Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:24]([Si:28](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:27])([CH3:26])[CH3:25].O>CN(C=O)C>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OC1CN(C(c2ccccc2)c2ccccc2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 1-Benzhydrylazetan-3-ol (2.0 g, 8.4 mmol) in DMF (20 ml) at 0° C. is treated with imidazole (0.57 g, 8.4 mmol) and t-butylchlorodiphenyl silane (2.31 g, 8.4 mmol). The reaction mixture is allowed to warm up to room temperature and stirred overnight. The mixture is poured into water (250 ml) and extracted with EtOAc (3×100 ml). The combined organic extracts are washed with water (2×100 ml), brine (100 ml) and dried over MgSO4. The solvent is removed in vacuo to yield the titled compound.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[C:28](=O)[C:29](=[O:35])[C:30]=3[O:31]C(C)C)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[NH3:37]>>[NH2:37][C:28]1[C:29](=[O:35])[C:30](=[O:31])[C:27]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:13]2[C:6]3=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]2[CH2:1][CH3:2])=[CH:16][CH:17]=1
Reactant: N
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2c(OC(C)C)c(=O)c2=O)cc1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2c(N)c(=O)c2=O)cc1
Reaction time: 16 h

Procedure:
3-[4'-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl)-4-isopropoxycyclobut-3-ene-1,2-dione (0.44 g; preparable as in Example 2) was stirred in saturated ethanolic ammonia solution (10 ml) at ambient temperature for 3 hours and then kept at ambient temperature for approximately 16 hours. The solvent was evaporated and the resulting residue was triturated with diethyl ether to give an off-white solid which was dried in vacuo to give 3-amino-4-[4'-(2-ethyl-5,7-dimethyl -3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]cyclobut-3-ene-1,2-dione (0.25g; m.p. 217° C.), an active compound of the present invention.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([CH3:8])[CH3:7])=[O:4].C(N(CC)C(C)C)(C)C.[F:18][C:19]1[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([CH:27]=1)[C:24](Cl)=[O:25]>ClCCl>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([CH:27]=1)[C:24]([NH:1][CH2:2][C:3]([NH:5][CH:6]([CH3:8])[CH3:7])=[O:4])=[O:25]
Reactant: O=C(Cl)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)NC(=O)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NC(=O)CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A solution of 2-amino-N-isopropylacetamide (11.3 g, 97.0 mmol) and N,N-diisopropylethylamine (20.1 g, 162 mmol) in dichloromethane (200 mL) was cooled using an ice water bath. A solution of 5-fluoro-2-nitrobenzoyl chloride (16.5 g, 81.0 mmol) in dichloromethane (200 mL) was added dropwise over 15 minutes. The resulting solution was stirred overnight. The reaction mixture was washed with 2N HCl solution (2×250 mL), brine (250 mL) and then dried over magnesium sulphate. The solution was filtered before concentrating under reduced pressure to afford 5-fluoro-N-(2-(isopropylamino)-2-oxoethyl)-2-nitrobenzamide (18.5 g, 65.0 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:24]=[C:23]([N:25]=[C:26]=[O:27])[CH:22]=[C:21]([Cl:28])[N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:26]([NH:25][C:23]2[CH:22]=[C:21]([Cl:28])[N:20]=[C:19]([Cl:18])[CH:24]=2)=[O:27])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C=Nc1cc(Cl)nc(Cl)c1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1cc(Cl)nc(Cl)c1
Yield: 39.1 %

Procedure:
Example 24 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 2,6-dichloro-4-isocyanatopyridine (0.0258 g) to give the title compound (0.0165 g). LC-MS (System A): Rt 2.46 mins, Mass Spectrum m/z 463 [MH+].
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]([OH:12])[CH2:7][NH:8][CH2:9][CH2:10][CH3:11])[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl>[CH2:1]([O:4][CH2:5][CH:6]([OH:12])[CH2:7][N:8]([CH2:9][CH2:10][CH3:11])[C:22](=[O:23])[CH2:21][Cl:20])[CH:2]=[CH2:3]
Reactant: O=C(Cl)CCl
Reactant: C=CCOCC(O)CNCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOCC(O)CN(CCC)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-allyloxy-3-n-propylamino-2-propanol (95.2 g.) in a mixture of dry methylene chloride (275 ml.), and triethylamine (80 ml.) is cooled to between -5°C. and 0°C. and a solution of chloroacetylchloride (42 ml.) in methylene chloride (60 ml.) is added dropwise with stirring during 2 hours. The mixture is allowed to warm to ambient temperature (18°-20°C.) and stirred at this temperature for 18 hours. The solution is washed with 2N hydrochloric acid (2 × 100 ml.) and then with water (100 ml.) and dried (MgSO4). Removal of the solvent under reduced pressure gives N-(3-allyloxy-2-hydroxypropyl)-N-n-propyl-α-chloroacetamide (119.7 g.) as an oil which is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Oc1cccc(Br)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.5 %

Procedure:
To a solution of 3-bromophenol (2 g, 11.56 mmol) in dimethylformamide (10 mL) was added sequentially cesium carbonate (11.30 g, 34.7 mmol) and ethyl 4-bromobutanoate (1.66 mL, 11.6 mmol) at room temperature. The heterogeneous reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was partitioned between ether (75 mL) and water (50 mL). The ether layer was collected, washed with brine (50 mL), dried over sodium sulfate, and concentrated to yield ethyl 4-(3-bromophenoxy)butanoate (3.3 g, 11.5 mmol, 99% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.25-1.29 (m, 3H), 2.07-2.15 (m, 2H), 2.48-2.54 (m, 2H), 3.99 (t, J=6.16 Hz, 2H), 4.13-4.15 (m, 1H), 4.16-4.19 (m, 1H), 6.80-6.84 (m, 1H), 7.05 (t, J=1.98 Hz, 1H), 7.06-7.09 (m, 1H), and 7.11-7.16 (m, 1H).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]4([C:55]([O:57][CH3:58])=[O:56])[CH2:54][CH2:53][CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[Cl:59][C:60]1[CH:68]=[CH:67][C:63]([C:64](Cl)=[O:65])=[CH:62][CH:61]=1>>[Cl:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:49]=[C:48]4[C:44]([CH2:45][N:46]([C:51]5([C:55]([O:57][CH3:58])=[O:56])[CH2:52][CH2:53][CH2:54]5)[C:47]4=[O:50])=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:65])=[CH:62][CH:61]=1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CCC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(Cl)cc5)cc4)cc3C2=O)CCC1
Yield: 96 %

Procedure:
The compound of example 577 was prepared analogous to compound of example 97 by reaction of compound of example 574 with 4-chloro benzoyl chloride.
Reaction SMILES: C(OC([O:11][C@@H:12]([C@@H:14]1[C@@H:17]([C@H:18]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[S:21])[CH3:19])[N:16]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[C:15]1=[O:36])[CH3:13])=O)C1C=CC=CC=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].Cl>ClCCCl.C(OCC)(=O)C>[OH:11][C@@H:12]([C@@H:14]1[C@@H:17]([C@H:18]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[S:21])[CH3:19])[N:16]([CH2:28][C:29]([OH:31])=[O:30])[C:15]1=[O:36])[CH3:13]
Reactant: C[C@@H](OC(=O)OCc1ccccc1)[C@H]1C(=O)N(CC(=O)OC(C)(C)C)[C@@H]1[C@@H](C)C(=S)c1ccccc1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: C[C@@H](O)[C@H]1C(=O)N(CC(=O)O)[C@@H]1[C@@H](C)C(=S)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 194.8 %

Procedure:
To a solution of (3S,4S)-3-[(1R)-1-benzyloxycarbonyloxyethyl]-4-[(1R)-1-phenylthiocarbonylethyl]-1-t-butoxycarbonylmethylazetidin-2-one (8.5 g) in 1,2-dichloroethane (185 ml), there was dropwise added a solution of boron tribromide (26.4 g) in 1,2-dichloroethane (100 ml) at -10° C. for 20 minutes, followed by stirring at the same temperature for 1 hour. Sodium bicarbonate (40 g) and ice-water (600 g) were added thereto while stirring, and the resultant mixture was diluted with ethyl acetate (200 ml). The aqueous layer was acidified with 2N hydrochloric acid (200 ml), extracted with ethyl acetate and combined with the organic layer. The combined organic layer was washed with brine (200 ml×3), dried over magnesium sulfate and evaporated in vacuo to give (3S,4S)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-phenylthiocarbonylethyl]-1-carboxymethylazetidin-2-one (10.4 g, 87.9%.).,
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[S:9]([CH2:12][C:13](OC)=[O:14])(=[O:11])=[O:10].Cl.[NH2:31][OH:32]>CO>[OH:32][NH:31][C:13](=[O:14])[CH2:12][S:9]([N:8]([CH3:7])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)(=[O:11])=[O:10]
Reactant: COC(=O)CS(=O)(=O)N(C)Cc1ccc(-c2ccccc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(Cc1ccc(-c2ccccc2)cc1)S(=O)(=O)CC(=O)NO
Yield: 87.7 %

Procedure:
Potassium carbonate (124 mg, 0.9 mmol) was added to a mixture of methyl 2-({methyl[(biphen-4-yl)methyl]amino}sulfonyl)acetate (100 mg, 0.3 mmol) and hydroxylamine hydrochloride (63 mg, 0.9 mmol) in methanol (3 ml). The mixture was heated to reflux for 18 hours. The mixture was cooled and partitioned between ethyl acetate and 0.1 M aqueous hydrochloric acid. The layers were separated, and the organic layer was dried (MgSO4), and the solvents were removed under reduced pressure. The residue was triturated with diisopropyl ether to give the titled compound as a colourless solid (88 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[O:27][CH:28]=[CH:29][CH:30]=2)=[O:25])=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]([C:26]2[O:27][CH:28]=[CH:29][CH:30]=2)=[O:25])=[CH:21][CH:22]=1)=[O:16]
Reactant: NNC(=O)c1ccc(NC(=O)c2ccco2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(NC(=O)c2ccco2)cc1
Temperature: 100 °C
Yield: 81 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added N-[4-(hydrazinocarbonyl)phenyl]-2-furamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 81 mg of the title compound (81%) as a yellow powder in 96.7% purity by HPLC (Rt: 4.05, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: O[CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].O1C(CCCCCCCCO)C1CCCCCC[CH2:29][C:30]([OH:32])=[O:31].OC(C(O)CCCCCCCCO)CCCCCCCC(O)=O.OCCCCCCCCCCCCCCCCCCCCCC(O)=O.OCCCCCCCCC=CCCCCCCCC(O)=O.C(O)(=O)CCCCCCCCCCCCCCCCCCCCC(O)=O>>[C:30]([OH:32])(=[O:31])[CH2:29][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)CCCCCCCC1OC1CCCCCCCCO
Reactant: O=C(O)CCCCCCCC(O)CCCCCCCO
Agent: O=C(O)CCCCCCCC(O)C(O)CCCCCCCCO
Agent: O=C(O)CCCCCCCC=CCCCCCCCCO
Agent: O=C(O)CCCCCCCCCCCCCCCCCCCCC(=O)O
Product: O=C(O)CCCCCCCC=CCCCCCCCC(=O)O

Procedure:
When the hydrolysis is carried out at a pH of about 6.5 to about 7.5 and a mixture of 9,16-dihydroxyhexadecanoic acid; 9,10-epoxy-18-hydroxyoctadecanoic acid; 9,10,18-trihydroxyoctadecanoic acid (phloionolic acid); 20-hydroxyeicasanoic acid; 22-hydroxydocosanoic acid; 18-hydroxyoctadec-9-enoic acid; docosandioic acid; and octadec-9-enedioic acid is obtained in a ratio of about 1.0-3.0:0-1.0:45.0-75.0:1.0-6.0:10.0-18.0:1.0-5.0:4.0-16.0:1.0-6.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([C:18]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:20]=3[N:19]=2)([CH2:15][CH:16]=[CH2:17])[CH3:14])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([C:13]([C:18]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:20]=3[N:19]=2)([CH2:15][CH:16]=[CH2:17])[CH3:14])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH2:7][CH2:6]2
Reactant: C=CCC(C)(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C=CCC(C)(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2c1CCN2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-2-(2-(5-methoxy-7-methyl-1H-indol-4-yl)pent-4-en-2-yl)-1H-benzo[d]imidazole-5-carbonitrile (Example 156-F) (150 mg, 0.405 mmol) in acetic acid (2.025 mL) was added sodium cyanoborohydride (38.2 mg, 0.607 mmol) and the reaction was stirred at room temperature for 1 hour. At this point the mixture was placed in an ice bath and quenched with NaOH (17.61 mL, 35.2 mmol) and then diluted with DCM. The layers were separated and the organic layer was dried over sodium sulfate, concentrated and absorbed onto silica and purified via FCC (0-100% EtOAc:heptanes) to give the title compound. MS (ESI+) m/z 373.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].CCN(C(C)C)C(C)C>N1C=CC=CC=1>[CH3:21][S:22]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Yield: 72.1 %

Procedure:
tert-Butyl 4-{(2-[(methylsulfonyl)amino]phenyl}-piperazinecarboxylate was prepared following the procedure for Preparation III using, tert-butyl 4-(2-aminophenyl)piperazinecarboxylate (4.4 g, 16 mmol), methanesulfonyl chloride (1.4 mL, 18 mmol) and DIEA (instead of pyridine) (3.1 mL, 18 mmol). The crude material was purified by flash chromatography (SiO2, 4:1 hexane:EtOAc) and concentrated in vacuo to afford the desired compound (4.1 g). MS (ESI, pos. ion) m/z: 356 (M+H), (ESI, neg. ion) m/z: 354 (M−H). Calc'd for C16H25N3O4S: 355.16.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O:16]C)=[O:15])[CH:11]=[N:10][C:9]=2[O:18][C@@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[CH:4][CH:3]=1.[Li+].[OH-].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[N:10][C:9]=2[O:18][C@@H:19]([CH3:24])[C:20]([F:22])([F:21])[F:23])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnc(O[C@@H](C)C(F)(F)F)c(-c2ccc(Cl)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](Oc1ncc(C(=O)O)nc1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
To a suspension of (S)-methyl 6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxylate (0.72 g, 2.00 mmol, Eq: 1.00) in tetrahydrofurane (7 ml) was added a 1M LiOH solution in water (2.59 ml, 2.59 mmol, Eq: 1.3) and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to remove tetrahydrofurane and diluted with water; acidified with 1M hydrochloric acid to pH 2 and extracted with ethyl acetate. The organic phase was dried with MgSO4; filtered, evaporated and dried to constant weight under high vacuum to yield the title compound as white solid (0.70 g, 100%). MS (EI): 345.0 (M−H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][O:29][CH3:30])=[CH:24][C:23]=2[CH2:31][OH:32])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].CI.[CH2:37](Cl)Cl>C1COCC1.[Cl-].[Na+].O>[CH3:37][O:32][CH2:31][C:23]1[CH:24]=[C:25]([CH2:28][O:29][CH3:30])[CH:26]=[CH:27][C:22]=1[CH2:21][N:9]1[CH:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: COCc1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(CO)c1
Reactant: ClCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: COCc1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(COC)c1
Yield: 64 %

Procedure:
To a cold (0° C.) solution of [2-(3,3″-Dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-5-methoxymethyl-phenyl]-methanol (0.085 g, 0.20 mmol) in THF (2 mL) was added a slurry of NaH (95% dry, 0.100 g, 4.17 mmol) in THF (2 mL) followed by neat MeI (0.25 mL, 4.02 mmol). The resultant mixture was stirred for 2.5 hours and treated with brine (5 mL) and CH2Cl2 (10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (4×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2—CH3OH—NH4OH) gave COMPOUND 55 (60 mg, 64%) as a colorless oil. 1H NMR (CDCl3) δ 1.65-1.73 (m, 3H), 2.00-2.07 (m, 1H), 2.20-2.41 (m, 8H), 3.21 (s, 6H), 3.56 (s, 2H), 3.97 (m, 2H), 4.18 (s, 2H), 4.22 (s, 2H), 6.77 (s,1H), 6.83-6.89 (m, 3H), 7.14-7.20 (m, 3H), 8.31 (d, 2H, J=3.6 Hz); 13C NMR (CDCl3) δ 19.22, 25.72, 28.37, 48.62, 57.85, 58.50, 66.60, 72.27, 74.68, 122.14, 125.94, 126.81, 129.51, 132.43, 135.29, 135.36, 138.11, 138.62, 146.56, 160.00; ES-MS m/z 446 (M+H). Anal. Calcd. For C28H35N3O2.0.3CH2Cl2: C, 72.16; H, 7.62; N, 8.92. Found: C, 71.88; H, 7.61; N, 8.95.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.CC(C)=O.C(O)C.[C-:28]#[N:29].[Na+]>O>[C:28]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1)#[N:29]
Reactant: [C-]#N
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: N#CCc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reaction time: 2 h

Procedure:
A solution of 5-bromomethyl-2-nitro-3-phenylbenzofuran (5 g., 0.015 mole) in 95 ml. of acetone is treated with 20 ml. of ethanol, and the mixture is heated to its reflux temperature. To this mixture is added 0.015 mole of sodium cyanide dissolved in 9 ml. of water, and refluxing is continued for about two hours. The mixture is evaporated under vacuum, then dichloromethane and water are added to the residue. The organic layer is separated, washed with water and dried. The organic layer is then evaporated under vacuum. The residue is purified by eluting twice with benzene through a silica gel column, followed by refluxing in 30 ml. of diethyl ether. The yellow precipitate is separated by filtration and recrystallized twice from benzene to provide 5-cyanomethyl-2-nitro-3-phenylbenzofuran, m.p. 166°-168° C.
Reaction SMILES: COC1C=CC(C[N:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[C:10]3[N:11]([CH:25]=[CH:26][N:27]=3)[N:12]=[C:13]([C:15]3[CH:24]=[CH:23][C:18]4[C:19]([NH2:22])=[N:20][O:21][C:17]=4[CH:16]=3)[CH:14]=2)=CC=1.C(O)(C(F)(F)F)=O>>[NH2:22][C:19]1[C:18]2[CH:23]=[CH:24][C:15]([C:13]3[CH:14]=[C:9]([NH:8][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:10]4[N:11]([CH:25]=[CH:26][N:27]=4)[N:12]=3)=[CH:16][C:17]=2[O:21][N:20]=1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(-c3ccc4c(N)noc4c3)nn3ccnc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1noc2cc(-c3cc(Nc4ccccc4)c4nccn4n3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of 6-(8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)benzo[d]isoxazol-3-amine from (1b) was added TFA (1 mL) and the solution stirred at RT for 1 hour. The reaction solution was concentrated in vacuo and then diluted with methanol and purified by preparative HPLC to provide the titled compound (3.90 mg, 17%). 1H NMR (500 MHz, CD3OD) δ ppm 8.26 (1H, s), 7.92 (1H, s), 7.86 (1H, d, J=8.6 Hz), 7.80 (1H, d, J=8.25 Hz), 7.52 (4H, m), 7.35 (1H, t, J=7.15 Hz), 7.27 (1H, s). LC/MS, m/e 343 (M+1). HPLC Rt, 2.52 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][N:9]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[CH2:10][CH2:11][N:12](C)[C:13](=O)OC(C)(C)C)=[O:4].C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:23]1[CH:22]=[C:21]([N:9]([CH2:10][CH2:11][NH:12][CH3:13])[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)NCCCN(CCN(C)C(=O)OC(C)(C)C)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCN(CCCNC(=O)OC)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
tert-butyl 2-((3-(methoxycarbonylamino)propyl)(3-chlorophenyl)amino)ethyl(methyl)carbamate (50 mg, 0.31 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 1 h, a solution of saturated sodium bicarbonate was added dropwise to adjust pH=7-8. The resulting mixture was extracted with CH2Cl2 (3×10 mL), washed with brine, dried over Na2SO4, concentrated in vacuo to afford methyl 3-((3-chlorophenyl)(2-(methylamino)ethyl)amino)propylcarbamate (40 mg, 95%).