Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:38])([F:37])[C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[N:20]1[CH2:36][CH2:35][C:23]2([CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[CH2:22][CH2:21]1>C(Cl)Cl>[CH2:27]1[C:23]2([CH2:35][CH2:36][N:20]([C:15]3[C:14]4[C:19](=[C:10]([C:9]([F:37])([F:38])[F:8])[CH:11]=[CH:12][CH:13]=4)[N:18]=[CH:17][CH:16]=3)[CH2:21][CH2:22]2)[CH2:24][CH2:25][NH:26]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccnc4c(C(F)(F)F)cccc34)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cccc2c(N3CCC4(CCNC4)CC3)ccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (1 ml) was added to a cooled (0° C.) solution of tert-butyl 8-(8-(trifluoromethyl)quinolin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.69 mmol, 1.0 eq.) in methylene chloride (4 ml) and the reaction mixture was stirred at 25° C. for 2 h. When the reaction was complete, the solvent was removed in vacuo in order to obtain the desired amine (AMN-27).
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:16][C:17]1[CH:18]=[C:19]2[C:20](=[CH:22][CH:23]=1)[N:21]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]2[OH:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1ccc(N)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(C)cc2c1O

Procedure:
Using the procedure of Example 2, ethyl ethoxymethylene malonate and 4-methyl-aniline were reacted and treated with phenyl oxide to obtain ethyl 6-methyl-4-hydroxy-3-quinoline-carboxylate melting at >260° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[N:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:8]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[N:6][CH:5]=1
Reactant: C=CC(=O)OCC
Reactant: Brc1cncnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1cncnc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 71.9 %

Procedure:
A mixture of 5-bromopyrimidine (5.93 g), ethyl acrylate (5.08 g), palladium acetate (0.112 g), triphenyl phosphine (0.23 g) and triethylamine (4.5 g) was stirred at 150° C. in a pressure vessel for 6 hours. After cooling overnight, water (50 ml) was added to the dark residue, and the product was extracted into toluene. Drying, charcoaling and evaporation gave a pale oil, which was triturated with pet, ether to obtain ethyl 3-(5-pyrimidyl)acrylate (4.78 g). 1H-NMR (CDCl3) δ 1.36 (3H, t), 4.27 (2H, q), 6.59 (1H, d), 7.62 (1H, d), 8.88 (2H, s), 9.20 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:34])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NC(=O)C2(CC(c3cccc(Cl)c3)Oc3ccc(Br)cc32)N1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1cccc(Cl)c1)Oc1ccc(Br)cc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A mixture of 6-bromo-2-(3-chlorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (470 mg, 1.16 mmol) and Lawesson's Reagent (468 mg, 1.16 mmol) in 1,4-dioxane (16 mL) was stirred at 110° C. overnight. The solvent was removed in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(3-chlorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (350 mg, 71%).
Reaction SMILES: Cl.[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:11]([CH2:19][CH2:20][C:21](OCC)=[O:22])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[O:22]=[C:21]1[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[C:11]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:19][CH2:20]1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CCC(=O)CCC(=O)OCC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC1=NN(c2ccccc2)C(=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a three neck flask equipped with a Dean-Stark trap, phenylhydrazine hydrochloride and diethyl 4-oxoheptanedioate (1 equiv.) were combined in toluene (1.15 M). The suspension was stirred 48 h at reflux. The reaction mixture was cooled to rt and concentrated under vacuum to afford the desired material as a brown oil which was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:25]N(C)C)[C:9]([C:11]1[S:24][C:14]2[C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=O.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:36][C:37]([NH2:39])=[NH:38]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:11]2[S:24][C:14]3[C:15]4[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=4[O:17][CH2:18][CH2:19][C:13]=3[CH:12]=2)=[N:38][C:37]([NH2:39])=[N:36][CH:25]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1ncc(-c2ccccc2Cl)c(-c2cc3c(s2)-c2ccccc2OCC3)n1
Temperature: 90 °C

Procedure:
To a solution of crude 2-(2-chlorophenyl)-1-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-3-(dimethylamino)prop-2-en-1-one (ca. 0.22 mmol) in ethanol (2 mL) was added potassium carbonate (87 mg, 0.63 mmol) and then guanidine hydrochloride (40 mg, 0.42 mmol). The whole was sealed and heated at 90° C. for 8 h, cooled to room temperature and concentrated. The residue was diluted with water and extracted with ethyl acetate. The combined organics were purified by reverse phase HPLC to give 282. MS (ESI) 406.2
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:13])([CH3:12])[C:8](=[CH2:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([CH:31]=[N:32][OH:33])=[CH:29][CH:28]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>C1COCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:13])([CH3:12])[C:8]1([CH2:9][OH:10])[O:33][N:32]=[C:31]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([CH3:14])[CH:24]=3)=[CH:35][CH:34]=2)[CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Reactant: C=C(CO)C(C)(C)O[SiH2]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(C3=NOC(CO)(C(C)(C)O[SiH2]C(C)(C)C)C3)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 60.5 %

Procedure:
A solution of Clorox® was added dropwise (1 mL) to a solution of the product from step 24a (0.52 g, 2.56 mmol) and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime (0.5 g, 1.71 mmol) from step 1b in THF (4 mL) under nitrogen atmosphere at room temperature. The reaction was stirred overnight, partitioned between ethyl acetate and water saturated with KH2PO4. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give an oil. The product was purified by FCC on silica gel eluting methylene chloride:ethyl acetate (50:50) to give {5-(tert-butyl-dimethyl-silanyloxymethyl)-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-methanol (0.51 g, 61%) as an oil. MS found: (M+H)+=493.
Reaction SMILES: [C:1](=[N:14][C:15]1[C:20]([F:21])=[C:19]([CH2:22]O)[CH:18]=[CH:17][N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.CC(C)([O-])C.[Li+].[CH2:35]([O:37][C:38](=[O:43])[CH2:39][C:40]([CH3:42])=[O:41])[CH3:36].[Na+].[I-].[Li+].[OH-]>C1COCC1.C(OCC)(=O)C>[CH2:35]([O:37][C:38](=[O:43])[CH:39]([CH2:22][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([N:14]=[C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:20]=1[F:21])[C:40](=[O:41])[CH3:42])[CH3:36]
Reactant: CCOC(=O)CC(C)=O
Reactant: OCc1ccnc(N=C(c2ccccc2)c2ccccc2)c1F
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccnc(N=C(c2ccccc2)c2ccccc2)c1F)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.3 %

Procedure:
A mixture of [2-(benzhydrylidene-amino)-3-fluoropyridin-4-yl]-methanol (compound 8c-4) (5 g, 16.3 mmol), methanesulfonyl chloride (1.52 mL, 19.6 mmol) and lithium tert-butoxide (in THF) (18 mL, 18 mmol) in THF (40 mL) was stirred at 0° C. for 1 hour. The mixture was added to a solution of acetoacetic acid ethyl ester (4.16 mL, 32.7 mmol), lithium tert-butoxide (in THF) (19.6 mL, 19.6 mmol) and NaI (2.5 g, 16.3 mmol) in THF (18 mL). The solution was stirred at 50° C. for 3 hours, 0.2N LiOH (in water) and ethyl acetate were added thereto, and the solution was washed with 0.2N LiOH (in water) and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled away under reduced pressure to yield the title compound (6.98 g, quant.).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH:10]([CH2:15][C:16]([O:18]CC)=[O:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].CO.[OH-].[Na+].Cl>C(=O)(O)[O-].[Na+]>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH:10]([CH2:15][C:16]([OH:18])=[O:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC1CCc2cc(NC(C)=O)ccc2O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ccc2c(c1)CCC(CC(=O)O)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the dark brown ethyl 6-acetamidochroman-2-ylacetate of Example 5 was added 3.5 L of methanol and 3.5 L of 1 N aqueous sodium hydroxide. After stirring the reaction mixture for 2 h at room temperature, the methanol was removed from the reaction mixture providing a dark, aqueous residue. The residue was transferred into a separatory funnel and extracted with 3×2 L of methylene chloride. Between each extraction step, the aqueous fraction was distilled to remove any organic solvent. The pH of the aqueous fraction was adjusted to about 2 with 2 N hydrochloric acid, affording a sticky, dark oil, which was separated. The acidic, aqueous fraction was extracted with 3×2 L of ethyl acetate. The ethyl acetate extracts and the dark oil were combined to form a homogenous solution. This solution was washed 2×2 L of brine and dried over 100 g of anhydrous sodium sulfate. Removing the ethyl acetate afforded a thick, blackish oil, which solidified overnight under vacuum. The dark brown solid was dissolved in saturated aqueous sodium bicarbonate to provide a black solution. The well-stirred, black solution was titrated with 3 N hydrochloric acid. At about pH 7.5, a black oil began to form on the walls of the flask. At about pH 7.0, more black oil formed, and the color of the solution changed from black to light yellow. The mixture was allowed to stand for about 5 min for the black oil to settle. The supernatant was decanted and acidified to about pH 2.0. The resulting white suspension was stirred for 30 min. The precipitate was filtered and dried at 50° C. under reduced pressure affording 350 g of 2-(6-acetamidochroman-2-yl)acetic acid as off-white crystals. The overall yield from 1347 g of 6-(tert-butyloxycarbonylamino)chroman-2-one from example 1 was 46.2%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].N12CCCN=[C:31]1[CH2:30][CH2:29][CH2:28][CH2:27]C2.BrCC1CCC1.O>C(O)C>[CH:28]1([CH2:27][O:1][C:2]2[CH:3]=[C:4]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])[N:14]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccn3)co2)cc1O
Reactant: C1CCC2=NCCCN2CC1
Agent: BrCC1CCC1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc(CCC(=O)c3ccccn3)co2)cc1OCC1CCC1

Procedure:
A 0.15 g quantity of 3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(pyridin-2-yl)propan-1-one obtained in Example 161 and 0.2 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 5 ml of ethanol. A 0.14 g quantity of (bromomethyl)cyclobutane was added thereto, and the mixture was heated and refluxed overnight. The reaction mixture was allowed to cool, water was then added thereto, and extraction was performed with ethyl acetate. After washing with water twice, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=5:1) to give 50 mg of white powdery 3-[2-(3-cyclobutylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(pyridin-2-yl)propan-1-one.
Reaction SMILES: [CH3:1][CH:2]([CH3:45])[C@H:3]([O:20][CH2:21][CH:22]([CH3:44])/[CH:23]=[CH:24]/[C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][C:31]([C@H:35]([NH:37][S@@:38]([C:40]([CH3:43])([CH3:42])[CH3:41])=[O:39])[CH3:36])=[N:32]2)=[CH:27][CH:26]=1)[C:4]([NH:6][C@@H:7]([CH3:19])[C:8]([N:10]1[CH2:15][CH2:14][CH2:13][C@@H:12]([C:16]([OH:18])=[O:17])[NH:11]1)=[O:9])=[O:5].[CH:46](N(CC)C(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:46][O:17][C:16]([C@@H:12]1[CH2:13][CH2:14][CH2:15][N:10]([C:8](=[O:9])[C@@H:7]([NH:6][C:4](=[O:5])[C@@H:3]([O:20][CH2:21][CH:22]([CH3:44])/[CH:23]=[CH:24]/[C:25]2[CH:34]=[C:33]3[C:28]([CH:29]=[CH:30][C:31]([C@H:35]([NH:37][S@@:38]([C:40]([CH3:43])([CH3:42])[CH3:41])=[O:39])[CH3:36])=[N:32]3)=[CH:27][CH:26]=2)[CH:2]([CH3:45])[CH3:1])[CH3:19])[NH:11]1)=[O:18]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(/C=C/c1ccc2ccc([C@@H](C)N[S@](=O)C(C)(C)C)nc2c1)CO[C@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)O)N1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: C[NH3+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCCN(C(=O)[C@H](C)NC(=O)[C@@H](OCC(C)/C=C/c2ccc3ccc([C@@H](C)N[S@](=O)C(C)(C)C)nc3c2)C(C)C)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 113.6 %

Procedure:
A cooled (0° C.) solution of 34b (500.1 mg, 0.645 mmol) in tetrahydrofuran/water (30 mL, 5:1) was treated with lithium hydroxide monohydrate (100.4 mg, 2.393 mmol). After stirring at 0° C. for 45 minutes, the reaction was quenched with hydrogen chloride solution (2 M, 1.2 mL) and the volatiles were removed in vacuo. The residual trichloroethanol was azeotroped off with toluene, toluene/methanol (2×), toluene then dried in high vacuo. The white solid was triturated with diethyl ether (2×) to provide crude (S)-1-{(S)-2-[(S)-3-methyl-2-((E)-2-methyl-4-{2-[(R)-1-((R)-2-methyl-propane-2-sulfinylamino)-ethyl]-quinolin-7-yl}-but-3-enyloxy)-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (LCMS (m/z) 644.4 [M+H], Tr=2.44 min) which was used without further purification. A cooled (0° C.) solution of crude (S)-1-{(S)-2-[(S)-3-methyl-2-((E)-2-methyl-4-{2-[(R)-1-((R)-2-methyl-propane-2-sulfinylamino)-ethyl]-quinolin-7-yl}-but-3-enyloxy)-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (0.645 mmol), N,N-diisopropylethylamine (0.56 mL, 3.225 mmol) and 4-dimethylaminopyridine (7.9 mg, 0.064 mmol) in dry tetrahydrofuran (210 mL) was treated with 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (294.3 mg, 0.774 mmol). The reaction was allowed to slowly warm to room temperature. After 16 h, the reaction was quenched with anhydrous methanol (5 mL). The volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of dichloromethane/methanol 1:0 to 9:1 to afford the title compound (482.0 mg) as an orange gum and as a 1:1 mixture of diastereoisomers. LCMS (m/z) 658.3 [M+H], Tr=2.68 min.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:5]=[C:4]([S:24][CH3:25])[N:3]=1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>>[CH3:28][N:29]([CH3:31])/[CH:30]=[CH:1]/[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[N:5]=[C:4]([S:24][CH3:25])[N:3]=1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Nc1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1c(/C=C/N(C)C)nc(SC)nc1Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in Example 1e by starting from ethyl 4-methyl-2-(methylthio)-6-(3-(trifluoromethyl)phenylamino)pyrimidine-5-carboxylate 1.76 g (4.74 mmol) and N,N-dimethyl formamide dimethylacetal (947 uL, 7.1 mmol) and continuing until the reaction yielded the crude title compound. This was used for the next step without further purification.
Reaction SMILES: C(=O)[CH2:2][CH2:3][CH:4]=[O:5].N1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=[O:10].C1COCC1.C>CC1OCCC1>[OH:10][CH:9]1[O:11][C@H:13]2[CH2:14][C:3]([CH:4]=[O:5])=[CH:2][C@H:12]2[CH2:8]1
Reactant: O=CCCC=O
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: O=CC1=C[C@H]2CC(O)O[C@H]2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The solution of succinaldehyde 8 from the first step (50.6 g, 0.588 mol) in 2-MeTHF was stirred at r.t. (S)-Proline (1.35 g, 11.8 mmol, 0.02 eq.) was added as a solid (Note: The reaction turns from a colourless suspension to a pink suspension over 10 min) and the reaction stirred at r.t. for 20 h. THF (294 ml) was added, followed by [Bn2NH2][OCOCF3] (3.67 g, 11.8 mmol, 0.02 eq.). The reaction was stirred for a further 20 h. Note: The reaction turns to a dark maroon suspension over 20 h. Activated charcoal (100 g) was added to the reaction and the volume of the reaction mixture was reduced by ½ under reduced pressure (˜300 mL). tert-Butyl methyl ether (TBME) (an equal volume to the volume of THF/2-MeTHF removed; 300 mL) was added slowly (over ˜15 mins) and with vigorous stirring of the mixture. Note: For the purposes of this example, slow addition of TBME helps to avoid the formation of oligomer aggregates. The mixture was stirred for 60 min before filtration of the resulting solids (through a sinter funnel; diameter: ˜10 cm). The solids were washed with 2-MeTHF (3×120 ml or until the product was not observed in the filtrate by TLC, 1:1 petroleum ether/EtOAc) and the filtrate was concentrated under reduced pressure. Note: For the purposes of this example, the filtrate should not be concentrated to complete dryness to help avoid solidifying the oligomers on the column, thereby clogging the column during the purification process. The material was purified by column chromatography (˜400 g silica), eluting with petroleum ether/EtOAc (8:2 to 5:5), to give the lactol 7 (as an approximately 2:1 mixture of diastereoisomers), as a brown oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+]([O-])=O)=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.O=P(Cl)(Cl)[Cl:15]>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(Cl)c(Br)c[n+]1[O-]
Yield: 79.5 %

Procedure:
To a solution of 5-bromo-2-methyl-4-nitropyridine N-oxide (558 mg, 2.41 mmol) in DCM (3 mL) at 0° C. was added dropwise a solution of POCl3 (1.3 mL, 7.22 mmol) in DCM (3.2 mL). After 12 h at 25° C. the solution was added to ice, adjusted to pH ˜8 and extracted several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 1.5% MeOH in DCM) yielding the title compound (426 mg, 80%) as a white solid: LCMS (ES) m/z=224 (M+H)+.
Reaction SMILES: [Cl:1][N:2]([C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].Br[CH2:24][CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][N:2]([C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:24][CH2:25][CH2:26][O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9]
Reactant: COc1cc2c(N(Cl)c3ccccc3F)ncnc2cc1O
Reactant: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(N(Cl)c3ccccc3F)ncnc2cc1OCCCOC1CCCCO1
Temperature: 90 °C
Yield: 48.7 %

Procedure:
A mixture of 4-(chloro-2-fluoroanilino)-7-hydroxy-6methoxyquinazoline (3.28 g, 10 mmol), (prepared as described for the starting material in Example 2), 1-bromo-3-tetrahydropyranyloxypropane (2.5 g, 11 mmol) and potassium carbonate (5.0 g, 36 mmol) in DMF (50 ml) was stirred and heated at 90° C. for 3 hours. The reaction mixture was allowed to cool, was diluted with water (500 ml) and extracted with ethyl acetate (3×100 ml). The extracts were combined, washed with water (×3), and then brine, and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by column chromatography eluting with ethyl acetate. The purified product was recrystallised from ethyl acetate/hexane to give 4-(chloro-2-fluoroanilino)-6-methoxy-7-(3-tetrahydropyran-2-yloxypropoxy)quinazoline (2.25 g, 49%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:18])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:21](Br)[C:22]#[CH:23].O>CN(C=O)C>[CH2:23]([N:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:10][C:9]1=[O:18])[C:22]#[CH:21]
Reactant: C#CCBr
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCn1c(-c2ccccc2)c(-c2ccccc2)oc1=O
Reaction time: 0.33 h
Yield: 45 %

Procedure:
4,5-Diphenyloxazol-2-one (500 mg, 2.11 mmol) was dissolved in DMF (4 ml) and sodium hydride (153 mg, 2.55 mmol) was added under nitrogen and with ice cooling over 20 minutes. After stirring for 20 minutes, propargyl bromide (210 μl, 2.79 mmol) was added. After stirring for 15 minutes with ice cooling and stirring at room temperature for 2 hours, water (20 ml) was added and the mixture was extracted with ethyl acetate. The extract was washed in turn with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(2-propynyl)-4,5-diphenyl-oxazol-2-one.
Reaction SMILES: ClC(Cl)(Cl)C([N:5]=C=O)=O.[CH2:10]([O:12][CH2:13][C:14]1[N:15]([CH2:42][CH2:43][CH3:44])[C:16]2[C:25]3[CH:24]=[C:23]([O:26][CH:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]4)[CH:22]=[CH:21][C:20]=3[N+:19]([O-])=[CH:18][C:17]=2[N:41]=1)[CH3:11].[OH-].[NH4+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[NH2:5][C:18]1[C:17]2[N:41]=[C:14]([CH2:13][O:12][CH2:10][CH3:11])[N:15]([CH2:42][CH2:43][CH3:44])[C:16]=2[C:25]2[CH:24]=[C:23]([O:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH:22]=[CH:21][C:20]=2[N:19]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCCn1c(COCC)nc2c[n+]([O-])c3ccc(OC4CCN(C(=O)OC(C)(C)C)CC4)cc3c21
Agent: O=C([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OC4CCN(C(=O)OC(C)(C)C)CC4)cc3c21
Reaction time: 1.5 h
Yield: 51.2 %

Procedure:
Trichloroacetyl isocyanate (1.22 mL, 10.2 mmol) was added dropwise a stirred solution of tert-butyl 4-{[2-(ethoxymethyl)-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}piperidine-1-carboxylate (4.5 g, 9.29 mmol) in dichloromethane (90 mL) at room temperature. After 1.5 hours, ammonium hydroxide (4.5 mL) was added and the mixture was allowed to stir for 1 hour. Saturated aqueous sodium carbonate (60 mL) and water (20 mL) were added to the mixture. After 30 minutes, the mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with chloroform (2×100 mL). The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 1-25% CMA in chloroform) followed by recrystallization from acetonitrile to yield 2.3 g of tert-butyl 4-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}piperidine-1-carboxylate as a gray solid, mp 179.5-181° C.