Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH3:15])=[CH:10][CH:9]=1>[I-].[K+].CC(C)=O>[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:25][CH:24]=2)[CH3:15])=[CH:10][CH:9]=1
Reactant: CC(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(C)(c2ccc(O)cc2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
Methyl bromoacetate (0.48 mL, 5 mmol) was added dropwise to an acetone solution (10 mL) including 1,1,1-tris(4-hydroxyphenyl)ethane (1.53 g, 5 mmol) potassium carbonate (0.79 g, 5 mmol) and potassium iodide (16 mg, 0.1 mmol). The addition was done at room temperature under argon. The mixture was refluxed for 24 h, and then it was cooled to room temperature and extracted with ethyl acetate. The combined organic layer was washed with 3% aqueous NaHCO3, a saturated brine solution, dried (Na2SO4) and then evaporated to dryness to give 1.61 g (85% yield) of the desired compound as a colorless semisolid. 1H-NMR (300 MHz, d6-DMSO): 1.96 [s, 3H, —CH3], 3.67 [s, 3H, —OCH3], 4.71 [s, 4H, —OCH2—], 6.57-6.64 [m, 4H, Ar—H], 6.72-6.81 [m, 6H, Ar—H], 6.85-6.92 [m, 2H, Ar—H].
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[CH:9][C:10]=1[C:11]#[N:12])C=C.CN1C(=O)[CH2:24][CH2:23][CH2:22]1>>[CH2:24]([C:6]1[C:5]([OH:4])=[C:10]([C:11]#[N:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:23]=[CH2:22]
Reactant: C=CCOc1cc(NC(=O)C(C)(C)C)ccc1C#N
Reactant: CN1CCCC1=O
Product: C=CCc1c(NC(=O)C(C)(C)C)ccc(C#N)c1O
Temperature: 25 °C

Procedure:
A solution of compound 10C (1.5 g, 5.8 mmol) in NMP (7 mL) was heated to 220° C. for 3 h. After cooling to rt, the reaction mixture was poured into ice/water, and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was chromatographed (silica gel) eluting with 0% to 50% EtOAc/hexane to furnish the title compound (0.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15](B4OC(C)(C)C(C)(C)O4)[CH:16]=[C:11]3[CH:10]=[CH:9]2)=[CH:5][CH:4]=1.Br[C:29]1[CH:42]=[CH:41][C:32]([CH2:33][N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)Cl.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>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:42]4[CH:29]=[CH:30][CH:31]=[C:32]([CH2:33][N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]5)[CH:41]=4)[CH:16]=[C:11]3[CH:10]=[CH:9]2)=[CH:26][CH:27]=1
Reactant: CN1CCN(Cc2ccc(Br)cc2)CC1
Reactant: COc1ccc(Cn2ccc3cc(B4OC(C)(C)C(C)(C)O4)cnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccc(Cn2ccc3cc(-c4cccc(CN5CCN(C)CC5)c4)cnc32)cc1
Temperature: 90 °C

Procedure:
A stirred solution of 1-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (147PG) (50 mg, 0.137 mmol) and 1-(4-bromobenzyl)-4-methylpiperazine (121) (37 mg, 0.137 mmol, 1.1 eq) in DME (10 mL) was degassed and purged with N2 for 10 min and Cs2CO3 (2.0 eq) was added and the reaction mixture purged and degassed again. To this reaction mixture was added Pd(PPh3)4 (0.04 eq) and the resulting reaction was heated at 90° C. for 12 hrs in sealed tube condition. After completion of the reaction the contents were was cooled and diluted with CH2Cl2 and filtered through Celite bed. The CH2Cl2 layer was completely distilled off to get the crude product. The crude was passed through 100-200 mesh silica gel, eluting the pure compound 1-(4-methoxybenzyl)-5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine 151 obtained with 5% MeOH in CH2Cl2 as an off-white coloured solid in 30 mg quantity.
Reaction SMILES: [CH2:1]([C:3]1([C:16]([O-:18])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)[CH3:2].[CH2:19](I)[CH3:20]>>[CH2:1]([C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:4]1)[CH3:2]
Reactant: CCI
Reactant: CCC1(C(=O)[O-])CCCN(C(=O)OC(C)(C)C)C1
Product: CCOC(=O)C1(CC)CCCN(C(=O)OC(C)(C)C)C1

Procedure:
The target was synthesized as in Production Example 11(1), using 1-tert-butyl 3-ethylpiperidine-1,3-dicarboxylate and ethyl iodide as the raw material.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[NH:4][C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[C:12](OC(=O)C)(=O)[CH3:13]>>[CH3:9][N:6]1[C:7]2[N:8]=[C:12]([CH3:13])[NH:1][C:2]=2[C:3](=[O:11])[NH:4][C:5]1=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(N)c(N)c(=O)[nH]c1=O
Product: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2C
Temperature: 25 °C

Procedure:
A solution of 5,6-diamino-1-methyluracil (2.5 g) in acetic anhydride (25 ml) was heated at reflux for 2 hours and then the acetic anhydride was evaporated under reduced pressure. The residue was dissolved in 10% aqueous sodium hydroxide solution (50 ml) and heated at reflux for 2 hours. After cooling to room temperature, the mixture was acidified to pH 4 by addition of concentrated hydrochloric acid. The precipitate was filtered, washed with water (15 ml), rinsed with acetone (15 ml) and dried under vacuum to provide 3,8-dimethylxanthine (1.8 g).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29]([C:33]([O-:35])=[O:34])[N:28]=[CH:27]4)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:36])[CH:19]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][Cl:46]>CN(C=O)C>[C:1]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[N:22]=[C:21]([NH:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29]([C:33]([O:35][C:9]([CH3:13])([CH3:10])[CH3:8])=[O:34])[N:28]=[CH:27]4)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:36][CH2:44][CH2:45][Cl:46])[CH:19]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c3cc(O)ccc3n2)c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3cc(OCCCl)ccc3n2)c1
Temperature: 85 °C
Yield: 111.8 %

Procedure:
To a mixture of 5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (1.50 g, 2.79 mmol) and potassium carbonate (1.64 g, 11.8 mmol) in anhydrous DMF (5 mL) was added 1-bromo-2-chloroethane (1.6 g, 11.2 mmol) The subsequent mixture was heated at 85° C. for 4 h, upon which it was allowed to cool to RT and it was poured onto ice-water. A solid was precipitated out, which collected via filtration and dried under vacuum. The solid was purified via silica gel column chromatography to give tert-butyl 5-(2-(3-butyramidophenyl)-6-(2-chloroethoxy)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.94 g, 1.56 mmol, 60%). HPLC retention time 7.479.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:26][CH2:27][CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[OH:29].C(N(CC)CC)C>O1CCCC1>[OH:29][CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:27][NH:26][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([CH:18]=1)[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Reactant: NCC(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCNCC(O)c2ccccc2)ccc1Cl
Temperature: 80 °C
Yield: 34.8 %

Procedure:
2-Chloro-5-(2-chloroethyl)amino-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)benzamide from Example 63 (0.1 g), 2-amino-1-phenylethanol (0.539 g) and triethylamine (0.5 ml) were dissolved in tetrahydrofuran (3 ml) and heated at 80° C. for 60 hours in a sealed tube. The reaction mixture was concentrated under reduced pressure, the residue was suspended in aqueous sodium hydrogen carbonate (30 ml), the product was extracted into ethyl acetate (3×30 ml), dried over magnesium sulphate filtered and concentrated under reduced pressure. Purification by NPHPLC eluting with 0 to 25% ethanol in dichloromethane gave title compound as a white solid (0.044 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12]Br.[CH3:14][Si:15]([CH3:31])([CH3:30])[CH2:16][CH2:17][O:18][CH2:19][N:20]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[CH2:22][C:21]1=O.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)C>CN(C=O)C>[N+:9]([C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[CH2:2][C:22]1([C:23]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:20]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:31])([CH3:30])[CH3:14])[CH2:21]1)[CH2:12]2)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCN1CC2(Cc3ccc([N+](=O)[O-])cc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 1,2-bis(bromomethyl)-4-nitrobenzene (40.9 g, 132 mmol, described in Intermediate 2) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (31.5 g, 119 mmol, described in Intermediate 1) in DMF (2 L) was added cesium carbonate (129 g, 397 mmol), portionwise, over 5 min. After 18 h, acetic acid (7.6 mL) was added and the mixture was concentrated to a volume of about 500 mL, then partitioned between EtOAc (1.5 L) and H2O (1 L). The organic layer was washed with H2O (1 L), then brine (500 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=412 (M+1).
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][OH:5].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>C(O)C>[N:6]1([CH2:1][C@@H:2]([OH:3])[CH2:4][OH:5])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: C1COCCN1
Reactant: OC[C@H]1CO1
Solvent: CCO
Product: OC[C@H](O)CN1CCOCC1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
A solution of (S)-glycidol (1.00 mL, 15.0 mmol) and morpholine (1.96 mL, 22.5 mmol, 2.5 equiv.) in abs. ethanol was heated in a microwave for 4 min. at 140 0° C., cooled to room temperature and concentrated at 70° C. under a 12 mbar vacuum to afford (2R)-3-(4-morpholinyl)-1,2-propanediol (2.47 g, 102%): 1H NMR (CDCl3) δ 2.37 (dd J=4.0, 12.4 Hz, 1H), 2.40-2.48 (m, 2H), 2.57 (dd, J=9.6, 12.4 Hz, 1H), 2.62-2.71 (m, 2H), 3.50 (dd, J=4.2, 11.4 Hz, 1H), 3.65-3.79 (m, 5H), 3.79-3.88 (m, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:37])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[C:30]=2[CH3:36])[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:35][C:31]1[C:30]([CH3:36])=[C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:37])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:16])([F:15])[F:17])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:34]=[CH:33][N:32]=1
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)c1C

Procedure:
The title compound was prepared from (2-{3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M127) (0.27 g, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (100 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Br[CH:27]1[CH2:32][CH2:31][O:30][C:28]1=[O:29]>CN(C)C=O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][N:8]([CH:27]3[CH2:32][CH2:31][O:30][C:28]3=[O:29])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C1OCCC1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCOC1=O
Temperature: 0 °C

Procedure:
4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (1.0 g) was added to a mixture of sodium hydride (0.158 g of a 60% dispersion in mineral oil) in dimethyl formamide (70 ml) with stirring under nitrogen at 0° C. The mixture was stirred at 0° C. for 1 hour and then α-bromo-γ-butyrolactone (0.60 g) in dimethylformamide (6 ml) was added dropwise with stirring at 0° C. The mixture was stirred at ambient temperature for 18 hours and then quenched with water (100 ml). The mixture was extracted with ethyl acetate. The combined extracts were dried and evaporated to give 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-butyrolactone as an oil which was used directly in b).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:11]=1[N+:24]([O-:26])=[O:25].[CH2:27]([CH:30]([NH2:34])[CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:34][CH:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[C:11]=1[N+:24]([O-:26])=[O:25]
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(Cl)c1
Reactant: CCCC(N)CCC
Product: CCCC(CCC)Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-]
Yield: 67.8 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester(0.50 g, 1.21 mmol), prepared substantially as described in Part C of Example 19a, and 1-propyl-butylamine (0.28 g, 2.42 mmol) were treated in the same manner as in Part C of Example 19a to produce 0.31 g (69%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-propyl-butyl)-amine: MS (AP) m/z 377.9 [(M+H)+, 100].
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15](=[O:17])[CH3:16].[N+:18]([O-])([OH:20])=[O:19]>O>[F:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([N+:18]([O-:20])=[O:19])=[CH:9][C:8]=1[C:15](=[O:17])[CH3:16]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(C)=O)c(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(F)c(C(C)=O)cc1[N+](=O)[O-]
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
Sulfuric acid (157 g, 85.2 ml, 1.6 mol) was cooled to −20° C. and 1-(2-fluoro-4-methoxyphenyl)ethanone (25 g, 149 mmol) was added portionwise in a manner that the temperature was kept below −15° C. Thereafter, a solution of sulfuric acid (64.4 g, 35 ml, 657 mmol) and fumic nitric acid (18.7 g, 12.4 ml, 297 mmol) was added dropwise within 20 minutes keeping the temperature below −15° C. After completion of the addition the viscous reaction mixture was stirred for additional 20 minutes at −15° C. For the workup, the reaction mixture was poured into a mixture of ice and water (400 ml) and stirring was continued for 10 minutes. The off-white suspension was filtrated and washed several times with water. The light yellow solid was dried at 45° C. before it was crystallized from a mixture of ethyl acetate and heptane (200 ml-600 ml, addition of charcoal). The 1-(2-fluoro-4-methoxy-5-nitro-phenyl)-ethanone (26.1 g, 82% yield) was obtained as pale yellow crystals. MS (ISP): m/z=214.2 [M+H]+. In addition, the regioisomer 1-(2-fluoro-4-methoxy-3-nitro-phenyl)-ethanone (0.6 g, 2% yield) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=O)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][C:31](=[O:34])[CH2:32][OH:33])[NH:26][C:25](=[O:35])[CH2:24]2>>[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][C:31](=[O:34])[CH2:32][OH:33])[NH:26][C:25](=[O:35])[C:24]2=[CH:18][C:9]1[NH:10][C:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]=2[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(CO)Nc1cc2c(cc1F)CC(=O)N2
Reactant: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Product: O=C(CO)Nc1cc2c(cc1F)C(=Cc1[nH]c3c(c1-c1ccc(F)cc1)C(=O)NCC3)C(=O)N2
Yield: 80.6 %

Procedure:
The title compound was prepared under the same conditions as described in Example 46 with 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide as starting materials to give N-{5-fluoro-3-[3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide (72 mg, 80.6%), as a red solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:13][C@H:12]1[CH2:22][OH:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:25].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.Cl>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:13][C@H:12]1[C:22]([OH:25])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1C[C@H](C2CCCCC2)C[C@H]1CO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1C[C@@H](C2CCCCC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To a solution of (2S-trans)-1-[(benzyloxy)carbonyl]-4-cyclohexyl-2-pyrrolidinemethanol (0.65 g) in dimethylformamide (10 ml) was added pyridinium dichromate (2.1 g). The mixture was stirred at room temperature for 16 hours and poured into crushed ice and hydrochloric acid (25 ml). Extraction with ethyl acetate followed by solvent evaporation yielded 0.4 g of (trans)-1-[(benzyloxy)carbonyl]-4-cyclohexyl-L-proline as a thick oil. The compound can be deprotected using catalytic hydrogenation as described in Method V.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9]O)=[C:4]([F:11])[CH:3]=1.[Br:12]P(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][Br:12])=[C:4]([F:11])[CH:3]=1
Reactant: OCc1c(F)cc(Br)cc1F
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Fc1cc(Br)cc(F)c1CBr
Temperature: 25 °C
Yield: 61.1 %

Procedure:
To a solution of (4-bromo-2,6-difluorophenyl)methanol (2 g, 8.97 mmol) in DCM (80 mL) was added tribromophosphine (2.91 g, 10.76 mmol) at 0° C. The resulting mixture was stirred at rt. After LCMS analysis showed the starting material had disappeared, the mixture was washed with aq NaHCO3 (40 mL) and brine (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=5/1) to yield a colorless oil of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (1.6 g, 5.48 mmol, 61.2% yield): 1H NMR (400 MHz, CD3OD) δ 7.12 (d, J=6.8 Hz, 2H), 4.47 (s, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C@H:38]1[OH:50]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@@H:37]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:39][C@H:38]4[OH:50])=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c10) and tert-butyl(3R*,4R*)-4-amino-3-hydroxy-piperidine-1-carboxylate (example C2) the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[N:7]=1.[C:12](OC(=O)C)(=[O:14])C.C(O)=O>O1CCCC1>[CH3:1][N:2]([C:3]1[S:4][C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[N:7]=1)[CH:12]=[O:14]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1nc(C)c(C(C)=O)s1
Solvent: O=CO
Solvent: C1CCOC1
Product: CC(=O)c1sc(N(C)C=O)nc1C
Reaction time: 2 h

Procedure:
To a solution of 2-methylamino-4-methyl-5-acetylthiazole (35 g) in tetrahydrofuran (700 ml) were added a mixture of acetic anhydride (94.5 ml) and formic acid (37.7 ml) at ambient temperature and the mixture was stirred for two hours. The reaction mixture was evaporated in vacuo. The residue was added to water and the resultant precipitate was collected by filtration and dried over phosphorus pentoxide to give 2-(N-methylformamido)-4-methyl-5-acetylthiazole (39.59 g).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[N:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[C:7]=1[C:8]#[N:9]>ClCCl.C(OCC)(=O)C>[Cl:5][C:6]1[N:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: COc1ccc(-c2ccnc(Cl)c2C#N)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1c(-c2ccc(O)cc2)ccnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A 1.0 M dichloromethane solution of boron tribromide (12.26 mL, 12.26 mmol) was added to a solution of 2-chloro-4-(4-methoxyphenyl)nicotinonitrile (300 mg, 1.226 mmol) in dichloromethane (10 mL). The mixture was stirred at room temperature for 2 h, diluted with ethyl acetate (50 mL), and carefully quenched with saturated sodium bicarbonate (20 mL). The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with water (30 mL), brine (30 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 10-50% ethyl acetate in hexanes, gave 2-chloro-4-(4-hydroxyphenyl)nicotinonitrile as a brown solid (50 mg, 18% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.55 (1H, δ, J=5.22 Hz), 7.49-7.62 (2H, m), 7.38 (1H, δ, J=5.22 Hz), 6.94-7.05 (2H, m); MS (ES+) m/z: 231 (M+H); LC retention time: 2.841 min (analytical HPLC Method A).
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:17][C:18]1[C:25]([F:26])=[CH:24][C:21]([C:22]#[N:23])=[C:20](F)[CH:19]=1>CN(C)C=O>[Cl:17][C:18]1[C:25]([F:26])=[CH:24][C:21]([C:22]#[N:23])=[C:20]([CH:19]=1)[O:1][CH:2]([CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9]
Reactant: CCCC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: N#Cc1cc(F)c(Cl)cc1F
Solvent: CN(C)C=O
Product: CCCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)c(F)cc1C#N

Procedure:
The subtitle compound was prepared according to the method of Example 3 step (b) using (3-hydroxyhexyl)methylcarbamic acid, 1,1-dimethylethyl ester and 4-chloro-2,5-difluorobenzonitrile in N,N-dimethylformamide.