Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][C@@H:12]2O)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]3)[CH2:3]1.F[C@@H:25]1C2[C@](C)(C=CC(=O)C=2)C2[C@H]([C@H]3[C@@](CC=2)(C)C(=O)CC3)C1>>[F:1][C@@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH:12]=2)([CH3:10])[C:8](=[O:23])[C:7](=[CH2:25])[CH2:6]3)[CH2:3]1
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Product: C=C1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)C1=O

Procedure:
Likewise diflorasone diacetate (6α,9α-difluoro-11β,17α,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-diacetate) can be produced using the process of the present invention. First, 6α-fluoro-11β-hydroxyandrosta-1,4-diene-3,17-dione (U.S. Pat. No. 2,867,630) is dehydrated to 6α-fluoroandrost-1,4,9(11)-triene-3,17-dione by means well known to those skilled in the art, see Steroid Reactions, C. Djerassi, Holden-Day, San Francisco, 1963 p. 238 & 239. The 16-methylene group is then added by the process of U.S. patent application Ser. No. 349,490 to produce 6α-fluoro-16-methyleneandrosta-1,4,9(11)-triene-3,17-dione (IIIB) which is converted by the process of the present invention to 6α-fluoro-17α-hydroxy-16-methylenepregna-1,4,9(11)-triene-3,20-dione (VIIB). The 21-hydroxy function of the corticoids is next introduced as described above followed by transformation of the 16-methylene group to a 16β-methyl group also described above to give 6α-fluoro-17α,21-dihydroxy-16β-methylpregna- 1,4,9(11)-triene-3,20-dione 21-acetate which is acylated according to the procedure described in U.S. Pat. No. 4,154,748 (Examples 6 and 7) to produce 6α-fluoro-17α,21-dihydroxy-16β-methylpregna-1,4,9(11)-triene-3,20-dione 17,21-diacetate (U.S. Pat. No. 3,980,778, Example 6). 6α-fluoro-17α,21-dihydroxy-16β-methylpregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate is then converted to diflorasone diacetate by the process of U.S. Pat. No. 3,980,778 (Examples 7 and 8).
Reaction SMILES: Br[CH2:2][CH2:3]/[CH:4]=[C:5](\[CH3:15])/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C-:16]#[N:17].[K+]>CN(C=O)C.O>[CH3:15]/[C:5](/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4]\[CH2:3][CH2:2][C:16]#[N:17]
Reactant: [C-]#N
Reactant: CCCCCCCCC/C(C)=C/CCBr
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCC/C(C)=C/CCC#N
Temperature: 70 °C
Reaction time: 24 h
Yield: 98.2 %

Procedure:
A mixture of the (E)-1-bromo-4-methyl-3-tridecene (3) (38.0 g, 138 mmols) and KCN (11.5 g, 176 mmols) in DMF (100 ml) and water (30 ml) was stirred for 24 hours at 70° C. Then, the mixture was poured into ice water (1 L) and extracted with ether (500 ml). The ether solution was washed with water, dried (MgSO4), and concentrated in a vacuum. The residue was subjected to silica gel chromatography, and eluted with n-hexane-ether (100:1) to obtain 30.0 g (98%) of (E)-5-methyl-4-tetradecenenitrile (4) as oily matter.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([O:20]CC)=[O:19])=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[OH-].[Na+]>C(O)C>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([OH:20])=[O:19])=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCOC(=O)COc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxyacetate (0.66 g), 1M sodium hydroxide solution (4 ml) and ethanol (20 ml) was heated on a steam bath for 30 minutes. The solvent was removed under reduced pressure and the residue was stirred for 1 hour with 1M hydrochloric acid (20 ml) at ambient temperature. The mixture was filtered to give 3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxyacetic acid, m.p. 246-248° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][CH2:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[CH:9][N:8]=1.O>C(O)C>[CH3:4][O:5][CH2:6][C:7]1[N:12]=[C:11]([N:2]([CH3:3])[CH3:1])[CH:10]=[CH:9][N:8]=1
Reactant: CNC
Reactant: COCc1nccc(Cl)n1
Solvent: O
Solvent: CCO
Product: COCc1nccc(N(C)C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 33% w/w solution of dimethylamine in ethanol (45 ml) was added dropwise to a stirred solution of 2-methoxymethyl-4-chloropyrimidine (7.54 g) in ethanol (100 ml), cooled over an ice bath. The mixture was allowed to warm to room temperature, and left to stand for 16 hours. After stripping, the residue was treated with water (100 ml), and extracted with chloroform. The extracts were dried (K2CO3) and stripped to give 2-methoxymethyl-4-dimethylaminopyrimidine (7.41 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH:11]=[N:12][O:13][CH3:14])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:15].C(N(CC)CC)C.CS(Cl)(=O)=O.Cl.[NH2:29][C:30]([CH3:35])([CH2:33][CH3:34])[C:31]#[CH:32]>O.O1CCCC1>[CH3:35][C:30]([NH:29][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([CH:11]=[N:12][O:13][CH3:14])[C:2]([NH2:1])=[C:3]([Cl:15])[CH:4]=1)([CH2:33][CH3:34])[C:31]#[CH:32]
Reactant: C#CC(C)(N)CC
Reactant: CON=Cc1cc(C(=O)O)cc(Cl)c1N
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CC(C)(CC)NC(=O)c1cc(Cl)c(N)c(C=NOC)c1
Temperature: -30 °C
Yield: 62 %

Procedure:
In a 100 ml, three-necked, round-bottomed flask fitted with a mechanical stirrer, nitrogen inlet and thermometer were placed 1.27 g (5.5 mmole) of the preceding 4-amino-3-chloro-5-methoxyiminomethylbenzoic acid, (25 ml of tetrahydrofuran and 2.31 ml (16.6 mmole) of triethylamine. The resulting well-stirred mixture was cooled to -30° C. and 0.47 ml (6.1 mmole) of methane sulfonyl chloride were added dropwise keeping the reaction temperature at -30° C. The resulting suspension was stirred at -30° C. during 30 minutes, after which 0.74 g (5.5 mmole) of 3-amino-3-methyl-1-pentyne hydrochloride were added over a 20 minute period. After the addition was completed, the reaction mixture was stirred at -30° C. for an additional 30 minutes. The reaction mixture was poured into water and extracted with methylene chloride (3×25 ml). The combined organic phases were washed sequentially with water (1×20 ml), 5% aqueous hydrochloric acid (2×20 ml), water (1×20 ml), 2% aqueous sodium hydroxide (2×20 ml) and then with water (1×20 ml) and dried over anhydrous magnesium sulfate. The solvent was removed using a rotary evaporator, yielding 1.05 g of the expected N-(3-methylpent-1-yn-3-yl)-4-amino-3-chloro-5-methoxyiminomethylbenzamide, used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[CH:8][CH:9]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1cccc(N)c1
Reaction time: 23 h
Yield: 90.3 %

Procedure:
A mixture of 5.5 g of N-(3-nitrophenyl)octadecanamide and 0.6 g of 10% palladium on carbon in 100 ml of ethyl acetate was shaken under an initial hydrogen pressure of 52 psi until uptake ceased after 23 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was recrystallized from methanol-water to give 4.6 g (90% yield, mp 98°-102°) of N-(3-aminophenyl)octadecanamide.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C@H:11]3[CH2:16][C@H:15]4[C@H:17]5[C@H:27]([CH2:28][CH2:29][C@:13]4([CH3:14])[C@H:12]3[OH:31])[C@:25]3([CH3:26])[C@H:20]([CH2:21][C@@H:22]4[O:30][C@@H:23]4[CH2:24]3)[CH2:19][CH2:18]5)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[O:1]1[C:5]2([CH2:6][CH2:7][N:8]([C@H:11]3[CH2:16][C@H:15]4[C@H:17]5[C@H:27]([CH2:28][CH2:29][C@:13]4([CH3:14])[C@H:12]3[OH:31])[C@:25]3([CH3:26])[C@H:20]([CH2:21][C@H:22]([OH:30])[C@@H:23]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[CH2:24]3)[CH2:19][CH2:18]5)[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC4(CC3)OCCO4)C[C@@H]12
Reactant: C1CCNCC1
Product: C[C@]12C[C@H](N3CCCCC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC4(CC3)OCCO4)C[C@@H]12
Yield: 87.5 %

Procedure:
16β-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-2α,3α-epoxy-5α-androstane-17β-ol is reacted with piperidine as described in Example 3 to give the title compound in a yield of 87.5%, m.p.: 183°-185° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nc2ccccc2s1)c1ccccc1
Temperature: 3 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
In a 100 ml three-necked flask equipped with magnetic stirrer, thermometer, dropping funnel and nitrogen inlet, 5.34 g (35.6 mmol) of 2-amino-benzothiazole are dissolved in 50 ml of pyridine and cooled to 3° C. using an ice bath. 5.0 g of benzoylchloride (35.6 mmol) are added dropwise within 20 minutes, keeping the temperature within the mixture below 5° C. Stirring is continued for another 15 minutes, then the mixture is poured on 500 ml of water. The white suspension is stirred for 1 hour, filtered, the white residue is washed 3 times with 100 ml of water, respectively, and dried over night at 50° C. and 30 mbar. 7.5 g crude product obtained are purified by flash-chromatography using hexane/ethylacetate 3:1 (v/v), yielding 5.8 g of the title product.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](=[O:25])[CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][C:10]=1[O:26][CH3:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:28]C(C)([O-])C.[K+].CI.O>C1COCC1.C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](=[O:25])[CH:18]([CH3:28])[C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:11][C:10]=1[O:26][CH3:27])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1cc(/C=C/C(=O)CC(=O)C(C)(C)C)ccc1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: O
Product: COc1cc(/C=C/C(=O)C(C)C(=O)C(C)(C)C)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.6 %

Procedure:
To a stirring solution of (E)-1-(4-tert-butyldimethylsilyloxy-3-methoxyphenyl)-6,6-dimethylhept-1-ene-3,5-dione (700 mg, 1.79 mmol) in THF (15 ml) under N2 was added potassium tert-butoxide (442 mg, 3.94 mmol) and stirred for a further 45 min at room temperature. A solution of methyl iodide (0.235 ml, 3.76 mmol) in THF (2 ml) was added and the mixture heated at reflux for 5 h. Water (25 ml) was added to the cooled mixture followed by DCM (25 ml). The organic layer was separated, washed with water (25 ml), dried (MgSO4(anh)), filtered and concentrated. The residue was purified by column chromatography on silica using dichloromethane as eluent to give the monomethyl alkylated product, (E)-1-(4-tert-butyldimethylsilyloxy-3-methoxyphenyl)-4,6,6-trimethylhept-1-ene-3,5-dione (540 mg, 74%):
Reaction SMILES: [OH-].[K+].C([O:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][C:8]=1[C:25]([CH3:28])([CH3:27])[CH3:26])(=O)C.Cl>CO>[CH2:18]([O:17][C:10]1[C:11]([C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:12][C:7]([OH:6])=[C:8]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:9]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)Oc1cc(C(C)(C)C)c(OCc2ccccc2)cc1C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(OCc2ccccc2)c(C(C)(C)C)cc1O
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of potassium hydroxide (1.51 g) in methanol (12 ml) was added 4-benzyloxy-2,5-di-t-butylphenyl acetate (4.9 g). The mixture was allowed to stand at ambient temperature overnight. The reaction mixture was neutralized with dilute hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate and evaporated to dryness to give the title compound (4.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[C:7]([Br:18])[CH:6]=2.[CH2:19](OC(OCC)OCC)C>Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1>[Br:18][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][C:14]([CH3:15])([OH:16])[CH3:17])[CH:19]=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(O)CNc1c(N)cnc2cc(Br)ccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(O)Cn1cnc2cnc3cc(Br)ccc3c21
Yield: 95 %

Procedure:
A 2-L round bottom flask was charged with 1-[(3-amino-7-bromoquinolin-4-yl)amino]-2-methylpropan-2-ol (25.5 g, 82.2 mmol), toluene (1 L), pyridine-HCl (0.1 g, 0.82 mmol, 0.01 eq) and triethylorthoformate (13.4 g, 90.4 mmol, 1.1 eq), and the reaction was heated at reflux for 2 hours. The reaction mixture was concentrated to dryness. The resulting pale yellow solid was slurried in 1% aqueous sodium carbonate solution (250 mL), collected by vacuum filtration, and air-dried on the funnel overnight to provide 25 g of 1-(7-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10]>O>[CH:1](=[N:13][C:9]([CH3:12])([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)N
Solvent: O
Product: CC(C)(C)N=Cc1ccccc1
Reaction time: 15 h
Yield: 88.2 %

Procedure:
To a three neck round bottom flask, equipped with a cold water condenser, 30 g of water and 26.5 g of benzaldehyde were added. The mixture was mixed with a magnetic stirrer at room temperature for 3 minutes. t-Butyl amine (22.1 g) was added to the reaction flask in one portion, followed by vigorous stirring for 15 hours. The agitation was stopped and the reaction mixture was allowed to stand for at least 15 minutes. The lower aqueous layer was separated from the reaction mixture. The upper layer was collected and dried over magnesium sulfate to give 35.5 g of product. 1H NMR (300 Hz, CDCl3, ppm): 8.29 (1H, s), 7.77 (2H, m), 7.40 (3H, m), 1.33 (9H, s).
Reaction SMILES: [O-:1][Si:2]([O-:4])=[O:3].[Na+:5].[Na+].[OH2:7]>>[Si:2]([O-:7])([O-:4])([O-:1])[O-:3].[Na+:5].[Na+:5].[Na+:5].[Na+:5]
Reactant: O
Reactant: O=[Si]([O-])[O-]
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
As a starting material for producing a silica sol, there was used a water glass having an SiO2 content of 28.5% by weight and an Na2O content of 9.5% by weight. 10.0 kg of the water glass was dissolved in 30.0 kg of water, to thereby obtain a diluted aqueous solution of sodium silicate having a sodium silicate content of 7.13% by weight in terms of SiO2.
Reaction SMILES: [Na].[NH2:2][C:3]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])=[CH:4][C:5]#[N:6].[C:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18].Cl>C(O)C.O.C(OCC)(=O)C>[CH2:17]([O:16][C:15](=[O:19])[NH:2]/[C:3](/[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])=[CH:4]\[C:5]#[N:6])[CH3:18]
Reactant: N#CC=C(N)c1ccc(F)cc1F
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)N/C(=C\C#N)c1ccc(F)cc1F

Procedure:
At 40° C., 769 mg (33.44 mmol) of sodium were dissolved in ethanol (41 ml). 4.14 g (22.29 mmol) of 3-amino-3-(2,4-difluorophenyl)prop-2-enonitrile and 5.79 g (49 mmol) of diethyl carbonate were added, and the reaction solution was stirred under reflux for 4 h. 200 ml of ethyl acetate and 150 ml of water were added to the reaction mixture and the pH was adjusted with hydrochloric acid to pH=5. The organic phase was separated off, dried over magnesium sulfate and concentrated on a rotary evaporator. The residue was triturated with diisopropyl ether and the white precipitate was filtered off with suction. More product was obtained by separating the mother liquor by preparative HPLC (Method 11). Drying under high vacuum gave a total of 4.92 g (49% of theory) of the product as a mixture of E and Z isomers which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:12]2=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])C1C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][C:18]([CH3:19])([CH3:20])[C:12]2=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC2(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCC2(C)C
Yield: 89.7 %

Procedure:
Intermediate 4, ethyl 3-(benzyloxy)-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-2-carboxylate, (650 mg, 1.9 mmol) was treated with 6 mL trifluoroacetic acid (16 hrs) then concentrated in vacuo. The remaining residue was dissolved in CH2Cl2 and washed with H2O. Concentration of the CH2Cl2 layer gave 430 mg of a solid (Yield=90%) which could be further purified by trituration with diethyl ether. 1H NMR (300 MHz, CDCl3) δ ppm: 10.81 (1 H, s) 4.45 (2 H, q, J=7.0 Hz) 3.97–4.12(2 H, m) 1.95–2.15 (2 H, m) 1.41 (3 H, t, J=7.1 Hz) 1.33 (6 H, s); LC/MS m/z 253 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=[O:18])[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:15]1([CH3:17])[O:14][C:13](=[O:18])[NH:12][C:11]2[CH:19]=[CH:20][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:3]=3)=[CH:9][C:10]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(Br)c3)cc21
Reactant: C#C[Si](C)(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#C[Si](C)(C)C)c3)cc21
Temperature: 80 °C
Yield: 91.8 %

Procedure:
A mixture of 6-(3-bromo-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.8 g, 2.4 mmol), trimethylsilylacetylene (1 g, 10 mmol), tetrakis(triphenylphosphine) palladium (0) (0.17 g, 0.24 mmol), and cuprous (I) iodide (0.05 g, 0.28 mmol) in triethyl amine (20 mL) was heated under nitrogen at 80° C. for 3 hours. The reaction mixture was cooled to rt and the solvent was removed. The residue was taken up in ethyl acetate (50 mL) and washed with 1N aqueous HCl (3×20 mL) and brine (20 mL). The organic layer was separated and dried (MgSO4). After removal of solvent, the residue was purified by a silica gel chromatography (hexane:ethyl acetate/3:1) to afford the title compound as a white solid (0.77 g, 92%): mp 240-242° C.; 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 7.74-7.69 (m, 2H), 7.61-7.58 (m, 2H), 7.48-7.40 (m, 2H), 6.96 (d, 1H, J=7.98 Hz), 1.67 (s, 6H), 0.25 (s, 9H); MS (EI) m/z 349([M+], 50%); Anal. Calc. For C21H23NO2Si 0.2 EtOAc: C, 71.32; H, 6.75; N, 3.82. Found: C, 71.08; H, 6.64; N, 3.82.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>O1CCCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][OH:13])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc(Oc2ccccc2)cc1
Reaction time: 0.75 h
Yield: 93.9 %

Procedure:
A solution of 4-phenoxybenzaldehyde (5.0 g, 25 mmol) in dry tetrahydrofuran (10 mL) at 0° C. was treated with borane (1M in tetrahydrofuran, 11.25 mL). After 45 minutes, the reaction was quenched with saturated NH4Cl, diluted with ethyl acetate, and washed with 1M HCl, 5% NaHCO3, and brine, and dried over Na2SO4, and concentrated under reduced pressure to give 4.7 g (92%) of 4-phenoxybenzyl alcohol.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][CH2:12][CH2:13]Cl)[CH:7]=[C:6]([CH3:15])[N:5]=2.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN1C(=O)CCC1>[CH3:1][C:2]1[N:3]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][CH2:12][CH2:13][NH:31][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH:7]=[C:6]([CH3:15])[N:5]=2
Reactant: NC1CCCCC1
Reactant: Cc1cc(C)c(-n2c(C)nc3c(NCCCl)cc(C)nc32)c(C)c1
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-n2c(C)nc3c(NCCNC4CCCCC4)cc(C)nc32)c(C)c1

Procedure:
Heat a solution of [2,5-dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-y1](2-chloroethyl)amine (0.04 g, 0.12 mmol), and cyclohexyl amine (0.13 mL g, 1.16 mmol) in dry NMP (2 mL) at 80° C. for 20 h. Pour the cooled mixture onto water (20 mL) and extract twice with ethyl acetate (20 mL). Wash the combined extracts with brine (20 mL), dry, and evaporate in vacuo. Purify by flash column chromatography (10% methanol in CH2Cl2 with 0.1% ammonium hydroxide) to obtain the title compound as a white solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]1[NH:9][CH2:8][CH2:7][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1.O1CCCC1.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25]>O>[CH3:3][CH:4]1[CH2:5][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:8][N:9]1[C:22]([O:23][CH2:24][CH3:25])=[O:26]
Reactant: CC1CN(Cc2ccccc2)CCN1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(Cc2ccccc2)CC1C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
580 Parts of a sodium hydroxide solution 1N in water were cooled in an ice bath and then there were added 44 parts of 3-methyl-1-(phenylmethyl)piperazine and 82.8 parts of tetrahydrofuran. A solution of 27.13 parts of ethyl carbonochloridate in 103.5 parts of tetrahydrofuran was added dropwise at a temperature at about 5° C. Upon completion, stirring was continued for 4 hours in an ice bath. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 55 parts (87.8%) of ethyl 2-methyl-4-(phenylmethyl)-1-piperazinecarboxylate as a residue (int. 36).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>C([O-])(O)=O.[Na+].C(OCC)C>[OH:5][C:4]1[CH:3]=[C:2]([O:10][S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])(=[O:20])=[O:19])[CH:9]=[C:7]([CH3:8])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
Orcinol monohydrate (1.42 g, 10 mmol) and 2-chlorobenzenesulfonyl chloride (2.43 g, 11 mmol) were mixed in saturated NaHCO3 (30 mL) and diethyl ether(30 mL). The biphasic mixture was stirred vigorously at room temperature for 2 days. The reaction mixture was quenched with 50 mL of water and extracted into ethyl acetate. (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (20% ethyl acetate in methylene chloride) to give the title compound as a pale-yellow liquid (2.15 g, 71%).