Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:12]([O:16][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH2:13][C:14]#[CH:15]
Reactant: C#CCCO
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCOc1ccc(I)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 58.3 %

Procedure:
A mixture of 1-fluoro-4-iodo-2-nitro-benzene (5.0 g, 0.02 mol), 3-butyn-1-ol (1.57 ml, 0.02 mol) and potassium carbonate (2.86 g, 0.02 mol) in N,N-dimethylformamide (20 ml) was heated to 100° C. for 18 hours. After cooling the mixture was distributed between ethyl acetate (400 ml) and water (100 ml). The organic layer was separated, washed with water (2×100 ml) and brine (100 ml), dried over MgSO4, filtered and pre-absorbed onto a small amount of silica. Purification by FCC (silica, 0-15% ethyl acetate in heptanes) provided 3.7 g (56%) of the title compound. 1H NMR (250 MHz, CDCl3) 8 ppm 2.06 (1H, t, J=2.66 Hz), 2.75 (2H, td, J=7.16, 2.74 Hz), 4.22 (2H, t, J=7.08 Hz), 6.88 (1H, d, J=8.83 Hz), 7.81 (1H, dd, J=8.83, 2.28 Hz), 8.11 (1H, d, J=2.28 Hz).
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[N:9]=[C:10]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:11]([C:17](O)=O)=[N:12]2.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[N:9]=[C:10]([NH:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C:11]([C:17]1[O:3][C:1]([CH3:2])=[N:4][N:5]=1)=[N:12]2
Reactant: CC(=O)NN
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2nc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2nc3cccc(Br)c3nc2NC(C)(C)C)o1
Temperature: 90 °C
Yield: 45 %

Procedure:
Acetic hydrazide (33 mg, 0.44 mmol) and 5-bromo-3-(tert-butylamino)quinoxaline-2-carboxylic acid (371a) (130 mg, 0.40 mmol) were combined in EtOAc (4 mL) to give a yellow solution. TEA (0.17 mL, 1.20 mmol) was added followed by 1-propanephosphonic acid cyclic anhydride (Aldrich; 50 wt. % solution in EtOAc, 0.59 mL, 1.00 mmol). The reaction was sealed and heated in an oil bath at 90° C. for 16 h. The reaction mixture was cooled to RT, partitioned between saturated NaHCO3 and EtOAc. The aq. layer was extracted with EtOAc and the combined organic layers were washed with brine, and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was adsorbed onto 1 g silica gel and purified by silica gel chromatography (12 g column) using a gradient of 0-20% EtOAc/hexanes to afford 8-bromo-N-(tert-butyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)quinoxalin-2-amine (67 mg, 0.18 mmol, 46% yield) as a yellow solid. m/z (ESI, +ve ion) 362.0/364.0 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[F:32])[C:27]#[N:28].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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:32][C:31]1[C:30]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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: CCO
Product: C[C@H](Oc1ccc(-c2cc(C#N)ccc2F)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 88 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxyl]enzeneboronic acid (0.20 g, Example 33), 3-bromo-4-fluorobenzonitrile (0.27 g), 2M aqueous sodium carbonate (0.76 ml) and tetrakis(triphenylphosphine)palladium (0) (0.019 g) in ethanol (5 ml) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.22 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C-:14]#[N:15].[K+].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na].CCCCCC>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][C:5]([C:14]#[N:15])=[N:6][CH:7]=1
Reactant: CC(C)CNc1nc(Cl)ncc1Br
Reactant: [C-]#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [Na]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)CNc1nc(C#N)ncc1Br
Temperature: 75 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a solution of (5-bromo-2-chloro-pyrimidin-4-yl)-isobutyl-amine (11.2 mmol) in DMSO (30 ml) is added potassium cyanide (22.5 mmol) and sodium p-toluenesulfonic acid (3.75 mmol) in DMSO(17 ml) at room temperature. The mixture is stirred at 75° C. for 18 h and diluted with AcOEt. The organic layer is washed with water and brine, dried over sodium sulfate and concentrated. Chromatography on silica gel (n-hexane:AcOEt=25:1, 15:1 and 12:1) gives the product in 84% yield. Rf=46 (n-hexane:AcOEt=3:1)
Reaction SMILES: [O:1]=[C:2]1[CH2:6][N:5]2[C:7](=[O:10])[CH2:8][CH2:9][CH:4]2[N:3]1[CH2:11][C:12]([O:14]CC)=O.[NH3:17]>CO>[O:1]=[C:2]1[CH2:6][N:5]2[C:7](=[O:10])[CH2:8][CH2:9][CH:4]2[N:3]1[CH2:11][C:12]([NH2:17])=[O:14]
Reactant: N
Reactant: CCOC(=O)CN1C(=O)CN2C(=O)CCC12
Solvent: CO
Product: NC(=O)CN1C(=O)CN2C(=O)CCC12
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
A solution of ethyl 2,5-dioxohexahydropyrrolo[1,2-a]imidazole-1-acetate (1.4 g, 6.18 mmol), in methanol (25 ml) was saturated with ammonia at 0° C. After stirring at room temperature for 16 hours the precipitate was collected, washed with methanol and dried to yield 0.9 g (75%) of the title compound, m.p. 182°-185° C. NMR (DMSO-d6): deltaH =7.50 and 7.10 (2s, 2H, CONH2); 5.25 (c.a. 1H, N--CH--N); 3.94 and 3.55 (ABq, J=16 Hz, 2H, N--CH2CO); 3.85 and 3.70 (ABq, J=16.5 Hz, 2H, N--CH2CONH2); 2.90 and 1.90 (c.a., 4H, CH2CH2). MS (E.I., 70 eV, 1.5 mA) m/z=139 (M--CH2CONH2)+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:11][CH:10]=2)N)=[CH:4][CH:3]=1.CC([O-])=O.[Na+].CC(O)=O.[C:38]([S:42][CH2:43][C:44](=O)[CH2:45][C:46]([CH2:53][CH3:54])([CH2:51][CH3:52])[C:47]([O:49][CH3:50])=[O:48])([CH3:41])([CH3:40])[CH3:39]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:9]3[C:14](=[CH:13][C:12]([O:15][CH2:16][C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=4)=[CH:11][CH:10]=3)[C:43]([S:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[C:44]2[CH2:45][C:46]([CH2:53][CH3:54])([CH2:51][CH3:52])[C:47]([O:49][CH3:50])=[O:48])=[CH:4][CH:3]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CCC(CC)(CC(=O)CSC(C)(C)C)C(=O)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCC(CC)(Cc1c(SC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)OC
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-(4-chlorobenzyl)-1-[4-(quinolin-2-ylmethoxy)phenyl]hydrazine from Example 1A, Step D, (660 mg, 1.7 mmol) and anhydrous NaOAc (160 mg, 1.95 mmol) in toluene (3 mL) was added glacial HOAc (1.5 mL). After 30 minutes, a solution containing methyl 5-(t-butylthio)-2,2-diethyl-4-oxopentanoate from Step B (402 mg, 1.47 mmol) in toluene (1 mL) was added and the reaction mixture stirred for 24 hours at room temperature and for 48 hours at 65° C. The reaction was then diluted with EtOAc, washed with NH4OAc buffer (25% w/v) and dried over MgSO4. Filtration and concentration gave a viscous oil which was purified by flash chromatography on silica gel (eluant: EtOAc-hexane 15:85) to give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[O:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:12]([C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)[O:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)([O-:14])=[O:13]
Reactant: OCCN1CCOCC1
Reactant: O=[N+]([O-])c1cc(F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCCN2CCOCC2)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 10 h
Yield: 46.5 %

Procedure:
A mixture of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (800 mg, 3.83 mmol), 2-morpholinoethanol (552 mg, 4.21 mmol) and K2CO3 (1586 mg, 11.48 mmol) in DMF (20 mL) was stirred at 90° C. for 10 h. The mixture was concentrated. To the residue was added DCM (150 mL) and the mixture was stirred for 10 min and then filtered. The filtrate was concentrated. The residue was purified by silica column chromatography (PE/EA=10:1˜5:1). All fractions found to contain product by TLC (PE/EA=5:1, Rf=0.6) were combined and concentrated to yield a yellow solid of 4-(2-(3-nitro-5-(trifluoromethyl)phenoxy)ethyl)morpholine (600 mg, 1.780 mmol, 46.5% yield): 1H NMR (400 MHz, CDCl3): δ 8.02 (s, 1H), 7.87 (s, 1H), 7.43 (s, 1H), 4.16 (t, J=5.6 Hz, 2H), 3.72-3.63 (m, 4H), 2.79 (t, J=5.6 Hz, 2H), 2.58-2.47 (m, 4H). ES-LCMS m/z: 321 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[OH:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1>CN1CCCC1=O>[I:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:17]3[CH2:18][CH2:19][CH2:20][C@H:16]3[CH2:15][OH:14])=[CH:3][C:4]([CH3:13])=[N:5]2)=[CH:10][CH:9]=1
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1cc(Cl)c2ccc(I)cc2n1
Solvent: CN1CCCC1=O
Product: Cc1cc(N2CCC[C@H]2CO)c2ccc(I)cc2n1
Temperature: 100 °C
Yield: 63.8 %

Procedure:
A solution of 3.5 g (11.5 mmol) of 4-chloro-7-iodo-2-methylquinoline and 2.92 g (28.8 mmol) of (S)-2-(hydroxymethyl)pyrrolidine in 1-methyl-2-pyrrolidone (50 ml) was heated at 100° C. (oil bath temperature) for 24 h under an argon athmosphere. In order to complete the reaction, 2.2 ml of (S)-2-(hydroxymethyl)pyrrolidine were added and the solution was heated at 100° C. for further 24 h under argon. The solution was then concentrated in a vacuo (4 mbar) at 100° C. The residue was applied to silica gel column with CH2Cl2/MeOH/NH4OH (95:5:0.2) as eluent. Combination of the purified fractions and concentration in vacuo gave 2.7 g (64%) of the desired (S)-[1-(7-iodo-2-methyl-quinolin-4-yl)-pyrrolidin-2-yl]-methanol as light brown solid. ISP mass spectrum, m/e: 369.1 (M+1 calculated for C15H17IN2O: 369).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:46]=[C:45]2[C:40]([CH:41]=[CH:42][C:43](=[O:52])[N:44]2[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:46]=[C:45]3[C:40]([CH:41]=[CH:42][C:43](=[O:52])[N:44]3[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCn1c(=O)ccc2ccc(CCl)cc21
Product: COCCCn1c(=O)ccc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.262 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.148 g of 7-chloromethyl-1-(3-methoxypropyl)-1H-quinolin-2-one are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.28 (2:1 EtOAc-heptane); Rt=5.91.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([OH:16])[CH:14]=3)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=2)[CH:4]=[N:3]1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CC(C)=O>[CH2:26]([O:16][C:13]1[CH:14]=[C:15]2[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:8][N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]2=[N:11][CH:12]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(O)cc23)cn1
Reactant: CCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CCCCCCOc1cnc2c(c1)c(-c1cnn(C)c1)cn2COCC[Si](C)(C)C
Yield: 48.3 %

Procedure:
According to the general procedure using: 27 (60 mg, 0.174 mmol), 1-bromohexane (117 μL, 1.74 mmol), K2CO3 (241 mg, 1.74 mmol) and n-Bu4NI (6.4 mg, 17 μmol) in acetone (4.0 mL) were heated at reflux overnight. Purification by PTLC using AcOEt:hexane=6:4 (v/v) as eluent gave 281 as a clear oil (36 mg, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][C:7](C(O)=O)=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.N>>[Br:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1
Reactant: NCCc1c(C(=O)O)[nH]c2ccc(Br)cc12
Agent: N
Agent: O=S(=O)(O)O
Product: NCCc1c[nH]c2ccc(Br)cc12
Yield: 58 %

Procedure:
A mixture of 1.00 g. (3.53 mmoles) of 5-bromo-tryptamine-2-carboxylic acid and 80 ml. of 10% aqueous sulfuric acid is stirred and refluxed for 30 hours. The pH of the mixture is adjusted to 9 with concentrated aqueous ammonia under cooling in an ice bath, and the alkaline mixture is extracted with 4×20 ml. of chloroform. The organic extracts are combined, washed with 5% aqueous sodium hydroxide solution and then with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate is evaporated in vacuo. 0.48 g. (58%) of 5-bromo-tryptamine are obtained as an oily residue.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1Cl.[OH-:16].[K+]>C(O)C.O>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[OH:16]
Reactant: [OH-]
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=c1c(Cl)c(O)cnn1-c1ccccc1

Procedure:
4,5-Dichloro-2-phenylpyridazin-3-one (2.4 g, 0.01 moles) was suspended in ethanol (50 ml) and potassium hydroxide (2.0 g, 0.03 moles) was added in water (20 ml). Refluxed for 4 hours. Evaporated to dryness and added water. Acidified to pH2 with c. hydrochloric acid. Filtered off the product as a buff solid and dried in a desiccator. (2.1 g) Took 0.5 g and dissolved in methanol, filtered and evaporated. Triturated with ether to give the product as a cream solid. (0.4 g, 76%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH2:38][CH2:39][CH2:40][S:41]([CH3:44])(=[O:43])=[O:42]>>[F:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][CH2:39][CH2:40][S:41]([CH3:44])(=[O:43])=[O:42])[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)CCN
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Product: CS(=O)(=O)CCNc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.101 g, 0.178 mmol) and 2-aminoethyl-methyl-sulfone (0.30 g, 2.436 mmol) the title compound was obtained as a yellow solid (72 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 7.93 (d, J=5.3 Hz, 1H), 7.62-7.75 (m, 1H), 7.36-7.51 (m, 1H), 7.17-7.36 (m, 5H), 5.72 (d, J=5.3 Hz, 1H), 3.71 (t, J=4.6 Hz, 4H), 3.59-3.68 (m, 2H), 3.46 (t, J=4.6 Hz, 4H), 3.34 (s, 2H), 3.02 (s, 3H). MS (ESI): 655.2 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:5]=[C:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])[NH:7][C:8]=1[CH3:9])[CH3:3].C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[CH2:2]([C:4]1[NH:5][C:6]2[N:7]([C:8]=1[CH3:9])[C:23](=[O:26])[CH:24]=[CH:25][C:10]=2[C:11](=[O:12])[C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)[CH3:3]
Reactant: CCc1nc(CC(=O)c2ccc(F)cc2)[nH]c1C
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CCc1[nH]c2c(C(=O)c3ccc(F)cc3)ccc(=O)n2c1C

Procedure:
The compound is prepared as described in example 20 with 200 mg (0.71 mmol) of 2-(4-Ethyl-5-methyl-1H-imidazol-2-yl)-1-(4-fluorophenyl)ethanone hydrochloride (example XVIII), 50 mg (0.92 mmol) of sodium methylate and 59.5 mg (0.71 mmol) methyl propiolate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C@H:16]3[O:25][C@@H:19]4[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@@H:18]4[C@@H:17]3[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C@H:16]3[O:25][C@@H:19]4[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@@H:18]4[C@@H:17]3[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@H]1[C@H]2OC(C)(C)O[C@H]2O[C@@H]1/C=C/c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H]1[C@H]2OC(C)(C)O[C@H]2O[C@@H]1CCc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the compound obtained from step g above (0.8 g) in ethyl acetate (15 mL), 10% palladium on charcoal (0.25 g) was added at room temperature. The system was evacuated with hydrogen and the reaction mixture was stirred for 4 hours at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through a celite pad, and concentrated to afford the title compound (0.75 g).
Reaction SMILES: C[O:2][C:3](=[O:48])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([O:29][CH2:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:36][CH:35]=2)[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[C:42]1([CH2:41][O:40][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH2:32][CH2:31][CH2:30][O:29][C:6]3[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]4[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:19][CH:20]=4)[CH:7]=3)[C:3]([OH:48])=[O:2])=[CH:35][CH:36]=2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COC(=O)c1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(OCCCOc2ccc(OCc3ccccc3)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(OCCCOc2ccc(OCc3ccccc3)cc2)c1
Yield: 93.8 %

Procedure:
A solution of 1.5 g (2.3 mmol) of 3,5-bis[3-[4-(phenylmethoxy) phenoxy]propoxy]benzoic acid methyl ester (prepared in Example 46) and 1.2 ml (7.2 mmol) of 6N NaOH in 25 ml of methanol and 10 ml of dioxane was stirred at reflux under argon for 19 hours. The solvents were removed at reduced pressure, the residue was acidified and the product was extracted with ethyl acetate. The dried extract was concentrated to a solid which was recrystallized from acetone-hexane to give 1.37 g (93% yield, mp 139°-140°) of 3,5-bis[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([OH:16])[C:13]([O:17][CH3:18])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH3:31])=[CH:25][C:23]=1[NH2:24].Cl.N1C=CC=CC=1>C(OCCO)C.C(=O)(O)[O-].[Na+]>[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH3:31])=[CH:25][C:23]=1[NH:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([OH:16])[C:13]([O:17][CH3:18])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20]
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2cc3c(Nc4cc(OC)c(Cl)cc4Cl)c(C#N)cnc3cc2cc1O
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
A mixture of 0.7 g (2.46 mmol) of 4-chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.57 g (2.95 mmol) of 2,4-dichloro-5-methoxyaniline and 0.28 g (2.46 mmol) of pyridine hydrochloride in 7 mL of 2-ethoxyethanol is heated at 120° C. for 2 hours, then cooled to room temperature. The product mixture is diluted with saturated solution of sodium bicarbonate and stirred for 15 minutes. The resulting solid is collected by filtration, washed with water and dried. The crude product is purified by silica gel chromatography, utilizing a 98:2 to 90:10 gradient of methylene chloride/methanol to give 0.71 g of 4-(2,4-dichloro-5-methoxyphenylamino)-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile as a yellow solid, mp, 238–240° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[CH3:17][N:18]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([O:34][CH3:35])[C:28](N(OC)C)=[O:29])=[CH:23][CH:22]=1)[CH3:19]>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:28](=[O:29])[CH:27]([C:24]3[CH:25]=[CH:26][C:21]([CH2:20][N:18]([CH3:19])[CH3:17])=[CH:22][CH:23]=3)[O:34][CH3:35])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(CN(C)C)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(CN(C)C)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(4-((dimethylamino)methyl)phenyl)-2-methoxyethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and 2-(4-((dimethylamino)methyl)phenyl)-N,2-dimethoxy-N-methylacetamide according to the procedure used in Example 30. Purification by chromatography (4% MeOH/CH2Cl2) gave the product as a pale yellow oil (0.004 g, 1% yield). MS: ink 488.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:14][C:15]#[N:16])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CN(C=O)C.CCCCCC>[CH3:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:14][C:15]1[NH:24][N:23]=[N:22][N:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CC#N)cc1OCc1c(C)cccc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(Cc2nnn[nH]2)cc1OCc1c(C)cccc1C
Temperature: 90 °C

Procedure:
A mixture of 2-(3-(2,6-Dimethylbenzyloxy)-4-methoxyphenyl)acetonitrile (Step E, 2.17 g, 7.5 mmol), sodium azide (0.590 g, 9.1 mmol) and ammonium chloride (0.486 g, 9.1 mmol) in dry DMF (20 ml) was heated under argon at 90° C. for 16 hours or until all the starting material is consumed, the reaction mixture was cooled, diluted with water and extracted with EtOAc (30 ml×4). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol 95:5) to give semi solid product. The semi solid was stirred with 1:2 ethyl acetate:hexane (15 ml) for 10 minutes, and filtered to give product as a white solid.