Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15].[CH3:21][O:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[C:25]([O:32][CH3:33])[N:24]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:28]3[C:23]([O:22][CH3:21])=[N:24][C:25]([O:32][CH3:33])=[CH:26][CH:27]=3)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15]
Reactant: COc1ccc(B(O)O)c(OC)n1
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)c(F)ccc12
Product: COc1ccc(-c2c(F)ccc3c(N)c(C(=O)NC4CCC4)nnc23)c(OC)n1
Yield: 59.5 %

Procedure:
Using Method A, 4-amino-8-bromo-7-fluoro-N-cyclobutyl-cinnoline-3-carboxamide (175 mg) and 2,6-dimethoxypyridin-3-yl boronic acid (206 mg) were reacted to afford the title compound (122 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.22 (d, 1H), 8.50 (m, 1H), 7.73 (t, 1H), 7.67 (d, 1H), 6.53 (d, 1H), 4.49 (m, 1H), 3.95 (s, 3H), 3.80 (s, 3H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=398 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:11]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:10][C:9]=1[OH:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([O:38][C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)/[CH:42]=[CH:43]/[CH2:44]O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:23]([O:22][C:11]1[CH:12]=[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:9]([OH:30])[C:10]=1[CH2:44]/[CH:43]=[CH:42]/[C:41]1[CH:46]=[CH:47][C:48]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[C:39]([O:38][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:40]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Oc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1Cc1ccccc1
Reactant: OC/C=C/c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: ClCCl
Product: Oc1c(C/C=C/c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)c(OCc2ccccc2)cc(OCc2ccccc2)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
At rt under an N2 atmosphere, 25% H2SO4/SiO2 (1.6 g, 4 mmol) was added in one batch to the stirred mixture of 2-benzyl-3,5-bis(benzyloxy)phenol (3.96 g, 10 mmol) and (E)-3,4-bis(benzyloxy)cinnamyl alcohol (3.46 g, 10 mmol) in dry CH2Cl2 (80 mL). The resulting mixture was stirred at rt overnight. After filtration and evaporation, the residue was purified by column chromatography on silica gel (EtOAc/n-hexane=1/7 v/v) and recrystallized from EtOAc and n-hexane to give a white solid, (3.4 g, 46.0% yield): mp 93-95° C.; 1H NMR (CDCl3, 400 MHz) δ 7.41-7.22 (m, 30H), 6.92 (s, 1H), 6.79 (s, 1H), 6.78 (d, f=4.0 Hz, 1H), 6.35 (A of AB, J=15.8 Hz, 1H), 6.26 (s, 1H), 6.13-6.07 (B of ABt, J=15.8, 5.0 Hz, 1H), 5.08 (s, 2H), 5.07 (s, 2H), 4.99 (s, 4H), 4.02 (s, 2H), 3.55 (d, J=5.0 Hz, 2H); 13C NMR (CDCl3, 400 MHz) δ 156.1, 155.6, 154.0, 148.9, 148.2, 141.1, 137.2, 137.1, 131.0, 130.1, 128.5, 128.4, 128.2, 127.8, 127.7, 127.6, 127.3, 127.2, 127.1, 126.5, 125.7, 119.7, 114.9, 112.4, 109.6, 107.3, 91.4, 71.1, 70.5, 70.3, 28.8, 26.6; HRMS (ESI): calcd for C50H44O5Na (M+Na) 747.3086. found 747.3096.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12](N)[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.N([O-])=[O:25].[Na+]>F>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([OH:25])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=N[O-]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)n2)CC1
Agent: F
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1CCN(c2ccc([N+](=O)[O-])c(O)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-(4-methylpiperazin-1-yl)-3-nitropyridin-2-amine (1.2 g, 5.0 mmol) in hydrogen fluoride.pyridine (15 mL) is cooled to 0° C. in an ice-water bath. Sodium nitrite (0.36 g, 5.2 mmol) is added in a single portion, and the mixture is stirred for 30 minutes at 0° C. The bath is removed and the mixture is heated for 15 minutes in an oil bath on a 70° C. hot plate. After cooling to room temperature, the reaction mixture is poured onto ice (50 g), neutralized with saturated aqueous sodium hydrogen carbonate solution, and basified with 10 N sodium hydroxide solution. The mixture is extracted 3× with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Eighty-percent of the crude residue is purified by reverse-phase HPLC to give 6-(4-methylpiperazin-1-yl)-3-nitropyridin-2-ol.trifluoroacetic acid salt (0.18 g, 7.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13](CC4C=CC(OC)=CC=4)[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:40])[F:41])[CH:33]=2)=[CH:43][CH:44]=1
Reactant: COc1ccc(Cn2c(=O)c3c(nc(CCCOc4cccc(OC(F)(F)F)c4)n3Cc3ccc(Cl)cc3)n(C)c2=O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)[nH]c(=O)c2c1nc(CCCOc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-1-(4-methoxybenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione (105 mg, 0.167 mmol) in DCM (4 mL) was added TFA (1 mL) dropwise followed by trifluoromethanesulfonic acid (0.25 mL) at 0° C. The reaction was stirred at 0° C. for 10 min, then at room temperature for 16 h. The reaction was quenched with saturated sodium bicarbonate and extracted with DCM. The organic phase was washed with water, dried over sodium sulfate, and concentrated to give 7-(4-chlorobenzyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propyl)-1H-purine-2,6(3H,7H)-dione (66 mg, 77.6% yield) as a yellow oil. LCMS retention time 2.868 min; LCMS MH+ 509.
Reaction SMILES: II.[CH2:3]([C@@H:10]1[C@@H:24]([OH:25])[CH2:23][C:22](=[O:26])[O:21][C@H:20](/[CH:27]=[CH:28]/[CH2:29][CH2:30][S:31]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:19][C:18](=[O:51])[NH:17][C@H:16]([CH3:52])[C:15](=[O:53])[NH:14][C@H:13]([CH2:54][S:55]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:12](=[O:75])[NH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.CO>[CH2:3]([C@H:10]1[NH:11][C:12](=[O:75])[C@@H:13]2[NH:14][C:15](=[O:53])[C@@H:16]([CH3:52])[NH:17][C:18](=[O:51])[CH2:19][C@@H:20]([CH:27]=[CH:28][CH2:29][CH2:30][S:31][S:55][CH2:54]2)[O:21][C:22](=[O:26])[CH2:23][C@@H:24]1[OH:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[C@H]1NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)C[C@H](O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC1=O
Agent: C[C@H]1NC(=O)C[C@H]2/C=C/CCSSC[C@@H](NC1=O)C(=O)N[C@H](Cc1ccccc1)[C@@H](O)CC(=O)O2
Agent: II
Agent: O=S([O-])([O-])=S
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1NC(=O)C[C@H]2C=CCCSSC[C@@H](NC1=O)C(=O)N[C@H](Cc1ccccc1)[C@@H](O)CC(=O)O2

Procedure:
To a stirred solution of iodine (99 mg, 0.39 mmol) in CH2Cl2/MeOH (9:1, 110 mL) was added dropwise a solution of 6D (40 mg, 0.0039 mmol) in CH2Cl2/MeOH (9:1, 60 mL) over 30 min, the reaction mixture was then allowed to stir for a further 30 min after which time sodium thiosulfate (40 mL, 0.05 M) was added. The layers were separated and the product was extracted with CH2Cl2 (3×25 ml) dried over MgSO4 and the solvent was removed in vacuo. Purification was then carried out by column chromatography on silica gel (1-5% MeOH/CH2Cl2) which gave an inseparable mixture of isomers 7D & 7D′ (1:1, 11 mg, 0.02 mmol, 54%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C([O-])(O)=O.[Na+].C(Cl)Cl>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9]1
Reactant: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 0.5 h

Procedure:
To (R)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (1.54 g, 3.67 mmol) at room temperature was added 10 mL of a 1:1 TFA:CH2Cl2 solution. The reaction mixture was stirred for 30 min and diluted with 10 mL of saturated NaHCO3 and 15 mL of CH2Cl2. The resulting emulsion was filtered, and the organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure to give (R)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol. LC/MS: m/z 321.2 (M+H)+ at 1.91 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][S:12][C:11](=[O:14])[NH:10][N:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][S:12][C:11](=[O:14])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C1NN=C(c2ccc(Cl)cc2)CS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1SCC(c2ccc(Cl)cc2)=NN1Cc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of the compound obtained in Step A (57.83 mmoles) in acetonitrile (260 ml) there are added 1-bromomethyl-4-nitro-benzene (63.61 mmoles) and potassium carbonate (231.32 mmoles). The reaction mixture is stirred at 80° C. for 1 hour under nitrogen. The reaction mixture is brought to ambient temperature and 100 ml of water are added. Extraction with ethyl ether (3×350 ml) is carried out and the organic phases are combined. The organic phase obtained is dried over sodium sulphate, filtered and evaporated to dryness. The solid is triturated in ethyl ether, filtered off and dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:40])[C:19]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:23][CH:22]=2)=O)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:42][O:43][NH2:44].N1C=CC=CC=1>CCO>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=[O:40])[C:19](=[N:44][O:43][CH3:42])[C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:23][CH:22]=2)[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)C(=O)c2ccc(OCCN3CCOCC3)c3ccccc23)cc1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(C(=O)Nc1cc(C(C)(C)C)nn1-c1ccc(C)cc1)c1ccc(OCCN2CCOCC2)c2ccccc12
Temperature: 45 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
Compound 13 (10 mg, 0.018 mmol) and methoxyamine hydrochloride (50 eqv., 0.92 mmol, 77 mg) were dissolved in 2 mL of EtOH. Pyridine (0.1 mL) was added and the mixture was stirred at 45° C. for 12 h. The solvent was then removed in vacuo and the crude solid was purified via LCMS to yield 8 mg of a white solid (76% yield; mixture of isomers). Expected mass=569. Observed mass=570.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[C:3]=1[CH3:26].[CH3:27][O:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32](B(O)O)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([O:28][CH3:27])=[CH:34][C:33]=5[CH3:35])[C:3]([CH3:26])=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C
Reactant: COc1cc(C)c(B(O)O)cn1
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: [Na+]
Solvent: COCCOC
Product: COc1cc(C)c(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C)cn1
Temperature: 120 °C
Yield: 63.9 %

Procedure:
To a mixture of N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (25 mg, 0.067 mmol) and 2-methoxy-4-methylpyridin-5-ylboronic acid (21 mg, 0.1 mmol) in DME (0.7 mL) and Na2CO3 (2M, 0.065 mL, 0.13 mmol) was added Pd(PPh3)4 (4 mg, 0.003 mmol). The mixture was heated in microwave oven at 120° C. for 30 min. The reaction was re-partitioned between EtOAc and H2O and the aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (0-20% EtOAc-Hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4,4′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (20 mg, 65%). 1H NMR (400 MHz, CDCl3) 8.05 (s, 1H), 7.86 (s, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.21-7.16 (m, 2H), 7.04 (d, J=8.2 Hz, 1H), 6.62 (s, 1H), 3.92 (s, 3H), 2.34 (s, 3H), 2.00 (s, 3H), 1.96 (s, 3H), 1.74 (dd, J=3.9, 6.9 Hz, 2H), 1.15 (dd, J=3.9, 7.0 Hz, 2H). Retention time: 2.00 min; ESI-MS m/z calc. 467.5. found 468.2 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CN(C)[CH:28]=[O:29].[NH4+].[Cl-].[Na+].[Cl-]>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH:28]([OH:29])[C:17]3[CH:16]=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][C:12]=3[C:11]2=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(C(=O)NCCCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(O)N(CCCc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of N-(3-phenylpropyl)-4-methoxybenzamide (5 g, 18.58 mmol) in dry THF (100 ml) is chilled to 5° in an ice/H2O bath. To this, n-butyllithium (1.6 m in hexanes, 59.46 mmol, 37 ml) is added slowly so that the temperature remains below 15°. After the addition is complete, the reaction is stirred for 5 minutes at 5°, followed by the addition of dimethylformamide (4.5 g, 61.31 mmol). After stirring for 1 hour at 10°, saturated NH4Cl solution (10 ml) is added, and the reaction is allowed to warm to room temperature. The reaction is poured into saturated NaCl solution (300 ml) and extracted into EtOAc (300 ml). The EtOAc phase is washed with 2N HCl (300 ml), H2O (300 ml) and saturated NaCl solution (300 ml) dried over MgSO4 and evaporated. The product is purified by chromatography (SiO2 ; 1:9 EtOAc/hexanes, 1:4 EtOAc/hexanes, 2:3 EtOAc/hexanes) yielding 2-(3-phenylpropyl)-5-methoxy-3-hydroxy-1-oxo-1,3-dihydrobenzo[c]pyrrole, as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[CH:19][C:20]5[N:21]([C:23]([CH:26]=[O:27])=[CH:24][N:25]=5)[CH:22]=4)=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.O.[BH4-].[Na+]>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[CH:19][C:20]5[N:21]([C:23]([CH2:26][OH:27])=[CH:24][N:25]=5)[CH:22]=4)=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(C=O)n5c4)n3n2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(CO)n5c4)n3n2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-[6-(1-Methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-imidazo[1,2-a]pyridine-3-carbaldehyde (Example 297, 50 mg, 0.140 mmol) was dissolved in MeOH (3 mL) and water (1 mL) then NaBH4 (2.6 mg, 0.070 mmol) was added. The RM was stirred at rt for 30 min. It was quenched with water and EtOAc. The precipitate formed was filtered off. The filtrate was concentrated then was triturated with MeOH. The salt was filtered off. The filtrate was concentrated and then triturated again with Et2O, The precipitate was filtered off and it was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM) to afford after evaporation of the solvent the title compound as a yellow solid (tR 0.6 min (conditions 2), MH+=360).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][CH:5]([F:29])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:17]([NH:19][C:20]1[N:25]=[C:24](Cl)[N:23]=[C:22]([O:27][CH3:28])[N:21]=1)=[O:18])(=[O:15])=[O:14]>O1CCOCC1.Cl>[F:4][CH:5]([F:29])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:17]([NH:19][C:20]1[N:25]=[C:24]([N:2]([CH3:3])[CH3:1])[N:23]=[C:22]([O:27][CH3:28])[N:21]=1)=[O:18])(=[O:15])=[O:14]
Reactant: COc1nc(Cl)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)n1
Reactant: CNC
Agent: Cl
Solvent: C1COCCO1
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)nc(N(C)C)n1
Reaction time: 0.5 h

Procedure:
3.0 g of dimethylamine are introduced at 20°-30° C., with cooling, into a solution of 8.2 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-(4-chloro-6-methoxy-1,3,5-triazin-2-yl)-urea in 80 ml of dioxane. After the formed suspension has been stirred for a further 30 minutes, it is taken up in 500 ml of 0.1 N hydrochloric acid, and the product which has precipitated is separated by filtration; yield: 7.7 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-(4-dimethylamino-6-methoxy-l,3,5-triazin-2-yl)-urea, m.p. 171°-172° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:16][CH:17]([N:19]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36]CC3C=CC=CC=3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:18])=[CH:10][C:11]=2[C:13]([NH2:15])=[O:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:16][CH:17]([N:19]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[OH:36])[C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH3:18])=[CH:10][C:11]=2[C:13]([NH2:15])=[O:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(CC(C)N(CCOc3ccccc3OCc3ccccc3)C(=O)OC(C)(C)C)cc(C(N)=O)c21
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCc2cc(CC(C)N(CCOc3ccccc3O)C(=O)OC(C)(C)C)cc(C(N)=O)c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.1 %

Procedure:
To a solution of 1-acetyl-5-[2-[N-tert-butoxycarbonyl-2-(2-benzyloxyphenoxy)ethylamino]propyl]indoline-7-carboxamide (358 mg) in methanol (6 ml) was added 10% palladium on carbon (35 mg), and the mixture was stirred under an atmosphere of hydrogen at room temperature for 5 hours. After the catalyst was filtered off, and the filtrate was concentrated to dryness to give 273 mg of 1-acetyl-5-[2-[N-tert-butoxycarbonyl-2-(2-hydroxyphenoxy)ethylamino]propyl]indoline-7-carboxamide as an amorphous powder.
Reaction SMILES: I[C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=1.[Li]CCCC.[CH3:19][O:20][C:21]1[C:26]([N:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][C:24]([C:42](=[O:47])N(OC)C)=[CH:23][N:22]=1>CCOCC>[CH:11]([N:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:2]([C:42]([C:24]2[CH:25]=[C:26]([N:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C:21]([O:20][CH3:19])=[N:22][CH:23]=2)=[O:47])=[CH:3]1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cc(I)c2cnccc21
Reactant: COc1ncc(C(=O)N(C)OC)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ncc(C(=O)c2cn(C(C)C)c3ccncc23)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-iodo-1-isopropyl-1H-pyrrolo[3,2-c]pyridine (Preparation 45, 250 mg, 0.875 mmol) in ether (5 mL) at −78° C. was added nBuLi (2.3M in hexane, 0.38 mL, 0.875 mmol) and the reaction stirred at this temperature for 30 minutes. A solution of di-tert-butyl {2-methoxy-5-[methoxy(methyl)carbamoyl]pyridin-3-yl}imidodicarbonate (Preparation 69, 300 mg, 0.729 mmol) in ether (2 mL) was added and the reaction continued to stir at this temperature for another 30 minutes. The reaction was warmed to room temperature for 2 hours before being quenched by the addition of saturated ammonium chloride solution. The reaction was extracted into EtOAc (3×15 mL), the combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified using preparative TLC eluting with EtOAc:DCM 50:50 to afford the title compound and taken on to the next step directly.
Reaction SMILES: FC1C=C([N+]([O-])=O)C=CC=1C=CC(O)=O.BrBr.Cl.C(O)(=O)C#C.BrCCCCCCCCCCCCCCCC.[F:41][C:42]1[CH:47]=[C:46]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH:45]=[CH:44][C:43]=1[C:65]#[C:66][C:67]([O:69]CC)=[O:68]>C(O)(=O)C.[OH-].[Na+].[OH-].[NH4+]>[F:41][C:42]1[CH:47]=[C:46]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH:45]=[CH:44][C:43]=1[C:65]#[C:66][C:67]([OH:69])=[O:68]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C#CC(=O)OCC)c(F)c1
Agent: BrBr
Agent: C#CC(=O)O
Agent: CCCCCCCCCCCCCCCCBr
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCNc1ccc(C#CC(=O)O)c(F)c1

Procedure:
Alternatively, the 2-fluoro-4-aminophenylpropiolic acid is prepared from 2-fluoro-4-nitrocinnamic acid by successive treatment with bromine in acetic acid, aqueous sodium hydroxide, ferric sulfate and ammonium hydroxide, and ethanolic hydrogen chloride. The propiolic acid is then converted to the corresponding ethyl ester and alkylated with 1-bromohexadecane in the manner of Example 9. The resulting ethyl 2-fluoro-4-(hexadecylamino)phenylpropiolate is hydrolyzed in the manner of Example 10 to yield 2-fluoro-4-(hexadecylamino)phenylpropiolic acid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[N:5]=[C:4]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[S:22][CH:23]=[C:3]12.C(N(C(C)C)CC)(C)C.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH2:38].F[P-](F)(F)(F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1>CC(N(C)C)=O>[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH:38][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:2](=[O:1])[C:3]3=[CH:23][S:22][C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:4]3=[N:5]2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(-n2nc3c4ccccc4scc-3c2=O)cc1
Reactant: CN(C)CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCNC(=O)c1ccc(-n2nc3c4ccccc4scc-3c2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(3-oxothiochromeno[4,3-c]pyrazol-2(3H)-yl)benzoic acid (55 mg, 0.17 mmol) was suspended in anhydrous dimethyl acetamide (1 ml). Diisopropyl-ethyl amine (46.5 mg, 0.36 mmol, 62 μl) was added followed by 3-dimethylaminopropylamine (17.5 mg, 0.17 mmol) and [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium hexafluoro phosphate (65 mg, 0.17 mmol). The mixture was stirred at room temperature for 4 h and was purified by preparative HPLC. The title compound was isolated as a brown solid. LCMS: m/z 407 [M+H]+ Activity **