Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](O)([CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[C:13]([NH:20][C:21](=[O:23])[CH3:22])[CH:12]=3)=[O:5])[CH3:2].FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>>[CH2:32]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[C:13]([NH:20][C:21](=[O:23])[CH3:22])[CH:12]=3)=[O:5])[CH3:33]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccc(NC(C)=O)cc1C2(O)C1CCN(C)CC1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccc(NC(C)=O)cc1C2=C1CCN(C)CC1
Yield: 3.5 %

Procedure:
Into a flask was placed compound 8f (0.3 g, 0.66 mmol) and trifluoromethanesulfonic acid (2 mL). After heating on a steam bath for 1 h the reaction was poured into 3 N NaOH and ice. The aqueous solution was extracted with CH2Cl2 and dried over sodium sulfate. The solvent was evaporated in vacuo and the resulting residue was passed through a flash column (silica gel; 90:10:1 CH2Cl2:CH3OH:NH4OH) to give 0.01 g of compound 9f. MS m/z=435 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]([CH3:13])[C:7](=[O:14])[CH2:6][CH2:5]2.[CH3:15][O:16][C:17]([C@@H:19]1[O:21][CH2:20]1)=[O:18].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C>[CH3:15][O:16][C:17](=[O:18])[CH:19]([OH:21])[CH2:20][NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]([CH3:13])[C:7](=[O:14])[CH2:6][CH2:5]2
Reactant: CN1C(=O)CCc2cc(N)cc(F)c21
Reactant: COC(=O)[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: COC(=O)C(O)CNc1cc(F)c2c(c1)CCC(=O)N2C
Yield: 62 %

Procedure:
6-Amino-8-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one (Step 3, 2.25 g, 0.0116 mol), methyl (2R)-glycidate (1.18 g, 0.0116 mol) and lithium trifluoromethanesulfonate (1.81 g, 0.0116 mol) in acetonitrile (10 ml) are heated at 90° C. overnight. The reaction is concentrated and the residue diluted with ethyl acetate, washed with water and saline, dried (MgSO4) and evaporated. The residue is purified by flash column chromatography (50% ethyl acetate/hexane) to give the title compound as a yellow solid (2.13 g, 62%); MS (m/z): [M+H]+=297.
Reaction SMILES: C(OC(=O)[NH:7][C@:8]([CH2:20][O:21][P:22]([O:29]C(C)(C)C)([O:24]C(C)(C)C)=[O:23])([CH3:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([NH2:18])[CH:12]=1)(C)(C)C.[ClH:35].C(O[C:39](=N)[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH2:47][CH3:48])[CH:41]=1)C>CO>[ClH:35].[NH2:7][C@:8]([CH3:19])([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]2[O:17][C:39]([C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH2:47][CH3:48])[CH:41]=3)=[N:18][C:13]=2[CH:12]=1)[CH2:20][O:21][P:22](=[O:23])([OH:24])[OH:29]
Reactant: CC(C)(C)OC(=O)N[C@](C)(CCc1ccc(O)c(N)c1)COP(=O)(OC(C)(C)C)OC(C)(C)C
Reactant: CCOC(=N)c1cccc(OCC)c1
Agent: Cl
Solvent: CO
Product: CCOc1cccc(-c2nc3cc(CC[C@@](C)(N)COP(=O)(O)O)ccc3o2)c1
Temperature: 25 °C

Procedure:
A solution of [(R)-3-(3-Amino-4-hydroxy-phenyl)-1-(di-tert-butoxy-phosphoryloxymethyl)-1-methyl-propyl]-carbamic acid tert-butyl ester (157.5 mg, 0.313 mmol) and 3-ethoxy-benzimidic acid ethyl ester hydrochloride in dry methanol (2 mL) was stirred for 20 minutes at 120° C. in a closed vial (microwave reactor). After cooling to RT the precipitate was filtered off, washed 2× with MeOH, 3× with water and 3× with diethyl ether. After drying in vacuum, the precipitate was dissolved in a mixture of diethyl ether/HCl (4 mL, 2M) and methanol (1 mL). After evaporation of the solvents the title compound was obtained as colorless crystals. 1H-NMR (CD3OD): δ=7.76 (d; 1H), 7.71 (s; 1H), 7.61 (bs; 2H), 7.47 (m; 1H), 7.37 (m; 1H), 7.14 (d; 1H), 4.24-4.00 (m; 4H), 2.89 (m; 2H), 2.10 (m; 2H), 1.47 (s; 6H); MS (ESI+): 421.4 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].C1([C@H]2[O:40][CH:39]([CH2:41][O:42][NH2:43])[CH2:38][CH2:37][O:36]2)C=CC=CC=1>>[OH:40][C@H:39]([CH2:38][CH2:37][OH:36])[CH2:41][O:42][NH:43][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: NOCC1CCO[C@@H](c2ccccc2)O1
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NOC[C@H](O)CCO)c(=O)n(C)c1=O
Yield: 60 %

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of Example 2 by treatment of compound 2A with O-((R)-2-Phenyl-[1,3]dioxan-4-ylmethyl)-hydroxylamine, followed by acid hydrolysis of the resulting material (total yield 60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.32 (s, 1 H) 11.97 (s, 1 H) 7.80 (dd, J=10.11, 1.77 Hz, 1 H) 7.58 (d, J=8.84 Hz, 1 H) 7.15 (t, J=8.59 Hz, 1 H) 4.90 (d, J=4.29 Hz, 1 H) 4.38 (t, J=5.05 Hz, 1 H) 3.71-3.90 (m, 2 H) 3.56-3.67 (m, 1 H) 3.44-3.53 (m, 2 H) 3.21 (s, 3 H) 2.96 (s, 3 H) 1.30-1.59 (m, 2 H). [M+H] calc'd for C17H20FIN4O6, 523; found, 523.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:18][CH2:17][C@:13]2([C:19]3[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=3[F:26])[NH:14][O:15][CH2:16][C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[NH2:14][C@@:13]1([C:19]2[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH2:17][O:18][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11][C@H:12]1[CH2:16][OH:15]
Reactant: Fc1ccc(Br)cc1[C@]12CO[C@@H](COCc3ccccc3)C[C@H]1CON2
Agent: [Zn]
Solvent: CC(=O)O
Product: N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Zinc powder (4.24 g) was added to a solution of (3aR,5R,7aS)-5-benzyloxymethyl-7a-(5-bromo-2-fluorophenyl)hexahydropyrano[3,4-c]isoxazole (2.74 g) in acetic acid (40 ml). After stirring at room temperature overnight, the insoluble matter was removed by filtration through celite. The solvent was evaporated under reduced pressure and ice was added to the residue, followed by neutralization with a 5 N sodium hydroxide solution. The aqueous layer was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (2.22 g).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH3:21])[CH2:8][CH:9]1[S:13][C:12](=N)[NH:11][C:10]1=[O:15])[CH3:3].[OH2:22]>C(O)C>[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH3:21])[CH2:8][CH:9]1[S:13][C:12](=[O:22])[NH:11][C:10]1=[O:15])[CH3:3]
Reactant: CCOc1ccc(CC2SC(=N)NC2=O)cc1OCC
Reactant: O
Agent: Cl
Solvent: CCO
Product: CCOc1ccc(CC2SC(=O)NC2=O)cc1OCC
Yield: 86 %

Procedure:
In a mixture of 60 ml ethanol and 60 ml 1N-HCl is dissolved 5.0 g of the 5-(3,4-diethoxybenzyl)-2-iminothiazolidin-4-one prepared above and the solution is heated under reflux for 8 hours. The reaction solution is cooled, and water is added thereto. The aqueous mixture is subjected to extraction with chloroform to give 4.3 g (86.0%) of 5-(3,4-diethoxybenzyl)thiazolidine-2,4-dione as crystals. Recrystallization from ethyl acetate-n-hexane yields colorless prisms melting at 98°-99° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[CH2:16]([C@@H:23]([CH2:34][OH:35])[C@H:24]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1F)[OH:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CS(C)=O>[CH2:16]([C@@H:23]1[C@@H:24]([OH:25])[C:26]2[C:31](=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=2)[O:35][CH2:34]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC[C@H](Cc1ccccc1)[C@@H](O)c1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O[C@H]1c2ccc(Br)cc2OC[C@@H]1Cc1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 49.3 %

Procedure:
A 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (6.55 L, 6.55 mol) was added-over 20 minutes to a solution of (1 R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl) -propane-1,3-diol (1975 g, 5.82 mol) in dimethyl sulfoxide (9.88 L) at ambient temperature. The mixture was slowly heated to 60° C. under aspirator vacuum to displace the tetrahydrofuran from the reaction mixture, and then heated at 60 to 65° C. for 5 hours under aspirator vacuum at which point the reaction was judged to be complete according to thin layer chromatography (hexanes/ethyl acetate, 2:1). The reaction mixture was cooled to ambient temperature and quenched by adding water (10 L) followed by 1 N aqueous hydrochloric acid (10 L). The resulting tan suspension was filtered, washed with water (2 L), and dissolved in ethyl acetate (12 L). This solution was washed with water (two times 12 L), concentrated to a low volume, dissolved in isopropyl ether (4 L), and concentrated under atmospheric pressure at 50 to 60° C. to 1.0 L, at which point solids began to precipitate. The resulting suspension was cooled to ambient temperature, stirred for 12 hours, concentrated to one-half its volume, cooled to 0 to 5° C., and filtered giving 916 g (49%) of (3S,4R)-3-benzyl-7-bromo- chroman-4-ol as a white solid. The filtrate was concentrated to a dark oil (906 g), dissolved in isopropyl ether (1.5 L) at reflux, cooled to ambient temperature, stirred, and filtered yielding an additional 82 g of solid. The filtrate was concentrated and chromatographed on silica gel (60-230 mesh) eluting with 3:1 hexanes/ethyl acetate. Product-rich fractions were concentrated and recrystallized from isopropyl ether yielding an additional 82 g of solid. The total yield of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol was 1080 g (58%): 1H NMR (400 MHz, CDCl3) 67 7.29-7.33 (m, 2H), 7.21-7.25 (m, 1 H 7.15-7.19 (m, 3H), 7.06-7.09 (m, 2H), 4.44 (bs, 1 H), 4.21 (dd, J=2.6, 11.3 Hz, 1 H) 3.97 (dd, J=4.5, 11.3 Hz, 1 H), 2.68 (dd, J=6.5, 13.8 Hz, 1 H), 2.51 (dd, J=9.1, 13.8 Hz,1 H), 2.18-2.23 (m, 1 H), 1.85 (d, J=4.3 Hz, 1 H); IR 3274 (br), 3181 (br), 1598, 1573, 1493, 1480, 1410, 1219, 1070, 1052, 1023, 859, 700 cm1; mp 143.5-144.0° C.
Reaction SMILES: S[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[CH:6]=2)[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Sc1cc2ccccc2s1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCN(c3cc4ccccc4s3)CC2)cc1
Yield: 46.5 %

Procedure:
To a solution of 2-mercaptobenzothiophene (1.8 g, 10.8 mmol) in toluene under nitrogen was added N-benzylpiperazine (1.88 ml, 10.8 mmol) and the mixture heated at reflux for 1.5 h. Left to cool, concentrated in vacuo and product recrystallised from diethyl ether-hexane to yield the title compound (1.55 g), m.p. 160°-161° C.
Reaction SMILES: CC1C=CC2C(=C3C(=CC=2)C=CC(C)=N3)N=1.CC(C)([O-])C.[Na+].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([SH:36])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[Mg].[NH2:38][C:39]1[CH:44]=[CH:43][C:42](I)=[CH:41][N:40]=1>[Cu]I.C1(C)C=CC=CC=1>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([S:36][C:42]2[CH:41]=[N:40][C:39]([NH2:38])=[CH:44][CH:43]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Reactant: Nc1ccc(I)cn1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: Cc1ccc2ccc3ccc(C)nc3c2n1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(N)nc2)CC1
Temperature: 110 °C
Reaction time: 24 h
Yield: 81.4 %

Procedure:
Add dry toluene (6.06 mL) to a mixture of 2,9-dimethyl-1,10-phenanthroline (76.52 mg), copper(I) iodide (69.27 mg), sodium tert-butoxide (475.59 mg), 4-mercapto-piperidine-1-carboxylic acid tert-butyl ester (583.5 mg), magnesium (49.10 mg) and 2-amino-5-iodopyridine (550 mg). Bubble nitrogen into the mixture with ultrasound and stir the suspension at 110° C. in a sealed tube for 24 h. Cool and filter through celite. Wash with toluene and remove the solvent under vacuum. Add hexane/EA (1/1) and filter through a celite/silica gel pad, washing twice with hexane/EA (1/1) and then EA. Remove the solvent under vacuum. Purify by silica gel column chromatography eluting with hexane/EA (50-75%) to afford 630 mg of the title compound. MS (ES+): m/z=310 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[F:31][C:32]([F:41])([F:40])[CH:33]1[CH2:38][NH:37][C:36](=[O:39])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+].OC1C=CC=CC=1C=NO>C(#N)C.[Cu-]=O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([N:37]3[CH2:38][CH:33]([C:32]([F:40])([F:41])[F:31])[CH2:34][CH2:35][C:36]3=[O:39])[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: O=C1CCC(C(F)(F)F)CN1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N3CC(C(F)(F)F)CCC3=O)c21
Temperature: 200 °C

Procedure:
Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was suspended in 2.5 ml of absolute acetonitrile, and 806 mg (4.82 mmol) of 5-(trifluoromethyl)piperidin-2-one, 157 mg (0.48 mmol) of caesium carbonate, 7 mg (0.05 mmol) of copper(I) oxide and 26 mg (0.19 mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture was heated in the microwave for 1 h at 200° C. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water, gradient 20:80→100:0). 15 mg (11% of theor.) of the target compound was obtained.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:38])[CH2:11][CH:12]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=1)[N:13]1[C:17](=[O:18])[C:16]2=[CH:19][C:20]([N+:23]([O-])=O)=[CH:21][CH:22]=[C:15]2[C:14]1=[O:26])C1C=CC=CC=1.C(OCC)(=O)C>C(OCC)(=O)C.CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[NH2:23][C:20]1[CH:19]=[C:16]2[C:17](=[O:18])[N:13]([CH:12]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=3)[CH2:11][C:10]([NH:9][OH:8])=[O:38])[C:14](=[O:26])[C:15]2=[CH:22][CH:21]=1
Reactant: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)ccc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccc(N)cc3C2=O)ccc1OC
Yield: 102 %

Procedure:
A mixture of N-Benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitrophthalimido)propionamide (2.3 g, 4.42 mmol) and Pd(OH)2/C (600 mg) in ethyl acetate/methanol/tetrahydrofuran (150 mL each) was shaken under hydrogen. After 24 hours the suspension was filtered through a pad of Celite, and then was washed with methanol (30 mL) and methylene chloride (30 mL). The filtrate was concentrated in vacuo to give an oil. The oil was stirred with ethyl acetate (10 mL) to afford 3-(4-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide as a yellow solid (1.8 g, 100% yield): mp, 193.0-195.0° C.; 1H NMR (DMSO-d6) δ1.31 (t, J=6.9 Hz, 3H, CH3), 3.05 (d, J=7.9 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 3.96 (q, J=7.0 Hz, 2H, CH2), 5.57 (t, J=7.9 Hz, 1H, NCH), 6.47 (br s, 2H, NH2), 6.77 (dd, J=2.0, 8.3 Hz, 1H, Ar), 6.83-6.88 (m, 3H, Ar), 6.99 (br s, 1H, Ar), 7.45 (d, J=8.3 Hz, 1H, Ar), 8.78 (br s, 1H, OH), 10.55 (1H, NH); 13C NMR (DMSO-d6) δ14.69, 34.51, 49.75, 55.45, 63.73, 106.82, 111.74, 112.38, 116.32, 116.73, 119.60, 124.89, 131.85, 134.18, 147.62, 148.42, 155.00, 166.111, 167.70, 168.00; Anal Calcd for C20H21N3O6: C, 60.14; H, 5.30; N, 10.52. Found: C, 60.00; H, 5.34; N, 10.30.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][OH:21])[C:10]=2[C:9]2[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=2[S:7]1)=[O:5])[CH3:2].[OH-].[K+].I[CH3:31]>CS(C)=O>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][CH2:20][O:21][CH3:31])[C:10]=2[C:9]2[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=2[S:7]1)=[O:5])[CH3:27]
Reactant: CI
Reactant: CCN(CC)C(=O)C1Sc2ccccc2-c2c1c1ccccc1n2CCO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCN(CC)C(=O)C1Sc2ccccc2-c2c1c1ccccc1n2CCOC
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a stirred solution of intermediate iv (from the synthesis described in Example 15) (60 mg, 0.158 mmol) in anhydrous DMSO 3 ml was added potassium hydroxide (84 mg, 1.58 mmol) and iodomethane (1.58 mmol, 0.12 ml) at room temperature. The mixture was then stirred under nitrogen for 30 minutes. The reaction was poured onto water 50 ml, extracted with dichloromethane 2×20 ml, washed with brine 2×20 ml. The organic was dried (MgSO4) and removed in vacuo. The residue was recrystallised from ethylacetate/hexane. The product was filtered and dried under vacuum to give a yellow solid 34 mg. Yield: 55%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[N:8]=[C:7]([Cl:13])[N:6]=[CH:5]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.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>[Cl:13][C:7]1[N:6]=[CH:5][C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=[C:2]([C:18]3[CH:17]=[C:16]([O:15][CH3:14])[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=3)[CH:3]=2)[N:8]=1
Reactant: Clc1ncc2cc(Br)cc(Cl)c2n1
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)cc(-c2cc(Cl)c3nc(Cl)ncc3c2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 41.2 %

Procedure:
A mixture of 6-bromo-2,8-dichloroquinazoline (4.0 g, 14.5 mmol), 3,5-dimethoxyphenylboronic acid (4.23 g, 16.0 mmol), cesium carbonate (9.42 g, 29.0 mmol) and Pd(PPh3)2Cl2 (220 mg, 0.70 mmol) in THF (200 mL) and water (10 mL) was degassed with nitrogen three times, and stirred at 80° C. for 5 hours. The reaction mixture was cooled to room temperature, directly concentrated and purified by silica gel chromatography (petroleum ether: dichloromethane=2:1˜1:1) to get the title compound as a yellow solid (2.0 g, 41%). MS (ES+) C16H12Cl2N2O2 requires: 334, 336, found: 335, 337 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:32])[CH3:31])[CH2:26][CH2:25]2)[CH:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)C.CC1CCC(NC2CCN(C(=O)C)CC2)CC1.C(OC(=O)CCSC1SC(N)=NC=1)C>>[C:30]([N:27]1[CH2:26][CH2:25][CH:24]([N:16]([C@H:17]2[CH2:18][CH2:19][C@H:20]([CH3:23])[CH2:21][CH2:22]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:9][N:10]=2)[CH2:29][CH2:28]1)(=[O:32])[CH3:31]
Reactant: CCOC(=O)CCSc1cnc(NC(=O)N(C2CCC(C)CC2)C2CCN(C(C)=O)CC2)s1
Agent: CC(=O)N1CCC(NC2CCC(C)CC2)CC1
Agent: CCOC(=O)CCSc1cnc(N)s1
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
3-{2-[3-(1-Acetyl-piperidin-4-yl)-3-(4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester prepared as described in general procedures (A) and (B) using 1-[4-(4-methyl-cyclohexylamino)-piperidin-1-yl]-ethanone and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:21]=[N:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[NH2:29][CH:30]1[CH2:34][CH2:33][O:32][CH2:31]1>>[O:32]1[CH2:33][CH2:34][CH:30]([NH:29][C:15]([C:14]2[CH:18]=[CH:19][N:20]=[CH:21][C:13]=2[NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[N:25][CH:24]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])=[O:17])[CH2:31]1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Reactant: NC1CCOC1
Product: O=C(NC1CCOC1)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Yield: 96 %

Procedure:
According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with 3-aminotetrahydro-furan, providing the title compound as yellow solid (96%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:14]([N:15]2[C:24](=[O:25])[C:23]3[C:18](=[C:19]4[CH:40]=[CH:39][CH:38]=[CH:37][C:20]4=[C:21]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([C:33](OC)=[O:34])=[N:31][CH:32]=4)[CH:22]=3)[N:17]=[CH:16]2)[CH2:13][CH2:12][O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].[Cl-].[NH4+].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(O)C.C(Cl)(Cl)Cl>[Si:1]([O:8][C@@H:9]1[C@@H:14]([N:15]2[C:24](=[O:25])[C:23]3[C:18](=[C:19]4[CH:40]=[CH:39][CH:38]=[CH:37][C:20]4=[C:21]([CH2:26][C:27]4[CH:32]=[N:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=4)[CH:22]=3)[N:17]=[CH:16]2)[CH2:13][CH2:12][O:11][CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O[Si](C)(C)C(C)(C)C)cnc3c3ccccc23)cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)O[C@H]1COCC[C@@H]1n1cnc2c(cc(Cc3ccc(CO)nc3)c3ccccc32)c1=O
Reaction time: 15 h

Procedure:
To a solution of methyl 5-{[3-((3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydro-2H-pyran-4-yl)-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl]methyl}pyridine-2-carboxylate (see Example 20, 0.250 g, 0.447 mmol) in 5 mL of ethanol was added sodium borohydride (0.034 g, 0.89 mmol). After 15 h, additional sodium borohydride (0.050 g, 1.32 mmol) was added. After 24 h, the mixture was treated with saturated aqueous ammonium chloride and extracted 2× with dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. To a solution of the residue in 3 mL of chloroform was added 2,3-dichloro-5,6-dicyanobenzoquinone (0.101 g, 0.447 mmol). After 15 min, the mixture was concentrated in vacuo and the residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane to provide 3-((3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydro-2H-pyran-4-yl)-6-{[6-(hydroxymethyl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 532.0 for [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[CH2:43](Br)[CH:44]=[CH2:45]>CCOCC>[CH2:45]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][O:27][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:35]([CH3:37])[CH3:36])[CH:44]=[CH2:43]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO[Si](C(C)C)(C(C)C)C(C)C)[nH]c2c1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccccc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-(2-{[(triisopropylsilyl)oxy]methyl}phenyl)-1H-indole-6-carboxylate in DMF (0.13 M) NaH (2 eq.) was added. After 20 min. allyl bromide (1.5 eq.) was added and the mixture stirred at RT for 2 h, diluted with Et2O, washed with sat aq. NH4Cl and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was subjected to flash chromatography (PE:EtOAc, 10:1). After evaporation of the solvents the product was obtained as yellow solid (67%).