Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[C:34](=[O:35])[N:33]([CH2:36][CH3:37])[CH2:32][CH2:31][N:30]([CH2:38][CH3:39])[C:29]=3[CH:40]=2)[C:21]([Cl:41])=[CH:20][N:19]=1>>[Cl:41][C:21]1[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[C:34](=[O:35])[N:33]([CH2:36][CH3:37])[CH2:32][CH2:31][N:30]([CH2:38][CH3:39])[C:29]=3[CH:40]=2)=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Reactant: CCN1CCN(CC)c2cc(Nc3nc(Cl)ncc3Cl)ccc2C1=O
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccc5c(c4)N(CC)CCN(CC)C5=O)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and 8-(2,5-Dichloro-pyrimidin-4-ylamino)-1,4-diethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one in an analogous manner to example 712. Product was isolated as a tan solid (0.080 g, 40%). Mp 100-106° C.; LCMS (m/e) 563 (M); 1H-NMR (DMSO, 400 MHz) δ 9.27 (s, 1H), 8.90 (s, 1H), 8.23 (s, 1H), 7.52-49 (d, 1H, J=8.59 Hz), 7.46-44 (d, 1H, J=8.33 Hz), 7.31-23 (s, 2H), 7.20-18 (d, 1H, J=7.84 Hz), 7.01-6.96 (d, 1H, J=8.34 Hz), 3.67-60 (br, 1H), 3.60-55 (q, 1H, J=6.82 Hz), 3.48-42 (t, 1H, J=5.06 Hz), 3.38-31 (s, 2H), 3.31-29 (t, 1H, J=6.57 Hz), 3.16-06 (q, 1H, J=6.82 Hz), 3.10-2.96 (m, 3H), 2.84-80 (br, 1H), 2.56-40 (br, 2H), 1.21-16 (t, 3H, J=7.07 Hz), 1.18-08 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:9]([O:12][CH2:13][CH2:14][O:15]C2CCCCO2)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl>CO>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:9]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(OCCOC2CCCCO2)ccc(Br)c1C
Agent: Cl
Solvent: CO
Product: COC(=O)c1c(OCCO)ccc(Br)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110 %

Procedure:
A solution of methyl 3-bromo-2-methyl-6-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]-benzoate (Cpd HH, 162 mg, 0.434 mmol) in MeOH (4 mL) was treated with 6N HCl (0.2 mL) and stirred at room temperature for 30 minutes. The solvent was concentrated in vacuum to 1 mL and the solution partitioned between DCM (25 mL) and NaHCO3 (sat., aq., 25 mL). The organic layer was concentrated under vacuum to give methyl 3-bromo-6-(2-hydroxyethoxy)-2-methylbenzoate (126a, 138 mg, 110% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:14]=[C:13]([NH2:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:6]=1)[CH:2]=[CH2:3].[C:19](OC(=O)C)(=[O:21])[CH3:20].C([O-])(=O)C.[Na+].[OH-].[Na+]>C1COCC1>[C:19]([NH:15][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:6]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[N:14]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCNc1nc(N)c2cc([N+](=O)[O-])ccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCNc1nc(NC(C)=O)c2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.8 %

Procedure:
300 mg (1.22 mmol) of 2-allylamino-4-amino-6-nitroquinazoline was dissolved in 5 ml of THF, and then 5.0 g (29.38 mmol) of acetic anhydride and 30 mg (0.37 mmol) of sodium acetate were added thereto, followed by stirring at room temperature for 12 hours. The reaction solution was neutralized with a 1 N aqueous sodium hydroxide solution. Crystals thus precipitated were filtered, followed by washing with water and drying to give 150 mg (42.7%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](/[CH:19]=[N:20]\[S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])=[N:4][CH:5]=[C:6](N2C(=O)C3C(=CC=CC=3)C2=O)[CH:7]=1.[Br:27]C1C(C=O)=NC(Br)=CC=1>>[Br:1][C:2]1[C:3](/[CH:19]=[N:20]\[S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])=[N:4][C:5]([Br:27])=[CH:6][CH:7]=1
Reactant: O=Cc1nc(Br)ccc1Br
Reactant: CC(C)(C)[S@](=O)/N=C\c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Product: CC(C)(C)[S@](=O)/N=C\c1nc(Br)ccc1Br

Procedure:
The title compound (42C) was prepared according to the method presented for the synthesis of compound 30C of Example 30 utilizing 42B. MS (m/z) 368.86 [M+H]+
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:3].[ClH:16]>O>[ClH:16].[CH3:3][NH+:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:1]
Reactant: CCCCCCCCCCCCN(C)C
Agent: Cl
Solvent: O
Product: CCCCCCCCCCCC[NH+](C)C
Reaction time: 8 h

Procedure:
43.3 g (0.2 mol) of N,N-dimethyldodecylamine were added in portions with stirring to 30.0 g (0.3 mol) of concentrated hydrochloric acid (37 wt. %). After the exothermic reaction (up to approx. 35° C.), the highly viscous mixture was diluted with 25 ml of concentrated hydrochloric acid and 25 ml of water and stirred overnight. The aqueous phase was then extracted with 100 ml of methylene chloride, the organic phase was washed once with 50 ml of water, dried with sodium sulfate and the solvent was removed under a vacuum. In order to remove any traces of water, the residue was resuspended in 50 ml of toluene and concentrated under a vacuum and the operation was then repeated in 80 ml of hexane. Once the solvent had again been removed by distillation under a vacuum, N,N-dimethyldodecylammonium hydrochloride was obtained as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:32])[CH2:9][C:10](=[O:31])[CH:11]=[C:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:30])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=3)[CH2:14][CH2:13]2)[CH:5]=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:32])[CH2:9][C:10](=[O:31])[CH:11]=[C:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:30])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=3)[CH2:16][CH2:17]2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1cc(C(=O)N2CCC(=CC(=O)CC(O)c3cncc(F)c3)CC2)ccc1OC(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC(=CC(=O)CC(=O)c3cncc(F)c3)CC2)ccc1OC(C)C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
A solution of 4-(5-fluoro-3-pyridyl)-4-hydroxy-1-[1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidylidene]butan-2-one (475 mg, 1.08 mmol) in dichloromethane (15 mL) was cooled to 0° C. and treated with Dess-Martin periodinane (457 mg, 1.08 mmol). The reaction mixture was stirred for 30 min and was treated with additional Dess-Martin periodinane (150 mg, 0.35 mmol). The reaction mixture was stirred for 30 min and was quenched by the addition of saturated aqueous sodium sulfite. The mixture was extracted with dichloromethane (3×50 mL) and the combined organics were washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified on silica gel utilizing a gradient of 60-100% ethyl acetate in hexanes to yield 1-(5-fluoro-3-pyridyl)-4-[1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidylidene]butane-1,3-dione (317 mg). 1H NMR (400 MHz, CDCl3) δ 16.25 (br s, OH), 8.81 (t, J=1.5 Hz, 1H), 8.52 (d, J=2.8 Hz, 1H), 7.82 (ddd, J=9.0, 2.7, 1.8 Hz, 1H), 7.18 (dd, J=11.4, 3.0 Hz, 2H), 6.76 (d, J=8.1 Hz, 1H), 6.08 (s, 1H), 5.86 (s, 1H), 4.50 (m, 1H), 3.65 (br s, 4H), 3.02 (br s, 2H), 2.36 (br s, 2H), 2.14 (s, 3H), 1.28 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 438.20, found 439.5 (M+1)+; Retention time: 2.15 minutes as a colorless oil (3 min run).
Reaction SMILES: C[O:2][C:3](=[O:12])[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][O:7][C:6]1=[O:11].O.CO.[OH-].[Na+]>C1COCC1>[O:11]=[C:6]1[N:5]([CH2:4][C:3]([OH:12])=[O:2])[CH2:10][CH2:9][CH2:8][O:7]1
Reactant: COC(=O)CN1CCCOC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CN1CCCOC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of 0.068 g (0.39 mmol) of methyl (2-oxo-1,3-oxazinan-3-yl)acetate from step B above in 6 mL of THF and 2 mL of water and 2 mL of methanol was added 0.60 mL (1.2 mmol) of an aqueous 2.0 M sodium hydroxide solution. The resulting mixture was stirred at ambient temperature for 3 h and then evaporated in vacuo to remove the methanol and THF. The aqueous phase was acidified with a 2 N hydrochloric acid solution until a pH of 2 was achieved and then extracted with a 30% isopropyl alcohol in chloroform mixture (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound as an off-white solid (0.06 g, 99%). 1H NMR (CD3OD, 500 MHz) δ: 4.32 (t, J=5.4 Hz, 2H), 4.03 (s, 2H), 3.41 (t, J=6.2 Hz, 2H), 2.10-2.05 (m, 2H). LC-MS: m/z (ES) 160 (MH)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:14])[CH2:10][CH2:11][CH2:12][Cl:13].[N:15]([O-])=O.[Na+]>Cl.O>[Cl:13][CH2:12][CH2:11][C:10]1[C:9](=[O:14])[C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:2][N:15]=1
Reactant: Nc1ccccc1C(=O)CCCCl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=c1c(CCCl)n[nH]c2ccccc12
Temperature: 25 °C

Procedure:
A solution of 1-(2-aminophenyl)-4-chlorobutan-1-one hydrochloride (b 11.3 g, 0.0427 mol) in concentrated hydrochloric acid (1200 ml) was cooled down to 0° with stirring. Then sodium nitrite (3.54 g, 0.051mol) in water (25 ml) was added dropwise. On completion of the addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. The solution was evaporated under reduced pressure to dryness. The solid obtained was washed with a solution of sodium acetate and collected by filtration to give the title compound, 5.32 g. Recrystallization from methanol gave the product, m.p. 201-203°.
Reaction SMILES: S(Cl)(Cl)=O.N1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH2:6]=[C:7]1[C:8]([CH3:9])([CH3:7])[CH2:10][CH2:9][C:8]1([CH3:10])[CH3:6]
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C=C1C(C)(C)CCC1(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The crude product from Part B (30 g) was dissolved in pyridine (150 ml), the solution cooled to 0° C. and treated (dropwise) with thionyl chloride (20 ml, 0.28 mole), maintaining a temperature of <5° C. The reaction mixture was stirred overnight, filtered and ether and water added. The phases were separated and the organic phase washed with water (2×200 ml) and dried (Na2SO4). The solvent was evaporated under reduced pressure to give 1-methylene-2,2,5,5-tetramethylcyclopentane (10.8 g) which was pure by GC.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:30])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([OH:28])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:29])[CH:17]=1>>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:28][C:21]1[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[C:25]2[C:20]=1[O:19][C:18](=[O:29])[CH:17]=[C:16]2[NH:15][C:14]1[C:13]([Cl:30])=[CH:12][N:11]=[CH:10][C:9]=1[Cl:8]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: BrCCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr

Procedure:
The title compound was prepared from 1,5-dibromopentane and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1H), 8.83 (s, 2H), 7.96 (d, 1H), 7.22 (d, 1H), 4.66 (s, 1H), 4.01 (t, 2H), 3.94 (s, 3H), 3.57 (t, 2H), 1.88 (m, 2H), 1.72 (m, 2H), 1.62 (m, 2H); MS (ESI): 500.7.
Reaction SMILES: [OH:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.[Cl:36][CH2:37][C:38]([CH2:40]Cl)=[CH2:39].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:36][CH2:37][C:38](=[CH2:39])[CH2:40][O:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:11]=[C:10]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Reactant: C=C(CCl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(CCl)COc1ccc(CNc2nc(Nc3ccc(C(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Yield: 36.7 %

Procedure:
A suspension of tert-butyl 4-((4-((4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (3 g), 3-chloro-2-(chloromethyl)prop-1-ene (1.15 g) and K2CO3 (1.69 g) in acetone (20 mL) was heated to reflux for 16 hours. The solvent was removed under vacuum. The residue was purified by silica gel column (hexanes:EtOAc=10:1 to 4:1) to give tert-butyl 4-(4-(4-(2-(chloromethyl)allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1.3 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][N:17](C=O)[CH2:18]2)=[CH:13][CH:12]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.Cl>C(Cl)Cl.CCOCC>[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][N:17]([C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[O:9])[CH2:18]2)=[CH:13][CH:12]=1
Reactant: O=C(O)C1CCOCC1
Reactant: O=CN1CCc2ccc(Br)cc2C1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O=C(C1CCOCC1)N1CCc2ccc(Br)cc2C1
Reaction time: 8 h
Yield: 108 %

Procedure:
To a solution of tetrahydropyran-4-carboxylic acid 130 mg (1 mmol) in DCM (5 mL) was added 7-bromo-3,4-dihydro-1H-isoquinoline-2-carbaldehyde (200 mg, 1 mmol), followed by TPTU (326 mg) and HOBt (148 mg). The solution was cooled to ice-water bath. To this solution was added ethyl diisopropylamine (0.4 mL). The yellow solution was allowed to stir under nitrogen overnight. LC/MS showed the reaction was complete. The reaction was quenched by addition of sodium bicarbonate solution (5 mL) and DCM (30 mL). The two layers were separated, and the aqueous layer was extracted with DCM (20 mL×2). The combined DCM extracts were washed with sodium bicarbonate (20 mL), and brine (15 mL×2), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with 5-10% MeOH in DCM to get a yellow semi-solid. This was taken in DCM and ether (5 mL) and treated with 0.5 mL of 1N HCl in ether. The white powder was collected and dried to get 0.35 g (100% yield) of the titled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:41]=[CH:40][C:22]([CH2:23][NH:24][C:25]2[CH:30]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([F:39])[CH:33]=3)[CH:28]=[CH:27][N:26]=2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]2[CH:30]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:14]([C:11]4([C:9]([NH:8][C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)=[O:10])[CH2:12][CH2:13]4)=[O:16])=[C:34]([F:39])[CH:33]=3)[CH:28]=[CH:27][N:26]=2)=[CH:40][CH:41]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: COc1ccc(CNc2cc(Oc3ccc(N)c(F)c3)ccn2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)cc1
Yield: 57 %

Procedure:
1-((4-Fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (see Example B1, 171 mg, 0.77 mmol), N-(4-methoxybenzyl)-4-(4-amino-3-fluorophenoxy)pyridin-2-amine (see PCT Publication No. WO 2008/046003, 200 mg, 0.59 mmol), TBTU (284 mg, 0.88 mol) and DIEA (0.12 ml, 0.73 mmol) were combined in DMF (1.5 mL) and the resultant mixture was stirred overnight. The reaction mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and EtOAc (20 mL). The organic was washed with water (10 mL), brine (10 mL), and 5% aqueous lithium chloride solution (10 mL), and was then dried over MgSO4 and concentrated in vacuo. Dichloromethane was added to the residue and the resultant slurry was filtered. The collected precipitate was washed with CH2Cl2 and dried in vacuo to provide N-(4-(2-(4-methoxybenzylamino)pyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (137 mg) as a white solid. The filtrate was concentrated and a second crop (46 mg, total yield 57%) was collected. MS (ESI) m/z: 545.1 (M+H+).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].Cl[C:15]1[C:20]([Cl:21])=[CH:19][C:18]([NH2:22])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1.O>CN(C=O)C>[Cl:21][C:20]1[C:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[C:18]([NH2:22])[CH:19]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c(Oc2ccccc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 64.2 %

Procedure:
To a solution of phenol (0.500 g, 5.31 mmol) in dry DMF (20 mL) was added solid sodium t-butoxide (0.510 g, 5.31 mmol). The mixture was heated to 100° C. for 60 min, then 4,5-dichloro-2-nitro-phenylamine (1.00 g, 4.83 mmol) was added and the reaction mixture was heated at 100° C. for 19 h. The reaction mixture was allowed to cool to ambient temperature. The reaction mixture was added to water and extracted with EtOAc. The combined organic layers were washed with 1M Na2CO3, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (hexanes:EtOAc, 5% to 30% over 20 minutes) to yield the titled compound as an orange solid (0.821 g, 64%). 1H NMR (400 MHz, CDCl3): 8.27 (s, 1H), 7.50-7.34 (m, 2H), 7.27 (d, J=8.9 Hz, 2H), 7.10 (dd, J=8.6, 1.1 Hz, 2H), 6.02 (s, 3H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:33][CH2:32][S:31][CH2:30][CH2:29]1>>[N:28]1([CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH:39]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:37][CH:36]=2)[CH2:29][CH2:30][S:31][CH2:32][CH2:33]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(CN2CCSCC2)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCSCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(thiomorpholin-4-yl-methyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol=15:1) C28H27N3O3S
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23](F)[CH:22]=[C:21]3[C:16]=2[C:17](=[O:26])[NH:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][OH:28]>>[C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:28][CH3:27])[CH:22]=[C:21]3[C:16]=2[C:17](=[O:26])[NH:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)(C)OCCN1CCC(Oc2cc(F)cc3nc[nH]c(=O)c23)CC1
Product: COc1cc(OC2CCN(CCOC(C)(C)C)CC2)c2c(=O)[nH]cnc2c1
Yield: 63.1 %

Procedure:
An analogous reaction to that described in example 137b, but starting with 5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-fluoroquinazolin-4(3H)-one (363 mg, 1 mmol) and methanol (162 μl, 4 mmol) at 110° C. for 2 hours yielded 5-{[1-(2-tert-butoxyethyl)piperidin-4-yl]oxy}-7-methoxyquinazolin-4(3H)-one (237 mg, 63% yield):
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=O.[BH4-].[Na+].CC1C=CC(S(O)(=O)=[O:23])=CC=1.BrC1C=C2C(=CC=1)OCC=C2.C[N+]1([O-])CCOCC1>O=[Os](=O)(=O)=O.O.CC(C)=O.CC(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][C:6](=[O:23])[CH2:5]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1CCOc2ccc(Br)cc21
Agent: O=[Os](=O)(=O)=O
Agent: Brc1ccc2c(c1)C=CCO2
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1COc2ccc(Br)cc2C1

Procedure:
The starting material 6-bromochroman-3-one (5A) was prepared from 6-bromochroman-4-one in a manner similar to that described in the literature (Synthesis, 1980, 621): 6-bromochroman-4-one was reduced with NaBH4 (1.2 eq, MeOH-DCM, 0° C. to RT, 2 h) and then eliminated with pTsOH (cat., toluene, reflux, 3 h, 90% for 2-steps). The resulting 6-bromochromene was subjected to osmylation (cat. OsO4, 1 eq. NMO, water-acetone-tBuOH, RT, overnight) and subsequent treatment with pTsOH (cat., toluene, reflux, 15 min, 86% for 2-steps) to provide 6-bromochroman-3-one (5A).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([NH2:12])=[S:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH3:13][C:14]([C:17]([CH2:19]Br)=O)([CH3:16])[CH3:15]>C(O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][CH:19]=[C:17]([C:14]([CH3:16])([CH3:15])[CH3:13])[N:12]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)C(=O)CBr
Reactant: C=CCN1CCN(C(N)=S)CC1
Solvent: CCO
Product: C=CCN1CCN(c2nc(C(C)(C)C)cs2)CC1

Procedure:
3.7 g of 4-allyl-1-piperazinyl-thiocarboxamide are added to a solution of 3.6 g of bromopinacoline in 40 cc of ethanol, and the reaction mixture is subsequently heated to the boil at reflux for 2 hours. The mixture is subsequently concentrated by evaporation in a vacuum, the residue is dissolved in a small amount of water and divided between ether and a concentrated aqueous sodium hydroxide solution. The ether phase is washed with water, dried over sodium sulphate and saturated with hydrogen chloride gas after filtration. The monohydrochloride of 2-(4-allyl-1-piperazinyl)-4-tert.butyl-thiazole crystallizes and has an M.P. of 212°-214° after recrystallization from ethanol/diisopropyl ether.
Reaction SMILES: [CH:1]1[S:5][CH:4]=[CH:3][C:2]=1[C:6]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])=O.O.[NH2:18][NH2:19]>C(O)C>[S:5]1[CH:4]=[CH:3][C:2]([C:6]2[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:11])[NH:19][N:18]=2)=[CH:1]1
Reactant: NN
Reactant: O=C(O)c1ccccc1C(=O)c1ccsc1
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ccsc2)c2ccccc12
Yield: 51.4 %

Procedure:
1.8 g of o-(3-thenoyl)benzoic acid and 580 mg of hydrazine hydrate were dissolved in 20 ml of ethanol, and the solution was refluxed for 4 hours. After cooling the solution, it was crystallized by adding ether, thereby obtaining 910 mg of 4-(3-thienyl)-1-phthalazinone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH:28]=O)=[CH:22]3)[CH2:15][CH2:14][CH2:13][CH2:12]1.N1CCCCC1>C(O)C>[N:11]1([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH:28]=[C:3]2[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]2=[O:10])=[CH:22]3)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1cc2cc(CCCN3CCCC3)ccc2[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2C1=Cc1cc2cc(CCCN3CCCC3)ccc2[nH]1
Temperature: 80 °C
Yield: 74 %

Procedure:
A mixture of oxindole (27 mg, 0.2 mmol), 5-(3-pyrrolidin-1-yl-propyl)-1H-indole-2-carbaldehyde (51 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol/ethyl acetate and dried to give 55 mg (74%) of the title compound.