Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)C.[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28]O)=[CH:23][CH:22]=1)([CH3:19])[CH3:18]>>[CH:17]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][O:14][C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][C:4]([OH:3])=[O:16])=[O:15])=[CH:13][CH:12]=2)=[CH:25][CH:26]=1)([CH3:19])[CH3:18]
Reactant: CC(C)Oc1ccc(CCO)cc1
Reactant: CCOC(=O)CNC(=O)c1ccc(O)cc1
Product: CC(C)Oc1ccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)cc1
Yield: 82 %

Procedure:
The same reaction as in Example 78 (78a) was conducted using N-(4-hydroxybenzoyl)glycine ethyl ester (which is the compound disclosed in J. Med. Chem., (1999), 42, 1041-1052, 397 mg, 2.20 mmol) and 2-(4-isopropoxyphenyl)ethanol (which is the compound disclosed in J. Chem. Soc. Perkin Trans. 1, (1983), 619-624, 447 mg, 2.00 mmol) to give 636 mg of the title compound (white powder, yield: 82%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[C:16]([C:21]([O:23]CC)=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(OCC)=O)=NC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[C:16]([C:21]([OH:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: CCOC(=O)c1ncc(OC)cc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C(=O)O

Procedure:
The title compound was prepared according to the procedure described in Step 4 of EXAMPLE 31 using (R)-ethyl 3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinate (EXAMPLE 33 Step 1) in stead of ethyl 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:14])[C:3]=1[OH:15].[H][H]>[Pt]=O.C(O)(=O)C>[CH3:1][CH:2]1[CH:7]([CH3:8])[CH:6]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:5][CH:4]([CH3:14])[CH:3]1[OH:15]
Reactant: [H][H]
Reactant: CC(C)=CCc1cc(C)c(O)c(C)c1C
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)CCC1CC(C)C(O)C(C)C1C
Yield: 53.4 %

Procedure:
A mixture of 2,3,6-trimethyl-4-(3-methyl-2-butenyl)phenol (30 g, 0.15 mol), platinum oxide (3 g), and acetic acid (150 mL) was hydrogenated at 50° C. and 200-300 psig until hydrogen uptake ceased. The mixture was filtered to remove the catalyst and the filtrate poured into water. The product was extracted with ethyl acetate and the extract washed successively with water, 5% sodium bicarbonate solution, and brine. The organic layer was dried, the solvent removed, and the residue fractionated to afford 17 g of the desired alcohol, bp 105°-110° C. (1 mm). NMR (CDCl3) δ0.7-2.2 (27H, complex pattern), 3.6 (1H, bs). IR (film) 3700, 1500, 1020, 970 cm-1. MS (m/e) 212 (M+), 123, 35, 69, 95.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C:13]2([C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)O)=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C:13]2([C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)[Cl:27])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(F)c2c(c1)C(O)(c1ncc[nH]1)c1cc(Br)ccc1O2
Solvent: c1ccccc1
Product: COc1cc(F)c2c(c1)C(Cl)(c1ncc[nH]1)c1cc(Br)ccc1O2
Yield: 95.4 %

Procedure:
7-Bromo-4-fluoro-9-(1H-imidazol-2-yl)-2-methoxy-9H-xanthen-9-ol (10 g, 25.6 mmol) was dissolved in 100 ml of benzene and thionyl chloride (18.66 ml, 256 mmol) was added. The solution was refluxed for 4 hours. The reaction was then concentrated to afford 2-(7-bromo-9-chloro-4-fluoro-2-methoxy-9H-xanthen-9-yl)-1H-imidazole (10 g, 24.41 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[N:4]=[CH:3]1.Cl.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-:27].[Na+]>O>[CH3:1][C:2]([CH3:17])([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[NH2:4])[CH:3]=[O:27].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)C1CCCCCCCCC(C)(C)C=N1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: NCc1ccccc1
Solvent: O
Product: CC(C)C(N)CCCCCCCCC(C)(C)C=O
Yield: 56.4 %

Procedure:
The procedure described in Example 2(b) is repeated, except that 68.5 g (0.5 mol) of 3,3-dimethyl-12-isopropyl-1-aza-cyclododecene, 50 g of 37% hydrochloric acid, 54 g (0.5 mol) of benzylamine and 200 ml of water are used. After neutralisation with 22 g (0.55 mol) of solid sodium hydroxide, 97 g (0.282 mol) of 2,2-dimethyl-11-isopropyl-11-amino-undecanal-benzylamine are obtained; yield 56.4% of theory.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:17][O:18][CH3:19])[C:9]([N:11]1[CH2:14][CH:13]([C:15]#[N:16])[CH2:12]1)=[O:10])(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH2:7][C@H:8]([CH2:17][O:18][CH3:19])[C:9]([N:11]1[CH2:14][CH:13]([C:15]#[N:16])[CH2:12]1)=[O:10]
Reactant: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@@H](N)C(=O)N1CC(C#N)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In a 25 mL round-bottomed flask, [(R)-2-(3-cyano-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (286 mg, 1.00 mmol) was dissolved in dichloromethane (4 ml). The reaction was cooled to 0° C. and trifluoroacetic acid (1.2 ml, 15.6 mmol) was slowly added. The reaction mixture was stirred at room temperature for 3 h then concentrated to provide 1-((R)-2-amino-3-methoxy-propionyl)-azetidine-3-carbonitrile trifluoroacetate as a colorless viscous oil which was used without further purification.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][C:3]#[C:4][CH2:5][CH3:6].[C:8](O)(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[C:1]([O:14][CH2:8][CH2:9][C:10]#[C:11][CH2:12][CH3:13])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)O
Reactant: CCC#CCCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCC#CCCOC(=O)CCCCC
Temperature: 25 °C

Procedure:
Into a 250 ml reaction flask equipped with condenser, stirrer, heating mantle, thermometer and Dean Stark trap is placed 29.4 grams (0.3 moles) of 3-hexyn-1-ol; 34.8 grams (0.3 moles) of n-hexanoic acid; 100 ml toluene and 0.2 ml concentrated sulfuric acid. With stirring, the reaction mass is refluxed for a period of four hours. At the end of the four hour period, the reaction mass is then cooled to room temperature and washed with two volumes of 10% sodium carbonate followed by two volumes of saturated sodium chloride solution. The reaction mass is then distilled on a one plate short path column yielding the following fraction:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[O:10]C[N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.O>[C:11]([NH:8][CH2:7][C:6]1[CH:15]=[C:2]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]=1[OH:10])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N1COc2c(cc(Br)cc2-c2ccccc2)C1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)NCc1cc(-c2cccnc2)cc(-c2ccccc2)c1O
Temperature: 60.5 °C
Yield: 49.7 %

Procedure:
A mixture of 6-bromo-3-(tert-butyl)-8-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (from Example 42, Step 2) (0.485 g, 1.41 mmol), pyridin-3-ylboronic acid (0.346 g, 2.0 equiv), and potassium carbonate (0.777 g, 4 equiv) in isopropanol (30 mL) and water (6 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)Pd (0) (90 mg, 5.5 mol %) was added and the resulting mixture was heated at 55-66° C. for 3 hours. The cooled reaction mixture was concentrated and the resulting residue was purified by column chromatograph to give 3-((tert-butylamino)methyl)-5-(pyridine-3-yl)-[1,1′-biphenyl]-2-ol (0.233 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1(/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:36]1([CH2:42][CH2:43][CH2:44]Br)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1(/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:44][CH2:43][CH2:42][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(/C=C/c2ccc(O)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(/C=C/c2ccc(OCCCc3ccccc3)c(C(F)(F)F)c2)COC(C)(C)OC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Compound 93-8 (400 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (397 mg) and 3-phenylpropylbromide (0.175 ml) were added, and the mixture was stirred at 50° C. for 2 hr, and at 70° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (560 mg) as a colorless oil.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH:14](C1C2C=CC=C(C#N)C=2CC1)=[O:15]>>[CH:14]([CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2)=[O:15]
Reactant: N#Cc1cccc2c1CCCC2=O
Reactant: N#Cc1cccc2c1CCC2C=O
Product: N#Cc1cccc2c1CCCC2C=O

Procedure:
5-Formyl-5,6,7,8-tetrahydronaphthalene-1-carbonitrile was prepared from 5-oxo-5,6,7,8-tetrahydronaphthalene-1-carbonitrile in an analogous fashion to that described above for the synthesis of 1-formyl-2,3-dihydro-1H-indene-4-carbonitrile (Steps B and C).
Reaction SMILES: C1CCCCC=1.O1CCCC1.B.[CH2:13]([N:20]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[C:35]1[C:36]([O:47][CH3:48])=[N:37][CH:38]=[C:39]([C:41]#[C:42][Si](C)(C)C)[CH:40]=1)[C:21](=[O:23])[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+].OO.Cl>C1COCC1.CO>[CH2:13]([N:20]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:26]=1[C:35]1[C:36]([O:47][CH3:48])=[N:37][CH:38]=[C:39]([C:41]#[CH:42])[CH:40]=1)[C:21](=[O:23])[CH3:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ncc(C#C[Si](C)(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1ccccc1)C(C)=O
Agent: B
Agent: Cl
Agent: OO
Solvent: C1CCOC1
Solvent: CO
Solvent: C1=CCCCC1
Product: C#Cc1cnc(OC)c(-c2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(C)=O)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To cyclohexene (0.12 mL, 1.14 mmol) in THF (0.3 mL) at 0° C. was added borane tetrahydrofuran complex (1M in THF; 0.53 mL, 0.53 mmol), and the reaction was stirred for 1.5 hours. N-Benzyl-N-[2-(2-methoxy-5-trimethylsilanylethynyl-pyridin-3-yl)-5-trifluoromethyl-benzyl]-acetamide (0.084 g, 0.15 mmol) in THF (2 mL) was added dropwise, and the reaction was stirred for 1 hour at room temperature. The mixture was cooled to 0° C., and MeOH (0.9 mL) was added, followed by 1N aqueous NaOH (0.53 mL, 0.53 mmol) and hydrogen peroxide (30%; 0.16 mL, 1.55 mmol), and the reaction was stirred for 1 hour at 0° C. and 1.5 hours at 40° C. The mixture was acidified with 1N aqueous HCl and extracted with EtOAc to give N-Benzyl-N-[2-(5-ethynyl-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-acetamide.
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([Br:12])=[CH:7][C:6]=1I.[C:15]([Si](C)(C)C)#C.Cl.[OH-].[K+]>C(N(CC)CC)C.C(O)(C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:12][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][C:9]=1[F:11])[NH:4][CH:3]=[CH:15]2
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Nc1cc(F)c(Br)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Fc1cc2[nH]ccc2cc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A mixture of 70 mg (0.1 mmol) Pd(PPh3)2Cl2 and 27 mg (0.142 mmol) CuI in triethylamine was refluxed under argon during 20 min, cooled to 0° C., treated with 7 g (0.019 mmol) (4-Bromo-5-fluoro-2-iodo-phenyl)-carbamic acid methyl ester, stirred 10 min at room temperature, treated with 2.95 (0.021 mmol) ethinyltrimethylsilane, and stirred 1 h at room temperature. 2M aqueous HCl and ice were added and the mixture extracted three times with EtOAc. The combined organic layers were washed subsequently with H2O and saturated aqueous NaCl, dried with MgSO4 and the solvent was evaporated. The crude product obtained was dissolved in 50 ml tert-butanol, treated with 3.2 g (0.023 mol) KOH and the resulting mixture refluxed for 1.5 h. The solvent was evaporated and the residue distributed between icy water and Et2O. The organic layer was washed with water and dried with MgSO4. Evaporation of the solvent and column chromatography on silica gel with hexane/EtOAc 9:1 gave of 3.2 g (80%) 5-Bromo-6-fluoro-1H-indole, MS: 213 (M, 1Br).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[O:22][CH3:23])[C:3]=1[CH:24]([CH2:29][CH2:30][CH3:31])[C:25]([O:27]C)=[O:26].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[O:22][CH3:23])[C:3]=1[CH:24]([CH2:29][CH2:30][CH3:31])[C:25]([OH:27])=[O:26]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1OC)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1OC)CCCC3
Temperature: 60 °C
Yield: 72.7 %

Procedure:
To a solution of methyl [2-methyl-4-(2-methoxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.108 g; 0.25 mmol) in methanol (2.5 mL) was added a solution of sodium hydroxide 5 N (0.5 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was crystallized from a mixture ethyl acetate-heptane to furnish 0.077 g (76%) of the title compound as a white solid.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(C(=O)C)CC[O:17]C=4N=3)=CC=2)CCC1.N1C=CN=C1CCN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:72][C:73]1([C:77]2[CH:82]=[CH:81][C:80]([C:83]3[C:84]([C:96]4[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=4)=[CH:85][C:86]4[N:91]([CH2:92][C:93]#[N:94])[CH2:90][CH2:89][O:88][C:87]=4[N:95]=3)=[CH:79][CH:78]=2)[CH2:76][CH2:75][CH2:74]1)(C)(C)C>>[NH2:72][C:73]1([C:77]2[CH:78]=[CH:79][C:80]([C:83]3[C:84]([C:96]4[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=4)=[CH:85][C:86]4[N:91]([CH2:92][C:93]([NH2:94])=[O:17])[CH2:90][CH2:89][O:88][C:87]=4[N:95]=3)=[CH:81][CH:82]=2)[CH2:76][CH2:75][CH2:74]1
Reactant: CC(=O)N1CCOc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC#N)CCO4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: NC(=O)CN1CCOc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21

Procedure:
Following the procedure for 1-(6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethanone, 1-((1H-imidazol-2-yl)ethyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(1-(cyanomethyl)-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (5 mg, 0.01 mmol) was reacted to afford the two title compounds (1 mg, 25% and 2 mg, 41%). LCMS: RT=3.99 min, M-16=380. 1H NMR (500 MHz, MeOD): 7.20-7.13 (8H, m), 7.09-7.07 (2H, m), 4.46 (2H, t), 3.54 (2H, s), 3.22 (2H, t), 2.46-2.40 (2H, m), 2.17-2.11 (2H, m), 1.97-1.94 (1H, m), 1.66-1.62 (1H, m). LCMS (Method A): RT=3.99 min, M-16=398. 1H NMR (500 MHz, D2O): 8.39 (2H, s), 7.27-7.22 (7H, m), 7.11-7.09 (2H, m), 6.89 (1H, s), 4.78 (2H, s), 4.48 (2H, t), 4.00 (2H, s), 3.50 (2H, t), 2.65-2.60 (2H, m), 2.53-2.47 (2H, m), 2.09-2.05 (1H, m), 1.86-1.79 (1H, m).
Reaction SMILES: Br[Si](C)(C)C.C([O:8][P:9]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][O:19][N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH2:29])([O:11]CC)=[O:10])C>ClCCl>[P:9]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][O:19][N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH2:29])([OH:11])([OH:10])=[O:8]
Reactant: CCOP(=O)(COCCCOn1cnc2c(N)ncnc21)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Nc1ncnc2c1ncn2OCCCOCP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
Bromotrimethylsilane (0.55 ml, 4.18 mmol) was added dropwise to a solution of 9-[3-(diethoxyphosphorylmethoxy)propoxy]adenine (0.25 g, 0.70 mmol) in dry dichloromethane (2 ml) and the reaction stirred under nitrogen at 25° C. for 3 h. After concentration in vacuo the residue was co-evaporated three times with methanol. Reverse-phase chromatography, eluting with 5% aqueous methanol gave 9-[3-(phosphonomethoxy)propoxy]adenine (152 mg, 71%) as a white solid; m.p. 246°-249° C. νmax (KBr) 3320, 3084, 1700, 1079 cm-1 ; δH [(CD3)2SO] 1.94(2H, t, J6.3 Hz, CH2CH2CH2), 3.56(2H, d, J8.5 Hz, CH2P), 3.70(2H, t, J6 Hz, CH2OCH2P), 4.43(2H, t, J6 Hz, NOCH2), 7.40(2H, br s, D2O exchangeable, NH2), 8.15(1H, s, H-2), 8.43(1H, s, H-8); Found: C, 34.15; H, 5.12; N, 21.89%; C9H14N5O5P.0.8H2O requires: C, 34.03; H, 4.95; N, 22.04%.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[CH2:15][CH2:14][CH2:13]4)[CH2:10][CH2:9][C@H:8]1[CH2:7][C:6](=O)[CH2:5][CH2:4]2.C(S)(S)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.B(F)(F)F.CCOCC>[Ni]>[CH3:17][C@:16]12[CH2:18][CH2:19][C@H:20]3[C@@H:11]([CH2:10][CH2:9][C@@H:8]4[C@:3]3([CH2:2][OH:1])[CH2:4][CH2:5][CH2:6][CH2:7]4)[C@@H:12]1[CH2:13][CH2:14][CH2:15]2
Reactant: C[C@@]12CCC[C@H]1[C@@H]1CC[C@H]3CC(=O)CC[C@]3(CO)[C@H]1CC2
Agent: [Ni]
Agent: CC(S)S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: C[C@@]12CCC[C@H]1[C@@H]1CC[C@H]3CCCC[C@]3(CO)[C@H]1CC2

Procedure:
The 3-deoxy series of 5α-androstan-19ols is prepared by converting the 19-hydroxy-5α-androstan-3-one to its 3-ethylenethioketal by reaction with ethanedithiol and an acid catalyst, such as p-toluenesulfonic acid or boron trifluoride etherate. The ethylenethioketal is then desulfurized with Raney nickel to yield the 5α-androstan-19-ol. A Jones oxidation or Pfitzner-Moffatt oxidation results in the formation of the corresponding 5α-androstan19-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.[C:26]([O:30][C:31](=[O:48])[CH2:32][N:33]1[CH2:38][CH2:37][CH:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[C:41]([O:46][CH3:47])[CH:40]=2)[CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27].C(N(CC)C(C)C)(C)C.COCC(O)C>>[C:26]([O:30][C:31](=[O:48])[CH2:32][N:33]1[CH2:34][CH2:35][CH:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:15]3[N:14]=[CH:13][C:12]4=[CH:11][CH:10]=[C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])[N:17]4[N:16]=3)=[C:41]([O:46][CH3:47])[CH:40]=2)[CH2:37][CH2:38]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1cc(C2CCN(CC(=O)OC(C)(C)C)CC2)ccc1N
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1cc(C2CCN(CC(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
Into an 8-dram vial Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (100 mg, 0.3 mmol), [4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-acetic acid tert-butyl ester (133 mg, 0.415 mmol), N,N-Diisopropylethylamine (150 uL, 0.86 mmol) and 1-Methoxy-2-propanol (2 mL, 20 mmol) were added. The reaction mixture was heated at 80° C. After 3 days, solvent was removed and the product, (4-{3-Methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetic acid tert-butyl ester, was purified by flash chromatography (ISCO, 40 g column, hexane; EtOAc 1:1) as a gum (79 mg, 54%). LCMS (E/I+) 544 (M+H). NMR 1H (MeOH-d4)-8.7 (s, 1H), 8.16 (d, 1H, J=8.28 Hz), 7.82 (d, 1H, J=7.56 Hz), 7.45 (m, 1H), 7.16 (d, 1H, J=8.32 Hz), 7.09 (m, 1H), 6.95 (d, 1H, J=4.67 Hz), 6.89 (d, 1H, J=4.68 Hz), 6.81 (s, 1H), 6.72 (s, 1H), 6.63 (m, 1H), 3.89 (s, 3H), 3.83 (s, 2H), 3.80 (s, 3H), 3.03 (m, 2H), 2.43 (m, 1H), 2.25 (m, 2H), 1.76 (m, 4H), 1.49 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([NH2:25])[C:22]3[CH:21]=[C:20]4[O:26][CH2:27][O:28][C:19]4=[CH:18][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>C(O)C.O1CCOCC1>[ClH:29].[ClH:29].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([NH2:25])[C:22]3[CH:21]=[C:20]4[O:26][CH2:27][O:28][C:19]4=[CH:18][C:17]=3[N:16]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(N)c3cc4c(cc3n2)OCO4)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1nc(NC2CCNCC2)nc2cc3c(cc12)OCO3

Procedure:
A solution of 4-(8-amino-[1,3]dioxolo[4,5-g]quinazolin-6-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.6 g, 1.55 mmol) in ethanol (5 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ESI): 288.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.[N:39]1([C:47](=O)[CH2:48]Cl)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[N:39]1([CH2:47][CH2:48][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:37][CH:38]=2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Reactant: O=C(CCl)N1CCCCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCCCCC3)cc2)C(C)C)c1
Yield: 61.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 1-azocan-1-yl-2-chloroethanone (22 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (20 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=1
Reactant: Cc1ccc(N)nc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Product: Cc1ccc2nc(-c3c(-c4ccccc4)noc3C)cn2c1
Yield: 21 %

Procedure:
As described for Example 2, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (112 mg, 0.4 mmol) was converted, using 2-amino-5-methylpyridine instead of 2-amino-3-methylpyridine, to the title compound (24 mg, 21%) which was obtained as a yellow oil. MS: m/e=290.1 [M+H]+.