Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:9][C:10]([C:12]2[C:17](C)=[CH:16][N:15]=[C:14](F)[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].[C:27]([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:27])[CH:13]=2)=[N:25][OH:26])=[CH:4][CH:3]=1
Reactant: Cc1cnc(F)cc1C(=O)CC(c1ccc(Br)cc1)C(C)(C)C
Reactant: O=C([O-])O
Reactant: NO
Agent: Cl
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(Br)cc2)C(C)(C)C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromo-phenyl)-1-(2-fluoro-5-methyl-pyridin-4-yl)-4,4-dimethyl-pentan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3.7:1) as a white foam, MS (ESI+): m/z=375.1062 ([M+H]+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11](Br)=[N:10][N:9]([C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=3)[C:8]2=[O:25])=[CH:4][CH:3]=1.[CH3:28][O-:29].[Na+]>CO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:29][CH3:28])=[N:10][N:9]([C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=3)[C:8]2=[O:25])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CC(=O)Nc1cccc(-n2nc(Br)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Agent: [Na+]
Solvent: CO
Product: COc1nn(-c2cccc(NC(C)=O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Reaction time: 1 h
Yield: 35 %

Procedure:
According to Scheme 2 Step 4: To a cooled solution of N-(3-(4-(4-chlorobenzyl)-6-bromo-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 2(C) (80 mg,0.18 mmol) in 0.5 mL of methanol (0.5 mL) at 0° C., was added a solution of sodium methoxide (2M) in Methanol (85 μL 0.18 mmol). After 1 h at 0° C. the reaction mixture was allowed to reach room temperature. After 1 h the reaction mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were washed successively with water, with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 5 g column, (Eluant: DCM/AcOEt/MeOH 80/18/2). 25 mg (35% yield) of N-(3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide were recovered.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:9]N(C(C)C)C(C)C.S(=O)(=O)(O)O>>[Cl:9][CH:5]([CH3:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7]
Reactant: CC(C)N(Cl)C(C)C
Reactant: CCCCCC(=O)O
Agent: O=S(=O)(O)O
Product: CC(Cl)CCCC(=O)O

Procedure:
147 parts by mass of the obtained caproic acid and an equivalent amount of N-chlorodiisopropylamine were added to 1,000 parts by mass of 84% sulfuric acid and were reacted for 5 hours at 25° C. to obtain 177 parts by mass of 5-chlorocaproic acid. Then 177 parts by mass of the 5-chlorocaproic acid were boiled with an aqueous solution of an equivalent amount of sodium hydroxide to obtain 129 parts by mass of δ-caprolactone. The 13C-NMR (100 MHz, TMS, CDCl3) of the synthesized δ-caprolactone was measured to obtain the following δ values: 19.90 ppm, 20.88 ppm, 34.27 ppm, 35.31 ppm, 70.44 ppm and 172.84 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:21])=[CH:13][N:12]=[C:11]([C:22]([NH2:24])=[O:23])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.CO>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:6]2[C:5]3[C:9](=[CH:10][C:2]([NH:1][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[CH:3][CH:4]=3)[NH:8][C:7]=2[C:11]([C:22]([NH2:24])=[O:23])=[N:12][CH:13]=1
Reactant: O=C(O)c1ccncc1
Reactant: NC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(N)ccc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(NC(=O)c3ccncc3)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.1 %

Procedure:
A mixture of 7-amino-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (25 mg, 0.078 mmol), isonicotinic acid (11.53 mg, 0.094 mmol), BOP (49.7 mg, 0.112 mmol), and N-methylmorpholine (0.037 mL, 0.337 mmol) in DMF (0.25 mL) was stirred at room temperature for 1.5 hr. The mixture was diluted with MeOH (1.5 mL) and subjected to prep LC. reverse phase HPLC purification. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution to pH 9. The precipitating product (10.8 mg, 0.025 mmol, 32.5% yield) was collected as a pale solid by suction filtration. LCMS (M+H)+=426.14. 1H NMR (500 MHz, DMSO-d6) δ: 11.95 (s, 1H), 10.96 (s, 1H), 6.80 (m, 2H), 8.44 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 7.89 (m, 2H), 7.79 (s, 1H), 7.71-7.67 (m, 2H), 7.54-7.48 (m, 2H), 7.42 (dd, J1=8.6 Hz, J2=1.9 Hz, 1H), 7.28 (d, J=8.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>>[C:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[C:2]([NH2:1])[N:3]=2)[CH2:22][CH2:23]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1ccc(F)cc1C(=O)c1ccc(Cl)nc1N
Product: COc1ccc(F)cc1C(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N

Procedure:
The title compound was prepared from (2-amino-6-chloropyridin-3-yl)-(5-fluoro-2-methoxyphenyl)methanone (Example 19) and 4-amino-1-N-Bocpiperidine (Astatech, >96%) using the procedure described in Step B. Example 6. HRMS, observed: 445.2252, Calcd for (M+H)+: 445.2246.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.Cl.[Cl:9][C:10]1[CH:11]=[C:12]([OH:30])[CH:13]=[C:14]([NH:16][C:17]2[C:18]3[C:25]4[CH2:26][CH2:27][NH:28][CH2:29][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:15]=1.[CH3:31][N:32]([CH3:41])[C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34]>>[Cl:9][C:10]1[CH:15]=[C:14]([NH:16][C:17]2[C:18]3[C:25]4[CH2:26][CH2:27][N:28]([C:5](=[O:7])/[CH:4]=[CH:3]/[CH2:2][N:38]5[CH2:37][CH2:36][N:35]([C:33]([N:32]([CH3:41])[CH3:31])=[O:34])[CH2:40][CH2:39]5)[CH2:29][C:24]=4[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:13]=[C:12]([OH:30])[CH:11]=1
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: O=C(O)/C=C/CBr
Reactant: Oc1cc(Cl)cc(Nc2ncnc3sc4c(c23)CCNC4)c1
Agent: Cl
Product: CN(C)C(=O)N1CCN(C/C=C/C(=O)N2CCc3c(sc4ncnc(Nc5cc(O)cc(Cl)c5)c34)C2)CC1

Procedure:
In analogy to Example 130, the title compound was prepared from (2E)-4-bromobut-2-enoic acid (84 mg, 0.41 mmol), 3-chloro-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 65A (100 mg, 0.27 mmol) and N,N-dimethylpiperazine-1-carboxamide (68 mg, 0.43 mmol) to yield 59 mg (38%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[Si:25]([O:32][CH2:33][C:34]1[CH:35]=[C:36]([CH:50]=[CH:51][C:52]=1[CH2:53][O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[O:37][CH2:38][C:39]1[S:43][C:42](/[C:44](/[CH2:48][CH3:49])=[CH:45]/[CH:46]=O)=[CH:41][CH:40]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].O>ClCCl.[Zn]>[Si:25]([O:32][CH2:33][C:34]1[CH:35]=[C:36]([CH:50]=[CH:51][C:52]=1[CH2:53][O:54][Si:55]([C:58]([CH3:60])([CH3:59])[CH3:61])([CH3:56])[CH3:57])[O:37][CH2:38][C:39]1[S:43][C:42](/[C:44](/[CH2:48][CH3:49])=[CH:45]/[CH:46]=[C:20]([Br:24])[Br:21])=[CH:41][CH:40]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC/C(=C\C=O)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC/C(=C\C=C(Br)Br)c1ccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
770 mg (11.7 mmol) of zinc, 3.09 g (11.7 mmol) of triphenylphosphine and 3.9 g (11.7 mmol) of carbon tetrabromide are stirred for 30 minutes at room temperature in 150 mol of dichloromethane. A solution of 3.3 g (5.9 mmol) of (E)-3-{5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-2-thienyl}pent-2-enal (described in Example 7(c)) in 30 mL of dichloromethane is then added dropwise. After stirring for 1 h at room temperature the reaction medium is treated with water and extracted with dichloromethane. After purification on silica gel (eluent: 95 heptane/5 ethyl acetate), the desired product is obtained in the form of a brown oil (m=3.9 g; Y=93%).
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][C:10]2([CH2:13][CH:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20](=[O:26])[NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16][CH2:15]3)[CH2:11]2)[CH2:9]1)=O)(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[CH2:11]1[C:10]2([CH2:27][CH2:28][NH:8][CH2:9]2)[CH2:13][CH:12]1[N:14]1[CH2:15][CH2:16][CH:17]([C:20]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:26])[CH2:18][CH2:19]1
Reactant: CC(C)(C)NC(=O)C1CCN(C2CC3(CCN(C(=O)OC(C)(C)C)C3)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)C1CCN(C2CC3(CCNC3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl-2-[4-(tert-butylcarbamoyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.627 g, 1.55 mmol) was dissolved in DCM (4 mL) and TFA (1 mL) was added. The reaction mixture was stirred at rt overnight under nitrogen, then the solvents were removed in vacuo, to give 1-(6-azaspiro[3.4]oct-2-yl)-N-tert-butylpiperidine-4-carboxamide trifluoroacetate (1:2) as an oil which was used directly without further purification. The residue was dissolved in DCM (8 mL) and NEt3 (0.056 g, 0.08 mL, 0.54 mmol) and ethyl chloroformate (0.024 mg, 0.02 mL, 0.22 mmol) were added and the reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 A, 12 mL per min, gradient 0% to 10% MeOH in DCM]) to give ethyl 2-[4-(tert-butylcarbamoyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.027 g, 41%) as an off-white solid as a mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].[CH3:12][O:13][C:14](=[O:25])[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][N:18]=[C:17](Cl)[CH:16]=1.CCOC(C)=O>C1COCC1.O>[CH3:12][O:13][C:14](=[O:25])[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][N:18]=[C:17]([O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:16]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)c1cc(Cl)ncc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(Oc2ccc(F)cc2F)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2,4 difluorophenol (Aldrich Chemical Co.) (2.68 mL, 1.1 eq) in THF (60 mL) at 0° C. was added sodium hydride (60% in oil) (1.123 g, 1.1 eq), and the resulting mixture was stirred from 0° C. to room temperature over 1 hour. This solution was then added to compound (1A) (5.79 g, 26.7 mmol), and the resulting mixture was heated at reflux for 2 hours. TLC analysis confirmed that the reaction was complete, and the mixture was cooled to room temperature. EtOAc (300 mL) and water (100 mL) were added, the resulting mixture was partitioned, and the layers were separated. The organic layer was washed with water (3×100 mL) and brine (1×100 mL). Then the EtOAc layer was dried over magnesium sulfate, filtered, concentrated, and pumped to give the titled compound (1B) as an off-white powder (7.99 g, M+=310, Mp=90.2–91.4° C.)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([N:16]2C(=O)[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][C:28](=O)[C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:36]4[CH2:41][CH2:40][S:39](=[O:43])(=[O:42])[CH2:38][CH2:37]4)=[CH:31][CH:30]=3)=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15].C1(C)C=CC=CC=1>O1CCCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]([C:22]2[C:23]([NH:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:35][N:36]4[CH2:37][CH2:38][S:39](=[O:42])(=[O:43])[CH2:40][CH2:41]4)=[CH:33][CH:34]=3)=[N:24][O:25][N:26]=2)=[N:18][OH:19])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)c1ccc(CN2CCS(=O)(=O)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=S1(=O)CCN(Cc2ccc(CNc3nonc3C(=NO)Nc3ccc(F)c(Br)c3)cc2)CC1
Temperature: 130 °C
Yield: 5.4 %

Procedure:
A solution of N-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-4-[(1,1-dioxidothiomorpholin-4-yl)methyl]-benzamide trifluoroacetate (20 mg, 28 μmol) in tetrahydrofuran (0.83 mL) was treated with 2.0 M of borane-dimethyl sulfide complex in toluene (42 μL, 85 μmol) was heated in the microwave at 130° C. for 5 min. The reaction mixture was treated with additional 2.0 M of borane-dimethyl sulfide complex in toluene (40 μL, 80 μmol) and heated in the microwave at 130° C. for 10 min. The reaction mixture was quenched with acetic acid, concentrated and purified by preparative LCMS to give the desired product (1 mg, 5%). LCMS for C21H23BrFN6O4S (M+H)+: m/z=553.0, 554.9.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([Cl:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:33]3[C:34]([CH3:40])=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=3)([C:27]3[N:31]([CH3:32])[N:30]=[N:29][CH:28]=3)[OH:26])[CH:8]=2)[N:3]=1.[NH:41]1[CH2:44][CH2:43][CH2:42]1.CN(C=O)C>CCOC(C)=O>[N:41]1([C:2]2[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)=[C:10]([Cl:24])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:33]4[C:34]([CH3:40])=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=4)([C:27]4[N:31]([CH3:32])[N:30]=[N:29][CH:28]=4)[OH:26])[CH:8]=3)[N:3]=2)[CH2:44][CH2:43][CH2:42]1
Reactant: Cc1ccc(C(O)(c2ccc3nc(Cl)c(Cc4ccc(-n5cccn5)cc4)c(Cl)c3c2)c2cnnn2C)c(C)n1
Reactant: C1CNC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(O)(c2ccc3nc(N4CCC4)c(Cc4ccc(-n5cccn5)cc4)c(Cl)c3c2)c2cnnn2C)c(C)n1
Temperature: 100 °C

Procedure:
{2,4-Dichloro-3-[4-(1H-pyrazol-1-yl)benzyl]quinolin-6-yl}(2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (198 mg, 0.347 mmol, Example 151), azetidine (70 μL, 1.04 mmol), and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature for 24 hours. The residue was taken up into EtOAc, transferred to a reparatory funnel and extracted twice with a saturated, aqueous NH4Cl solution. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to provide the title compound. MS (ESI): mass calcd. for C33H31ClN8O, 590.2. m/z found, 591.5 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 8.07-8.02 (m, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.64-7.56 (m, 2H), 7.38-7.31 (m, 1H), 7.08-6.99 (m, 4H), 6.98 (s, 1H), 6.88-6.77 (m, 2H), 5.89 (d, J=1.9 Hz, 1H), 4.29 (s, 2H), 4.12 (t, J=7.5 Hz, 4H), 3.93 (s, 3H), 2.47 (s, 3H), 2.34 (s, 3H), 2.31-2.18 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH2:19][CH2:18]3)[CH2:13][CH2:14][CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>ClCCl.CCN(C(C)C)C(C)C>[N:25]1([C:23]([N:20]2[CH2:19][CH2:18][CH:17]([CH2:16][N:12]([CH2:13][CH2:14][CH3:15])[CH:8]3[CH2:9][C:10]4[CH:11]=[C:2]([NH:1][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:3]=[CH:4][C:5]=4[CH2:6][CH2:7]3)[CH2:22][CH2:21]2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCCN(CC1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(N)cc2C1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(NC(=O)C(C)C)cc2C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (4-{[(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidin-1-yl)-morpholin-4-yl-methanone (200 μL of 0.25 M in dichloromethane, 50 μmol) was added 220 μL of a 0.25 M solution of isobutyryl chloride in dichloromethane and 30 μL of DIEA. The solution was allowed to stir for 72 h at 25° C. under N2 and was then concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford N-(7-{[1-(morpholine-4-carbonyl)-piperidin-4-ylmethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl)-isobutyramide (8.6 mg) 96, [M+H]+=485.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:20]=[C:19]3[C:15]([CH:16]=[N:17][N:18]3[CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1.Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([CH:16]=[N:17][N:18]4[CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:14][CH:13]=3)=[O:10])=[CH:4][CH:3]=2)=[CH:31][CH:32]=1
Reactant: O=C(Cc1ccc(O)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(OCc2ccc(F)cc2)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1
Reaction time: 6 h

Procedure:
A mixture of 2-(4-hydroxy-phenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]-acetamide (45.0 mg, 0.124 mmol), 1-bromomethyl-4-fluoro-benzene (35.0 mg, 0.185 mmol), Cs2CO3 (60.0 mg, 0.184 mmol) in 2 mL of DMF was shaken for 6 hours and concentrated under reduced pressure. The residue was dissolved in a 1:1 mixture of dimethyl sulfoxide/MeOH (1.5 mL) and purified by preparative reverse-phase HPLC. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.82 (m, 2 H), 1.98 (m, J=7.02, 7.02 Hz, 2 H), 3.02 (m, 2 H), 3.48 (m, 2 H), 3.68 (m, 4 H), 4.65 (t, J=6.24 Hz, 2 H), 5.07 (s, 2 H), 6.97 (m, 2 H), 7.11 (m, 1 H), 7.21 (m, 2 H), 7.27 (m, 2 H), 7.48 (m, 2 H), 7.71 (m, 1 H), 8.08 (s, 1 H), 8.26 (s, 1 H), 10.35 (s, 1 H); MS (ESI) m/z 473 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Cl.[S:6]([O-:9])([O-:8])=[O:7].[Na+:10].[Na+]>O>[CH3:1][O:2][CH2:3][CH2:4][S:6]([O-:9])(=[O:8])=[O:7].[Na+:10]
Reactant: COCCCl
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COCCS(=O)(=O)[O-]
Temperature: 25 °C
Yield: 128 %

Procedure:
2-Chloroethyl methyl ether (10 g, 0.106 mol) was added at RT to a suspension of sodium sulfite (13.35 g, 0.106 mol) in 30 mL of H2O. The resulting biphasic mixture was stirred at reflux for 48 hours before being cooled to RT (clear monophasic solution), and evaporated. The white residue was turned into a powder and was then washed with 100 mL of an 8/2 mixture of Et2O and toluene, before being dried to give 22 g sodium 2-methoxy-ethanesulfonate (129% yield, contaminated with excess sodium sulfite). Used as is in step 2.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5](=[O:25])[CH2:6][N:7]([C:9]([C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])=[O:10])[CH3:8].OS([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:3][O:4][C:5](=[O:25])[CH2:6][N:7]([C:9]([C:11]1[C:20]2[C:15](=[C:16]([Br:1])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])=[O:10])[CH3:8]
Reactant: COC(=O)CN(C)C(=O)c1c(OC)ccc2cc(OC)ccc12
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CN(C)C(=O)c1c(OC)ccc2c(Br)c(OC)ccc12
Yield: 66.8 %

Procedure:
A solution of bromine (1.75 mL, 34.05 mmol) in acetic acid (40 mL) was added over 25 minutes to a stirred solution of N-[(2,6-dimethoxy-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester (10.70 g, 33.72 mmol, described in Example 2) in acetic acid (120 mL). After an additional 10 minutes the reaction was diluted with water (900 mL) and NaHSO3 (2.0 g) was added. The resulting precipitate was collected by filtration, washed with water and dried to give 8.93 g (67% yield) of the title compound, m.p. 142°-144° C.
Reaction SMILES: [S:1]1[C:5]([C:6]#[N:7])=[CH:4][N:3]=[CH:2]1.Cl.[NH2:9][OH:10].CCN(C(C)C)C(C)C>CCO>[S:1]1[C:5]([C:6](=[N:9][OH:10])[NH2:7])=[CH:4][N:3]=[CH:2]1
Reactant: NO
Reactant: N#Cc1cncs1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=NO)c1cncs1
Yield: 72.3 %

Procedure:
Hydroxylamine hydrochloride (3.07 g, 44 mmol) was added to a solution of 1,3-thiazole-5-carbaldehyde (5 g, 44 mmol) and pyridine (3.7 mL) in DCM (25 mL). The reaction mixture was stirred overnight at room temperature and then washed once with water. The product was recovered by filtration to give 5.23 g of 1,3-thiazole-5-carbaldehyde oxime (yield 92%). 1,3-thiazole-5-carbaldehyde oxime (2.5 g, 19.5 mmol, 1 equiv) was dissolved in 12 mL of dioxane and then TEA (6.8 mL, 2.5 equiv) was added. The reaction mixture was cooled to 0° C. and then trifluoroacetic anhydride (3.0 mL, 1.1 equiv) was added dropwise to the reaction. The solution was stirred overnight at room temperature and then 1.1 equivalent of trifluoroacetic anhydride was added to complete the reaction. The solution was stirred overnight at room temperature and then evaporated. The residue was dissolved in DCM and then washed five times with water. The organic layer was dried over MgSO4 and then evaporated under reduced pressure to give 1.25 g of 1,3-thiazole-5-carbonitrile (Yield 58%). 1,3-thiazole-5-carbonitrile (1 g, 9.08 mmol, 1 equiv), hydroxylamine hydrochloride (0.95 g, 1.5 equiv) and DIEA (2.5 mL, 1.6 equiv) were mixed in absolute EtOH (30 mL). The reaction mixture was refluxed 5 h and then the solvent was evaporated under reduced pressure. The residue was dissolved in AcOEt, washed twice with water and once with brine. The organic layer was dried over MgSO4 and then evaporated under reduced pressure to give 940 mg of 1,3-thiazole-5-amidoxime (yield 72%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:39])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[O:35][C:34]([C:36](O)=[O:37])=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-].CC[N:44]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:39])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[O:35][C:34]([C:36]([NH2:44])=[O:37])=[CH:33][CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)o2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(N)=O)o2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 75 °C
Yield: 52.1 %

Procedure:
To a solution of rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid prepared in Example 145 (60 mg, 0.1 mmol) in N,N-dimethylformamide (2 mL) was added NH4Cl (28 mg, 0.5 mmol), EDCI (40 mg, 0.2 mmol), HOBT (28 mg, 0.2 mmol) and NEt3 (0.029 mL, 0.2 mmol). The reaction mixture was heated at 75° C. for 20 h. The mixture was cooled to room temperature, and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc) to give rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid amide as a white solid (30 mg, 50%).