Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([C:11]2[S:15][C:14]([CH:16]=O)=[CH:13][CH:12]=2)=[N:3]1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:16][C:14]3[S:15][C:11]([C:4]4[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[N:2]([CH3:1])[N:3]=4)=[CH:12][CH:13]=3)[CH2:31][CH2:30]2)[CH:24]=1)=[O:21]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cn1nc(-c2ccc(C=O)s2)cc1C(F)(F)F
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4cc(C(F)(F)F)n(C)n4)s3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2-thiophenecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 491.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([Cl:28])[CH:3]=1.[C:29]([C:31]1[N:32]=[CH:33][C:34]([NH:37][C:38](=O)[O:39]C2C=CC=CC=2)=[N:35][CH:36]=1)#[N:30]>CN(C)C=O>[Cl:28][C:4]1[CH:3]=[C:2]([NH:1][C:38]([NH:37][C:34]2[CH:33]=[N:32][C:31]([C:29]#[N:30])=[CH:36][N:35]=2)=[O:39])[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][CH2:8][N:9]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14]
Reactant: N#Cc1cnc(NC(=O)Oc2ccccc2)cn1
Reactant: CC(C)(C)OC(=O)N(CCOc1ccc(N)cc1Cl)Cc1ccc(F)cc1F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOc1ccc(NC(=O)Nc2cnc(C#N)cn2)cc1Cl)Cc1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
To a solution of tert-butyl 2-(4-amino-2-chlorophenoxy)ethyl(2,4-difluorobenzyl)-carbamate (1.6 g, 3.87 mmol) in N,N-dimethylformamide (4 mL) at RT were phenyl 5-cyanopyrazin-2-ylcarbamate (1.39 g, 5.81 mmol) (Example 10) and N,N,N-diisopropylethylamine (0.751 g, 5.81 mmol) added. The reaction mixture was heated at 60° C. for 1.5 hours then the reaction mixture was poured into ice-water (100 mL) and allowed to stand for 30 minutes. The resulting precipitate was collected, washed with water and air dried. The crude product was purified by column chromatography on neutral silica gel using 0-2% methanol in DCM to give the title compound (0.53 g, 26% yield).
Reaction SMILES: [C:1]12([CH2:11][C:12]([OH:14])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([N:17](C(F)(F)C(F)C(F)(F)F)CC)C>N>[C:1]12([CH2:11][C:12]([NH2:17])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: CCN(CC)C(F)(F)C(F)C(F)(F)F
Agent: N
Product: NC(=O)CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
1-Adamantaneacetic acid (11.7 g, 0.06 mole) was dissolved in N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine (13.4 g, 0.06 mole) during which time a highly exothermic reaction occurred. The reaction mixture was allowed to cool to room temperature and cold aqueous ammonia (250 ml) was added slowly. The 1-adamantaneacetamide was isolated as described in example 1 to yield 10.5 g, 90.6 %; mp 173.6-174.0° C. The analytical sample was recrystallized from cyclohexane and sublimed. Anal. Calcd. for C12H19NO: C, 74.63; H, 9.89; N, 7.25. Found: C, 74.36; H, 9.84; N, 7.15.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=[O:14])=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:11]=[C:12]([CH2:13][OH:14])[CH:15]=[CH:16][CH:17]=2)=[CH:2]1
Reactant: O=Cc1cccc(-c2csc3ccccc23)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc(-c2csc3ccccc23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a solution of 3-(1-benzothien-3-yl)benzaldehyde (2.1 g, 8.81 mmol) in anhydrous tetrahydrofuran (30 mL) was added lithium aluminum hydride (0.37 g, 9.75 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction solution was ice-cooled, and sodium sulfate decahydrate (3.0 g, 5.74 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The precipitated insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:5-1:3) to give the title compound (2.0 g, yield 95%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N+:3]=1[O-:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N+:3]([O-:10])=[CH:4][C:5]([CH2:8][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: [O-][n+]1cc(CCl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: [O-][n+]1cc(CN2CCOCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.5 %

Procedure:
A mixture of 2-chloro-5-(chloromethyl)pyridine 1-oxide (1.16 g, 6.52 mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem. 1979, 16, 333), morpholine (1.14 g, 13.0 mmol), and potassium carbonate (0.90 g, 6.52 mmol) in acetonitrile (30 mL) was stirred at room temperature for 72 h. The solvent was removed in vacuo and the residue was purified on a silica gel column using chloroform/ethanol, (9:1), as the eluent affording 1.2 g (81% yield) of the title compound as a colorless solid: mp 72-74° C.; 1H NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 7.39 (d, J=8 Hz, 1H), 7.16 (dd, J=8, 2 Hz, 1H), 3.65 (t, J=5 Hz, 4H), 3.40 (s, 2H), 2.40 (t, J=4 Hz, 4H); 13C NMR (CDCl3, 100 MHz) δ 140.4, 135.9, 126.6, 126.6, 66.8, 59.2, 53.4; MS (ESP) m/z 229 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C(C)=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Brc1ccc(-c2ccc(Br)cn2)nc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
A reaction vessel was charged with 6.0 g of 2,5-dibromopyridine, 7.0 ml of bistributyltin, and 120 ml of xylene, followed by heating and stirring at 60° C. for 15 minutes. Further, 700 mg of tetrakis(triphenylphosphine)palladium was added thereto, followed by stirring at 120° C. for 8 hours. After cooling to room temperature, the insoluble materials were removed by filtration, and the filtrate was washed with 150 ml of an aqueous ethylenediamine tetraacetate solution. The organic layer was dehydrated with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (carrier: silica gel, eluent: cyclohexane/toluene) to obtain 1.7 g (yield 42%) of 5,5′-dibromo-[2,2′]bipyridine as a yellow powder.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Ic1ccc(OCc2ccccc2)cc1
Reactant: OC1CN2CCC1CC2
Product: c1ccc(COc2ccc(OC3CN4CCC3CC4)cc2)cc1

Procedure:
3-Hydroxy quinuclidine (Aldrich, 2.54 9, 20 mmol) was treated with 1-benzyloxy-4-iodo-benzene (Aldrich, 3.10 g, 10 mmol) according to the procedure of Example 14A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.40) as an oil (1.30 g, yield, 42%). 1H NMR (MeOH-d4, 300 MHz) δ 1.45–1.56 (m, 1H), 1.64–1.80 (m, 2H), 2.00–2.10 (m, 1H), 2.15–2.24 (m, 1H), 2.76–3.10 (m, 5H), 3.40–3.46 (m, 1H), 4.48 (m, 1H), 5.10 (s, 2H), 6.73–6.96 (m 4H), 7.20–7.40 (m, 5H) ppm. MS (DCl/NH3) m/z 310 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH:16]([B-](F)(F)F)=[CH2:17].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:13][C:12]([F:15])([F:14])[O:11][C:4]1[CH:3]=[C:2]([CH:16]=[CH2:17])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(Br)cc1OC(F)(F)F
Reactant: C=C[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=Cc1ccc(C(=O)O)c(OC(F)(F)F)c1
Temperature: 80 °C
Yield: 46.9 %

Procedure:
To a stirred solution of 4-bromo-2-(trifluoromethoxy)benzoic acid (1 g, 3.67 mmol) in DMSO (20 mL) was added potassium vinyltrifluoroborate (1.47 g, 11.02 mmol) and potassium carbonate (1.52 g, 11.02 mmol). The reaction mixture was degassed with argon for 30 min Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.13 g, 0.18 mmol) was added and the reaction mixture was heated to 80° C. for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2×50 mL), washed with brine, and dried over Na2SO4. Concentration under reduced pressure furnished the crude compound which was purified by flash column chromatography to afford the product as pale yellow gummy material (0.4 g, 47%): 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=8.1 Hz, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.35 (s, 1H), 6.78 (dd, J=17.4.1, 11.1 Hz, 1H), 5.92 (d, J=17.4 Hz, 1H), 5.51 (d, J=10.8 Hz, 1H); ESIMS m/z 232.97 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=O.[OH-].[K+]>C(O)C>[Br:10][C:7]1[CH:6]=[C:3]2[C:2](=[N:9][CH:8]=1)[N:1]=[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH:11]=[CH:4]2
Reactant: Nc1ncc(Br)cc1C=O
Reactant: CC(=O)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(-c2ccc3cc(Br)cnc3n2)cc1
Yield: 65 %

Procedure:
A mixture of 2-amino-5-bromonicotinaldehyde [prepared by the method of Duggan et al., WO 9818461] (5.53 g, 27.5 mmol), 4-fluoroacetophenone (3.0 mL, 24.8 mmol) and 20% aqueous potassium hydroxide (3.5 mL) in ethanol (400 mL) was heated at reflux for 1 hour. The reaction mixture was allowed to stand at room temperature, the crystals formed collected under suction, washed with ethanol and dried in vacuo to afford 6-bromo-2-(4-fluorophenyl)-1,8-naphthyridine (4.86 g, 65%). 1H NMR (500 MHz, CDCl3) δ 9.12 (1H, d, J 2.5 Hz), 8.34 (1H, d, J 2.5 Hz), 8.32-8.28 (2H, m), 8.18 (1H, d, J 8.5 Hz), 7.99 (1H, d, J 8.5 Hz), 7.25-7.19 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:26].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=1[O:42][CH3:43]>[Cu]I>[C:38]([C:37]1[CH:40]=[CH:41][C:34]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:12]3[S:13][CH:14]=[CH:15][N:16]=3)(=[O:9])=[O:10])=[CH:4][C:3]=2[OH:26])=[C:35]([O:42][CH3:43])[CH:36]=1)#[N:39]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(N)c(O)c2)cc1
Reactant: COc1cc(C#N)ccc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(Nc3ccc(C#N)cc3OC)c(O)c2)cc1
Temperature: 110 °C

Procedure:
A microwave vial was charged with 4-amino-3-hydroxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (0.185 g, 0.472 mmol) (INTERMEDIate AD), cesium carbonate (0.384 g, 1.179 mmol), 4-bromo-3-methoxybenzonitrile (0.05 g, 0.236 mmol, Combi Blocks) and copper(i) iodide (0.011 g, 0.059 mmol). The vial was sealed and flushed with argon, and wrapped with aluminum foil to exclude light, then DMF (0.5 mL) was added. The reaction was heated to 110° C. for 2 hr to give intermediate 4-((4-cyano-2-methoxyphenyl)amino)-3-hydroxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide. The reaction was cooled to rt, and chloroacetic acid chloride was added dropwise (0.038 ml, 0.472 mmol). The solution was maintained at rt for 30 min. At this time, 10 mL of saturated ammonium chloride solution was added, and the mixture was further diluted with 10 mL of DCM. The layers were separated and the aqueous layer was extracted with DCM (2×10 mL). To the aqueous layer was added n-(2-hydroxyethyl)ethylenediaminetriacetic acid, trisodium salt hydrate (500 mg, Sigma Aldrich) to aqueous to decomplex Cu from the product. The resulting aqueous solution was extracted with DCM (1×10 mL). The combined organics were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product, 4-(4-cyano-2-methoxyphenyl)-N-(4-methoxybenzyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.133 g, 0.236 mmol, 100% yield) was taken forward without further purification.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[CH:17]=[N:16][CH:15]=[N:14][C:13]=2[NH:12][CH:11]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH:24]=O.C(O)(=O)C.C([BH3-])#N>C(O)C>[F:1][C:2]1[N:7]=[C:6]([NH:8][CH2:24][C:23]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:21]([O:20][CH3:19])[CH:22]=2)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[CH:17]=[N:16][CH:15]=[N:14][C:13]=2[NH:12][CH:11]=1
Reactant: Nc1ccc(Cc2c[nH]c3ncncc23)c(F)n1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(CNc2ccc(Cc3c[nH]c4ncncc34)c(F)n2)cc(OC)c1OC

Procedure:
In a 2 mL microwave vial, 6-fluoro-5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-ylamine (68, 9.72 mg, 0.04 mmol) and 3,4,5-trimethoxy-benzaldehyde (69, 15.7 mg, 0.08 mmol) were dissolved in 600 μL of 95:5 ethanol:acetic acid, and silica supported cyanoborohydride (50 mg, 1 mmol/g, 0.05 mmol) was added. The reaction was irradiated for 10 minutes at 160° C. in a microwave. The vial was centrifuged to condense the silica and the supernatant was removed by pipette into another vial. The residual silica was rinsed with 500 μL of ethanol, centrifuged and the supernatant added to the first supernatant. The solvents were removed under vacuum and the resulting material dissolved in dimethyl sulfoxide for purification by HPLC. Samples were purified on Phenomenex C18 column (50mm×10 mm ID) with mobile phase A of 0.1% trifluoroacetic acid in water, mobile phase B of 0.1% trifluoroacetic acid in acetonitrile, 20-100% B over 16 minutes at a flow rate of 6 mL/min. Appropriate fractions were collected and solvents removed under vacuum to provide the desired compound. MS (ESI) [M+H+]+=424.3.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(Cl)(=O)C([Cl:23])=O.CN(C)C=O.CC(C)=O>C(Cl)(Cl)Cl>[Cl:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cnc2ccc([N+](=O)[O-])cc2c1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)c1cnc2ccc([N+](=O)[O-])cc2c1Cl

Procedure:
To a suspension of 3a in chloroform were added 4 equivalents of oxalyl chloride followed by 0.1 equiv. of dimethylformamide. The solution was refluxed for 3 hours and was quenched with 5 M sodium hydroxide solution at 4° C. The chloroform layer was collected, washed with 100 mL water and brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Product was obtained by recrystallization using acetone. 1H-NMR (CDCl3) δ (ppm): 1.48 (3H, t, J=7.08 Hz), 4.55 (2H, q, J=7.08 Hz), 8.31 (1H, d, J=9.27 Hz), 8.62 (1H, m), 9.36 (2H, m). m/z 281.7 (MH+).
Reaction SMILES: C(C1C=CC(C(C2C=CC(CC(C)C)=CC=2)CC2C=C(C=CC=2)C(O)=O)=CC=1)C(C)C.[CH2:32]([C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:53]2[CH:58]=[CH:57][C:56]([CH2:59][CH:60]([CH3:62])[CH3:61])=[CH:55][CH:54]=2)[CH2:43][C:44]2[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=2)[C:47](Cl)=[O:48])=[CH:38][CH:37]=1)[CH:33]([CH3:35])[CH3:34].C(Cl)(=O)C(Cl)=O.[NH:69]1[C:77]2[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=2)[CH:71]=[CH:70]1.C[Mg]Br.Cl>O1CCCC1.CCOCC.C(OCC)(=O)C>[CH2:32]([C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:53]2[CH:58]=[CH:57][C:56]([CH2:59][CH:60]([CH3:62])[CH3:61])=[CH:55][CH:54]=2)[CH2:43][C:44]2[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=2)[C:47]([C:71]2[C:72]3[C:77](=[CH:76][CH:75]=[CH:74][CH:73]=3)[NH:69][CH:70]=2)=[O:48])=[CH:38][CH:37]=1)[CH:33]([CH3:35])[CH3:34]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)Cc1ccc(C(Cc2cccc(C(=O)Cl)c2)c2ccc(CC(C)C)cc2)cc1
Agent: CC(C)Cc1ccc(C(Cc2cccc(C(=O)O)c2)c2ccc(CC(C)C)cc2)cc1
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(C(Cc2cccc(C(=O)c3c[nH]c4ccccc34)c2)c2ccc(CC(C)C)cc2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
3-[2,2-Bis(4-isobutylphenyl)ethyl]benzoic acid (1 g) was converted to 3-[2,2-bis(4-isobutylphenyl)ethyl]benzoyl chloride (1.13 g) with oxalyl chloride as an usual manner. To a solution of indole (0.918 g) in tetrahydrofuran (15 ml) was added 3M solution of methyl magnesium bromide in ether (3 ml) at 20° C., and the mixture was stirred at 20° C. for 1 hour. A solution of 3-[2,2-bis(4-isobutylphenyl)ethyl]benzoyl chloride (1.13 g) in tetrahydrofuran (15 ml) was added to the mixture at 20° C. After stirred at 20° C. for 1 hour, the mixture was poured into a mixture of 1N-hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water, aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (50 g) eluting with a mixture of hexane and ethyl acetate (20:1) to give 3-[3-[2,2-bis(4-isobutylphenyl)ethyl]benzoyl]indole (468 mg) as pale red crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[NH2:8]
Reactant: COc1ccc(F)cc1Oc1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc(F)cc1Oc1ccc(N)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iron powder (2.0 g) was added to a solution of the product from step (i) (1.95 g) in acetic acid (40 ml) and the mixture stirred at RT overnight. The mixture was filtered and the filtrate evaporated under reduced pressure. The residue was partitioned between aqueous sodium hydrogencarbonate soln and ethylacetate, the organics dried and evaporated under reduced pressure.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:17]=[C:16]([O:24][CH3:25])[N:15]=2)[CH2:10][CH:9]1[C:26](=[O:38])[NH:27][C:28]1([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:30][CH:29]1[CH:31]=[CH2:32])=[O:7])(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:20]([C:18]1[N:17]=[C:16]([O:24][CH3:25])[N:15]=[C:14]([O:13][CH:11]2[CH2:12][CH:8]([C:6]([OH:7])=[O:5])[CH:9]([C:26](=[O:38])[NH:27][C:28]3([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:30][CH:29]3[CH:31]=[CH2:32])[CH2:10]2)[CH:19]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(C(C)(C)C)nc(OC)n2)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(C(C)(C)C)nc(OC)n2)CC1C(=O)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
Compound 3f was dissolved in DCM (20 ml). Triethyl silane (0.6 ml, 3.75 mmol) and TFA (20 ml) were added. The reaction mixture was stirred at RT for 1.5 h. The solvent was co evaporated with toluene and the crude residue was purified by column chromatography (DCM→DCM/MeOH (90/10)) which gave the title compound, (583 mg, 96%), MS (M+H)+476.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:11](Br)=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].[C:13](=O)=[O:14].C([Li])(C)(C)C.CN(C)C=O>CC(C)=O.O.O1CCCC1>[CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:13]=[O:14])=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: Cc1oc2c(Br)cccc2c1C
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc2c(C=O)cccc2c1C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
17 g (75.6 mmol) of 2,3-dimethyl-7-bromobenzofuran and 250 ml of tetrahydrofuran are introduced under an inert atmosphere into a 1 liter round-bottomed flask. The mixture is cooled to -78° C. by a bath of dry ice in acetone. 60 ml of tert-butyllithium (1.4M in pentane) are added dropwise and the reaction mixture is allowed to stir for 10 minutes. 17.5 ml of N,N-dimethylformamide (227 mmol) are then added dropwise and the reaction mixture is allowed to return to room temperature. 100 ml of water are added and then extraction is carried out with ethyl acetate (3×80 ml). The organic phases are combined, dried over magnesium sulphate and concentrated. The residue is purified by chromatography on a silica column (elution solvent cyclohexane: ethyl acetate 9:1). 11.97 g (Yield: 91%) of 2,3-dimethyl-7-formylbenzofuran are obtained. M.p. =56-58° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6]1)([OH:3])=O.C(OC(=O)C)(=O)C>C1(C)C=C(C)C=C(C)C=1>[CH2:6]1[C:5]2([CH2:8][C:9](=[O:10])[O:11][C:1](=[O:3])[CH2:4]2)[CH2:7]1
Reactant: O=C(O)CC1(CC(=O)O)CC1
Solvent: Cc1cc(C)cc(C)c1
Solvent: CC(=O)OC(C)=O
Product: O=C1CC2(CC2)CC(=O)O1
Temperature: 100 °C

Procedure:
350 g crude (1-carboxymethyl-cyclopropyl)-acetic acid (2.2 mole, 92% purity, from step 1) are suspended in a mixture of 350 ml of mesitylene and 678 g of acetic anhydride (6.6 mole, 3 eq) and heated to 100° C. Upon reaching that temperature, the pressure is reduced to approximately 200 mbar and 45% of the solvent mixture are distilled off (distillation takes approx. 1 h). Then the mixture is slowly cooled to 0-5° C. and the precipitate is collected by filtration. The filter cake is washed with 87 ml of cold mesitylene and then dried in vaccuo at 40° C.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[N:10][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=2)[CH:22]=[O:23])=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[N:10][C:11]([C:17]2[CH:24]=[C:21]([CH2:22][OH:23])[CH:20]=[N:19][CH:18]=2)=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: OCc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.5 %

Procedure:
To a solution of 5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinaldehyde (from example 191, 1.0 g, 2.4 mmol) in ethanol (15 mL) was added NaBH4 (0.28 g, 7.19 mmol). Upon completion of addition, the reaction mixture was stirred at RT for 4 h. After this time, a saturated solution of ammonium chloride was added and the resulting mixture was extracted into ethyl acetate. The organic layer was separated, dried, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel column chromatography using 2% methanol in DCM as the eluent to provide pure (5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)pyridin-3-yl)methanol (0.71 g, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.51 (s, 1H), 8.72 (s, 1H), 8.63 (s, 1H), 8.23 (d, 1H, J=4.8 Hz), 7.88 (dd, 1H, J=7.6 Hz, 8.4 Hz), 7.85-7.80 (m, 1H), 7.73 (dt, 1H, J=1.2 Hz, 7.6 Hz), 7.61-7.48 (m, 5H), 7.33 (d, 2H, J=19.2 Hz), 7.27 (d, 1H, J=14 Hz), 7.23 (dt, 1H, J=1.6, 7.2 Hz), 6.87 (t, 1H, J=4.0 Hz, 1H), 5.47 (t, 1H, J=5.6), 4.75 (d, 2H, J-4 Hz), 4.67 (d, 2H, J=5.6 Hz). LCMS Method U: retention time 1.46 min; [M+1]=420.2; HPLC Method A2: purity 99.5%, retention time=5.77 min.