Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].Br[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]=[C:17]([O:19][C@H:20]4[C@H:24]5[O:25][CH2:26][C@@H:27]([OH:28])[C@H:23]5[O:22][CH2:21]4)[NH:18][C:13]3=[CH:12][C:11]=2[Cl:29])=[CH:6][CH:5]=1.[C:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:32])[CH3:31]>O1CCOCC1.O>[OH:28][C@@H:27]1[CH2:26][O:25][C@@H:24]2[C@H:20]([O:19][C:17]3[NH:18][C:13]4[C:14]([N:16]=3)=[N:15][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:36]5[CH:37]=[CH:38][C:33]([C:30](=[O:32])[CH3:31])=[CH:34][CH:35]=5)=[CH:5][CH:6]=3)=[C:11]([Cl:29])[CH:12]=4)[CH2:21][O:22][C@H:23]12
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(Br)cc3)c(Cl)cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2ccc(-c3nc4nc(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)[nH]c4cc3Cl)cc2)cc1
Temperature: 80 °C

Procedure:
LiOH (0.41 ml, 1.230 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (41.8 mg, 0.051 mmol) were added to a stirred solution of (3R,3aR,6R,6aR)-6-[[5-(4-bromophenyl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (225.2 mg, 0.497 mmol) and 4-acetylphenylboronic acid (100.3 mg, 0.612 mmol) in dioxane (4.0 ml) and water (0.59 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 80° C. for 18 h. The reaction mixture was then partitioned between EtOAc (50 ml) and water (50 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×50 ml), dried over Na2SO4, filtered, and evaporated under reduced pressure to give a yellow solid. The solid was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile+0.05% TFA flush. The desired fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a light yellow solid. LC-MS: calculated for C26H22ClN3O5 491.12 observed m/e: 492.10 (M+H)+ (Rt 1.14/2 min); 1H NMR δ (ppm) (CD3OD): 8.11 (d, J=8.5 Hz, 2H), 7.85 (d, J=8.5 Hz, 2H), 7.83 (s, 1H), 7.77-7.82 (m, 4H), 5.55 (qt, J=5 Hz, 1H), 4.97 (t, J=5.3 Hz, 1H), 4.47 (t, J=4.8, 1H), 4.27-4.30 (m, 1H), 4.17 (dd, J=5.8, J=10.3, 1H), 4.11 (dd, J=4.8 Hz, J=10.3, 1H), 3.90 (t, J=7.5 Hz, 1H), 3.60 (t, J=8.8 Hz, 1H) 2.65 (s, 3H).
Reaction SMILES: CO[C:3](=[O:20])[CH2:4][C:5]1([C:16]([O:18][CH3:19])=[O:17])O[N:12]2[C:7]([C:8]([CH3:15])([CH3:14])[O:9][CH2:10][CH2:11]2)=[N:6]1.[OH2:21]>CC1C=CC(C)=CC=1C>[OH:21][C:4]1[C:3](=[O:20])[N:12]2[C:7]([C:8]([CH3:14])([CH3:15])[O:9][CH2:10][CH2:11]2)=[N:6][C:5]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: O
Reactant: COC(=O)CC1(C(=O)OC)N=C2N(CCOC2(C)C)O1
Agent: Cc1ccc(C)c(C)c1
Product: COC(=O)c1nc2n(c(=O)c1O)CCOC2(C)C
Temperature: 22.5 °C

Procedure:
A solution of the above crude methyl 2-(2-methoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylate (8.34 g) in 1,2,4-trimethylbenzene (80 mL) was heated at 155° C. for 9 h. The resulting dark mixture was cooled to 20-25° C. and diluted with water (50 mL). The product was extracted into 0.5M Na2CO3 (2×50 mL). The organic layer was discarded. The aqueous phases were combined and washed with CH2Cl2 (40 mL). The organic wash was discarded. The aqueous solution was acidified to pH 2.0 with 6M sulfuric acid (9.0 mL) and the product extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layers were evaporated in vacuo. The residue was redissolved in isopropanol (75 mL) at 75° C. and the solution was treated with activated charcoal (0.85 g) at 75-80° C. for 20 min. The charcoal was removed by filtration and washed with hot isopropanol. The combined filtrate and wash was concentrated in vacuo to 40 mL. The resulting slurry was cooled slowly with stirring to 10° C. and stirred for 1 h. The solid was filtered, washed with cold isopropanol (10 mL) and dried in vacuo at 40-45° C. to afford methyl 3-hydroxy-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate as an off-white crystalline solid (3.68 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:3]([OH:5])=[O:4].Cl[C:14]([O:16][CH3:17])=[O:15]>O1CCOCC1.[OH-].[Na+]>[CH3:17][O:16][C:14]([NH:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:15]
Reactant: NC(Cc1ccccn1)C(=O)O
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)N[C@@H](Cc1ccccn1)C(=O)O
Temperature: 60 °C
Reaction time: 7 h
Yield: 65.1 %

Procedure:
A solution of 2-amino-3-pyridin-2-yl-propionic acid (0.168 g, 1.0 mmol) in 1,4-dioxane (1.0 mL) and 1 N NaOH (3.6 mL) was treated with methyl chloroformate (0.153 mL, 2.0 mmol), stirred at 60° C. for 7 hours, and extracted with dichloromethane. The aqueous phase was acidified to pH 7 with 1 N HCl and evaporated to dryness. The resulting solid was trituated with 3:1 dichloromethane/isopropanol, filtered, and the filtrate was concentrated to yield a yellow solid (0.146 g, 65%) which was used for the next step without further purification.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].[Br:12]C(Cl)(Cl)Cl.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]([C:4]([Br:12])([CH2:10][CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Br
Reactant: CCOC(=O)C(CC)C(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CCOC(=O)C(Br)(CC)C(C)=O
Yield: 56.5 %

Procedure:
In a 10 mL round-bottom flask, 1.58 g of ethyl 2-acetylbutyrate (10 mmol), 2.1 g bromotrichloromethane (10.5 mmol), and 200 mg of tetra-n-butylammonium fluoride trihydrate (0.632 mmol) were mixed at 24° C. for 1 h. Gas chromatographic analysis of the resulting mixture showed the presence of 1.34 g of ethyl 2-acetyl-2-bromobutyrate (56% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]([OH:11])=O.[CH:12]1([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:26]=[C:27]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]4[CH3:40])[C:28]4[CH2:33][NH:32][CH2:31][C:29]=4[N:30]=3)=[CH:21][CH:20]=2)=[O:17])[CH2:14][CH2:13]1>>[CH:12]1([NH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[N:26]=[C:27]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]4[CH3:40])[C:28]4[CH2:33][N:32]([C:9](=[O:11])[CH2:8][CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][C:2]5=[O:1])[CH2:31][C:29]=4[N:30]=3)=[CH:23][CH:24]=2)=[O:17])[CH2:13][CH2:14]1
Reactant: O=C(O)CCN1CCCC1=O
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(C(=O)CCN1CCCC1=O)C2

Procedure:
Method as example 127 using 3-(2-oxopyrrolidin-1-yl)propanoic acid and (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) as starting materials. Purified by prep HPLC at low pH to afford a white solid. (35.3 mg, 0.066 mmol, 29%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S.O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH3:17])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2ccccc2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: COc1ccc(-c2ccc(C(C)=O)cc2)cc1F
Reaction time: 10 h
Yield: 75.9 %

Procedure:
Three grams of said 3-fluoro-4-methoxybiphenyl was dissolved in 14 ml of carbon disulfide, and 1.17 g of acetyl chloride and 2.36 g of aluminum chloride were added, followed by stirring the mixture for 10 hours. Twenty milliliters of 10% hydrochloric acid and then 5 ml of water were added, and the precipitate was filtered and washed with water. The resulting crude crystals were recrystallized from ethanol to obtain 2.75 g of 3'-fluoro-4'-methoxy-4-acetylbiphenyl (yield 76%).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:8]=2[CH:26]([OH:29])CO)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[C:8]=2[CH:26]=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(C(O)CO)n(CC(=O)N(C)C)c2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(C=O)n(CC(=O)N(C)C)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-(1,2-dihydroxyethyl)-1-[2-(dimethylamino)-2-oxoethyl]-1H-indole-6-carboxylate (from Step 3) in THF/water (0.05 M, 1:1, v:v) cooled to 0° C. was added sodium periodate (1.2 eq.). The resulting mixture was allowed to warm to RT and left stirring for a further 3 h. The mixture was diluted with EtOAc and 5% aq. citric acid solution. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were extracted with aqueous citric acid (2% solution), sat. aq. NaHCO3 solution and brine. The organic phase was then dried over Na2SO4 and evaporated in vacuo. The residual material was then crystallised from EtOAc with PE. The product was obtained as an off-white solid (83%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[CH:7][CH:6]=1.I[CH2:24][CH3:25]>>[CH2:24]([N:13]([CH:11]([C:8]1[CH:9]=[N:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:21])[F:22])=[CH:6][CH:7]=1)[CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH3:25]
Reactant: CCI
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(OCC(F)(F)F)nc1
Product: CCN(C(=O)OC(C)(C)C)C(C)c1ccc(OCC(F)(F)F)nc1
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (0.24 g, colorless oil) from tert-butyl (1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)carbamate (0.22 g, 0.69 mmol, Step-1 of Amine-3) and iodoethane instead of iodomethane by the similar manner in Step-2 of Amine-3.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[C:15]3[O:20][CH2:19][O:18][C:16]3=[CH:17][C:11]2=[N:10]1.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>C(N(CC)CC)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[C:15]3[O:20][CH2:19][O:18][C:16]3=[CH:17][C:11]2=[N:10]1
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1ccc(O)c(-n2nc3cc4c(cc3n2)OCO4)c1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc(O)c(-n2nc3cc4c(cc3n2)OCO4)c1

Procedure:
According to the procedure of Example 2, a sample of 2-(2-hydroxy-5-aminophenyl)-5,6-methylenedioxybenzotriazole is treated with methacryloyl chloride in the presence of triethylamine to yield 2-(2-hydroxy-5-methacrylamidophenyl)-5,6-methylenedioxybenzotriazole. The corresponding chloro, methoxy and methylenedioxy compounds of the acrylamidophenyl series may be produced according to the general synthetic routes disclosed above for the corresponding methacrylamidophenyl compounds.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][N:2]=1.Cl.[NH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[N:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][N:2]=1
Reactant: CCOC(=O)CCCN
Reactant: O=Cc1ccnnc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN=Cc1ccnnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
In a 25 ml, three-necked flask fitted with a magnetic stirrer under inert atmosphere, pyridazine-4-carbaldehyde x66 (0.93 g, 8.6 mmol) and ethyl 4-aminobutanoate hydrochloride x67 (1.58 g, 9.5 mmol) are dissolved in CHCl3 (15 ml). Triethylamine (1.3 ml, 9.5 mmol) and MgSO4 (2 g) are added and the mixture is stirred at room temperature for 4 h. The mixture is filtered, washed with water, dried over MgSO4 and concentrated to give 1.92 g (100%) of crude ethyl 4-[(pyridazin-4-ylmethylene)amino]butanoate x68, which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29].Cl>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=2[N+:28]([O-:30])=[O:29])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 95.8 %

Procedure:
A solution of 4-Benzyloxy-phenol (2.00 g, 0.01 mol) and potassium hydroxide (1.12 g, 0.02 mol) in anhydrous dimethylsulfoxide (20 mL) was stirred at room temperature for 10 minutes under a nitrogen atmosphere. A solution of 4-chloro-3-nitrobenzoic acid (2.01 g, 0.01 mol) in dimethylsulfoxide (5 mL) was added and the mixture heated to 120° for 1 hour. The reaction was then cooled in an ice bath and poured into 100 mL of ice-water. The mixture was acidified with concentrated HCl to pH 3 then the resultant solid was colleted by vacuum filtration, washed with water and dried in a vacuum oven to provide the title product (3.5 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:10]([OH:13])=[C:6]([C:7]([OH:9])=O)[CH:5]=1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:10]([OH:13])=[C:6]([C:7]([NH:20][C:19]2[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=[C:17]([C:16]([F:15])([F:28])[F:29])[CH:18]=2)=[O:9])[CH:5]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(O)c(C(=O)O)c1
Product: COC(=O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 91.5 %

Procedure:
Using 4-hydroxyisophthalic acid 1-methyl ester and 3,5-bis(trifluoromethyl)-aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C>CS(C)=O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH2:3][CH2:2]1
Reactant: OCc1csc(N2CCOCC2)n1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1csc(N2CCOCC2)n1

Procedure:
The reaction described in Preparation 44 was repeated but using 2.4 g of 2-morpholinothiazol-4-ylmethanol, 5.7 g of sulfur trioxide pyridine complex. 3.6 g of triethylamine and 30 ml of dimethyl sulfoxide, giving the title compound as pale yellow needles.
Reaction SMILES: NC1CCC=CO1.C(#N)C=C.N12CCN(CC1)CC2.C(C1C=CC2C=CC=CC=2O1)#N.[O:32]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[CH:35]=[CH:34][CH:33]1[C:42]([OH:44])=[O:43].[OH-].[Na+]>C(O)C.[Pd]>[O:32]1[C:37]2[C:36](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:35][CH2:34][CH:33]1[C:42]([OH:44])=[O:43]
Reactant: O=C(O)C1C=Cc2ccccc2O1
Agent: [Pd]
Agent: C1CN2CCN1CC2
Agent: N#CC1C=Cc2ccccc2O1
Solvent: C=CC#N
Solvent: CCO
Product: O=C(O)C1CCc2ccccc2O1

Procedure:
An alternative route to the dihydroaminopyran, O, again starting with Aldehyde M, is described in Thorberg et al., supra. Aldehyde M is reacted with acrylonitrile and 1,4-diazabicyclo[2.2.2]octane (DABCO) at reflux. The cyanobenzopyran is converted to the corresponding benzopyran carboxylic acid with aqueous sodium hydroxide. The benzopyran carboxylic acid (Q) is esterified using a mineral acid in ethanol and reduced by hydrogenation over 5% Pd/C to provide a chroman carboxylic acid. The chroman carboxylic acid is reacted with diphenylphosphorazidate and trimethylamine in benzene at reflux followed by addition of benzyl alcohol and an additional 24 hours at reflux. This provides a benzyloxycarbonyl (SOC) protected amine (R). Hydrogenation of the BOC protected amine provided racemic aminochroman (Q) (Step v). The racemic amine (Q) was resolved using the technique described in WO 93/07135 (Step vi). The resolved (R)-amine (P) is converted to a compound having formula VII following the procedures described in WO 95/11891 (Step vii).
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.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:26]([O:25][C:23](=[O:24])[NH:21][C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)[CH3:27]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (280 mg, 1 mmol) and p-N,N-dimethylaminopyridine (61 mg, 0.5 mmol) in pyridine (5 mL) was added ethyl chloroformate (0.11 mL, 1.2 mmol) at room temperature. The resulting mixture was stirred at room temperature for 5 h. After evaporation the residue was extracted with ethyl acetate/water and the organic phase was dried over sodium sulfate and concentrated. Chromatography (SiO2, heptane/ethyl acetate=100:0 to 70:30) afforded the title compound (260 mg, 73%) as a white solid. MS: m/e=355.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:9]([C:11]3[CH:12]=[N:13][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:16]=3)=[CH:10][C:3]=12.Br[C:33]1[C:34]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:51])[N:48]([CH3:50])[CH3:49])=[CH:42][CH:41]=2)=[N:35][N:36]([CH2:38][CH3:39])[CH:37]=1>>[CH2:38]([N:36]1[CH:37]=[C:33]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:23]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)(=[O:24])=[O:25])[C:9]([C:11]4[CH:12]=[N:13][C:14]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[CH:15][CH:16]=4)=[CH:10][C:3]=23)[C:34]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:51])[N:48]([CH3:50])[CH3:49])=[CH:42][CH:41]=2)=[N:35]1)[CH3:39]
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccc(N3CCOCC3)nc2)cc2c(Br)ccnc21
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc(N4CCOCC4)nc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described for Intermediate 32 with 4-bromo-2-[6-(4-morpholinyl)-3-pyridinyl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine. Using this product crude and following the procedure described in Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea provided the title product. ESMS [M+H]+: 677.4
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[CH3:30][C:31]1([CH2:34]O)[CH2:33][CH2:32]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:30][C:31]3([CH3:34])[CH2:33][CH2:32]3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CC1(CO)CC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC2(C)CC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a solution of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1.5 g), (1-methylcyclopropyl)methanol (0.44 g) and tributylphosphine (1.9 mL) in THF (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.9 g) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.36 g, 21%).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:4]=[C:5]([C@H:9]([NH2:20])[CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[O:6][C:7]=1[CH3:8].[CH3:21][CH2:22][CH2:23][CH2:24][C:25](=O)[CH2:26][CH2:27][CH2:28][CH3:29]>C(O)(C)C>[ClH:1].[CH2:24]([C:25]1([CH2:26][CH2:27][CH2:28][CH3:29])[C:12]2[NH:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]=2[CH2:10][C@H:9]([C:5]2[O:6][C:7]([CH3:8])=[C:3]([CH3:2])[N:4]=2)[NH:20]1)[CH2:23][CH2:22][CH3:21]
Reactant: CCCCC(=O)CCCC
Reactant: Cc1nc([C@H](N)Cc2c[nH]c3ccccc23)oc1C
Agent: Cl
Solvent: CC(C)O
Product: CCCCC1(CCCC)N[C@@H](c2nc(C)c(C)o2)Cc2c1[nH]c1ccccc21
Yield: 9.3 %

Procedure:
To a solution of (1R)-1-(4,5-dimethyl-1,3-oxazol-2-yl)-2-(1H-indol-3-yl)-1-ethanamine hydrochloride (1.2 g, 3.6 mmol) in isopropanol (20 ml) was added 5-nonanone (3.1 ml, 20 mmol) and the mixture was refluxed for about 24 hours. The solvent was evaporated under reduced pressure. To the residue was added water (20 ml) followed by NaHCO3 (10%) solution until neutral pH, followed by ethyl acetate (3×15 ml). After decantation and extraction the combined organic extracts were washed with water (20 ml) and dried over MgSO4. The solvent was evaporated under reduced pressure to afford an oil which was purified by column chromatography on silica gel using ethyl acetate/heptane 7:3 as eluent. The resulting oil was dissolved in ethyl acetate (15 ml) and a solution of HCl in ethyl acetate (1N) was slowly added at about 20° C. to give a precipitate. The suspension was stirred a few minutes and the precipitate collected by filtration, washed with diethyl ether, and dried to afford 0.14 g the desired product as the hydrochloride salt. Melting point: 128-134° C.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[CH3:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:24][C@H:25]([CH3:29])[CH2:26][NH:27][CH3:28])[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[OH:30]>>[OH:3][CH2:2][C:1]([N:27]([CH2:26][C@H:25]([O:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[C:14]([NH:13][C:11]1[CH:10]=[CH:9][C:8]([OH:30])=[C:7]([CH3:6])[CH:12]=1)=[N:15][CH:16]=[N:17]2)[CH3:29])[CH3:28])=[O:5]
Reactant: O=C(O)CO
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN(C)C(=O)CO)c23)ccc1O
Yield: 81 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 2-methyl-4-({5-[(1R)-1-methyl-2-(methylamino) ethoxy]quinazolin-4-yl}amino)phenol to give 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]-N-methylacetamide as an orange solid in 81% yield; NMR spectrum (DMSO-d6) 1.38 (d, 3H), 2.15 (s, 3H), 2.96 (s, 3H), 3.35 (dd, 1H), 4.02 (s, 2H), 4.21 (m, 2H), 5.18 (m, 1H), 6.83 (d, 1H), 7.27 (m, 1H), 7.38 (s, 1H), 7.46 (d, 1H), 7.92 (t, 1H), 8.70 (s, 1H), 9.52 (s, 1H), 10.68 (s, 1H); Mass spectrum MH+ 397.