Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25]C(=O)C)[CH:18]=2)[CH2:10][CH2:9][CH:8]([C:11]([F:14])([F:13])[F:12])[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].CC(=O)OCC.Cl>CO>[CH3:1][O:2][C:3]([C:5]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([OH:25])[CH:18]=2)[CH2:6][CH2:7][CH:8]([C:11]([F:14])([F:13])[F:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OC(C)=O)c2)CCC(C(F)(F)F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)CCC(C(F)(F)F)CC1
Reaction time: 2 h
Yield: 63.5 %

Procedure:
105 mg of 1-(3-Acetoxy-4-methoxy-benzoylamino)-4-trifluoromethyl-cyclohexanecarboxylic acid methyl ester and 7.0 mg of K2CO3 were stirred in 4 ml of anhydrous methanol for 1 h at room temperature. Then, 10.4 mg of K2CO3 were added and stirring was continued for 2 h at room temperature. 10 ml of EA and 10 ml of a 1N aqueous HCl-solution were then added. The layers were separated and the aqueous layer was extracted twice using 10 ml of EA each. The combined organic layers were washed twice using 10 ml of a saturated aqueous NaHCO3-solution, once using 10 ml of a 1N aqueous HCl-solution, and once using a 10 ml of a saturated aqueous NaCl-solution. The organic layer was then dried using MgSO4 and evaporated to yield 60 mg of the title compound that was used without further purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]1[O:23][N:22]=[C:21]([CH:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25])[N:20]=1.CO>CCCCCCC>[CH3:28][CH:27]([CH3:29])[CH2:26][CH:24]([NH:25][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:21]1[N:20]=[C:19]([CH3:18])[O:23][N:22]=1
Reactant: Cc1nc(C(N)CC(C)C)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Solvent: CCCCCCC
Solvent: CO
Product: Cc1nc(C(CC(C)C)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 5-methyl-α-(2-methylpropyl)-1,2,4-oxadiazole-3-methanamine (CAN 1155538-06-9) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/8% ethanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 385.2234 (M+H)+, αD20 (MeOH)=−24.8°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][C:7]([NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)([CH3:9])[CH3:8].[S:24](Cl)(=[O:27])(=[O:26])[NH2:25].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[C:22]([C:3]1[C:2]([NH:1][S:24](=[O:27])(=[O:26])[NH2:25])=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]([NH:10][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)([CH3:9])[CH3:8])#[N:23]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(COc1cccc(N)c1C#N)NC(=O)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(COc1cccc(NS(N)(=O)=O)c1C#N)NC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of N-(1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-yl)isonicotinamide (10.76 g, 34.67 mmol) in DMA (35 mL) was added sulfamoyl chloride (7.98 g, 69.34 mmol) at room temperature under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen overnight. The resulting solution was poured into 200 mL of ice cooled NaHCO3 aqueous and stirred for 30 minutes, the precipitate was collected by filtration, after dry obtained 12.2 g of clean product as an off white solid in 90% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.47 (s, 6H), 4.32 (s, 2H), 6.93 (d, J=8.8 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 7.23 (s, 2H), 7.53 (t, J=8.8 Hz, 1H), 7.67 (d, J=6 Hz, 2H), 8.29 (s, 1H), 8.66 (d, J=6.4 Hz, 2H), 9.45 (s, 1H). MS 390 (MH+).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([C:14]([NH2:16])=[O:15])[CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[O:21][CH2:22][CH2:23][NH2:24].S([O-])([O-])(=O)=O.[Mg+2]>ClCCl>[CH3:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[O:21][CH2:22][CH2:23][N:24]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([C:14]([NH2:16])=[O:15])[CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1
Reactant: NC(=O)c1ccnc(N2CCC(=O)CC2)n1
Reactant: COc1ccccc1OCCN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccccc1OCCN=C1CCN(c2nccc(C(N)=O)n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.6 g (0.0118 mol) of 2-(4-oxopiperidin-yl)pyrimidine-4-carboxamide, 1.97 g (0.0188 mol) of 2-(2-methoxyphenoxy)ethylamine, 4.26 g (0.0354 mol) of magnesium sulphate and 152 ml of dichloromethane are introduced into a 500 ml flask and the mixture is stirred at room temperature for 24 hours.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])=[CH:7][CH:6]=1)=[O:4].O[Li].O>C1COCC1.O>[F:18][C:2]([F:1])([F:17])[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)CCCc1ccc(C(=O)C(F)(F)F)s1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCc1ccc(C(=O)C(F)(F)F)s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
Methyl 4-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)butanoate (250 mg, 0.89 mmol) was dissolved in THF-H2O (15 MI, 2:1 v/v) and cooled to 0° C. LiOH.H2O (35 mg, 0.89 mmol) was added and the reaction mixture was allowed to warm up to room temperature and stirred for 1.5 h. Solvent was removed under reduced pressure and the aqueous layer was washed with EtOAc. The Ph of the aqueous layer was adjusted to 2-3 using 1.5N HCl. The product was extracted with EtOAc. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to get 4-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)butanoic acid (220 mg, crude), which was carried through without further purification. 1H NMR (300 MHz, DMSO-d6) δ 12.13 (br s, 1H), 8.00-7.98 (m, 1H), 7.21-7.19 (d, J=3.9 Hz, 1H), 2.98-2.93 (t, J=7.7 Hz, 2H), 2.31-2.26 (m, 2H), 1.93-1.83 (m, 2H). MS (ESI) m/z: Calculated for C10H9F3O3S: 266.02. found: 264.8 (M−H)−
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][NH2:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.Br[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([N:13]2[CH2:14][CH2:15][CH:16]([CH2:19][NH:20][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:17][CH2:18]2)(=[O:11])=[O:12])=[CH:4][CH:3]=1
Reactant: Brc1ncccn1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccc(F)cc2)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCc1ccc(F)cc1)N1CCC(CNc2ncccn2)CC1

Procedure:
A mixture of 0.3 g of C-{1-[2-(4-Fluoro-phenyl)-ethanesulfonyl]-piperidin-4-yl}-methylamine, 0.3 g of 2-bromopyrimidine, 25 mL of 2-propanol and 0.3 mL of N,N-diisopropylethylamine was heated to reflux overnight. Purification of the residue obtained after concentration under reduced pressure by preparative chromatography, eluting with ethyl acetate gave a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=2)[CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C1COCC1.C(O)(=O)C>>[C:21]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=2)[CH:3]=1)(=[O:23])[CH3:22]
Reactant: CNC(=O)c1ccc(N)cc1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(=O)c1ccc(NC(C)=O)cc1Nc1nc(Cl)ncc1Cl

Procedure:
4-Amino-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (0.135 g, 0.000432 mol), Acetic anhydride (0.0428 mL, 0.000454 mol), THF (5 mL, 0.06 mol) and Acetic acid (0.024 mL, 0.43 mol) were stirred at rt for 16 h. Product isolated as white ppt (80 mg, 52%).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure A, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][C:25]([CH3:30])=[CH:26][C:27]=3[CH3:29])[N:22]([CH3:31])[CH:21]=2)[C:9]1=[O:32])[CH2:5][CH2:6][CH3:7].[Li+].[OH-]>O1CCOCC1.O>[O:32]=[C:9]1[N:8]([C@H:4]([CH2:5][CH2:6][CH3:7])[C:3]([OH:33])=[O:2])[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][C:25]([CH3:30])=[CH:26][C:27]=2[CH3:29])[N:22]([CH3:31])[CH:21]=1
Reactant: CCC[C@H](C(=O)OC)n1c(=O)c2ccccc2n(Cc2cn(C)c3cc(C)cc(C)c23)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC[C@H](C(=O)O)n1c(=O)c2ccccc2n(Cc2cn(C)c3cc(C)cc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-[2,4-dioxo-1-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-1,4-dihydro-2H-quinazolin-3-yl]-pentanoic acid methyl ester (50 mg, 0.11 mmol) in 1,4-dioxane (10 mL) and water (2 mL) is added LiOH (5.4 mg, 0.22 mmol) at room temperature. The solution is stirred at 60° C. for 4 hours. The solution is concentrated and water is added to the residue. The solution is acidified by 12N HCl in an ice-bath. The precipitated white solid is collected by filtration and is dried under vacuum to afford the title product. : LCMS (ESMS): m/z 434.89 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH2:8][N:7]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH:4]=1.[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]=O)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.ClCCCl>[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][NH:1][CH2:2][C:3]3[CH2:8][N:7]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH:4]=3)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CC(C)(C)OC(=O)NN1CCC=C(CN)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NN1CCC=C(CNCc2ccc3c(c2)OCCO3)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of tert-butyl 5-aminomethyl-3,6-dihydro-2H-pyridine-1-carbamate (0.7 g, 3.3 mmol) and 1,4-benzodioxane-6-carbaldehyde (0.54 g, 3.3 mmol) in THF (2 ml) and DCE (4 ml) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.770 g, 3.81 mmol) was then added thereto. The reaction mixture was stirred at room temperature for 5 hours and filtered through Hydromatrix (wetted with saturated NaHCO3 solution) and the filtrate was concentrated. The residue was purified by chromatography on silica gel (EtOAc/hex 2/1 and then EtOAc/MeOH 9/1).
Reaction SMILES: [H-].[Na+].[N+](C(C)C)([O-])=[O:4].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[F:18]>C(O)C>[Cl:17][C:13]1[C:12]([F:18])=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH:10]=[O:4]
Reactant: CC(C)[N+](=O)[O-]
Reactant: Fc1c(Cl)cccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: O=Cc1cccc(Cl)c1F
Reaction time: 0.17 h

Procedure:
Ethanol (100 mL) was added to sodium hydride (60% sodium hydride content, 4.7 g) at 0° C. under argon atmosphere, and the mixture was stirred for 10 minutes. 2-Nitropropane (11 mL) was added to the reaction mixture, and after the thus-obtained mixture was stirred for 10 minutes, 1-(bromomethyl)-3-chloro-2-fluorobenzene (10 g) was added thereto, followed by stirring at room temperature for 3.5 hours. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was partitioned between diethyl ether and water. The organic layer was sequentially washed with 1N aqueous sodium hydroxide, water, and saturated brine, and was dried over sodium sulfate anhydrate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7), to thereby give crude 3-chloro-2-fluorobenzaldehyde (5.5 g) as a pale-yellow oily compound. Methanol (20 mL) was added to sodium hydride (60% sodium hydride content, 1.6 g) under argon atmosphere at 0° C., and the thus-obtained mixture was stirred for 10 minutes. After the reaction mixture was cooled to −20° C., a solution of the crude 3-chloro-2-fluorobenzaldehyde (5.5 g) and methyl 2-azidoacetate (5.0 g) in methanol (10 mL) was added thereto within 20 minutes. After the reaction mixture was heated to 0° C., the mixture was stirred for 2.5 hours, and water (40 mL) was added thereto. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with a mixture of methylene chloride and ethyl acetate. The extract was washed with saturated brine, and was dried over sodium sulfate anhydrate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (toluene:hexane=3:17), to thereby give crude 2-azido-3-[(3-chloro-2-fluoro)phenyl]acrylic acid methyl ester (2.6 g). This compound was dissolved in xylene (50 mL), and the solution was stirred at 130-140° C. for 3 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride). The thus-obtained compound was crystallized from diethyl ether-hexane, to thereby give the title compound (440 mg).
Reaction SMILES: BrC(C)[C:3]#[N:4].C([NH+](CC)CC)C.[N+:13]([C:16]1[C:21]2[N:22]([CH2:25][C:26]([O-])=O)[CH:23]=[N:24][C:20]=2[CH:19]=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[N+:13]([C:16]1[C:21]2[N:22]([CH:25]([CH3:26])[C:3]#[N:4])[CH:23]=[N:24][C:20]=2[CH:19]=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=C([O-])Cn1cnc2cccc([N+](=O)[O-])c21
Reactant: CC(Br)C#N
Agent: CC[NH+](CC)CC
Product: CC(C#N)n1cnc2cccc([N+](=O)[O-])c21

Procedure:
The compound was synthesised from 4(7)-nitro-1H-benzimidazole (1.0 g, 6.1 mmol) and 2-bromopropanenitrile (0.58 mL, 6.5 mmol) according to the procedure described for the synthesis of (7-Nitro-1H-benzimidazol-1-yl)acetic acid triethylammonium salt, part A, in a is 0.14 g (11%) yield. MS (ESI) m/z: 217.16 [M+H]. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.01 (d, J=7.0 Hz, 3H) 6.08 (q, J=7.1 Hz, 1H) 7.48 (t, J=8.1 Hz, 1H) 8.09 (m, 1H) 8.16 (dd, J=8.0, 1.0 Hz, 1H) 8.89 (s, 1H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br>>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: Ic1n[nH]c2ncccc12
Reactant: Fc1ccccc1CBr
Product: Fc1ccccc1Cn1nc(I)c2cccnc21
Yield: 95.7 %

Procedure:
In analogy to example 24A, 25.00 g (102.031 mmol) of 3-iodo-1H-pyrazolo[3,4-b]pyridine (synthesis described in WO 2006/130673, scheme D) were reacted with 21.21 g (112.234 mmol) of 2-fluorobenzyl bromide. 34.49 g of the title compound were obtained (95% of theory).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N: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.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[F-].[Cs+]>COCCOC>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=2[CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2Br)CC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2-c2ccc(Cl)cc2)CC1

Procedure:
A solution of EXAMPLE 22A (5.82 g, 16.394 mmol) in DME (80 mL) was treated with 4-chlorophenylboronic acid (3.089 g, 19.673 mmol), CsF (7.476 g, 49.182 mmol) and (Ph3P)2Pd(OAc)2 (1.228 g, 1.639 mmol), heated to reflux for 4 hours, and filtered. The filtrate was partitioned between aqueous NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel column chromatography with 15% ethyl acetate/hexane to provide the desired product. MS (ESI) m/e 386, 388 (M+H)+.
Reaction SMILES: Br[C:2]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:5]2[N:6]([CH3:24])[C:7]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:15]N(CC4C=CC=CC=4)[CH2:13][CH2:12]3)=[N:8][C:4]=2[CH:3]=1.[OH-].[Na+].[H][H]>[Pd].O1CCCC1>[CH3:24][N:6]1[C:5]2[C:25]3[C:30]([CH:2]=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH:26]([C:25]2[CH:30]=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:15][CH2:16]1)=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: Cn1c(CCN2CCN(Cc3ccccc3)CC2)nc2cc(Br)c3ccccc3c21
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(CCN2CCC(c3ccccc3)CC2)nc2ccc3ccccc3c21

Procedure:
A mixture of 8.32 g (0.0185 mole) of the compound of Example 16, 0.9 g of 10% Pd-C catalyst, and 150 cc of tetrahydrofuran containing 20 cc of 1M NaOH is shaken in a Paar hydrogenator under about 5.4 atm. of hydrogen pressure until hydrogenolysis is completed. The catalyst is filtered and the mother liquor is concentrated to remove the solvent. The residue is taken up with methylene chloride, and washed with water. Upon evaporating the solvent, 6.1 g of a crude product are obtained which is recrystallized from acetone yielding 4.74 g of the compound of the title. M.p. 181.5°-182.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:30]1([CH2:35][B-](F)(F)F)[CH2:34][CH2:33][CH2:32][CH2:31]1.[K+]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:35][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: F[B-](F)(F)CN1CCCC1
Agent: [K+]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCCC3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and potassium pyrrolidin-1-ylmethyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 1): tR=0.92 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10](=O)[NH:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[CH:17]=1.P(Cl)(Cl)([Cl:29])=O>CCN(C1C=CC=CC=1)CC>[Cl:29][C:10]1[C:9]2[C:14](=[CH:15][C:6]3[CH:5]=[C:4]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:3]([O:2][CH3:1])=[CH:17][C:7]=3[CH:8]=2)[N:13]=[CH:12][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cc3c(=O)[nH]cnc3cc2cc1OCCN1CCOCC1
Solvent: CCN(CC)c1ccccc1
Product: COc1cc2cc3c(Cl)ncnc3cc2cc1OCCN1CCOCC1
Temperature: 25 °C

Procedure:
A mixture of 0.3 g (0.844 mmol) of 7-methoxy-8-(2-morpholin-4-yl-ethoxy)-3H-benzo[g]quinazolin-4-one in 8 mL of phosphorus oxychloride and 1 mL of diethylaniline is refluxed for 15 minutes. After allowing to cool to room temperature, phosphorus oxychloride and diethylaniline are removed in vacuo. A 5 mL portion of toluene is added to the crude product mixture, and the solvents are again removed in vacuo. This step is repeated one more time. The product mixture is placed in an ice bath, and to this is added 10 mL of an ice-cooled solution of saturated sodium bicarbonate. This is extracted twice with a 95:5 mixture of methylene chloride/methanol, then with 1:1 tetrahydrofuran/ethyl acetate. The organic layers are combined, dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography, eluting with a solvent gradient of 98:2 to 4:1 methylene chloride/methanol, provided 0.229 g of 4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinazoline as a yellow solid, mp 166-168° C.
Reaction SMILES: [CH:1]1([N:4]([CH:26]2[CH2:28][CH2:27]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH2:22])=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:30][C:31](=O)[CH2:32][CH2:33][CH3:34]>>[CH:26]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][CH:30]=[C:31]([CH2:32][CH2:33][CH3:34])[N:22]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:27][CH2:28]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Reactant: CCCC(=O)CBr
Product: CCCc1csc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)n1

Procedure:
Prepared from N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B) and 1-bromopentan-2-one using the same procedure as reported for 2.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[N:34]=[CH:33][C:32]([OH:35])=[CH:31][N:30]=2)[CH:24]=[CH:23][N:22]=[N:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[N:34]=[CH:33][C:32]([O:35][CH2:2][C:3]3[N:4]=[C:5]([CH:8]=[CH:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=4)[O:6][CH:7]=3)=[CH:31][N:30]=2)[CH:24]=[CH:23][N:22]=[N:21]1
Reactant: FC(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1cnc(CCCCn2ccnn2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(C=Cc2nc(COc3cnc(CCCCn4ccnn4)nc3)co2)cc1
Reaction time: 2 h

Procedure:
A mixture of 4-chlormethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazole (0.144 g, 0.50 mmol), 2-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidin-5-ol (0.078 g, 0.357 mmol) and cesium carbonate (Cs2CO3) (0.175 g, 0.536 mmol) in DMF (10 ml) is kept at 80° C. for 2 h. After cooling ethyl acetate (25 ml) is added, the mixture is washed with sat. NH4Cl and brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate (100%)->ethyl acetate/methanol 9:1) and 2-(4-[1,2,3]-triazol-1-yl-butyl)-5-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyrimidine can be isolated as a white solid. Yield 40 mg (24%).