Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1.[F:13][C:14]1[CH:15]=[C:16]([C:20](O)=[O:21])[CH:17]=[N:18][CH:19]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1([NH:4][C:5]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=2[NH:12][C:20]([C:16]2[CH:17]=[N:18][CH:19]=[C:14]([F:13])[CH:15]=2)=[O:21])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cncc(F)c1
Reactant: Nc1ccc(F)cc1NC1CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1NC1CC1)c1cncc(F)c1

Procedure:
To a solution of the title compound from N2-cyclopropyl-4-fluorobenzene-1,2-diamine (0.065 g, 0.39 mmol) in dichloromethane (1.96 mL) were added 5-fluoropyridine-3-carboxylic acid (0.061 g, 0.43 mmol), EDC (0.082 g, 0.43 mmol), HOBt (0.066 g, 0.43 mmol), and diisopropylethylamine (0.280 mL, 1.56 mmol). The reaction was stirred at room temperature overnight, then diluted with dichloromethane, washed sequentially with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (30-50% ethyl acetate in hexanes) provided the title compound: LCMS m/z 290.14 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.90 (s, 1 H), 8.66 (d, J=2.0 Hz, 1 H), 7.97 (d, J=8.3 Hz, 1 H), 7.48 (br s, 1 H), 7.19 (m, 1 H), 6.92 (d, J=10.9 Hz, 1 H), 6.52-6.49 (m, 1 H), 4.50 (br s, 1 H), 2.47-2.44 (m, 1 H), 0.81-0.77 (m, 2 H), 0.54-0.51 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[O:7][CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)=[O:44]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1OC1CCNCC1
Yield: 9 %

Procedure:
Following the procedures as described in Example 113, tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yloxy)piperidine-1-carboxylate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 120 as a white solid (20 mg, 9.0%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 7.64-7.40 (m, 3H), 7.27 (t, J=8.7, 2H), 4.39-4.11 (m, 1H), 3.60 (s, 3H), 2.94 (dt, J=12.5, 3.9, 2H), 2.50-2.40 (m, 2H), 2.03-1.81 (m, 2H), 1.53 (td, J=13.2, 4.0, 2H). ESIMS m/z=435.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@@H:8]([CH3:12])[NH:7][C:6]=2[C:5]([N+:13]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[C:11]2[O:10][CH2:9][C@@H:8]([CH3:12])[NH:7][C:6]=2[C:5]([NH2:13])=[CH:4][CH:3]=1
Reactant: C[C@@H]1COc2c(F)ccc([N+](=O)[O-])c2N1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1COc2c(F)ccc(N)c2N1
Reaction time: 16 h
Yield: 103.4 %

Procedure:
A suspension of (R)-8-fluoro-3-methyl-5-nitro-3,4-dihydro-2H-benzo[1,4]oxazine (183 mg, 0.86 mmol) and 10% Pd/C (37 mg) in EtOAc (12 mL) and IMS (1.2 mL) was stirred under a H2 balloon for 16 h. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give the title compound as a pale yellow oil (162 mg, quant.). 1H NMR (CDCl3, 300 MHz): δ 6.36 (1H, dd, J=10.6, 8.6 Hz), 6.14 (1H, dd, J=8.6, 4.6 Hz), 4.19 (1H, dd, J=10.4, 2.7 Hz), 3.65 (1H, dd, J=10.4, 8.0 Hz), 3.44 (1H, dqd, J=8.0, 6.5, 2.7 Hz), 3.13 (3H, br s), 1.17 (3H, d, J=6.5 Hz)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[CH:4][CH:3]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.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>[OH:23][C:12]1[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=3)=[CH:3][CH:4]=2)[C:14](=[O:15])[C:13]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nn(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 37.2 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(4-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 61, 40 mg, 0.094 mmol), 4-trifluoromethylphenylboronic acid (22 mg, 0.10 mmol), potassium carbonate (40 mg, 0.290 mmol), and tetrakis(triphenylphosphine)palladium (0) (6 mg, 5 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes, diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was washed with brine, dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 15-95% acetonitrile/water (0.1% TFA)) to afford the title compound (17.1 mg, 0.035 mmol, 37% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.89 (s, 1H), 12.98 (br. s., 1H), 10.19 (t, J=5.68 Hz, 1H), 7.88 (d, 2H), 7.81 (d, 2H), 7.72 (d, J=8.34 Hz, 2H), 7.43 (d, J=8.34 Hz, 2H), 5.32 (s, 2H), 4.10 (d, J=5.56 Hz, 2H), 3.20 (sept, J=6.78 Hz, 1H), 1.22 (d, J=6.82 Hz, 6H). MS (ES+) m/e 490 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[NH2:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C@H:22]3[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]3)[N:16]=2)=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].CN(C=O)C>C(#N)C.CO.CCOCC>[OH:4][CH2:3][CH2:2][NH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C@H:22]3[CH2:23][CH2:24][C@H:25]([OH:28])[CH2:26][CH2:27]3)[N:16]=2)=[CH:8][CH:7]=1
Reactant: OCCBr
Reactant: Nc1ccc2cnn(-c3ccnc(N[C@H]4CC[C@H](O)CC4)n3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOCC
Product: OCCNc1ccc2cnn(-c3ccnc(N[C@H]4CC[C@H](O)CC4)n3)c2c1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
2-Bromoethanol (42 μL, 0.6 mmol) was added to a mixture of trans-4-[4-(6-amino-indazol-1-yl)-pyrimidin-2-ylamino]-cyclohexanol (100 mg, 0.30 mmol) and sodium bicarbonate (25 mg, 0.30 mmol) in acetonitrile (1 mL), and the resulting mixture heated to 80° C. for 2 h. DMF (0.5 mL) was added, and the resulting mixture heated to 80° C. overnight. A second aliquot of 2-bromoethanol (20 μL) was added, and heating continued for 3 days. The resulting mixture was diluted with MeOH, and Et2O was added. The gummy residue which crashed out of solution was purified by preparative TLC to give trans-4-{4-[6-(2-hydroxyethylamino)-indazol-1-yl]-pyrimidin-2-ylamino}-cyclohexanol (29 mg) as a yellow solid. MS=369 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=O.[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:15]2[C@@H:16]3[C@@H:21]([C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)=[O:7])[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(O)c(F)c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 40 %

Procedure:
The title compound is prepared from 3-fluoro-4-hydroxy-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 40% of theory; LC (method 4): tR=1.94 min; Mass spectrum (ESI+): m/z=326 [M+H]+.
Reaction SMILES: C([NH:4][C:5]1[N:14]=[C:13](C2N=CNN=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:20])[CH:11]=2)[N:6]=1)(=O)C.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[NH2:4][C:5]1[N:14]=[C:13]([NH:27][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:20])[CH:11]=2)[N:6]=1
Reactant: NC1CCCCC1
Reactant: CC(=O)Nc1nc(-c2nc[nH]n2)c2cc(Br)ccc2n1
Product: Nc1nc(NC2CCCCC2)c2cc(Br)ccc2n1
Yield: 93 %

Procedure:
This compound was synthesized from the product of example 11, i.e. 2-acetamido-6-bromo-4-(1,2,4-triazolyl)-quinazoline and cyclohexylamine in 93% yield, using the procedure described for example 17. The product was characterized by its mass spectrum as follows: MS (m/z): 321 ([M+H]+, 100).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([C:20]#[N:21])[CH:15]=1.C([O-])(=O)C.[K+].[Br:27]Br.S([O-])(O)=O.[Na+]>C(O)(=O)C.ClCCl.O>[Br:27][C:15]1[C:16]([C:20]#[N:21])=[N:17][N:18]([CH3:19])[C:14]=1[CH2:13][CH2:12][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11]
Reactant: Cn1nc(C#N)cc1CCN1C(=O)c2ccccc2C1=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: Cn1nc(C#N)c(Br)c1CCN1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a mixture of 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carbonitrile (8.50 g, 30.3 mmol) and potassium acetate (4.50 g, 45.5 mmol) in acetic acid (40 mL) and dichloromethane (120 mL) was slowly added bromine (6.79 g, 42.5 mmol). The mixture was stirred overnight. Saturated aqueous sodium hydrogensulfite was added until the mixture became colorless, then the mixture was concentrated under reduced pressure to form a slurry. Water (200 mL) was added to the slurry and a white solid was isolated by filtration, washed with water, and dried to afford 9.15 g of 4-bromo-5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carbonitrile as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[CH:9][C:8]=1[N+:22]([O-])=O)C.O1C2C=CC=CC=2CC(=O)N1.NC1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[F:21][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]3[O:6][CH2:5][C:4](=[O:3])[NH:22][C:8]=3[CH:9]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)COc1ccc(C#Cc2cccc(F)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C1Cc2ccccc2ON1
Solvent: Nc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1COc2ccc(CCc3cccc(F)c3)cc2N1
Temperature: 23 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
To a solution of [4-(3-fluoro-phenylethynyl)-2-nitro-phenoxy]-acetic acid ethyl ester (1.72 g, 5.01 mmol, 1 equiv) in ethyl acetate (50 mL) was added palladium on carbon (500 mg, 10 wt. %, wet, Degussa type). The reaction vessel was placed under an atmosphere of hydrogen (balloon) and stirred at 23° C. for 15 h. At this time LCMS analysis indicated the reaction contains a mixture of the desired benzoxazinone product (major) and uncyclized aniline (minor). The mixture was filtered through a pad of Celite, washing with ethyl acetate (100 mL). The solution was concentrated, then re-dissolved in ethyl acetate (100 mL) and refluxed for 2 h. LCMS analysis indicates no improvement in cyclized:uncyclized ratio. Para-toluenesulfonic acid hydrate (111 mg) was added and resulting solution was refluxed for a further 1 h. The solution was cooled to 23° C. then washed successively with water, 1.0 N aqueous hydrochloric acid, saturated aqueous brine (100 mL each), dried (MgSO4), filtered and concentrated. The product was purified using an Isco CombiFlash automated chromatography system. The residue was loaded onto a 80 g silica gel column as a solution in dichloromethane (5 mL) then eluted with methanol in dichloromethane (0-5% methanol linear gradient over 18 column volumes at a flow rate of 60 mL/min) to give 1.15 g (4.24 mmol, 85%) of the title compound as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:29])[C:14]([CH2:24][CH:25]4[CH2:28][CH2:27][CH2:26]4)([CH3:23])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH:25]1([CH2:24][C:14]2([CH3:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]([OH:22])=[C:12]([C:7]3[NH:6][C:5]4[CH:30]=[CH:31][C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:3][C:4]=4[S:9](=[O:11])(=[O:10])[N:8]=3)[C:13]2=[O:29])[CH2:28][CH2:27][CH2:26]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CC2CCC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(CC2CCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reaction time: 12 h
Yield: 81.1 %

Procedure:
To a stirring solution of Example 56 (0.080 g, 0.189 mmol) and pyridine (0.122 mL, 1.512 mmol) in dichloromethane was added methanesulfonyl chloride (0.017 mL, 0.227 mmol) dropwise over 5 minutes and the resulting reaction mixture stirred for 12 hours. The solution was concentrated in. vacuo and purified by flash chromatography on SiO2 eluting with a 0-100% ethyl acetate/hexane gradient yielding the title compound (0.079 g, 84% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85 m, 2 H) 1.15 m, 1 H) 1.26 m, 4 H) 1.47 m, 3 H) 1.57 (s, 3 H) 1.72 m, 2 H) 2.14 m, 1 H) 2.31 (m, 1 H) 3.08 (s, 3H) 7.53 m, 1 H) 7.61 (dd, J=11.77, 2.21 Hz, 1 H) 8.15 (d, J=7.35 Hz, 1 H) 10.25 (s, 1 H) 13.83 (s, 1 H). MS (ESI+) m/z=516 (M+H)+.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:27])([CH3:26])[C:8]12[O:15][C:12]([C:16]([CH3:24])([CH3:23])[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH:13]=[CH:14]1)[CH2:11][C:10](=[O:25])[CH2:9]2)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([SiH2:5][O:6][C:7]([CH3:27])([CH3:26])[C:8]12[O:15][C:12]([C:16]([CH3:24])([CH3:23])[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH2:13][CH2:14]1)[CH2:11][C:10](=[O:25])[CH2:9]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)C12C=CC(C(C)(C)O[SiH2]C(C)(C)C)(CC(=O)C1)O2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[SiH2]OC(C)(C)C12CCC(C(C)(C)O[SiH2]C(C)(C)C)(CC(=O)C1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A mixture of 1,5-bis-(tert-butyl-dimethyl-silanyloxymethyl)-8-oxa-bicyclo[3.2.1]-oct-6-en-3-one (200 mg, 4.84 mmol)(Lee, K. and Cha, J. K., J. Amer. Chem. Soc., 123:5590-5591 (2001)) and 5% Pd/C (30 mg) in 10 mL of MeOH was stirred at RT under H2 (balloon pressure) for 8 h. The Pd catalyst was removed by filtration on Celite, and the filtrate was concentrated to give 200 mg (100%) of the title compound as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C21H42O4Si2, 415.2 (M+H), found 415.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1>CN(C)C=O.O1CCCC1>[CH3:1][O:2][C:3](=[O:9])[CH:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:5](=[O:8])[CH2:6][CH3:7]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCC(=O)C(Cc1ccc(F)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Oxopentanoic acid methyl ester (7.5 g) was added to a stirred suspension of sodium hydride (60% in oil, 4.6 g) in N,N-dimethylformamide (20 mL) and tetrahydrofuran (80 mL) at 0° C. and the resulting mixture stirred at 0° C. for 30 minutes. A solution of 1-bromomethyl-4-fluorobenzene (7.0 mL) in tetrahydrofuran was added and the resulting mixture warmed to room temperature and then stirred at this temperature for 17 hours. The mixture was partitioned between ethyl acetate and water and the aqueous phase extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (19:1 by volume) to afford title compound, 1.0 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH3:24])([CH3:23])[C:10]3[NH:11][C:12]4[C:17]([C:18]=3[C:19](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH:16][CH:15]=[C:14]([C:21]#[N:22])[CH:13]=4.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:44][C:45]1([CH3:52])[O:49][C@H:48](CO)[CH2:47][O:46]1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1.C1COCC1>[CH3:44][C:45]1([CH3:52])[O:49][C@H:48]([CH2:1][O:2][C:3]2[C:8]3[C:9]([CH3:24])([CH3:23])[C:10]4[NH:11][C:12]5[C:17]([C:18]=4[C:19](=[O:20])[C:7]=3[CH:6]=[CH:5][CH:4]=2)=[CH:16][CH:15]=[C:14]([C:21]#[N:22])[CH:13]=5)[CH2:47][O:46]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: COc1cccc2c1C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](COc2cccc3c2C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)O1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, 7-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound W3, 15 mg, 0.05 mmol) and triphenylphosphine (40 mg, 3 eq.) were added with THF (1 ml), further added dropwise with ((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (20 mg, 3 eq.) and 2.19 N toluene solution of diethyl azodicarboxylate (68 μL, 3 eq.), and the mixture was stirred at 50° C. for 2 hr. After cooling, the reaction solution was added with ethyl acetate, washed with brine, dried over sodium sulfate, and filtered. The residues obtained after concentration under reduced pressure were purified by preparative TLC (ethyl acetate/dichloromethane), and the resulting solid was washed with dichloromethane to obtain the target compound (brown powder, 5 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)[CH:7]=[CH:8][N:9]=1.[ClH:19].CO.[CH:22](=O)[CH2:23][CH3:24].C([BH3-])#N.[Na+].Cl>CO>[ClH:19].[ClH:19].[CH2:22]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:6]([CH2:10][C:11]2[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=2)[CH:7]=[CH:8][N:9]=1)[CH2:23][CH3:24]
Reactant: CCC=O
Reactant: NCCSc1nccn1Cc1cc(F)cc(F)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNCCSc1nccn1Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-(2-aminoethylthio)-1-(3,5-diflorobenzyl)imidazole (2.69g, 0.010 mole) in absolute methanol (25 ml) is added 5N hydrochloric acid-methanol (1 ml, 0.005 mole) followed by propionaldehyde (4.25 g, 0.10 mole) and sodium cyanoborohydride (0.38 g, 0.006 mole). The reaction mixture is stirred at 25° C. for 72 hours and then concentrated hydrochloric acid is added until the pH is at least 2. The volatiles are removed in vacuo and then the residue is partitioned between water and ether. The layers are shaken together and separated, the pH of the aqueous extract is adjusted to greater than 10 with solid potassium hydroxide and then the product is extracted into ether. The ether extract is dried with anhydrous magnesium sulfate and then hydrogen chloride in ether is added slowly until a slight excess is present. The precipitated solid is filtered and recrystallized from ethanol ether to give 2-(2-propylaminoethylthio)-1-(3,5-difluorobenzyl)imidazole dihydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:21]=C)[C:15]2[O:19][CH:18]=[CH:17][C:16]=2[CH:20]=1)(=[O:11])=[O:10].I([O-])(=O)(=O)=[O:24].[Na+].Cl>O1CCOCC1.N1C(C)=CC=CC=1C.O.[Os](=O)(=O)(=O)=O>[CH:21]([C:14]1[C:15]2[O:19][CH:18]=[CH:17][C:16]=2[CH:20]=[C:12]([S:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])(=[O:10])=[O:11])[CH:13]=1)=[O:24]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(S(=O)(=O)Nc2ccccc2C)cc2ccoc12
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1cccc(C)n1
Product: Cc1ccccc1NS(=O)(=O)c1cc(C=O)c2occc2c1

Procedure:
N-(2-Methylphenyl)-7-vinyl-1-benzofuran-5-sulfonamide (1.03 g, 3.3 mmol; Intermediate 59) was dissolved in dioxane (30 mL) and 2,6-lutidine (0.8 mL). Osmium tetroxide (84 mg, 0.33 mmol) was added with stirring followed by a solution of sodium periodate (2.82 g, 13.2 mmol) in water (10 mL). After stirring for 90 minutes, 1 M HCl (40 mL) was added followed by water (200 mL). The precipitated product was collected by filtration, washed with water and dried under vacuo. Yield: 0.95 g (91%) of an off white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C#N

Procedure:
The title compound was prepared from [2-amino-4-cyano-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J29) (304 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a light red foam (440 mg, 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=1.CO[CH:23](OC)[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[F:19])[NH:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: Nc1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Reactant: COC(CCN1CCOCC1)OC
Product: Fc1ccc(Nc2ncnc3ccc(NCCCN4CCOCC4)cc23)cc1Cl
Yield: 84 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-amino-4-(3'-chloro-4'-fluoroanilino)quinazoline was reacted with 3-morpholinopropionaldehyde dimethyl acetal to give 4-(3'-chloro-4'-fluoroanilino)-6-(3-morpholinopropylarnino)quinazoline in 84% yield;