Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][C:14]#N)[N:12]=2)=[CH:4][CH:3]=1.COCCO.[OH-:22].[K+].[OH2:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][C:14]([OH:24])=[O:22])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O
Reactant: [OH-]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CC#N
Agent: [K+]
Solvent: COCCO
Product: Cc1oc(-c2ccc(Br)cc2)nc1CC(=O)O
Yield: 60 %

Procedure:
The crude 2-(4-bromophenyl-4-(cyanomethyl)-5-methyloxazole (assume 0.22 mol) was combined with 2-methoxyethanol (630 mL) and 85% solid KOH (74.6 g, 1.33 mol) in water (360 mL) was added to the reaction. The mixture was heated to reflux for 3 h, cooled, quenched with 2 M HCl (500 mL), and extracted with CH2Cl2. The organic layer was dried (MgSO4), and the solvent removed in vacuo, using toluene to azeotropically remove residual 2-methoxyethanol. The crude product (57.3 g) was recrystallized from toluene (450 mL) to give 39.8 g (60%) of 2-(4-bromophenyl)-5-methyl-4-oxazoleacetic acid as an off-white powder: Rf=0.23 in 10% MeOH/CH2Cl2; 1H NMR (500 MHz, CDCl3) 9.00 (br s, 1H), 7.85-7.83 (m, 2H), 7.58-7.56 (m, 2H), 3.62 (s, 3H), 2.36 (s, 3H); 13C (125 MHz, CDCl3) 173.8, 159.0, 146.2, 132.0, 129.1, 127.6, 125.9, 124.7, 31.5, 10.2; IR (CHCl3) 2923, 1699, 1641, 1481, 1428, 1306, 1234, 1010, 829, 727 cm−1; UV (EtOH)max 288 nm (19626).
Reaction SMILES: C[O-].[Na+].[C:4]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][CH:8]=1)(=[O:6])[CH3:5].[CH3:16][O:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.CO>CN(C)C=O>[CH3:16][O:17][C:18]1[O:22][C:21](/[CH:23]=[CH:5]/[C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][CH:8]=2)=[O:6])=[CH:20][CH:19]=1
Reactant: COc1ccc(C=O)o1
Reactant: CC(=O)c1ccc(C(N)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(/C=C/C(=O)c2ccc(C(N)=O)cc2)o1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (in portions) was added, over a time interval of about three minutes, to 4-acetyl-benzamide (1.38 g, 8.5 mmol) and 5-methoxy-furan-2-carbaldehyde (1.31 g, 10.6 mmol) in a 1:1 mixture of methanol and dimethylformamide (16 mL). The resulting solution was placed under N2 and stirred overnight at 45° C. The reaction mixture was then evaporated to dryness under vacuum, followed by the addition of water and brine (100 mL) to the resulting residue. The aqueous solution was extracted with ethyl acetate (125 mL×3) and the combined organic layers were washed with brine (100 mL) and dried over MgSO4. The crude reaction mixture of 4-[(E)-3-(5-methoxy-furan-2-yl)-acryloyl]-benzamide and unreacted 4-acetyl acetamide is used without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([CH:15]2[CH2:17][CH2:16]2)[NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.[Cl:18][C:19]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>CN(C=O)C.Cl[Pd]Cl>[Cl:18][C:19]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([CH:8]([CH:15]3[CH2:17][CH2:16]3)[NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCS(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1
Yield: 84.9 %

Procedure:
A mixture of N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (5 g, 15.66 mmol), 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (as prepared in Example 1, step 1; 4.13 g, 15.66 mmol), sodium carbonate (15.66 mL, 31.3 mmol) and PdCl2 (dppf).CH2Cl2 adduct (0.320 g, 0.392 mmol) in DMF (100 mL) was heated to 100° C. for 25 min. After concentration, the residue was dissolved into CH2Cl2 and filtered through a pad of Na2SO4. The solution was absorbed into celite and concentrated. The residue was purified by flash column (ethyl acetate/heptane, 30%-50%-80%, v/v) and yielded the title compound as a colorless solid (5.0 g). Chiral separation by chiral HPLC (Chiralpak AD-H using Supercritical fluid chromatography. 25% Methanol at 65 grams per minute with supercritical CO2) afforded enantiomer 1 (S)—N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (retention time=3 min), and enantiomer 2 (R)—N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (retention time=4 min). ESI-MS m/z: 376.2 [M+H]+, 1H NMR (400 MHz, CDCl3): δ 0.37-0.40 (m, 1H), 0.51-0.55 (m, 1H), 0.57-0.68 (m, 1H), 0.70-0.77 (m, 1H), 1.15-1.27 (m, 3H), 2.70-2.88 (m, 2H), 3.85 (dd, J=5 Hz, 9 Hz, 1H), 4.68 (d, J=5 Hz, 1H), 7.53 (dd, J=1.5 Hz, 8 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.73 (d, J=8 Hz, 1H), 7.80 (t, J=2 Hz, 1H), 8.67 (d, J=2 Hz, 1H), 8.72 (d, J=2 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=3)[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccc(F)c(C)c3)oc2C)c1)C(=O)O
Yield: 48 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole, the title compound was obtained in 48% yield as a colourless solid. MS: (M+H)+ 437.3.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](O)=[O:10])[CH:5]=[CH:4][N:3]=[N:2]1.B.C1COCC1.CO.O>C1COCC1>[N:1]1([C:6]2[CH:7]=[C:8]([CH2:9][OH:10])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=C(O)c1cccc(-n2ccnn2)c1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OCc1cccc(-n2ccnn2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cooled (0° C.) solution of the minor isomer 3-(1H-1,2,3-triazol-1-yl)benzoic acid (210 mg; 1.11 mmol) in anh. THF (3 ml) was treated dropwise with a BH3.THF (1.0 M in THF; 2.77 ml; 2.77 mmol), and this mixture was stirred at 0° C., under nitrogen, for 1 h, and then at rt for 17 h. The resulting reaction mixture was then cooled to 0° C., and treated successively with MeOH (10 ml) and water (10 ml). The organic solvents were removed under reduced pressure, and the resulting aq. layer was extracted with DCM (3×10 ml). The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded (3-(1H-1,2,3-triazol-1-yl)phenyl)methanol as a pale yellow solid. LC-MS (conditions A): tR=0.38 min.; [M+H]+: 176.18 g/mol.
Reaction SMILES: [CH2:1]([C@H:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][C@@H:6]([C:17]([OH:19])=[O:18])[NH:5]1)[CH2:2][CH3:3].C(N(CC)CC)C.[C:27](=[S:29])=[S:28].[CH3:30]I>CO>[CH2:1]([C@H:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][C@@H:6]([C:17]([OH:19])=[O:18])[N:5]1[C:27]([S:29][CH3:30])=[S:28])[CH2:2][CH3:3]
Reactant: CCC[C@@H]1N[C@H](C(=O)O)Cc2c1[nH]c1ccccc21
Reactant: S=C=S
Reactant: CI
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC[C@H]1c2[nH]c3ccccc3c2C[C@@H](C(=O)O)N1C(=S)SC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
(1RS,3RS)-cis-n-Propyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (450 mg) is dissolved in 80% methanol (10 ml), and thereto are added triethylamine (350 mg) and carbon disulfide (270 ml). The mixture is stirred at room temperature for 30 minutes, and methyl iodide (490 mg) is added to the mixture. The mixture is stirred at room temperature for 2 hours, and then distilled to remove the solvent. Water is added to the mixture, and the aqueous solution is acidified with 5% HCl, and extracted with ethyl acetate. The extract is washed with water, dried and then distilled to remove the solvent. The residue is treated with aqueous ethanol to give the title compound (350 mg, 59%) as pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1)=[O:6]
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Nc1ccc(Br)cc1C(=O)Nc1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 209.2 %

Procedure:
A mixture of 2-amino-5-bromo-benzoic acid (2 g, 9.26 mmol) and SOCl2 (4 mL) in toluene (20 mL) was stirred at 130° C. for 2 h. After being concentrated, the residue was dissolved in tetrahydrofuran (50 mL) and phenylamine was added dropwise at 0° C. Then the reaction mixture was heated to 90° C. for 4 h. The mixture was cooled to room temperature, quenched with saturated aqueous K2CO3 (20 mL) and extracted with ethyl acetate (50 mL*3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with silica gel column chromatograph (PE:EtOAc=4:1) to give 2-amino-5-bromo-N-phenylbenzamide (2.82 g, yield: 99%) as white solid. MS (M+H)+: 291/293.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C@:3]([OH:8])([CH3:7])[C:4]([OH:6])=[O:5].[N+](=[CH2:13])=[N-]>CCOCC>[F:1][C:2]([F:10])([F:9])[C@:3]([OH:8])([CH3:7])[C:4]([O:6][CH3:13])=[O:5]
Reactant: C=[N+]=[N-]
Reactant: C[C@](O)(C(=O)O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)[C@](C)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (3.0 g, 17.4 mmol) in 60 ml of ether was added a solution of diazomethane in ether until a yellow coloration remained. The reaction mixture was then stirred 30 min at room temperature and concentrated to dryness to afford the title compound. 1H NMR (400 MHz, acetone-d6): δ 5.67 (s, 1H), 3.85 (s, 3H), 1.57 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[S:24](=[O:38])(=[O:37])[NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[CH:31]=[CH:30]2)[C:17]([O:19][CH3:20])=[O:18]>>[Cl:8][C:7]1[C:2]([N:25]([CH2:26][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[N:32]([CH3:36])[CH:31]=[CH:30]3)[S:24]([C:23]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[CH3:13])(=[O:37])=[O:38])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(ccn3C)c2)c(C)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(ccn3C)c2)c2ncc(C(F)(F)F)cc2Cl)c(C)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 3-methyl-4-(N-((1-methyl-1H-indol-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 11).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(O)c1ccc2ccccc2c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cc(Cl)ccc2C1c1ccc2ccccc2c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Crude rac-6-chloro-3-hydroxy-3-naphthalen-2-yl-1,3-dihydro-indol-2-one (0.15 g, 0.48 mmol) (from Example 47a supra) was suspended in a mixture of triethylsilane (0.23 mL, 1.44 mmol) (Aldrich) and trifluoroacetic acid (0.83 g, 7.2 mmol) and heated in an 90° C. oil bath for 17 hours. After cooling to room temperature, mixture was diluted with ethyl acetate and treated with solid sodium carbonate (1 g). After stirring for 30 minutes, mixture was extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-naphthalen-2-yl-1,3-dihydro-indol-2-one as brown solid. (Yield 0.08 g, 56%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[F:17])=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.[B:24](OC)([O:27]C)[O:25]C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[F:17])=[C:4]([B:24]([OH:27])[OH:25])[CH:3]=1
Reactant: Fc1cc(Cl)ccc1COc1ccc(Cl)cc1I
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Product: OB(O)c1cc(Cl)ccc1OCc1ccc(Cl)cc1F

Procedure:
As for reaction 1, using 90.5 g 4-chloro-1-{[(4-chloro-2-fluorophenyl)methyl]oxy}-2-iodobenzene, 228 ml isopropylmagnesium chloride and 47.42 g trimethyl borate. Yield 66.8 g. NMR showed trace impurities. LCMS OK.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Cl:11][CH2:12][C:13](Cl)=[O:14]>C1COCC1>[Cl:11][CH2:12][C:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)=[O:14]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
2-Amino-5-nitropyridine (19) (4.0 g, 28.8 mmol) was dissolved in THF (300 mL). TEA (12.0 mL, 86.1 mmol) was added and the stirred mixture cooled to 0° C. Chloroacetyl chloride (7.0 mL, 87.9 mmol) was added dropwise. The stirred solution was allowed to warm to rt then stirred at this temperature for 1 hour. The mixture was heated at reflux for 1 hour. The solvent was evaporated in vacuo and the residue partitioned between DCM (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The layers were separated and the organic phase washed with saturated brine solution (50 mL), then separated, dried over MgSO4, filtered and concentrated in vacuo. Approximately half the crude product was purified by column chromatography (Biotage SP1) eluting with isohexane→30% EtOAc-isohexane, combining the crude material with this purified product. The combined material was triturated with EtOAc-isohexane to provide the title compound as a brown solid (3.6 g, 58%); Rf: 0.45 (3:1 isohexane-EtOAc).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.Cl.[CH2:17]([C:19]([OH:21])=[O:20])[CH3:18].[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)([O-:24])=[O:23]>>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[NH:8][C:7](=[O:12])[C:6]4[NH:13][CH:14]=[CH:15][C:5]=4[C:4]=3[CH:3]=2)(=[O:33])=[O:32])=[CH:29][CH:30]=1)([O-:24])=[O:23].[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18]
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: CCC(=O)O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(NS(=O)(=O)c3ccc([N+](=O)[O-])cc3)cc2c2cc[nH]c12
Yield: 5.5 %

Procedure:
This compound is prepared according to synthesis 43, from 60 mg (0.20 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 64) and 45 mg (0.21 mmol) of 4-nitro-benzenesulfonyl chloride. After purification by preparative LCMS, 5 mg (6%) of 8-(4-nitro-benzenesulfonylamino)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a light brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32]C)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:12][C:11]1=2)[CH3:2].Br.[C:36](O)(=O)C>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32])[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([C:20]([O:22][CH2:23][CH3:36])=[O:21])[CH:13]=[CH:12][C:11]1=2)[CH3:2]
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OC)C1CCCc2cc(C(=O)OC)ccc21
Reactant: CC(=O)O
Agent: Br
Product: CCOC(=O)CCCCN(CCc1ccccc1O)C1CCCc2cc(C(=O)OCC)ccc21
Temperature: 135 °C

Procedure:
8.7 g (18.6 mmol) of the compound from Example 2A were stirred in 90 ml of a 33% strength solution of hydrogen bromide in glacial acetic acid under reflux overnight. After addition of another 90 ml of hydrogen bromide solution, the mixture was stirred at a bath temperature of 135° C. for a further night. The mixture was then concentrated under reduced pressure, another 40 ml of the solution of hydrogen bromide in glacial acetic acid were added to the residue and the mixture was stirred at a bath temperature of 110° C. for another night. The mixture was then once more concentrated to dryness. The residue, which comprised 77% of the dicarboxylic acid compound 5-{(4-carboxybutyl) [2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid [LC-MS (Method 2): Rt=0.64 min; MS (ESIpos): m/z=412 [M+H]+], was subjected to incipient dissolution in 190 ml of ethanol, and 1.65 ml of thionyl chloride were added dropwise. The mixture was stirred at 70° C. overnight and then concentrated under reduced pressure. The residue (about 13 g) was taken up in ethyl acetate and washed twice with dilute aqueous sodium carbonate solution. The organic phase was dried over sodium sulphate and concentrated. The crude product (8.8 g) was purified by flash chromatography on silica gel using the mobile phase cyclohexane/ethyl acetate 5:1.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[NH:8][CH:7]=1.S(C)C>C1COCC1>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[NH:8][CH:7]=1
Reactant: CNC(=O)CC(c1ccccc1)c1c[nH]c2cccnc12
Solvent: CSC
Solvent: C1CCOC1
Product: CNCCC(c1ccccc1)c1c[nH]c2cccnc12
Temperature: 25 °C

Procedure:
To a RT solution of N-methyl-3-phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propionamide (25.3 mg, 0.091 mmol) in THF (5 mL) was added BH3.SMe2 (10 M in THF, 18 μL). The resulting mixture was refluxed for 2 h, cooled to RT, and quenched by addition of MeOH and HCl (concentrated, 3 drops). The mixture was then heated at reflux for 15 min, cooled to RT, concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH), affording N-Methyl-[3-phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propyl]-amine. MS M+H=266.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Br:23])=[C:20]([CH3:22])[CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:33][C:34](=O)[NH:35][C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]3=[O:48])=[CH:38][C:37]=2[F:49])=CC=1)([O-])=O>>[F:49][C:37]1[CH:38]=[C:39]([N:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]2=[O:48])[CH:40]=[CH:41][C:36]=1[NH:35][C:34]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Br:23])=[C:20]([CH3:22])[CH:21]=2)=[O:16])[CH2:9]1)=[O:33]
Reactant: Cc1cc(C(=O)NC[C@H]2CCNC2)sc1Br
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)NC[C@H]2CCN(C(=O)Nc3ccc(-n4ccccc4=O)cc3F)C2)sc1Br

Procedure:
57.3 Using general method H, 5-bromo-4-methyl-thiophene-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (R)-3-{[(5-bromo-4-methyl-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. White solid. MS 530.8 ([M−H]−)
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][C:21](Cl)=[O:22])[CH2:16][CH2:15]3)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29]([O:33][CH2:34][CH3:35])[N:28]=[C:27]([NH2:36])[CH:26]=1>N1C=CC=CC=1.C(OCC)(=O)C>[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29]([O:33][CH2:34][CH3:35])[N:28]=[C:27]([NH:36][C:21](=[O:22])[CH2:20][CH:17]2[CH2:18][CH2:19][N:14]([CH2:13][C:11]3[O:10][N:9]=[C:8]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:12]=3)[CH2:15][CH2:16]2)[CH:26]=1
Reactant: CCOc1nc(N)cc(N)c1C#N
Reactant: O=C(Cl)CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOc1nc(NC(=O)CC2CCN(Cc3cc(-c4ccccc4)no3)CC2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A mixture of the compound prepared in Example 59 (100 mg) and 4,6-diamino-2-ethoxynicotinonitrile (50 mg, prepared according to the preparation reported in Szczepankiewicz, B. G.; et al. J. Med. Chem. 2006, 49, 3563 and references therein) in pyridine (1.5 mL) was heated to 50° C. overnight and then 80° C. for six days. The mixture was cooled to room temperature, diluted with ethyl acetate and washed twice with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=4:1) to obtain the title compound (18 mg) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:20][C:21]1([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22]1>>[F:15][C:11]1([F:14])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]([C:16](=[O:18])[NH:20][C:21]2([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)[CH2:23][CH2:22]2)[CH2:10]1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)CC1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)C3CC(F)(F)CCN3C(=O)OC(C)(C)C)CC2)cc1
Yield: 69.4 %

Procedure:
The title compound (D68) (688 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 1-(tert-butoxycarbonyl)-4,4-difluoropiperidine-2-carboxylic acid (600 mg; described in WO2010148197) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (566.5 mg). Reaction time: 5 hrs
Reaction SMILES: [C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([O:38]C)=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[C:21]([O:26][CH3:27])[CH:22]=[CH:23][C:24]=3[N:25]=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].O.C1COCC1.O[Li].O.Cl>CCOC(C)=O>[C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([OH:38])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[C:21]([O:26][CH3:27])[CH:22]=[CH:23][C:24]=3[N:25]=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1nc3ccc(OC)cc3nc1O2
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2nc3c(nc2c1)O[C@@H]1C[C@@H](C(=O)O)N(C1)C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCC3
Temperature: 20 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A solution (0.1 M) of methyl (1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylate in a 1:1 mixture of H2O/THF was treated with LiOH.H2O (3 eq). The resulting mixture was stirred at 20° C. for 18 h, acidified with aqueous HCl (0.2 M) and diluted with EtOAc. The organic phase was separated, washed with aqueous HCl (0.2 M) and brine then dried. Removal of the volatiles afforded the title compound (98%) as a solid. MS (ES+) m/z 555 (M+H)+