Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[O:36])[CH:30]=[CH:31][C:32]=1[F:33].C(N(CC)CC)C.Cl>C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:36])[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(F)c(Cl)c4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.50 g, 1.80 mmol) and 3-chloro-4-fluorophenylisocyanate (0.31 g, 1.80 mmol) in acetonitrile (20 mL), was added triethylamine (0.51 mL, 3.60 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (20 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give 1-(3-chloro-4-fluoro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.47 g, 78% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.40 min (98.65%); mp: 224-226° C.; 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 1H), 2.29-2.47 (m, 1H), 2.55-2.66 (m, 1H), 2.81-3.01 (m, 1H), 4.31 (m, J=17.2 Hz, 1H), 4.37-4.53 (m, 3H), 5.11 (dd, J=13.2, 5.1 Hz, 1H), 6.86 (t, J=5.9 Hz, 1H), 7.18-7.33 (m, 2H), 7.44 (d, J=7.9 Hz, 1H), 7.52 (s, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.78 (dd, J=6.8, J=1.7 Hz, 1H), 8.88 (s, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.1, 42.7, 47.0, 51.5, 116.6 (d, J=22.0 Hz), 117.8 (d, J=6.6 Hz), 119.0 (d, J=11.0 Hz), 121.9, 122.9, 126.9, 130.3, 137.7 (d, J=3.3 Hz), 142.3, 144.6, 150.2, 153.4, 155.0, 167.9, 170.9, 172.8; LCMS: MH=445/447; Anal Calcd for C21H18ClFN4O4: C, 56.70; H, 4.08; N, 12.59. Found: C, 56.54; H, 3.93; N, 12.23.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:30]([SnH:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33]>>[F:17][C:2]([F:1])([F:16])[C:3]([O:11][Si:12]([CH3:14])([CH3:15])[CH3:13])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4]/[CH:5]=[CH:6]/[Sn:34]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(CCCC)(O[Si](C)(C)C)C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(O[Si](C)(C)C)C(F)(F)F

Procedure:
A stirred mixture of 6.66 g. of 4-trifluoromethyl-4-trimethylsiloxy-1-octyne and 26 mg. of azobisisobutyronitrile, under argon, is treated with 6.95 ml. of tri-n-butyl tin hydride, via a syringe. After treatment, a condenser is attached to the reaction vessel and the reaction mixture, under argon, is slowly heated to 130°-135° C. and maintained at this temperature for 1.5 hours. Subsequent fractional distillation of the reaction mixture at approximately 0.07 mm pressure gives the desired product, b.p. 125°-135° C. (containing a minor amount of the corresponding cis isomer).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12](O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8](/[CH:11]=[CH:12]/[C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)CS(=O)(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(/C=C/S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 68 %

Procedure:
A solution of 4-chlorophenyl sulfonylacetic acid (0.01 mol) and 4-methoxybenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 68-70% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][NH:11][CH:12]=1.[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][N:11]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1ccccc1-c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.1 %

Procedure:
To a solution of 4-(2-bromophenyl)-1H-imidazole (880 mg, 3.94 mmol) in 10 mL DMF, were added TEA (0.605 mL, 4.34 mmol) and trityl chloride (1.21 g, 4.34 mmol). The mixture was stirred at rt for 14 h, then diluted with EtOAc. The organic phase was washed with H2O (2×) and brine, dried (Na2SO4), filtered through a 1″ pad of silica gel and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 1.34 g of Intermediate 217.1 as an off-white solid. LCMS (50 to 100% B, 4 min gradient, A 95% H2O/5% CH3CN/0.1% TFA, B=5% H2O/95% CH3CN/0.1% TFA) RT=0.77 min, 465.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([O:22]CC)=O)[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:36][NH2:37]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH:36][NH2:37])=[O:22])[CH2:17][CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)CC1

Procedure:
Synthesized according to General Procedure C: 6{10} (2.02 g, 4.26 mmol, 1 equiv.), anhydrous hydrazine (0.40 mL, 12.8 mmol, 3 equiv.), ethanol (8.6 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{10} (3.00 g, 81%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.13 (br s, 1H), 7.45-7.44 (m, 4H), 7.37-7.33 (m, 4H) 7.31-7.27 (m, 2H), 6.92 (d, 1H, J=2.0 Hz), 6.87 (d, 1H, J=8.0 Hz), 6.77 (dd, 1H, J=2.0, 8.0 Hz), 5.17 (s, 2H), 5.15 (s, 2H), 3.84 (br s, 2H), 3.39 (s, 2H), 3.06 (s, 2H), 2.48 (br s, 4H), 2.37 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.5, 148.6, 148.1, 137.3, 137.3, 131.1, 128.4, 128.3, 127.7, 127.6, 127.3, 127.2, 122.0, 116.0, 114.6, 71.3, 71.1, 62.3, 60.5, 53.6, 52.8.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]([F:33])([F:32])[C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:14][O:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>CS(C)=O.C(OCC)(=O)C>[F:9][C:10]([F:32])([F:33])[C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:27]=1)[CH2:14][O:15][CH2:16][C:17]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:2][O:18]1
Reactant: C[S+](C)(C)=O
Reactant: O=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CO2)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
Trimethylsulfoxonium iodide (185 mg, 0.84 mmol) was dissolved in anhydrous dimethylsulfoxide (2 ml). Sodium hydride (60 wt % in mineral oil, 36 mg, 0.9 mmol) was added to the solution and followed by addition of (2-(3,5-bis(trifluoromethyl)benzyloxy)-1-phenylethanone). After stirred for 1 hour, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried with magnesium sulfate, concentrated, and the residue was purified by flash chromatography on silica gel to give the desired product. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 7.76 (s, 1 H) 7.69 (s, 2 H) 7.40–7.45 (m, 2 H) 7.34–7.39 (m, 2 H) 7.30–7.34 (m, 1 H) 4.65–4.72 (m, 2 H) 4.23 (d, J=11.90 Hz, 1 H) 3.79 (d, J=11.60 Hz, 1 H) 3.11 (d, J=5.19 Hz, 1 H) 2.82 (d, J=5.19 Hz, 1 H); LRMS [ESI, MNa+] m/z calcd for C18H14O2F6Na 399.08, found 398.97.
Reaction SMILES: N[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([F:15])[C:3]=1C=NO.[C:19](OCC)(=[O:21])C>C(O)C.C(O)(=O)C.[Ni]>[F:15][C:4]1[CH:3]=[C:2]([CH:19]=[O:21])[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)c(C=NO)c1F
Agent: [Ni]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ccc(C=O)cc1F
Reaction time: 1 h
Yield: 56 %

Procedure:
tert-Butyl 4-amino(hydroxyimino)methyl-2-fluorobenzoate (WO 2011/016469) (3.90 g, 17.6 mmol) was dissolved in ethanol (40 mL) and acetic acid (40 mL). Raney nickel (ca. 10 g) was added to the mixture at room temperature, and the resulting mixture was stirred for 1 hour under hydrogen flow. After the insoluble material was removed by filtration through Celite, water was added to the filtrate, and the resulting mixture was extracted three times with ethyl acetate, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then water and a saturated aqueous solution of sodium hydrogen carbonate were added to the mixture. The resulting mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→2:1, v/v) to give the title compound (2.21 g, yield: 56%).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:20]#[CH:21])[CH:19]=1)[C:15]#[N:16].N>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:20]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:21]=2)[CH:19]=1)[C:15]#[N:16]
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1cc(Cl)cc(C#N)c1
Agent: N
Product: N#Cc1cc(Cl)cc(-c2cc(-c3cccnc3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and the product of Example 66A (82 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.62 (ddd, J=8.0, 4.9, 0.7 Hz, 1H), 7.97 (s, 1H), 8.24 (dd, J=2.0, 1.4 Hz, 1H), 8.28 (dt, J=8.1, 1.9 Hz, 1H), 8.34 (t, J=1.7 Hz, 1H), 8.41 (t, J=1.4 Hz, 1H), 8.75 (dd, J=4.7, 1.7 Hz, 1H), 9.09 (d, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 282 (M+H)+, 284 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]([N:8]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:9][CH2:10][C:11]([O:13]CC)=O)=[O:7])[CH3:2].[O-]CC.[Na+]>C(O)C>[CH:16]1([N:8]2[CH2:9][CH2:10][C:11](=[O:13])[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:22])[C:6]2=[O:7])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)CCN(C(=O)CC(=O)OCC)C1CCCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1C(=O)CCN(C2CCCCC2)C1=O

Procedure:
N-Cyclohexyl-N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester (5.40 g, 17.2 mmol) was heated with sodium ethoxide (2.34 g, 3.44 mmol) in refluxing ethanol (100 ml) for 3 hours. The cooled solution was concentrated, water (100 ml) was added and the solution washed with ether then isohexane. It was acidified with c. sulphuric acid to pH 2. The oily precipitate was extracted into dichloromethane, washed with brine, dried (MgSO4) and concentrated to a yellow oil weighing 3.6 g (67%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][SH:8])[CH2:4][CH3:5])[CH3:2].[CH:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17](Br)[CH3:18])[CH2:13][CH2:12]1)=[O:10]>CO.[OH-].[K+]>[CH:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([S:8][CH2:7][CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH3:18])[CH2:13][CH2:12]1)=[O:10]
Reactant: CCN(CC)CCS
Reactant: CC(Br)C1CCN(C=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)CCSC(C)C1CCN(C=O)CC1
Temperature: 40 °C

Procedure:
To a solution of N,N-diethylaminoethylmercaptan (4 g, 0.03 mole) in methanol (10 ml), 5 N potassium hydroxide in methanol (5 ml) was added, followed by (B) (5.5 g, 0.025 mole). The mixture was heated to 40° C. for 20 hours. After removal of the solvent in vacuo, the residue was diluted with ether (50 ml) and filtered. The filtrate was washed with two 5 ml portions of 2 N sodium hydroxide followed by water and dried. The solvent was stripped in vacuo, and the residue was chromatographed on "Florisil" (100 g), eluting with ether followed by ethyl acetate-methanol (8:2) to give (C) as a faintly yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[O:12][CH2:13][CH2:14][O:15][C:5]=3[C:4]=2[N:3]1[CH2:16][CH:17]=O.[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl.CO>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[O:12][CH2:13][CH2:14][O:15][C:5]=3[C:4]=2[N:3]1[CH2:16][CH2:17][N:19]1[CH2:20][CH2:21][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CCn1c(=O)ccc2ccc3c(c21)OCCO3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc4c(c32)OCCO4)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
(9-oxo-2,3-dihydro[1,4]dioxino[2,3-h]quinolin-10(9H)-yl)acetaldehyde (1.5 g; 6.12 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (1.84 g; 9.18 mmol) were dissolved in a 1:1 mixture of chloroform and MeOH (50 ml:50 ml) and stirred at rt for 30 mins. NaBH(OAc)3 (5.81 g; 27.54 mmol) was added and the reaction left overnight. The solvents were then removed and the residues purified by column chromatography on silica gel using a 0-12% MeOH/DCM gradient to give the desired product (1 g; 38%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:34][CH2:35][C:36]1[CH:37]=[C:38]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)[CH:43]=2)[CH:39]=[CH:40][CH:41]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:34][CH2:35][C:36]4[CH:37]=[C:38]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]6[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:53][CH2:54]6)[CH:43]=5)[CH:39]=[CH:40][CH:41]=4)=[O:28])=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (0.072 g, 0.16 mmol) in DMF (1 mL) was added 1,1-dimethylethyl 4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-1-piperazinecarboxylate (0.061 g, 0.160 mmol), HBTU (0.100 g, 0.192 mmol), and TEA (0.045 mL), 0.320 mmol). This mixture was stirred at room temperature for 3 h. The reaction mixture was purified using a Gilson HPLC (with 0.1% TFA) to afford the title compound. LC-MS m/z 815 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[ClH:27]>O>[ClH:27].[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:13]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(CCCOCCCCCBr)cc1
Agent: Cl
Solvent: O
Product: COc1ccc(CCCOCCCCCNCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
1-[3-[(5-Bromopentyl)oxy]propyl]-4-methoxybenzene (2.0 g) was added to benzylamine (6 ml) at 120° under nitrogen. The solution was stirred for 2 h at 120° then added (hot) to 2N hydrochloric acid (50 ml) and water (25 ml). The resulting precipitate was collected by filtration, washed with 2N hydrochloric acid, water and ER then dried at 50° under vacuum to give the title compound as a white solid (1.79 g) m.p. 118°-121°. The following compound was prepared in a similar manner:
Reaction SMILES: [CH3:1][C:2]1([C:13]([O:15]C(C)(C)C)=[O:14])[C:6](=[CH:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH:4]([CH3:12])[O:3]1.[H][H]>C(OCC)(=O)C.CO>[CH3:1][C:2]1([C:13]([OH:15])=[O:14])[CH:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH:4]([CH3:12])[O:3]1
Reactant: COC(=O)C=C1CC(C)OC1(C)C(=O)OC(C)(C)C
Reactant: [H][H]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CC1CC(C)OC1(C)C(=O)O
Yield: 93.8 %

Procedure:
2,5-Dimethyl-3-methoxycarbonylmethylene-2-tetrahydrofuroic acid, t-butyl ester (28 mg, obtained from Step A) was dissolved in 0.25 mL of ethyl acetate and 0.25 mL of methanol. This mixture was hydrogenated under a balloon of hydrogen at room temperature for 1.25 h. The reaction mixture was filtered over a pad of celite, and the crude product obtained after removal of volatiles was purified via a silica gel SepPak, providing 21 mg of the desired compound cleanly (75% yield), homogeneous by TLC (Rf=0.2 in 10/1 hexane/ethyl acetate)
Reaction SMILES: C(S)[CH2:2][S:3]([O-])(=O)=O.[Na+].[Br:9][C:10]1[C:11](Cl)=[N:12][C:13]([Cl:16])=[N:14][CH:15]=1.O>C(#N)C>[Br:9][C:10]1[C:11]([S:3][CH3:2])=[N:12][C:13]([Cl:16])=[N:14][CH:15]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: O=S(=O)([O-])CCS
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CSc1nc(Cl)ncc1Br
Yield: 58.6 %

Procedure:
2 g of MeSNa (28.5 mmol; 1 eq.) and 6.5 g of 5-bromo-2,4-dichloropyrimidine (28.5 mmol, 1 eq.) were stirred in 50 mL dry acetonitrile at rt for 24 h. Then the mixture was poured into water, extracted with DCM, dried (Na2SO4) and evaporated to dryness. The product was recrystallized from hexane to yield 4 g of Intermediate 12 (70% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:44])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[CH:22][C:21]=3[O:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:44])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=3[O:35][CH2:36][C:37]([OH:39])=[O:38])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(C)(C)OC(=O)COc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Cl)cc4[nH]c(=O)c(=O)n2c34)c(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 171 %

Procedure:
A suspension of (S)-9-chloro-5-[p-tert-butoxycarbonylaminomethyl-o-(tert-butoxycarbonylmethoxy) phenylcarbamoylmethyl]-6,7-dihydro-1H, 5H pyrido[1,2,3-de]quinoxaline-2,3-dione (1.30 g) in 4N hydrogen chloride in 1,4-dioxane (50 mL) was stirred for 20 h at room temperature and 2N hydrochloric acid (35 mL) was added. The mixture was stirred further for 1 h and concentrated in vacuo. The residue was recrystallized from water to give 900 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(CO)ccc1Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(COc2ccccc2)ccc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24.5 %

Procedure:
The product from Example 221a (0.5 g, 2.15 mmol) was combined with phenol (0.203 g, 2.15 mmol) and triphenylphosphine (0.735 g, 2.80 mmol) in anhydrous THF (7 mL) under nitrogen and the resulting solution cooled in an ice bath. To the cold solution was added dropwise diisopropylazodicarboxylate (0.467 mL, 2.37 mmol). Stirring at 0° C. was continued for 15 min then the cold bath was removed and the reaction mixture allowed to warm to room temperature and 90 min before quench and workup by pouring into dilute HCl and extraction with ether. The combined extracts were dried MgSO4, filtered and concentrated under vacuum giving the crude title compound that was purified by flash chromatography on silica gel eluting with EtOAc-hexanes to give the title compound (0.162 g, 25%).
Reaction SMILES: [ClH:1].Cl.O[NH:4][C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[N:19]=[C:18]1[NH2:34])=[NH:6].O>[Ni].CO>[ClH:1].[ClH:1].[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)[N:19]=[C:18]1[NH2:34])(=[NH:4])[NH2:6]
Reactant: N=C(NO)c1cccc2c1CCC2=Nn1cc(-c2ccc(-c3ccccc3)cc2)nc1N
Agent: [Ni]
Agent: Cl
Solvent: O
Solvent: CO
Product: N=C(N)c1cccc2c1CCC2=Nn1cc(-c2ccc(-c3ccccc3)cc2)nc1N

Procedure:
Analogously to Example 2, a mixture of 9.27 g (18.54 mmol) of 1-[4-(N-hydroxy-amidino)-2,3-dihydro-1H-inden-1-ylideneamino]-2-amino-4-(4-biphenylyl)-imidazole dihydrochloride, 800 ml of water, 820 ml of methanol and 7.3 g of Raney nickel is hydrogenated at 25°-51° C. and under normal pressure until the absorption of hydrogen has ceased. The reaction mixture is then filtered, the filtrate is acidified to pH 1 with concentrated hydrochloric acid, and concentration is carried out by evaporation in vacuo. Recrystallization of the residue twice from ethanol yields the title compound, m.p. 269°-270° C. (decomp.), 1H-NMR (DMSO/D2O): δ=8.32 (d, 1H); 8.03 (s, 1H); 7.62-7.83 (m, 8H); 7.35-7.53 (m, 3H); 3.36 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:29](=[O:30])[C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (288 mg, 1.1 mmol) was dissolved in dichloromethane at -78° C. and treated with 4-methylmorpholine (0.25 mL, 2.27 mmol, 2 eq.) and 3,4,5-trimethoxy-benzoyl chloride (250 mg, 1.1 mmol, 1 eq) in dichloromethane (3 mL). The solution was allowed to warm to 0° C. and stir for 1 hour. The solution was washed with 1N HCl and 5% sodium bicarbonate and the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (30 g) with a gradient of 50% ethyl acetate in hexane to 6% methanol in dichloromethane to give 353 mg (71%) of the title compound.