Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:2].[H-].[Na+].[Br:20][CH2:21][CH2:22][CH2:23]Br>CN(C)C=O>[Br:20][CH2:21][CH2:22][CH2:23][N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1
Reactant: BrCCCBr
Reactant: N#Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)c(-c1ccccc1)nn2CCCBr
Reaction time: 0.17 h

Procedure:
To a solution of 4.2 g of the 5-cyano-3-phenylindazole in 20 ml of dimethylformamide, 0.8 g of 60% sodium hydride was added, and the mixture was stirred for 10 minutes. The mixture was added dropwise to a mixture of 7 ml of 1,3-dibromopropane and 10 ml of dimethylformamide under cooling with ice. The mixture was stirred for 10 minutes at room temperature and extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel to produce 3.5 g of 1-(3'-bromopropyl)-5-cyano-3-phenylindazole (recrystallization from ethanol provided a m.p. of 100° to 102° C.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH2:8][CH:7]=[CH:6][CH2:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[OH-].[Na+].O.[C:16]([O:20][C:21](N=[N+]=[N-])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([O:20][C:21]([NH:1][CH2:2][C:3]1[CH2:8][CH:7]=[CH:6][CH2:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: NCC1=C(CC(=O)O)CC=CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1=C(CC(=O)O)CC=CC1

Procedure:
To a stirred solution of 8.0 g. (0.048 mole) of α-(2-aminomethyl-1,4-cyclohexadienyl)acetic acid and 3.8 g. (0.096 mole) of NaOH in 150 ml. of water was added a solution of 10.3 g. (0.072 mole) of t-butoxycarbonylazide in 80 ml. of THF and the mixture was stirred for 18 hours at room temperature. The THF was removed under reduced pressure and the residual solution was washed with ether (2×100 ml.), acidified with 6 N HC1 and extracted with ether (3×100 ml.). The combined extracts were washed with water (2×100 ml.) and a saturated NaCl solution (100 ml.), dried with Na2SO4 and evaporated to dryness.
Reaction SMILES: [O:1]=[C:2]1[CH:8]=[N:7][C:6](=O)[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]1[CH2:14][CH2:15][CH3:16].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:23][NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl>[CH:25]1([N:24]([C:6]2[C:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=3[N:3]([CH2:14][CH2:15][CH3:16])[C:2](=[O:1])[CH2:8][N:7]=2)[CH3:23])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCCn1c(=O)cnc(=O)c2ccccc21
Reactant: CNC1CCCCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCN1C(=O)CN=C(N(C)C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,5-dioxo-1-propyl-1,4-benzodiazepine (see Example 8) (10.0 g, 0.046 mol) in dichloromethane (200 ml) was added phosphorus pentachloride (11.5 g, 0.055 mol) in dichloromethane (400 ml) over 30 minutes. The reaction mixture was stirred at room temperature for 2 h then the solvent was removed under vacuum and the resulting oil was dried under high vacuum. The oil was redissolved in dichloromethane (200 ml) and a solution of N-methylcyclohexylamine (15.6 g, 0.138 mol) in dichloromethane (125 ml) was added dropwise. When the addition was complete, the reaction mixture was allowed to stir for 18 hours. The solution was washed with saturated sodium hydrogen carbonate solution (100 ml), and the aqueous layer was reextracted with dichloromethane (2×100 ml). The combined organic layers were washed with brine (100 ml), dried (sodium sulphate), filtered and concentrated in vacuo. The residue was dissolved in a small amount of dichloromethane and purified by flash column chromatography, eluted with 2% methanol/0.5% 0.88 ammonia solution/dichloromethane (3 litres) then 5% methanol/0.5% 0.88 ammonia solution/dichloromethane. Yield=15.8 g (quantitative), as a brown oil. 1H NMR (DMSO)δ0.68 (3H, t, J=7.3 Hz), 1.84-2.04 (3H, m), 2.72 (3H, s), 3.40 (1H, d, J=12.2 Hz), 3.54 (1H, m), 3.88 (1H, d, J= 12.2 Hz), 4.22 (1H, m), 7.34 (1H, m), 7.50 (1H, d, J=7.43 Hz), 7.60 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)([CH:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(O)(c2ccc(C)cc2)C2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(O)(c2ccc(C)cc2)C2CCNCC2)cc1
Yield: 59.9 %

Procedure:
A solution of 38.5 g (0.1 mole) of α,α-bis(4-methylphenyl)-1-(phenylmethyl)-4-piperidinemethanol in 500 ml of absolute ethanol was hydrogenated at 50 psi and 60° C. over 5% palladium on carbon in a Parr apparatus for 3 days. The cooled mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give a glass as residue. The glass was crystallized from 2-propanol to yield 17.7 g (60%) of white solid, m.p. 150°-153° C.
Reaction SMILES: [F:1][C:2]1([F:15])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([NH2:12])[C:5]=2[O:4][C:3]1([F:14])[F:13].[C:16]([O:20][C:21](=[O:29])[N:22]([CH2:26][CH2:27]Cl)[CH2:23][CH2:24]Cl)([CH3:19])([CH3:18])[CH3:17].[H-].[Na+]>CN(C=O)C>[C:16]([O:20][C:21]([N:22]1[CH2:26][CH2:27][N:12]([C:11]2[C:5]3[O:4][C:3]([F:13])([F:14])[C:2]([F:1])([F:15])[O:7][C:6]=3[CH:8]=[CH:9][CH:10]=2)[CH2:24][CH2:23]1)=[O:29])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1cccc2c1OC(F)(F)C(F)(F)O2
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2OC(F)(F)C(F)(F)O3)CC1
Reaction time: 1 h
Yield: 33.1 %

Procedure:
An intermediate compound, 1-(2,2,3,3-Tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine, was produced as follows: To the mixture of 2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-ylamine (8.9 g, 40 mmol) and bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester (14.5 g, 60 mmol) in DMF (200 mL) was added NaH (3.2 g, 60% oil dispersion, 80 mmol) at 0° C. and the resulting mixture was stirred at the same temperature for 1.0 h. No reaction was observed by TLC. The mixture was further stirred at room temperature for 4.0 h until LCMS indicated the starting material disappeared. The reaction was quenched with aq. NH4Cl, extracted with EtOAc, washed with brine, dried and concentrated. The residue was purified by flash chromatography (Et3N:EtOAc:heptane/1:10:100) to afford 4-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (5.2 g, 33%) as colorless crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][NH:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.[SiH](CC)(CC)CC>C(O)(C(F)(F)F)=O>[CH:1]1[C:10]2[C@H:11]3[CH2:17][NH:16][CH2:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: c1cc2c3c(c1)c1c(n3CCC2)CCCNC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c3c(c1)[C@H]1CNCCC[C@H]1N3CCC2
Reaction time: 72 h
Yield: 82.6 %

Procedure:
To a solution of 5,6,9,10,11,12-hexahydro-4H,8H-azepino[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (240 mg, 1.06 mmol) in TFA (4.0 ML) was added Et3SiH (2.0 mL). The mixture was stirred for 3 days then concentrated in vacuo. The residue was dissolved in dilute AcOH and washed with Et2O. The aqueous solution was basified with 1N NaOH. A white solid was precipitated and filtered to yield the title compound as a pale yellow viscous oil (200 mg, 83%). MS (CI, NH3): 229.4 (base, M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[OH:20].C(C1N=C(C2C=C(O[CH:42]3[CH2:59][CH:58]4[CH:44]([C:45](=[O:65])[N:46]([CH3:64])[CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][CH:53]5[C:55]([C:61]([OH:63])=[O:62])([NH:56][C:57]4=[O:60])[CH2:54]5)[CH2:43]3)C3C(=C(C)C(OC)=CC=3)N=2)SC=1)(C)C>>[F:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:18])[CH3:19])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:42]1[CH2:59][CH:58]2[CH:44]([C:45](=[O:65])[N:46]([CH3:64])[CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][CH:53]3[C:55]([C:61]([OH:63])=[O:62])([NH:56][C:57]2=[O:60])[CH2:54]3)[CH2:43]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1F
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1F

Procedure:
The title compound was prepared from 8-fluoro-4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxyquinoline (72) and alcohol 43 following the procedure (steps D-F) reported for the preparation of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (46): m/z=651 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:10]([O:12][C:13](=[O:25])[C:14](=[CH:21]N(C)C)[C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH3:11].C([O-])(=O)C.[Na+]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:21]=[N:9][N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:15]=1[C:16]([F:17])([F:18])[F:19])=[O:25])[CH3:11]
Reactant: NNC1CCCCC1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C2CCCCC2)c1C(F)(F)F
Temperature: 70 °C
Yield: 58.5 %

Procedure:
Cyclohexyl-hydrazine hydrochloride (0.276 g, 1.59 mmol, CAS #24214-73-1, purchased from Aldrich), 2-dimethylaminomethylene-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (0.459 g, 1.67 mmol) and anhydrous sodium acetate (0.188 g, 2.29 mmol) were combined in ethanol (2.9 mL) and heated at 70° C. for 15 hours. After cooling to room temperature, the reaction mixture was partitioned between methylene chloride and water. The organic phase was washed with water and brine. Each aqueous phase was back extracted with a second portion of methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography, eluting with a 5-40% ethyl acetate-hexanes gradient, yielded 1-cyclohexyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.270 g, 55%). Mass spectrum: m/z: 291.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[F:11].[C:13]([CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)#[CH:14]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:15]1([C:13]#[C:14][C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[C:5]([F:11])[CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(Br)cc1F
Reactant: C#CC1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CC2CCCC2)cc1F
Temperature: 80 °C
Yield: 93.4 %

Procedure:
4-Bromo-2-fluorobenzoic acid methyl ester (1.0 g, 4.0 mmol) was dissolved in triethylamine (5 mL). To the mixture was added copper iodide (38 mg, 5 mol %), followed by PdCl2(PPh3)2 (140 mg, 5 mol %) and ethynylcyclopentane (0.85 mL, 6.3 mmol). The mixture was heated in a sealed pressure tube at 80° C. for 3 hours. After completion of the reaction, the triethylamine was removed under vacuum and the residue was dissolved in EtOAc and filtered through Celite®. The organic layer was washed with water, brine, and dried (Na2SO4), filtered and the mixture concentrated under vacuum. The residue was purified using column chromatography on sililca using EtOAc-hexane (0-100% gradient) as eluent to give the product (0.92 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[N:8]=[CH:7][C:6]([C:16]#[N:17])=[C:5]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1.C(N(CC)C(C)C)(C)C.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>C1COCC1.C(=O)(O)[O-].[Na+]>[Br:25][C:21]1[CH:20]=[C:19]([NH:18][C:5]2[C:4]3[C:9](=[C:10]([CH2:12][N:13]([CH3:14])[CH3:15])[CH:11]=[C:2]([NH:1][C:35](=[O:38])[CH:36]=[CH2:37])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:16]#[N:17])[CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)Cc1cc(N)cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cc(CN(C)C)c2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 6-amino-4-[(3-bromophenyl)amino]-8-dimethylaminomethyl-3-quinolinecarbonitrile (0.20 g, 0.50 mmol) and N,N-diisopropylethylamine (0.13 ml, 0.75 mmol) in 3.4 ml of THF at 0° C. was added acryloyl chloride (0.045 ml, 0.55 mmol) during 5 m. After stirring for 3 h at 0° C. the mixture was diluted with sodium bicarbonate solution. The resulting solid was filtered off, washed with water, dried, and subjected to chromatography on silica gel with methylene chloride-ethyl acetate-methanol-triethylamine to give a yellow solid; mass spectrum (electrospray, m/e) M+H 449.9, 452.0.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[BH4-].[Na+]>C(O)(=O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=Cc1ccccc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1CCC(N2C(=O)c3cccc(NCc4ccccc4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 17 h
Yield: 15.6 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.0 g, 3.7 mmol) and benzaldehyde (0.4 ml, 3.9 mmol) in acetic acid (20 ml) was stirred at room temperature for 17 h, then was heated to reflux for 3 h. The mixture was cooled to room temperature. To the stirred mixture was added sodium borohydride (140 mg, 3.7 mmol) and kept at room temperature for 18 h. The mixture was then heated to reflux for 2 h. To the mixture was added additional benzaldehyde (0.4 ml, 3.9 mmol) during reflux. After 30 min of reflux the reaction was allowed to cool to room temperature. To the mixture was added sodium borohydride (180 mg, 4.8 mmol) and the mixture stirred at room temperature for 3 days. The solvent was removed in vacuo to yield an oil. The oil was diluted with ethyl acetate (90 ml) and aqueous sodium hydrogen carbonate (sat, 100 ml). The organic layer was separated and was washed with aqueous sodium hydrogen carbonate (sat, 2×100 ml), brine (100 ml) and dried over MgSO4. The solvent was removed in vacuo to give a solid. The solid was purified by column chromatography (Silca Gel, 50% EtOAc:CH2Cl2) to give a yellow solid. The solid was further purified by column chromatography (KP-C18-HS, 35:65 CH3CN:0.1% CF3COOH in water) to give 2-(2,6-dioxo(3-piperidyl))-4-[benzylamino]isoindoline-1,3-dione as a yellow solid (210 mg, 16% yield): mp, 209-211° C.; 1H NMR (DMSO-d6) δ 2.02-2.08 (m, 1H, CHH), 2.46-2.63 (m, 2H, CH2), 2.82-2.97 (m, 1H, CHH), 4.56 (d, J=6.2 Hz, 2H, CH2), 5.07 (dd, J=5.3, 12.4 Hz, 1H, NCH), 6.96 (d, J=8.6 Hz, 1H, Ar), 7.02 (d, J=7.0 Hz, 1H, Ar), 7.19-7.40 (m, 6H, Ar, NH), 7.51 (dd, J =7.5, 8.4 Hz, 1H, Ar), 11.11 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.15, 30.99, 45.44, 48.59, 109.58, 110.74, 117.63, 126.95, 126.99, 128.53, 132.21, 136.09, 138.95, 146.09, 167.27, 168.78, 170.07, 172.79; Anal Calcd for C20H17N3O4: C, 66.11; H, 4.72; N, 11.56. Found: C, 65.96; H, 4.60; N, 11.49.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([F:22])[CH:13]=1.[H-].[Na+].Br[CH2:26][CH3:27].O>CN(C)C(=O)C>[CH2:26]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([F:22])[CH:13]=1)[CH3:27]
Reactant: CCBr
Reactant: COc1cc(C=O)c(F)cc1OCc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCn1c(COc2cc(F)c(C=O)cc2OC)nc2ccccc21
Yield: 89 %

Procedure:
To a solution of 4-(1H-benzoimidazol-2-ylmethoxy)-2-fluoro-5-methoxy-benzaldehyde (215, 4.0 g, 13 mmol) in N,N-dimethylacetamide (80 mL) was added sodium hydride (60% dispersion in mineral oil, 0.65 g, 16 mmol) portion wise. After the addition was complete, the reaction was stirred for 30 minutes after which bromoethane (1.2 mL, 16 mmol) was added and then allowed to stir for several hours. The reaction mixture was then poured into water (1 L) with stirring and the precipitated solid was filtered, washed with water and dried to give the desired compound (216, 3.8 g, 87% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=O)[CH3:10].[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO.C(O)(=O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1/[C:9](=[N:21]/[NH:20][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[CH3:10]
Reactant: NNC(=O)c1ccccc1
Reactant: CC(=O)c1c(O)cccc1O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1ccccc1)c1c(O)cccc1O
Temperature: 120 °C
Yield: 56.3 %

Procedure:
1-(2,6-Dihydroxyphenyl)ethanone (100 mg, 0.657 mmol) and benzohydrazide (89 mg, 0.657 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (100 mg) as a solid. 1H NMR (400 MHz, CD3OD): δ 7.59 (m, 2H), 7.49 (m, 1H), 7.39 (m, 2H), 7.11 (t, 1H, J=8.0 Hz), 6.45 (m, 2H), 2.35 (s, 3H). ESI-MS: 271.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)=[O:38]
Reactant: O=C(NCC1CNCCO1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: COCC(=O)Cl
Product: COCC(=O)N1CCOC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (morpholin-2-ylmethyl)-amide (example A147) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:30][C:31]1[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=1.CN(C)C=O>>[Cl:30][C:31]1[N:32]=[CH:33][N:34]=[C:35]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)[CH:36]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2cc(Cl)ncn2)C3)cc1

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.196 g, 0.376 mmol), 4,6-dichloropyrimidine (0.112 g, 0.752 mmol) N,N-Diisopropylethylamine (0.150 mL, 0.861 mmol) and dry N,N-Dimethylformamide (1.1 mL, 14 mmol) were combined, The reaction was microwaved on 200 watts, 120° C. for 20 minutes on a CEM microwave. The reaction mixture was concentrated and chromatographed through silica gel (40 g, 0-10% MeOH in dichloromethane), and purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.69 (s, 1H), 8.41 (s, 1H), 8.20 (d, J=8.7, 2H), 7.50 (d, J=8.7, 2H), 7.12 (s, 1H), 6.20 (t, J=5.6, 1H), 4.72 (s, 3H), 4.12 (s, 1H), 4.08-3.92 (m, 1H), 3.88 (d, J=9.4, 1H), 3.80 (s, 1H), 3.64 (dt, J=25.7, 10.3, 4H), 3.43 (t, J=12.6, 1H), 3.17-3.04 (m, 2H), 2.75 (s, 2H), 1.26 (d, J=6.7, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+509.2 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[NH2:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][CH:44]=[CH:43]2>ClC(Cl)C>[NH:45]1[C:46]2[C:42](=[CH:41][C:40]([NH:39][C:5]3[C:4]4[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([I:1])[CH:3]=4)[N:8]=[CH:7][N:6]=3)=[CH:48][CH:47]=2)[CH:43]=[CH:44]1
Reactant: COc1cc2nc[nH]c(=O)c2cc1I
Reactant: Nc1ccc2[nH]ccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: COc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2cc1I
Temperature: 50 °C
Yield: 27.1 %

Procedure:
In a round bottom flask 6-Iodo-7-methoxy-3H-quinazolin-4-one (500 mg, 1.65 mmol), triphenyl phosphine polymer (2.75 gm, 3 mmol/gm) and carbon tetrachloride (2.53 gm, 16.5 mmol) were combined in 3 mL of dichloroethane and heated at reflux for 5 hours. 5-Aminoindole (686 mg, 1.65 mmol) was added to the mixture and heated at 50° C. overnight. Reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel 20% MeOH/1% ammonium hydroxide (NH4OH)/CHCl3 to provide 186 mg (28%) of product as a pale yellow solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24](O)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:42][CH:43]([B:46]1[O:50][C:49]([CH2:52][CH2:53][CH:54]([CH3:63])[CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])([CH3:51])[C:48]([CH3:65])([CH3:64])[O:47]1)[CH2:44][CH3:45]>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24]([NH:42][CH:43]([B:46]3[O:50][C:49]([CH2:52][CH2:53][CH:54]([CH3:63])[CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])([CH3:51])[C:48]([CH3:64])([CH3:65])[O:47]3)[CH2:44][CH3:45])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCC(N)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(NC(=O)[C@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Temperature: -10 °C
Reaction time: 0.12 h
Yield: 58.3 %

Procedure:
0.5 g (1.42 mmol) of N-[(9-fluorenyl)methoxycarbonyl]-L-leucine was dissolved in 7 ml of dichloromethane. 0.6 ml (5.7 mmol) of N-methylmorpholine was added and the solution was cooled to -10° C. under a nitrogen atmosphere. 0.22 ml (1.7 mmol) of isobutyl chloroformate was added and the solution was stirred for 7 minutes at -10° C. 1 g (2.13 mmol) of tert-butyl 5-[2-(1(RS)-aminopropyl)-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate was added and the mixture was stirred at room temperature for 16 hours, then diluted with dichloromethane and extracted with 2M hydrochloric acid. The organic phase was extracted with 2M hydrochloric acid and saturated sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulphate. After evaporation the residue was purified by chromatography on silica gel using ethyl acetate/hexane (1:2) for the elution. There was obtained 0.56 g of tert-butyl 5-[2-[1(RS)-[[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]amino]propyl]-4(RS) ,5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate as an oil; MS: m/e 677 [M+H]+.