Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][CH2:11][CH2:12][C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([NH2:18])[CH2:14][C:15]([CH3:17])=[CH2:16])[CH3:9])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][C@:13]([CH2:14][C:15]([CH3:17])=[CH2:16])([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:18][C:33]2=[O:35])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=C(C)CC(N)(CCNC(C)c1ccc(Br)cc1)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Reaction time: 3 h
Yield: 133.1 %

Procedure:
To a solution of N1-[1-(4-Bromo-phenyl)-ethyl]-5-methyl-3-phenyl-hex-5-ene-1,3-diamine (2.97 g, 0.007 mol) and Et3N (3.53 g, 0.035 mol) was added triphosgene (0.58 g, 0.002 mol) at 0° C. The resulting mixture was stirred for 3 h. The mixture was washed with water, the organic layer was separated, and concentrated to give the crude (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-methylallyl)-4-phenyltetrahydropyrimidin-2(1H)-one (1.1 g, 40%). which was purified by column chromatography. 1H NMR (CDCl3): δ=1.24 (s, 3H), 1.38 (m, 1H), 1.43 (d, 3H), 1.56 (m, 1H), 1.88 (m, 1H), 2.09 (m, 1H), 2.12 (m, 1H), 2.44 (m, 1H), 2.64 (m, 2H) 4.72 (s, 1H), 4.83 (s, 1H), 5.21 (s, 1H), 5.74 (m, 1H), 6.90 (m, 2H), 6.92-7.14 (m, 2H), 7.18-7.38 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7]([OH:13])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].Br[CH2:19][C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[N:22](C(OC(C)(C)C)=O)[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[C:7](=[O:13])[N:8]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:22][N:21]=2)[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccnc(O)c1Oc1cc(Cl)cc(Br)c1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccn(Cc2n[nH]c3ncccc23)c(=O)c1Oc1cc(Cl)cc(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(3-bromo-5-chlorophenoxy)-4-methylpyridin-2-ol (11-5; 75 mg, 0.238 mmol) and tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (74.4 mg, 0.238 mmol) was added potassium carbonate (33 mg, 0.238 mmol) and the resulting mixture was stirred at 25° C. for 18 hours. After this time, the mixture was filtered and then purified on Gilson LC using a Luna column (10μ, C18, 250×21.2 cm) eluting with 5-95% ACN/water with 0.1% TFA). The desired fractions were concentrated to dryness and the resulting solid was dissolved in trifluoroacetic acid (2 mL) This solution was concentrated on the rotary evaporator to give the title compound. LRMS (M+1)=446.7
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.Cl.[NH:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])N>COC(C)(C)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[N:2][N:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:5]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)CNN
Reactant: CN(C)C=C(C(=O)c1ccccc1)c1ccc(F)cc1
Agent: Cl
Solvent: COC(C)(C)C
Product: CCOC(=O)Cn1ncc(-c2ccc(F)cc2)c1-c1ccccc1
Yield: 95.7 %

Procedure:
Following the procedure of example 1B, 13.8 g (0.0645 mol) of 2-(4-fluorophenyl)-1-phenylethanone was reacted with 20 mL of dimethyl formamide dimethyl acetal to yield 13.6 g of 3-(dimethylamino)-2-(4-fluorophenyl)-1-phenyl-2-propen-1-one, mp 115°-116° from isopropyl acetate. The enamine (10.5 g, 0.039 mol) was reacted with 6.03 g (0.039 mol) of ethyl hydrazinoacetate hydrochloride to yield 12.1 g of product mp 86°-87° C. from methyl-t-butyl ether.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[C:15]([Cl:16])=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[Cl:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[N:20]([O-])=O.[Na+].O.O.[Sn](Cl)Cl.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)(=O)C.O.Cl.C(Cl)(Cl)Cl>[C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[C:15]([Cl:16])=[CH:14][C:12]([NH:13][N:20]=[CH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:11][C:10]=2[Cl:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Cc2c(Cl)cc(N)cc2Cl)cc1
Reactant: O=Cc1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)c1ccc(Cc2c(Cl)cc(NN=Cc3ccccc3)cc2Cl)cc1
Reaction time: 1 h
Yield: 65.3 %

Procedure:
In 10 ml of acetic acid was dissolved 1.0 g of 4-(4-Acetylbenzyl)-3,5-dichloroaniline. To the solution was then added 1.0 ml of 35% hydrochloric acid. To the mixture was added dropwise, while cooling at temperatures ranging from 8-10° C., a solution of 0.3 g of 98.5% sodium nitrite in 1.0 ml water. The reaction mixture was stirred for one hour under the same conditions, to which was then added 2.0 g of Tin (II) chloride dihydrate dissolved in 2.0 ml of 35% hydrochloric acid. The reaction mixture was stirred for 3 hours at room temperature. To the mixture then added 20 ml of water and 20 ml chloroform. To the mixture was added dropwise, while cooling at the temperatures ranging from 5-10° C., 0.36 g of benzaldehyde. The reaction mixture was stirred for 30 minutes under the same conditions. After completion of the reaction, followed by extraction with 20 ml of chloroform. The extract was washed with water and sturated sodium hydrogen carbonate solution, dried over an hydrous magnesium sulfate, and concentrated to provide 0.88 g of the title compound as a colorless crystals, m.p.137-139° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([CH2:32][CH:33]=O)=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28])([O-:21])=[O:20]>>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([CH2:32][CH2:33][N:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:13](=[O:18])[CH2:14]2)=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28])([O-:21])=[O:20]
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1CC=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1CCN1CCN(CCc2ccc([N+](=O)[O-])cc2)C(=O)C1

Procedure:
The title compound was prepared from 1-[2-(4-Nitrophenyl)ethyl]piperazin-2-one and Methyl 5-nitro-2-(2-oxoethyl)benzoate following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 457 [M+1]+.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][CH2:5][CH2:4][O:3]1.[O:7]=[CH:8][C:9](=[CH2:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>>[CH3:10][C:9]1[CH2:11][CH2:1][C:2]2([O:3][CH2:4][CH2:5][CH2:6]2)[O:7][CH:8]=1
Reactant: C=C(C)C=O
Reactant: C=C1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1=COC2(CCCO2)CC1
Temperature: 75 °C

Procedure:
A stirred mixture of 20.0 g of 2-methylenetetrahydrofuran, 17.7 g of reagent grade methacrolein and 0.4 g of potassium carbonate was maintained at 75° C. under nigrogen atmosphere for 7 days. Distillation of the reaction mixture yielded 19.1 g of the desired product, b.p. 65°-66° C. (4 torr.).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2.O.[OH:16]S(O)(=O)=O>C(O)(=O)C.C(O)(=O)CC.[O-2].[O-2].[O-2].[Cr+6]>[CH3:14][O:13][C:10]1[CH:9]=[C:8]2[C:3](=[C:2]([Cl:1])[C:11]=1[Cl:12])[C:4](=[O:16])[CH2:5][CH2:6][CH2:7]2
Reactant: O=S(=O)(O)O
Reactant: COc1cc2c(c(Cl)c1Cl)CCCC2
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CCC(=O)O
Solvent: CC(=O)O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)CCC2
Temperature: 70 °C
Reaction time: 20 h

Procedure:
Chromium trioxide (28 g., 0.028 mole) in 83% acetic acid (12 ml.) is added slowly at 0° C. to a stirred solution of 5,6-dichloro-7-methoxytetralin (4 g., 0.073 mole) in a mixture of acetic acid (90 ml.) and propionic acid (20 ml.). The resulting dark mixture then is kept for 20 hours at 20°-25° C. The resulting dark green solution is poured into a mixture of water (900 ml.) and 96% H2SO4 (10 ml.). The mixture is heated to 70° C., cooled to 0° C. and the precipitate is collected, washed with water, and dried. The dried product is sublimed twice at 100° C. at ca. 0.5 mm. and then crystallized from methanol to obtain 6-methoxy-7,8-dichloro-1-tetralone (1 g.), melting point 132°-132.5° C. The identity of the product is established by proton magnetic resonance (pmr).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][CH2:2][NH:1][C:10](=[O:12])[CH3:11]
Reactant: NCCc1ccccn1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)NCCc1ccccn1

Procedure:
The title compound is prepared by the procedure of Example 12 using 25 g of 2-(2-aminoethyl)pyridine, 22.2 ml of acetic anhydride, 2.57 g of 4-dimethylaminopyridine and 100 ml of pyridine. The residue is purified by column chromatography (silica gel:20% methyl alcohol/ethyl acetate) to give 7.5 g of desired product as a yellow oil.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.Cl.[C:28]1([CH2:34][C:35]([NH2:43])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:4]([O:3][C:1]([NH:8][CH2:9][C:10]([NH:43][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:36])[CH2:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:12])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(N)(Cc1ccccc1)c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)NC(C)(Cc1ccccc1)c1ccccc1
Reaction time: 2.25 h

Procedure:
A reaction vessel was charged with dichloromethane (360 l) and Boc-glycine (32.6 kg, 186.3 mol). Triethylamine (18.8 kg, 186.1 mol) was added cautiously keeping the temperature below 25° C. The mixture was cooled to below -5° C. and pivaloyl chloride (trimethylacetyl chloride, 22.4 kg, 185.9 mol) in dichloromethane (40 l) was added at such a rate as to keep the temperature below -5° C. This was washed in with dichloromethane (2 l). The mixture was then stirred at below -5° C. for 2-2.5 h and then 1,2-diphenyl-2-propylamine hydrochloride (40 kg, 161.1 mol, dry weight estimate, actual weight including moisture 42.94 kg) was added as a solid through the manway keeping the temperature below -5° C. Triethylamine (28.4 kg, 281.2 mol) was then added keeping the temperature below -5° C. This was washed in with dichloromethane (2 l). The mixture was stirred at below -5° C. for 2.75-3.25 h, water (400 l) was added and the mixture stirred for at least 15 min. The organic layer was separated and washed with dilute hydrochloric acid made up from concentrated hydrochloric acid (40 l) and water (400 l). The organic layer was again separated and then about 80% (360 l) of the dichloromethane was removed by distillation. Isopropyl alcohol (140 l) was then charged and distillation continued until the head temperature reached 80° C. The solution was then cooled and isopropyl alcohol added to make up to a total weight of 200 kg. This solution was then divided in two by weight and each half used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11].F>[Cr].[Co]>[CH3:8][C:4]1[C:3]([OH:9])=[C:2]([CH3:1])[CH:7]=[C:6]([C:10]([CH3:11])=[O:12])[CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)c1O
Agent: [Co]
Agent: [Cr]
Agent: F
Product: CC(=O)c1cc(C)c(O)c(C)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
(36.6 g, 0.30 mol) of 2,6-dimethylphenol are mixed in an Hastelloy C autoclave with 0.315 mol of acetic anhydride and 9 mols of hydrogen flouride. The temperature is raised to 50° C. and the reaction runs for 3 hours. After extraction and wash, 47.4 g of a gray to purple solid mass of 3,5-dimethyl4-hydroxyacetophenone is obtained. This solid is then esterified by refluxing with 4 mols of acetic anhydride for 19 hours. After removal of acetic acid and acetic anhydride by vacuum distillation the 3,5-dimethyl-4-acetoxyacetophenone is flash distilled to yield 47.7 g of a slightly yellow liquid. 0.1 mol of the 3,5-dimethyl-4-acetoxyacetophenone, 1.2 g of 5% Pd/C as catalyst and 100 ml ethanol are mixed in an autoclave and the autoclave is charged with hydrogen gas at a pressure of 215-220 mm Hg and the reaction is run for about 21/2 hours at a temperature of about 25°-30° C. Additional catalyst is added as needed. The catalyst is then removed and the ethanol evaporated to yield 21.5 g of a colorless oil which is (3,5-dimethyl-4-acetoxyphenyl)ethanol. 0.168 mol of (3,5-dimethyl-4-acetoxyphenyl)ethanol is added to a flask with 0.35 g KHSO4 and 0.5 g t-butyl catechol. The flask is heated to 185 to 190° C. at 1.5 to 2.0 mm Hg. A colorless liquid is distilled. After the addition of 0.15 g of t-butyl catechol, and redistillation, 26.1 g of 3,5- dimethyl-4-acetoxystyrene monomer is produced. The compound has a boiling point of 90°-91° C. at 0.5 mm of Hg and the yield is 81.8%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([CH:8]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[OH:9])[CH:7]=1.C1(C)C=CC=CC=1>ClCCl.[O-2].[Mn+4].[O-2]>[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:19])=[O:9]
Reactant: Cc1ccc(Br)cc1C(O)c1nc2ccccc2s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(Br)cc1C(=O)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
To a solution of the above 5-bromo-2-methylphenyl-(benzothiazol-2-yl)methanol (2.60 g) in dichloromethane (30 ml)-toluene (10 ml) was added manganese (IV) oxide (3.42 g), and the mixture was stirred at room temperature for 3 hours. Insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure to give 5-bromo-2-methylphenyl benzothiazol-2-yl ketone (2.45 g) as colorless crystals. APCI-Mass m/Z 332/334 (M+H). (3) The above 5-bromo-2-methylphenyl benzothiazol-2-yl ketone was treated in a manner similar to Reference Example 14-(1) to give 1-(benzothiazol-2-ylmethyl)-5-bromo-2-methylbenzene as oil. APCI-Mass m/Z 318/320 (M+H).
Reaction SMILES: N1CCOCC1.[C:7]1([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[C:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1)([OH:22])=[O:21].N#N.[N-]=C=O>CO.C(Cl)Cl>[CH3:16][C:15]1[CH:14]=[C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:29]([C:26]2[CH:25]=[CH:24][C:23]([C:20]([OH:22])=[O:21])=[CH:28][CH:27]=2)[N:30]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: N#N
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: C1COCCN1
Solvent: CO
Product: Cc1cc(-c2ccccc2)n(-c2ccc(C(=O)O)cc2)n1
Reaction time: 2.5 h
Yield: 48.1 %

Procedure:
A suspension of polymer-supported morpholine (Example 12), 1-phenyl-1,3-butanedione (81.5 mg, 0.5 mmol) and 4-carboxyphenyl hydrazine hydrochloride (113 mg, 0.6 mmol) in MeOH (2 mL) was shaken for 2.5 hours. The methanol was blown off under a stream of N2. DCM (4 mL) and polymer-supported isocyanate (Example 4A, 350 mg) were added and the reaction mixture shaken for 16 hours. An additional portion of polymer-supported isocyanate (120 mg) was added. After 4 hours the resin was filtered and washed with DCM (2×1.5 mL). The combined organic phases, when concentrated to dryness, gave 4-(3-methyl-5-phenyl-pyrazol-1-yl)-benzoic acid (67 mg, 48%), mp 159-162° C. Predicted mass for (C17H14N2O2+H)+, 278.1055.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[OH:11])=[CH:9][C:4]=2[O:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cccc(C(O)c2ccc3c(c2)OCO3)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cccc(C(=O)c2ccc3c(c2)OCO3)c1

Procedure:
To a stirred solution of benzo[1,3]dioxol-5-yl-(3-methoxy-phenyl) -methanol (2.23 g crude, 7.6 mmol) in CH2Cl2 (20 mL) at room temperature was added activated MnO2 powder (3.5 g, 40 mmol) and kept adding 23 equivalents of MnO2 every 35 h until HPLC showed disappearance of the starting material. The black suspension was filtered through a Celite pad, concentrated in vacuo to give benzo[1,3]dioxol-5-yl-(3-methoxy-phenyl)-methanone as an oil (1.78 g, 89% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCCCOC(=O)CCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOC(=O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A suspension of 1.00 g of 4-(tert-butoxycarbonylamino)piperidine and 0.72 ml of triethylamine in 6 ml of dry N,N-dimethylformamide was stirred at an inner temperature of 50° C., and added dropwise with a solution of 0.79 g of n-butyl chloroacetate in 4 ml of dry N,N-dimethylformamide. Stirring was continued at the same temperature for 1 hour. Then, the reaction mixture was added with water, and the precipitated crystals were collected by filtration. The crystals were washed successively with water and n-heptane to obtain 1.46 g of colorless scales (mp: 115.5-116.5° C.).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37]O)[CH2:31][CH2:30]1)(=[O:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:25])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCN(CCCO)CC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.6 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline (14 g, 41.3 mmol), (prepared as described for the starting material in this example hereinbefore), 3-(4-acetylpiperazin-1-yl)propan-1-ol (9.2 g, 49.5 mmol) and triphenylphosphine (12.9 g, 49.5 mmol) were stirred together in methylene chloride (210 ml). Diisopropyl azodicarboxylate (9.75 ml, 49.5 mmol) was added dropwise and an ice/water bath was used to keep the temperature of the reaction mixture between 15 and 18° C. After the end of addition the reaction mixture was allowed to warm to ambient temperature and stirred for 3 hours. The mixture was filtered and concentrated under reduced pressure and the resulting viscous oil dissolved in acetone (280 ml) and stirred for 45 minutes. The solid that formed was filtered off and dried under vacuum. The solid was purified by chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4) to give 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (12.5 g, 60%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(OCC)C.C([Mg]Br)C=C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:38]=[C:37]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH:36]=[CH:35][C:34]=2[C:44]2[O:45][C:46](=[O:54])[C:47]3[CH:53]=[CH:52][N:51]=[CH:50][C:48]=3[N:49]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:38]=[C:37]([N:39]3[CH2:40][CH2:41][CH2:42][CH2:43]3)[CH:36]=[CH:35][C:34]=2[C:44]([NH:49][C:48]2[CH:50]=[N:51][CH:52]=[CH:53][C:47]=2[C:46]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=2)=[O:54])=[O:45])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2-c2nc3cnccc3c(=O)o2)CC1
Agent: C=CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2cnccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
A solution of 2-amino-5-chloropyridine (52 mg, 0.4 mmol) in THF (10 mL) was cooled to 0° C. and treated with a 1 M diethyl ether solution of allylmagnesium bromide (0.4 mL). The mixture was stirred for 5 minutes before adding 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-pyrido[3,4-d][1,3]oxazin-4-one (100 mg, 0.2 mmol). The reaction mixture was stirred overnight at ambient temperature then concentrated to dryness under vacuum. The residue was treated with brine (5 mL) and CHCl3 (20 mL). The layers were separated and the organic layer was chromatographed using 1% MeOH in CHCl3 to give 125 mg (0.2 mmol, 99%) of product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([Br:31])[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:33]([O:37][C:38](N1CCCC1C1NC(C2C=CC3C(=CC=C(Br)C=3)C=2)=CN=1)=O)(C)(C)C.COC(NC(C1CCOCC1)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([CH:6]1[CH2:8][CH2:38][O:37][CH2:33][CH2:7]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([Br:31])[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Agent: COC(=O)NC(C(=O)O)C1CCOCC1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C1CCOCC1
Yield: 43 %

Procedure:
This compound was synthesized using the same procedure used to synthesize (1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester from 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.469 g, 1.13 mmol) using Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (0.295 g, 1.356 mmol). [2-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid methyl ester (0.264 g, 43% yield). LCMS-ESI+: calc'd for C26H29BrN4O4: 540.14 (M+); Found: 542.08 (M+H+).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][C:19]3[S:22][CH:23]=[CH:24][C:18]=3[CH2:17]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O-:25][Mn](=O)(=O)=O.[K+]>CC(C)=O>[O:25]=[C:17]1[C:18]2[CH:24]=[CH:23][S:22][C:19]=2[CH2:20][CH2:21][N:16]1[CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sccc3C2)CC1
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCN2CCc3sccc3C2=O)CC1
Reaction time: 1 h

Procedure:
A solution of 2-3 (3.25 g, 0.0093 moles) in acetone (100 ml) was treated at room temperature with KMnO4 (2.93 g, 0.0185 moles) and the resulting mixture was stirred for 1 hour. The mixture was then filtered (silica gel pad), concentrated and the residue purified by flash chromatography on silica gel eluting with EtOAc (2)/hexanes (3) to give pure 2-4 as an oil.