Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][N:36]=2)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:38]2[CH:37]=[N:36][C:35]([N:32]3[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]3)=[CH:40][CH:39]=2)[CH:3]=1)=[O:16]
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C)CC4)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1

Procedure:
To a stirred solution of 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (2 g, 4.65 mmol) in DMF (100 mL) was added 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (1.55 g, 5.12 mmol) followed by a solution of sodium carbonate (1.23 g, 11.62 mmol) in water (10 mL) and the contents were degassed with argon for 30 min. After that PdCl2(PPh3)2 (326 mg, 0.464 mmol) was added and the contents again degassed with argon for 10 min. The reaction mixture was stirred at reflux for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude product (2.8 g). The crude compound was purified by column chromatography over silica gel (100-200 mesh, eluent: 0-10% MeOH: DCM), and the obtained product was further triturated with diethyl ether (100 mL) to afford the title compound as an off white solid (1.2 g, 50%). 1H NMR (DMSO-d6, 400 MHz): δ 1.493 (d, J=6.4 Hz, 6H), 2.092 (s, 3H), 2.286 (s, 3H), 2.409 (s, 3H), 2.424 (s, 3H), 2.632 (s, 4H), 3.621 (s, 4H), 4.603-4.685 (m, 3H), 5.880 (s, 1H), 6.606 (d, J=8.8 Hz, 1H), 7.016 (s, 1H), 7.261 (s, 1H), 7.433 (s, 1H), 7.675-7.704 (dd, J=9 Hz, 2.4 Hz, 1H), 8.425 (d, J=2.0 Hz, 1H), 11.699 (brs, 1H); LCMS (ES+): 525.23 [M−H].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([F:16])=[CH:4][N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([NH2:26])[CH:21]=[N:22][C:23]=1[O:24][CH3:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:16][C:5]1[CH:6]=[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[C:2]([NH:26][C:20]2[CH:21]=[N:22][C:23]([O:24][CH3:25])=[C:18]([F:17])[CH:19]=2)=[N:3][CH:4]=1
Reactant: COc1ncc(N)cc1F
Reactant: Cc1nc(N)nc(-c2cc(F)cnc2Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(F)cc2-c2nc(C)nc(N)n2)cc1F
Reaction time: 0.08 h
Yield: 41.7 %

Procedure:
A solution of 4-(2-chloro-5-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (100 mg, 0.417 mmol) and 5-fluoro-6-methoxypyridin-3-amine (120 mg, 0.844 mmol) (Anichem, NJ, USA) in THF (2.0 mL) was cooled in an ice bath under nitrogen. A THF solution of LiHMDS (1 M in THF, 2500 μL, 2.500 mmol) was added dropwise. After 5 min, the cooling bath was removed. After a total of 22 min, HCl (5 N, 0.5 mL) was added. After 5 min, EtOAc (10 mL) and saturated NH4Cl (10 mL) were added. The organic layer was washed with water (2×5 mL). The combined aqueous layers were extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was suspended in MeOH (5 mL) and filtered. The solid was washed with MeOH (2×2 mL), DCM (3×3 mL) and EtOAc (3×3 mL) to give the first batch of product as a brown solid. The combined washings were concentrated and purified on silica using 0-3% MeOH in DCM. The dark blue fraction contained the desired product (m/z 346) as a second batch. The combined product batches was suspended in ether (4 mL) and filtered to give the final product as a green solid (60 mg). LCMS (ES, pos.): calcd for C15H13F2N7O: 345.1. found: 346.2 (M+H)−. 1H NMR (400 MHz, d6-DMSO) δ 11.78 (s, 1H); 8.56 (dd, J=9.78, 2.93 Hz, 1H); 8.38 (br. s., 2H); 8.28 (dd, J=12.81, 1.86 Hz, 1H); 7.97 (br. s., 1H); 7.84 (br. s., 1H); 3.93 (s, 3H); 2.44 (s, 3H). 19F NMR (377 MHz, d6-DMSO) δ −140.84 (s, 1 F); −139.70 (s, 1 F).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1.[CH2:39](I)[CH3:40]>O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[O:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]([CH2:39][CH3:40])[C:30](=[O:38])[O:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:27][CH:28]=1
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCCC4)cc3)c2cc1OC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OC1CCCCC1)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (7 mg), and cyclohexyl N-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (35 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of ethyl iodide (52 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (35 mg, yield 93%).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([OH:26])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].C(N(CC)CC)C.[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>CN(C)C=O>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][C:38](=[O:39])[NH:37][CH2:35][CH3:36])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CCN=C=O
Reactant: CN(C)CCNC(=O)c1cccc2nc3ccc4c(O)cccc4c3nc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Oc1cccc2c1ccc1nc3cccc(C(=O)NCCN(C)C)c3nc12

Procedure:
A mixture of 4-hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide: hydrobromide salt (540 mg), triethylamine (0.51 mL) and ethyl isocyanate (0.29 mL) was stirred in dry N,N-dimethylformamide (3 mL). The product slowly precipitated from the reaction mixture and was collected by filtration and washed with ether to yield the title compound as a yellow solid (210 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Br:11]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[C:3]=1[CH2:10][Br:11]
Reactant: Cc1c(Cl)cccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cccc(Cl)c1CBr
Yield: 46 %

Procedure:
To a refluxing solution of 3-chloro-2-methylbenzonitrile (2.0 g, 13.2 mmol) in 20 mL of CCl4 was added 2.6 g (14.4 mmol, 1.1 eq) of N-bromosuccinimide and 0.2 g of AIBN. The solution was refluxed for 3 hours and then cooled, diluted with 500 mL of CH2Cl2 and washed with 200 mL of H2O and 200 mL of brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resultant oil was flash chromatographed with 5:1 hexane/ethyl acetate to yield the titled compound (1.4 g, 46%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]([NH2:10])=[C:8]([C:11]2[C:15](=[NH:16])[N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:13](=[O:26])[N:12]=2)[N:7]=[CH:6]1.[CH:31](OCC)(OCC)OCC>CC#N.S(=O)(=O)(O)O>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:14]2[C:15]3=[N:16][CH:31]=[N:10][C:9]4[N:5]([CH2:4][C:3]5[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=5[Cl:1])[CH:6]=[N:7][C:8]=4[C:11]3=[N:12][C:13]2=[O:26])=[CH:19][CH:20]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc(CN2C(=N)C(c3ncn(Cc4ccccc4Cl)c3N)=NC2=O)cc1
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: COc1ccc(Cn2c3ncnc4c(ncn4Cc4ccccc4Cl)c-3nc2=O)cc1
Yield: 83.6 %

Procedure:
To a suspension of 20 (3.5 g, 8.29 mmol, 1 equiv) in MeCN (30 mL), triethyl orthoformate (6.2 mL, 41.46 mmol, 5 equiv) was added followed by 4 drops of sulfuric acid. The reaction mixture was heated at reflux for 1.5 h until starting material was disappeared (TLC). The precipitated product was filtered, washed with diethyl ether and dried under vacuum to afford the pure product 21 (RK-12) as a pale yellow solid (3 g, 85%). IR: 1745 (C═O str.), 1621, 1586, 1248, 1171, 759 (C—Cl str.) cm−1. 1H NMR (400 MHz, d6-DMSO): δ=3.71 (s, 3H, OCH3), 5.09 (s, 2H, CH2), 5.68 (s, 2H, CH2), 6.86 (d, J=8.7 Hz, 2H, Ar—H), 6.98-6.99 (m, 1H, Ar—H), 7.25-7.27 (m, 1H, Ar—H), 7.30 (d, J=8.7 Hz, 2H, Ar—H), 7.34-7.38 (m, 1H, Ar—H), 7.53-7.55 (m, 1H, Ar—H), 8.70 (s, 1H, Ar—C═N—H), 8.86 (s, 1H, Imid-H). MS (ESI+ve) m/z: 433.2 (M+H)+, 455.1 (M+Na)+.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH2:8]([O:10][C:11](=[O:19])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[CH3:9].Cl>CN(C=O)C.O>[CH2:8]([O:10][C:11](=[O:19])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:7][S:4]([CH3:3])(=[O:6])=[O:5])[CH3:9]
Reactant: CCOC(=O)COCCCCBr
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COCCCCNS(C)(=O)=O
Temperature: 100 °C
Yield: 17.1 %

Procedure:
To a mixture of NaH (60% in oil, 167 mg, 4.18 mmol) and DMF (10 mL) was added a solution of methanesulfonamide (398 mg, 4.18 mmol) in DMF (5 mL). The mixture was heated at 100° C. for 1.5 h and was cooled to room temperature. A solution of (4-bromo-butoxy)-acetic acid ethyl ester (1.000 g, 4.182 mmol) in DMF (10 mL) was added and the reaction was heated at 100° C. for 21 h. Water was added to the cooled reaction mixture and the aqueous solution was acidified to pH=2 with concentrated HCl. The aqueous solution was extracted with EtOAc (4×) and the organic solution was dried (MgSO4), filtered, and concentrated. The product was purified by flash chromatography (60% EtOAc/hexanes) to afford the title compound (181 mg). 1H NMR (400 MHz, CDCl3) δ 4.90 (m, 1H), 4.20 (q, 2H), 4.04 (s, 2H), 3.54 (m, 2H), 3.16 (m, 2H), 2.93 (s, 2H), 1.69 (m, 4H), 1.26 (t, 3H); MS 254.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8](Cl)=[O:9].[CH3:22][NH:23][CH3:24]>O1CCCC1.O>[CH3:22][N:23]([CH3:24])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=2[F:1])[CH:6]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 3-(2,4-difluorophenoxy)-4-nitrobenzoyl chloride (2.2 g) in tetrahydrofuran (8 ml) was added dropwise to a stirred solution of dimethylamine (50% in water; 2 ml) in water (10 ml) at 5° C. The mixture was stirred for 30 minutes at 5° C. and for 1 hour at room temperature. The mixture was concentrated and extracted with chloroform. The extract was washed with water, dried, and concentrated under reduced pressure. The residue (2.4 g) was solidified with a mixture of hexane and ethanol to give pale brown powder of N,N-dimethyl-3-(2,4-difluorophenoxy)-4-nitrobenzamide (2.0 g).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[C:10]([C:20]([F:23])([F:22])[F:21])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1([C:30]2N=C(C(N3CCCCCC3)=O)C3[C:32](=[CH:33]C=CC=3)[N:31]=2)C=CC=CC=1>>[CH2:30]([N:31]([CH2:32][CH3:33])[C:17]([C:15]1[C:14]2[C:9](=[C:10]([C:20]([F:21])([F:23])[F:22])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=1)=[O:19])[CH3:24]
Reactant: O=C(O)c1cc(-c2ccccc2)nc2c(C(F)(F)F)cccc12
Reactant: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCCCCC1
Product: CCN(CC)C(=O)c1cc(-c2ccccc2)nc2c(C(F)(F)F)cccc12

Procedure:
The 2-phenyl-8-trifluoromethylquinoline-4-carboxylic acid can be prepared by the process described by D. W. BOYKIN et al., J. Med. Chem., 11 (2), 273-277 (1968).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([CH2:37][OH:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH3:2].[C:39](Cl)(=[O:41])[CH3:40]>>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOc1cc(CC(=O)NC(CO)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1
Product: CCOc1cc(CC(=O)NC(COC(C)=O)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1

Procedure:
Prepared analogously to Example 37 from benzyl 2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate with acetyl chloride. Calculated: molecular peak m/e=558; Found: molecular peak m/e=558
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH:13](OS(C)(=O)=O)[CH3:14])[CH2:9]2)=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.ClC1C=CC(N2CCC(C(OS(C3C=CC(C)=CC=3)(=O)=O)C)C2)=C([N+]([O-])=O)C=1.[N-:51]=[N+:52]=[N-:53].[Na+]>CN(C)C=O.O>[N:51]([CH:13]([CH:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N+:20]([O-:22])=[O:21])[CH2:9]1)[CH3:14])=[N+:52]=[N-:53]
Reactant: CC(OS(C)(=O)=O)C1CCN(c2ccc(Cl)cc2[N+](=O)[O-])C1
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)OC(C)C2CCN(c3ccc(Cl)cc3[N+](=O)[O-])C2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(N=[N+]=[N-])C1CCN(c2ccc(Cl)cc2[N+](=O)[O-])C1
Temperature: 80 °C
Yield: 88.3 %

Procedure:
A mixture of methanesulfonic acid 1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethyl ester (285.9 mg), toluene-4-sulfonic acid 1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethyl ester (55.2 mg) and sodium azide (185 mg) in N,N-dimethylformamide (ca. 5 mL) was heated at 80° C. overnight. The reaction mixture was cooled, diluted with water and extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 90/10) to give 214 mg (76% yield) of 3-(1-azido-ethyl)-1-(4-chloro-2-nitro-phenyl)-pyrrolidine.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].CS([C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][N:26]=1)(=O)=O.O>C1COCC1>[CH3:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([O:14][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)=[N:26][CH:27]=1)(=[O:33])=[O:32]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Oc3ccccc3)cc2)nc1
Yield: 88 %

Procedure:
To 4.75 g of 4-phenoxyphenol dissolved in a 20 ml THF/20 ml DMSO mixture was added 2.9 g of t-BuOK and then 6.0 g of 2,5-bis(methylsulfonyl)pyridine, and the resulting mixture heated at 58° C. for 11/2 hrs. The reaction mixture was cooled overnight and then poured into 200 ml of water and stirred. A pink-white solid precipitated which was recovered and then dried on a porous plate. Recrystallization and ethanol/CH2Cl2 gave purified 5-(methylsulfonyl)-2-(4-phenoxyphenoxy)pyridine, (88% yield), as slightly pink shiny plates, m.p. 136.5°-138° C.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19](O)=[O:20])=[CH:14][C:13]=3[CH:22]=2)=[CH:5][CH:4]=1.[CH3:24][N:25]([CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[CH3:1][N:2]([CH3:23])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([NH:37][C:36]4[CH:38]=[CH:39][C:33]([CH2:32][N:25]([CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH3:24])=[CH:34][CH:35]=4)=[O:20])=[CH:14][C:13]=3[CH:22]=2)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCO3)cc1
Temperature: 25 °C
Yield: 28.2 %

Procedure:
To a solution of 7-(4-dimethylaminophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4-(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.11 g) and triethylamine (0.2 ml) in dimethylformamide (15 ml) was added diethyl cyano-phosphate (0.11 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-(4-dimethylaminophenyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 149) (0.07 g) as pale brown crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].CCO[C:29]([CH3:31])=[O:30]>CN1C(=O)CCC1>[F:22][C:21]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][N:18]2[CH3:23])=[CH:14][C:13]=1[C@@H:11]([C:8]1[N:6]2[N:7]=[C:2]([N:10]3[CH2:9][CH2:8][N:6]([CH3:5])[C:29](=[O:30])[CH2:31]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: C[C@@H](c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Reactant: CCOC(C)=O
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C[C@@H](c1cc2cnn(C)c2cc1F)c1cnc2ccc(N3CCN(C)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 5 h

Procedure:
6-Chloro-3-[(S)-1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Intermediate E, 50.0 mg, 0.152 mmol), KF (26.4 mg, 0.455 mmol) and 1-methylperazine-2-one hydrochloride (51.9 mg, 0.455 mmol) were suspended in NMP (1 mL). The RM was stirred at 180° C. for 5 h. The mixture was diluted with EtOAc and washed with NaHCO3 10% (2×) and water (4×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afforded the title compound as a light brown foam (tR 3.66 min (conditions 5), (tR 12.22 min (conditions 2), MH+=408.2, 1H-NMR in DMSO-d6: 7.92 (s, 1H); 7.83 (d, 1H); 7.49 (m, 3H); 7.11 (d, 1H); 4.78 (m, 1H); 4.00 (d, 1H); 3.95 (s, 3H); 3.86 (d, 1H); 3.67 (m, 2H); 3.30 (m, 2H); 2.80 (s, 3H); 1.71 (d, 3H)).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[CH3:44][C:45]1[S:46][C:47]([CH3:54])=[C:48]([CH2:50][C:51](O)=[O:52])[N:49]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[CH3:44][C:45]1[S:46][C:47]([CH3:54])=[C:48]([CH2:50][C:51]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:52])[N:49]=1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1nc(CC(=O)O)c(C)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1nc(CC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c(C)s1
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 2-(2,5-dimethyl-1,3-thiazol-4-yl)acetic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH: CH2Cl2 3:97) to afford 2-(2,5-dimethyl-1,3-thiazol-4-yl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.7 g, 76%) as a white solid: mp 140-142° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=1.39 min. (99%); 1H NMR (DMSO-d6) δ 2.04-2.09 (m, 1H), 2.31 (s, 3H), 2.56 (s, 3H), 2.51-2.63 (m, 2H), 2.84-2.91 (m, 1H), 3.56 (s, 2H), 4.73 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.76-7.85 (m, 3H), 8.58 (t, J=6.0 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 10.84, 18.56, 21.95, 30.91, 35.85, 37.94, 48.82, 121.81, 127.03, 127.91, 131.46, 133.21, 134.60, 139.26, 145.51, 160.87, 166.94, 167.48, 169.51, 169.79, 172.73; Anal. Calcd. for C21H20N4O5S: C, 57.27; H, 4.58; N, 12.72; S, 7.28. Found: C, 57.13; H, 4.71; N, 12.45; S, 7.18.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.[PH2:25]([O-:27])=[O:26].[Na+]>O>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])=[CH:6][C:7]=1[PH:25](=[O:26])[OH:27])([O-:13])=[O:12]
Reactant: O=[PH2][O-]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[PH](=O)O

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (1.8 g, 4.97 mmol), sodium hypophosphite (0.88 g, 9.94 mmol) and cupric sulfate (180 mg) in 20 ml of methyl nitrile/water (4:1) is heated under reflux for 24 hours. The reaction is poured into water, extracted with methylene chloride, dried and chromatographed (silica gel, eluting with 10% methanol/chloroform) to yield 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid.
Reaction SMILES: [OH-].[Na+].Cl.[N+:4]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[NH:12])=[CH:9][CH:8]=1)([O-:6])=[O:5].[Cl:16][C:17]([SH:20])(Cl)Cl.ClCCl>O>[Cl:16][C:17]1[S:20][N:13]=[C:11]([C:10]2[CH:9]=[CH:8][C:7]([N+:4]([O-:6])=[O:5])=[CH:15][CH:14]=2)[N:12]=1
Reactant: N=C(N)c1ccc([N+](=O)[O-])cc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2nsc(Cl)n2)cc1
Reaction time: 2 h
Yield: 40.3 %

Procedure:
A solution of 75.6 gm of sodium hydroxide in 100 ml of water was added to a stirred mixture of 101.4 gm of p-nitrobenzamidine hydrochloride, 70 gm of perchloromethyl mercaptan and 760 ml of dichloromethane, while keeping the temperature below -5° C. After additional 2 hours at -5° C., the resulting suspension was filtered, and the organic phase was separated, evaporated to dryness, and the residual solid was recrystallized from 95% ethanol, yielding 45 gm of the title compound, m.p. 143°-145° C.