Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[N+:24]([O-])=O)[O:5][CH2:6][C:7]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12]>C(O)(=O)C.[Fe]>[NH2:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][CH2:6][C:7]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:8]=2[O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc([N+](=O)[O-])c(F)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(N)c(F)c1
Yield: 61.3 %

Procedure:
By the method of Example 2, Step A, 3.35 g (0.0091 mole) of methyl 2-[2-(3-fluoro-4-nitrophenoxymethyl)-5-methylphenoxy]propionate was reacted with 2.80 g (0.050 mole) of powdered iron in 100 mL of acetic acid, yielding 1.86 g of methyl 2-[2-(4-amino-3-fluorophenoxymethyl)-5-methylphenoxy]propionate as an amber syrup. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [C:1]1(/[C:7](/[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[C:8](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>C1(C)C(C)=CC=CC=1>[C:1]1(/[C:7](/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:21][CH:20]=2)=[C:8](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[C:9]([F:12])([F:11])[F:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(/C(=C(\c2ccccc2)C(F)(F)F)c2ccccc2)cc1
Reactant: ClCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: FC(F)(F)/C(=C(\c1ccccc1)c1ccc(OCCN2CCCC2)cc1)c1ccccc1
Yield: 61.4 %

Procedure:
2.72 g (8 mmoles) of (E)-1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)-propene, prepared as described in Example 26, are reacted in xylene with sodium hydride and then with 2-chloroethyl-pyrrolidine as described in Example 26. The product is crystallized from hexane. 2.15 g (61.4%) of the desired compound are obtained; m.p.: 84.5°-86° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.[CH:17](=O)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Na].C([BH3-])#N>CO.O>[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8]2
Reactant: O=CCCc1ccccc1
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CNCC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na]
Solvent: O
Solvent: CO
Product: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(CCCc1ccccc1)CC2
Reaction time: 6 h
Yield: 93.3 %

Procedure:
A solution of the product from Example 5 (1 g, 3.24 mmol) and hydrocinnamaldehyde (0.94 g, 7 mmol) in 2:1 MeOH/H2O (50 mL) was treated with sodium i 15 cyanoborohydride (0.56 g, 9 mmol) portionwise under nitrogen and stirred for six hours. The solvent was decanted and the semi-solid was dissolved in dichloromethane, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude compound was chromatographed on silica gel (eluted with 25% ethyl acetate in hexane) to give the title compound (1.18 g, 94% yield) as a brown oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:12]([Br:28])=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2)(=[O:3])[CH3:2].[Br:29]N1C(=O)CCC1=O>ClCCl>[C:1]([O:4][CH2:5][C:6]1[C:14]([CH2:15][C@@H:16]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:12]([Br:28])=[C:11]2[C:7]=1[C:8]([Br:29])=[N:9][NH:10]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)C[C@H](Cc1cc(Br)c2[nH]nc(Br)c2c1COC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
(S)-Diethyl 2-((4-(acetoxymethyl)-7-bromo-1H-indazol-5-yl)methyl)succinate (555 mg, 1.219 mmol) was dissolved in dichloromethane (20 mL). N-Bromosuccinimide (250 mg, 1.405 mmol) was added to the mixture followed by a small amount of silica gel. Reaction stirred at room temperature for 1 hour. Mixture was concentrated some by roto-vap. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as clear colorless oil in 84% yield. MS (M−H)−=533.1, 531.2, 535.1.
Reaction SMILES: [CH3:1]S(O)(=O)=O.[OH:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[CH:16]=2)[NH:11][C:10]=1[C:24]([OH:26])=[O:25]>CO>[CH3:1][O:25][C:24]([C:10]1[NH:11][C:12]2[C:17]([C:9]=1[CH2:8][CH2:7][OH:6])=[CH:16][C:15]([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)=[CH:14][CH:13]=2)=[O:26]
Reactant: CS(=O)(=O)O
Reactant: O=C(O)c1[nH]c2ccc(Cn3cncn3)cc2c1CCO
Solvent: CO
Product: COC(=O)c1[nH]c2ccc(Cn3cncn3)cc2c1CCO
Yield: 93.6 %

Procedure:
2.7 ml (42 mmoles) of methanesulphonic acid were added to a suspension de 6 g (21 mmoles) of the 3-(2-hydroxyethyl)-5-[1,2,4]triazol-1-ylmethyl-1H-indol-2-carboxylic acid in 120 ml of methanol. The mixture was left under stirring at reflux temperature for 3 hours. The solvent was evaporated to dryness under reduced pressure, the residue dissolved with 20 ml of a saturated bicarbonate solution and extracted 3 times with ethyl acetate. The combined organic phases were dried and evaporated to dryness, and the evaporated solid recrystallised from isopropyl alcohol/heptane to give 5.9 g (93%) of the title ester as a yellow crystalline solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si](C)(C)C)=[C:7]([N+:17]([O-:19])=[O:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[C:7]([N+:17]([O-:19])=[O:18])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C#C[Si](C)(C)C)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Yield: 81.7 %

Procedure:
(4-tert-Butyl-2-nitro-phenylethynyl)-trimethyl-silane (3.167 g, 11.51 mmol) and potassium carbonate (3.18 g, 23.0 mmol) were stirred in 75 mL methanol for 20 minutes. The resulting mixture was partitioned between ethylacetate and water. The ethylacetate layer was washed with brine, dried over anhydrous MgSO4, concentrated in vacuo, and purified by flash chromatography with gradient elution with 0 to 5% ethylacetate/hexanes to yield 4-tert-Butyl-1-ethynyl-2-nitro-benzene (1.910 g, 9.398 mmol).
Reaction SMILES: CO[CH:3]([O:10]C)[C@@H:4]1[O:8][CH2:7][C@@H:6]([OH:9])[CH2:5]1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O-])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(C(O)=O)(F)(F)F.[OH-].[Na+].[BH4-].[Na+]>O1CCOCC1>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:9][C@@H:6]2[CH2:7][O:8][C@@H:4]([CH2:3][OH:10])[CH2:5]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: COC(OC)[C@H]1C[C@H](O)CO1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@@H](CO)C2)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3S-trans)-tetrahydro-5-(dimethoxymethyl)-3-furanol-4-methylbenzenesulfonate, (Compound IV(e), 10.0 g, 31.6 mmole), 1% CF3CO2H (50 mL), and dioxane (80 mL) in a 250 mL round bottom flask fitted with a reflux condenser was warmed to 80° C. for five hours. After cooling to room temperature, the solution was adjusted to pH 7.0 using 1N NaOH, treated with NaBH4 (1.2 g, 31.7 mmole), and allowed to stir at room temperature for an additional 30 minutes. The solvent was partially removed, then extracted with EtOAc (100 mL×3). The organic fraction was dried over MgSO4, filtered, evaporated and purified by flash column chromatorgraphy (60% EtOAc/40% Hexane) to afford 3.6 g or recovered starting material and 2.7 g (49% based on recovered starting material) of Compound IV(c).
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[CH3:31][O:32]C1C=C(C=CC=1)C=O>>[CH3:31][O:32][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:3]=1)[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: COc1cccc(C=O)c1
Product: COc1cccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)c1

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 3-methoxybenzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 422 (M+H) IC50 (p70S6K) “+++”
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:13][C:14]1[NH:19][C:18](=[O:20])[CH:17]=[C:16]([NH2:21])[N:15]=1>>[NH2:13][C:14]1[NH:19][C:18](=[O:20])[C:17]2[CH:2]=[C:3]([CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:21][C:16]=2[N:15]=1
Reactant: O=C(CCl)CCc1ccccc1
Reactant: Nc1cc(=O)[nH]c(N)n1
Product: Nc1nc2[nH]c(CCc3ccccc3)cc2c(=O)[nH]1
Yield: 39 %

Procedure:
FIG. 19 presents the method used to synthesize 2-amino-6-phenethyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 9. Phenylpropanoyl chloride7 was reacted with CH2N2 in the presence of gaseous hydrogen chloride and ether to produce 1-chloro-4-phenyl-2-butanone 8. 1-chloro-4-phenyl-2-butanone 8 was reacted with 2,6-diamino-3H-pyrimidin-4-one 1 to produce 2-amino-6-phenethyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 9 at a 39% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]([CH2:15][CH2:16][CH:17]=O)=[CH:13][N:12]=[CH:11]2)=[CH:5][CH:4]=1)#[N:2].CC(C)([O-])C.[K+]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]3[CH:11]=[N:12][CH:13]=[C:14]3[CH2:15][CH2:16][CH:17]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CCC=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1ccc(C2=CCCc3cncn32)cc1

Procedure:
A solution of 0.24 g of 1-p-cyanophenylmethyl-5-(2-formylethy)-1H-imidazole in 10 ml of anhydrous ethanol is refluxed under nitrogen for 2 hours with 20 mg of potassium tert-butoxide, cooled and evaporated to yield the title compound.
Reaction SMILES: Cl.[Br:2][C:3]1[S:4][C:5]([CH2:8][NH2:9])=[CH:6][N:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].C(N(CC)C(C)C)(C)C>ClCCl>[Br:2][C:3]1[S:4][C:5]([CH2:8][NH:9][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])(=[O:19])=[O:18])=[CH:6][N:7]=1
Reactant: NCc1cnc(Br)s1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCc1cnc(Br)s1)c1ccccc1Cl

Procedure:
In analogy to example 1, step 1, 2-bromo-5-aminomethyl-thiazole hydrochloride was reacted with 2-chlorobenzenesulfonylchloride and N,N-diisopropyl ethyl amine in dichloromethane to give N-(2-bromo-thiazol-5-ylmethyl)-2-chloro-benzenesulfonamide as an off-white solid. MS: 367.0 ([M+H]+)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)C=CC=CC=1.C([Li])CCC>O1CCCC1>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1/[CH:21]=[CH:1]/[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: c1ccc([P+](Cc2ccccn2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(/C=C/c2ccccn2)c1
Yield: 45.4 %

Procedure:
Using the procedure of Preparation H1, 750 mg of methyl 3-formylbenzoate, 2.14 g of triphenyl 2-pyridylmethyl phosphonium chloride and 2.0 ml of a 2.5M solution of n-butyl lithium in 30 ml of dry tetrahydrofuran gave 496 mg of the titled product.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([O:13]C)=[O:12])=[CH:9][N:8](COC(=O)C(C)(C)C)[C:5]2=[N:6][CH:7]=1.[OH-].[K+]>O.O1CCOCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c[nH]c2ncc(Br)nc12
Temperature: 25 °C

Procedure:
A mixture of methyl 2-bromo-5-(pivaloyloxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (370 mg, 1 mmol), potassium hydroxide (280 mg, 5 mmol) in 2.5 mL of water and 5 mL of 1,4-dioxane was heated to reflux for 90 mins. The reaction mixture was cooled to room temperature, solvent evaporated, residue acidified with 1N HCl, filtered and dried to give 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid as a brown solid (320 mg, crude), material used in the next step without further purification. LCMS: (M+H)+=242/244; (M+Na)+=264/266.
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl-:14]>C(Cl)(Cl)Cl>[CH2:1]([S:13][Cl:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCS
Reactant: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCSCl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of dodecane thiol (1.00 mL, 4.17 mmol, Aldrich) in 20 mL CHCl3 was added suliryl chloride (0.74 mL, 9.19 mmol, Aldrich), and the regulting mixture was stirred at room temperature for 18 h. Removal of solvent (aspirator), afforded dodecansulfenyl chloride that was determined to be sufficiently pure by 1H NMR.
Reaction SMILES: Br[C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C>C(O)C.[Pd]>[C:8]1([C:5]2[N:4]=[C:3]([C:14]([OH:16])=[O:15])[CH:2]=[CH:7][N:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1nc(-c2ccccc2)ncc1Br
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(O)c1ccnc(-c2ccccc2)n1
Yield: 83.6 %

Procedure:
A solution of 500 mg 5-bromo-2-phenyl-4-pyrimidinecarboxylic acid and 1 mL N,N-diisopropylethylamine in 5 mL of ethanol was hydrogenated at 40 psi of H2 for 16 hr using 200 mg of 10% palladium-on-carbon as catalyst. The catalyst was filtered off and the ethanol removed by evaporation under reduced pressure. The residue was dissolved in water, acidified with 3N hydrochloric acid and the precipitate was collected by filtration. This material was air dried to yield 300 mg of 2-phenyl-4-pyrimidinecarboxylic acid as a white solid which was used in the next step without further purification or characterization. A solution of 150 mg of 2-phenyl-4-pyrimidinecarboxylic acid in 1 mL of thionyl chloride was heated at 70° C. for 1 hr, cooled to room temperature and the excess thionyl chloride removed by evaporation under reduced pressure to yield 145 mg of 2-phenyl-4-pyrimidinecarboxylic acid chloride which was used in the next step without further purification or characterization.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:19]1[CH:20]=[C:21]([CH3:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26]>CS(C)=O>[CH3:28][C:21]1[CH:20]=[CH:19][C:24]([N+:25]([O-:27])=[O:26])=[C:23]([O:1][C:2]2[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)[CH:22]=1
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc([N+](=O)[O-])c(Oc2cc(C(F)(F)F)nn2C)c1
Temperature: 70 °C
Yield: 41.2 %

Procedure:
5-Hydroxy-1-methyl-3-trifluoromethylpyrazole (8.30 g, 50 mmol) and powdered potassium carbonate (8.29 g, 60 mmol) were stirred together in dimethylsulfoxide (40 ml) for 30 minutes. 3-Fluoro-4-nitrotoluene (7.76 g, 50 mmol) was added and the mixture heated at 70° C. for 17 h, then cooled to room temperature. The mixture was partitioned between diethyl ether and water, the ethereal extract washed with water and brine, dried over magnesium sulfate, filtered and the filtrate evaporated. The residue was further purified by flash column chromatography over silica gel, and the desired fraction collected and triturated with hexane to give the desired product as a pale yellow solid (6.20 g), m.p. 88°-90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[CH2:6][N:7]([CH3:9])[CH3:8].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:9][N:7]([CH2:6][C:5]1[CH:10]=[CH:11][C:12]([NH2:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:8]
Reactant: COc1cc(CN(C)C)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(CN(C)C)ccc1N
Yield: 93.8 %

Procedure:
A mixture of (3-methoxy-4-nitrobenzyl)dimethylamine (1.5 g, 7.1 mmol) and 5% Pd—C (0.2 g) in ethyl acetate (75 mL) was shaken under 50 psi of hydrogen for 24 hours. The mixture was filtered through Celite and evaporated, providing 1.2 g of the product as a light grey oil, in 93% yield: 1H NMR (CDCl3) δ 2.22 (s, 6H), 3.32 (s, 2H), 3.74 (br, 2H), 3.86 (s, 3H), 6.62-6.67 (m, 2H), 6.78 (s, 1H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Na+]>C(OCC)(=O)C.O.O1CCCC1>[Br:19][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Reactant: BrC(Br)(Br)Br
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCCBr)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a tetrahydrofuran (110 mL) solution of 10.7 g of tert-butyl 4-(3-hydroxypropyl)-1-piperidinecarboxylate was added 19.0 g of carbon tetrabromide under cooling with water, to which 15.0 g of triphenylphosphine was then added over a period of 13 minutes. This mixture was stirred at room temperature for 2 hours and 30 minutes and allowed to stand for 13 hours. To the reaction mixture were added water, ethyl acetate, and a saturated sodium chloride aqueous solution. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) to provide 13.2 g of tert-butyl 4-(3-bromopropyl)-1-piperidinecarboxylate as colorless oily form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[CH:18])=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[N:26]=[CH:25][C:24](I)=[CH:23][N:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[C:18][C:24]4[CH:23]=[N:22][C:21]([NH2:20])=[N:26][CH:25]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: Nc1ncc(I)cn1
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(Cl)cc3)cn12
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(C#Cc3cnc(N)nc3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-3-ethynyl-8-methyl-imidazo[1,2-a]pyridine (example C.21) (267 mg, 1 mmol) and commercially available 2-amino-5-iodopyrimidine (221 mg, 1 mmol) according to general procedure II. Obtained as an off-white solid (60 mg, 17%). MS (ISP) 360.1 [(M+H)+], 362 [(M+2+H)+]; mp 263° C.
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[NH2:7][C:8]1[C:9]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=O)=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.[BH4-].[Na+]>N1C=CC=CC=1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH:18]2[C:9]3[C:8](=[C:17]4[C:12](=[CH:11][CH:10]=3)[CH2:13][CH2:14][CH2:15][NH:16]4)[NH:7][S:3](=[O:5])(=[O:4])[N:2]2[CH3:1])=[CH:21][CH:22]=1
Reactant: Nc1c(C(=O)c2ccc(F)cc2)ccc2cccnc12
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(F)cc2)c2ccc3c(c2NS1(=O)=O)NCCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.8 %

Procedure:
N-methylsulfamoyl chloride 213 (729.9 mg, 5.63 mmol) was added to a solution of (8-amino-quinolin-7-yl)-(4-fluoro-phenyl)-methanone 367 (500 mg, 1.88 mmol) in pyridine (20 ml) and the mixture was stirred at room temperature for 18 h. NaBH4 (213 mg, 5.63 mmol) was added and stirring was continued at room temperature for 16 h. The reaction was quenched by the addition of water (20 ml) and the aqueous phase was extracted with EtOAc (30 ml). The organic phase was washed with brine (15 ml), dried (Na2SO4) and concentrated n vacuo. The crude residue was purified by column chromatography with heptane/EtOAc as the eluent to give the title compound (12 mg, 2%).
Reaction SMILES: B.[CH:2]1([C:5]([N:7]2[CH:14]3[CH2:15][N:10]([C:11]4[CH:19]=[C:18]([NH:20][C:21](=O)[CH2:22][CH2:23][CH3:24])[CH:17]=[CH:16][C:12]=4[CH2:13]3)[CH2:9][CH2:8]2)=O)[CH2:4][CH2:3]1.Cl.[OH-].[Na+]>O1CCCC1.O>[CH:2]1([CH2:5][N:7]2[CH:14]3[CH2:15][N:10]([C:11]4[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:17]=[CH:16][C:12]=4[CH2:13]3)[CH2:9][CH2:8]2)[CH2:3][CH2:4]1
Reactant: CCCC(=O)Nc1ccc2c(c1)N1CCN(C(=O)C3CC3)C(C2)C1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCNc1ccc2c(c1)N1CCN(CC3CC3)C(C2)C1

Procedure:
Borane in tetrahydrofuran (1 M, 250 ml.) was added slowly to a mixture of 4-cyclopropanecarbonyl-9-butyramido-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (the product of part A of this example) and tetrahydrofuran (200 ml.) and the resulting mixture was heated under reflux. Water was added dropwise, and the tetrahydrofuran was boiled off. The mixture was acidified with hydrochloric acid, heated on a steam bath, basified with sodium hydroxide, and extracted with chloroform. The chloroform extract was dried, filtered and concentrated to dryness. Crystallization of the resulting orange oil from hexane afforded 4-cyclopropylmethyl-9-butylamino-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (4.8 g., m.r. 84°-85° C.), the compound of Formula I wherein Q is cyclopropylmethyl, R is hydrogen and R' is butyl.
Reaction SMILES: [OH:1][C@H:2]1[CH2:24][C@@:23]2([CH3:25])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:26])[C@@H:17]([OH:22])[C:18]([O:20]C)=[O:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:28])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:27])[CH:6]=[CH:5]1.[OH-].[Na+].Cl.O>CO>[OH:1][C@H:2]1[CH2:24][C@@:23]2([CH3:25])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:26])[C@@H:17]([OH:22])[C:18]([OH:20])=[O:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:28])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:27])[CH:6]=[CH:5]1
Reactant: COC(=O)[C@H](O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)[C@@H](O)C(=O)O
Reaction time: 0.33 h

Procedure:
To a solution of the product of Example 9 (Product 9A), 500 mg, in methanol (50 ml), 1N NaOH (1 ml) was added. After 20 min in ice bath, the mixture was neutrlized with 0.1N HCl and 300 ml of distilled water was added. After extracting with ethyl acetate (300 ml), the organics was evaporated and recrystallization from methanol gave 360 mg of (20R)-11β,17,20-trihydroxy-3-oxo-1,4-pregnadien-21-oic acid as white prism, m.p.=213°-214° C. 1H-NMR (Me2SO-6) δ1.03(s,3H,13-CH3), 1.39(s,3H,10-CH3), 3.94(s,1H,20-H), 4.19(m,1N,11-H), 5.90(s,1H,4-H), 6.13(dd,1H,J=10 and 2 Hz,2-H), 7.31(d,1H,J=10 Hz,2-H), 8.30(s,1H,20-COOH).