydrous stannous chloride (28.1 g) in conc. hydrochloric acid (30 g) was added thereto at once, followed by stirring at 0° to 5° C. for 3 hours. Celite (50 g) was added to the reaction mixture, which was neutralized with 10% aqueous sodium hydroxide solution below 10° C. The resulting mixture was filtered, and the filtrate was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give 7-fluoro-4-propargyl-2H-1,4-benzoxazin-3(4H)-on-6-yl-hydrazine (8.2 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[N:3]=1.[OH:20][CH:21]([CH2:24][OH:25])[CH2:22][NH2:23]>CN(C)C=O.O>[Cl:19][C:14]1[CH:13]=[C:12]([C:4]2[N:3]=[C:2]([NH:23][CH2:22][CH:21]([OH:20])[CH2:24][OH:25])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: Clc1ccc(-c2nc(Cl)c3ccccc3n2)cc1Cl
Reactant: NCC(O)CO
Solvent: O
Solvent: CN(C)C=O
Product: OCC(O)CNc1nc(-c2ccc(Cl)c(Cl)c2)nc2ccccc12
Reaction time: 4 h

Procedure:
A mixture of 46.5 g. (0.15 mole) of 4-chloro-2-(3,4-dichlorophenyl)quinazoline in 500 ml of dimethylformamide and 29 g (0.31 mole) of 2,3-dihydroxypropylamine was heated on a steam bath with stirring for 4 hrs. Diluted the mixture with water until turbid and cooled in an ice bath. The colorless solid was filtered and recrystallized from methyl alcohol (Darco). The product was collected as colorless needles melting at 155°-160° (with previous softening) in a yield of 49 g. (90%). Further recrystallization from nitromethane gave 39 g. melting at 162°-164°. Anal. Calcd. for C17H15Cl2N3O2 : C, 56.06; H, 4.15; N, 11.54 Found: C, 55.63; H, 4.04; N, 11.49.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>CN(C)C=O>[O:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[O:22][CH2:21][CH2:20][CH2:19][N:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13](=[O:15])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2n(CCCOC2CCCCO2)c2ccccc12
Temperature: 80 °C
Yield: 32.7 %

Procedure:
To a solution of acridone (15 g, 0.077 mol) in dry dimethylformamide (200 ml), sodium hydride (3.7 g, 0.092 mol, 60% dispersion in mineral oil) was added in 4 portions under an atmosphere of nitrogen. The reaction mixture was stirred until gas evolution had ceased. A solution of 2-(3-bromo-1-propyloxy)tetrahydro-2H-pyran (21.7 g, 0.092 mol) in dry dimethylformamide (100 ml) was added dropwise. The reaction mixture was heated to 80° C. for 4 h and stirred overnight at room temperature. The reaction mixture was poured onto ice water (800 ml) and extracted with ethyl acetate (4×200 ml). The combined ethyl acetate extracts were washed with water (3×300 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was dissolved in diethyl ether (150 ml) and unchanged starting material was filtered off. The solvent was evaporated in vacuo and the residue was crystallised from 96% ethanol (150 ml), filtered and washed with ethanol (96%, 30 ml) and diethyl ether (50 ml). This procedure was repeated twice, yielding 8.5 g (33%) of 10-(3-(tetrahydro-2H-pyran-2-yloxy)-1-propyl)acridin-9-one as yellowish crystals. M.p. 140.5°-141.5° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[OH:31])[C:21]([Cl:32])=[CH:20][N:19]=1.Cl.O1CCOCC1>CC(O)C>[Cl:32][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[OH:31])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4O)n3)cc2CC1
Temperature: 140 °C
Yield: 27.7 %

Procedure:
3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (76 mg, 0.34 mmol) and trans-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexanol (100 mg, 0.38 mmol, 1.1 eq) were dissolved in IPA (3 mL). 4.0 M HCl in dioxane (95 μL, 0.38 mmol, 1.1 eq) was added and the reaction was heated at 140° C. in a microwave for 2.5 hours. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain trans-2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexanol as a pink foam (42 mg, 28%). LCMS (m/e) 446 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.93 (s, 1H), 7.35-7.22 (m, 2H), 7.04 (d, 1H, J=8.1 Hz), 6.78 (s, 1H), 5.17 (d, 1H, J=7.1 Hz), 3.96-3.85 (m, 1H), 3.60-3.54 (m, 2H), 3.38 (s, 3H), 3.00-2.85 (m, 4H), 2.81-2.65 (m, 6H), 2.20-2.10 (m, 2H), 1.85-1.77 (m, 2H), 1.45-1.10 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH:10]=[CH2:11].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:10]=[CH2:9]
Reactant: Oc1ccc(F)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 336.3 parts of 4-fluorophenol, 417.5 parts of allyl bromide, 420 parts of potassium carbonate and 480 parts of acetone is stirred and refluxed for 8 hours. After cooling to room temperature, 2250 parts of water are added. The aqueous layer is separated and extracted twice with ether. The combined extracts are washed successively twice with sodium hydroxide solution 10% and twice with sodium chloride solution, dried over potassium carbonate, filtered and evaporated. The oily residue is distilled in vacuo, yielding 381.8 parts of 4-allyloxy-fluorobenzene; bp. 93° C at 23 mm. pressure; nD20 : 1.4950; d2020 : 1.070.
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[CH2:12][O:11]1)[CH3:9].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:10]1([C@H:8]([OH:7])[CH3:9])[CH2:12][O:11]1
Reactant: C[C@@H](OC1CCCCO1)C1(c2ccc(F)cc2F)CO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@@H](O)C1(c2ccc(F)cc2F)CO1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
2-[(1R)-1-(3,4,5,6-Tetrahydro-2H-pyran-2-yl)oxyethyl]-2-(2,4-difluorophenyl)oxirane (82 g; manufactured by a method disclosed in Japanese Laid Open Application Hei 04/074168-A) and 6.3 g of pyridinium p-toluenesulfonate were dissolved in 600 ml of ethanol and the solution was stirred at 55° C. for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 1 liter of ethyl acetate and the resulting solution was washed with water (2×200 ml). The aqueous layer was extracted with ethyl acetate (2×100 ml). The organic layers were combined, washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluate ; hexane:ethyl acetate=10:1 to 8:1 to 3:1) to give 31.5 g of (1R)-1-[2-(2,4-difluorophenyl)-2-oxiranyl]ethanol as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH:5]2[CH3:12].[CH3:13][N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]#[N:20]>>[CH3:13][N:14]1[C:18]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH:5]3[CH3:12])=[CH:17][CH:16]=[C:15]1[C:19]#[N:20]
Reactant: Cn1cccc1C#N
Reactant: CC1CC(=O)c2ccc(Br)cc21
Product: CC1CC(=O)c2ccc(-c3ccc(C#N)n3C)cc21
Yield: 76 %

Procedure:
1-Methyl-5-(3-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrile as an orange solid (0.65 g, 76%) was prepared from 5-bromo-3-methyl-indan-1-one and 1-methyl-2-cyanopyrrole according to the same coupling procedure as described in example 2. MS (ES) m/z 251.2; Anal. Calcd for C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C, 76.49; H, 5.49; N, 11.10. HRMS: calcd for C16H14N2O+H+, 251.1179; found (ESI, [M+H]+), 251.1179.