Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.CN(CCN(C)C)C.[CH2:20]([NH:22][C:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([F:35])=[CH:27][CH:26]=1)=[O:24])[CH3:21].[CH3:36][Si:37](Cl)([CH3:39])[CH3:38]>C1COCC1>[CH2:20]([NH:22][C:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([F:35])=[CH:27][C:26]=1[Si:37]([CH3:39])([CH3:38])[CH3:36])=[O:24])[CH3:21]
Reactant: CCNC(=O)c1ccc(F)c2ccccc12
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCNC(=O)c1c([Si](C)(C)C)cc(F)c2ccccc12
Temperature: -90 °C
Reaction time: 0.08 h
Yield: 20.4 %

Procedure:
A 1.3 M solution of s-BuLi in cyclohexane (40.7 mL, 52.9 mmol) was added to a liquid nitrogen-cooled solution of TMEDA (8.68 mL, 57.5 mmol) in THF (50 mL), maintaining the reaction temperature at -90° C. throughout the addition. The resulting solution was stirred 5 min, a solution of N-ethyl-4-fluoro-1-naphthalene-carboxamide (5.00 g, 23.0 mmol) in THF (15 mL) was added, and the resulting purple solution was stirred for 10 min at -90° C. TMSCl (8.76 mL, 69.0 mmol) was added, and after 10 min the cold bath was removed. The mixture slowly warmed to RT. The mixture was quenched with 100 mL 25% citric acid and extracted with ether (3×200 mL). The combined extracts were dried (MgSO4) and concentrated to a yellow powder which was purified by chromatography with ethyl acetate/hexanes to give 1.36 g of the desired amide, a 20% yield. m.p. 134-136° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].CCN(CC)CC.Br[C:16]1[C:17]([CH:34]([CH3:36])[CH3:35])=[N:18][N:19]([C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[N:19]([C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[N:18]=[C:17]([CH:34]([CH3:36])[CH3:35])[C:16]=2/[CH:3]=[CH:2]/[C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:23]=1
Reactant: CC(C)c1nn(-c2cnccn2)c(-c2ccc(F)cc2)c1Br
Reactant: C=CC(=O)OCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(C(C)C)nn(-c2cnccn2)c1-c1ccc(F)cc1
Yield: 58.6 %

Procedure:
Bis(triphenylphosphine) palladium (II) chloride (2.55 g, 3.6 mmol) and ethyl acrylate (49.2 mL, 454 mmol) were dissolved in DMF (200 mL) and Et3N (200 mL) at reflux under an inert atmosphere. The bromopyrazole (32.82 g, 91 mmol, Step B) was then added and the reaction was refluxed overnight. An additional 0.005 eq of catalyst and 10 mL of ethyl acrylate were added to push the reaction to completion. The reaction was cooled and partitioned between H2O and EtOAc. The organic layer was dried (MgSO4) and evaporated to give a brown oil. Elution from a 6-inch silica column gave 20.3 g (59%) of a tan solid. Recrystallization from hexanes produced a brilliant white solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:10][NH2:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:12](OCC)(OCC)OCC>>[Br:1][C:2]1[N:3]2[CH:12]=[N:11][N:10]=[C:4]2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)nc1NN
Reactant: CCOC(OCC)OCC
Product: COc1ncc(Br)n2cnnc12
Temperature: 130 °C

Procedure:
A 100 mL round bottom flask was charged with 5-bromo-3-hydrazinyl-2-methoxypyrazine (0.5 g crude, ˜1.9 mmol) and triethyl orthoformate (5 mL). The resulting mixture was heated at 130° C. overnight. TLC indicated a complete conversion. Work-up: the reaction mixture was concentrated. The residue was purified by flash column chromatography on silica gel with a 1:50 methanol/dichloromethane, to afford 0.28 g (66% for 2 steps) of the product as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.93 (s, 1H), 7.47 (s, 1H), 4.18 (s, 3H). MS m/z: 229 (M+H+).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[C:24]([CH2:28]O)[CH:25]=[CH:26][CH:27]=2)=[N:20][CH:21]=1.[F:30][C:31]1[CH:32]=[C:33]([C:38]2[CH:39]=[CH:40][C:41](=[O:44])[NH:42][N:43]=2)[CH:34]=[C:35]([F:37])[CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:30][C:31]1[CH:32]=[C:33]([C:38]2[CH:39]=[CH:40][C:41](=[O:44])[N:42]([CH2:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:19]4[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][N:20]=4)[CH:23]=3)[N:43]=2)[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: O=c1ccc(-c2cc(F)cc(F)c2)n[nH]1
Reactant: Cc1ccc(-c2cccc(CO)c2)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4.2 134 mg (0.66 mmol) of diisopropyl azodicarboxylate are added to a solution of 88 mg (0.44 mmol) of [3-(5-methylpyridin-2-yl)phenyl]methanol, 138 mg (0.66 mmol) of 6-(3,5-difluorophenyl)-2H-pyridazin-3-one and 174 mg (0.66 mmol) of triphenylphosphine in 3.5 ml of THF. The reaction mixture is stirred at room temperature for 18 hours. The mixture is evaporated, and the residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent: 6-(3,5-difluorophenyl)-2-[3-(5-methylpyridin-2-yl)benzyl]-2H-pyridazin-3-one (“A9”) as colourless crystals; ESI 390.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=O)=O.[CH:38]1[C:50]2[CH:49]([CH2:51][O:52][C:53]([NH:55][C@@H:56]([CH2:64][SH:65])[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[O:54])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]=2[CH:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:24]([O:23][C@H:8]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:7][S:65][CH2:64][C@@H:56]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[NH:55][C:53](=[O:54])[O:52][CH2:51][CH:49]1[C:50]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=2[C:43]2[C:48]1=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCOC[C@H](COS(=O)(=O)C(F)(F)F)OCCCCCCCCCCCC
Reactant: CC(C)(C)OC(=O)[C@H](CS)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2,3-bis(dodecyloxy)propyl trifluoromethanesulfonate (1 eq) in ethanol (0.15 M) was added (R)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-mercaptopropanoate (8, 1.5 eq) and potassium carbonate (1 eq). The reaction mixture was stirred at 60° C. for 30 minutes. The salt from the reaction was filtered off and the filtrate was concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-40% EtOAc/Hex to give the product.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([O:23][CH3:24])=[C:8]([O:21][CH3:22])[CH:9]=2)[N:4]=1.O.[SH:26][C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[NH:29][CH:30]=[N:31]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([O:23][CH3:24])=[C:8]([O:21][CH3:22])[CH:9]=2)[N:4]=[C:3]1[CH2:2][S:26][C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][NH:31]2
Reactant: COc1cc2nc(CCl)n(-c3ccccc3Cl)c(=O)c2cc1OC
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nc(CSc3ncnc4[nH]cnc34)n(-c3ccccc3Cl)c(=O)c2cc1OC
Yield: 65.5 %

Procedure:
Prepared according to Procedure C using Intermediate 2a (200 mg, 0.546 mmol), 6-mercaptopurine monohydrate (102 mg, 0.601 mmol), K2CO3 (83 mg, 0.601 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 172 mg of an off-white solid (65%), mp 160-180° C. (gradually decomposes). 1H NMR (DMSO-d6) δ: 13.55 (br s, 1H); 8.49 (s, 1H); 8.44 (s, 1H); 7.72 (d, J=6.9 Hz, 1H); 7.66 (d, J=6.9 Hz, 1H) 7.38-7.54 (m, 3H); 7.22 (s, 1H); 4.36-4.52 (m, 2H); 3.94 (s, 3H); 3.89 (s, 3H). 13C NMR (DMSO-d6) ppm: 160.1, 155.4, 151.5, 151.1, 149.4, 143.2, 134.6, 132.3, 131.6, 131.5, 130.4, 128.7, 113.6, 108.4, 105.8, 56.5, 56.1, 32.0. MS (ES): m/z 481.1 (M+). Anal. calcd. for C22H17ClN6O3S.0.5C2H6O.0.05KCl: C, 54.41; H, 3.97; Cl, 7.33; N, 16.55; S, 6.32. Found: C, 54.43; H, 3.94; Cl, 7.69; N, 16.69; S, 6.52.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]#[N:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:18]=1
Reactant: N#Cc1ccco1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccco2)sc2ccccc12
Yield: 18.9 %

Procedure:
A mixture of methyl thiosalicylate (1.01 g, 6.0 mmol), 2-furonitrile (0.57 g, 6.0 mmol), triethylamine (1.5 ml, 10.7 mmol) and toluene (20 ml) was refluxed for 24 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-ethanol to give the titled compound (0.26 g, 19%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1[CH2:21][S:18](=[O:20])(=[O:19])[O:17][CH2:16]1>O1CCCC1>[CH2:1]([O:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH:14][CH2:16][CH2:15][CH2:21][S:18]([OH:20])(=[O:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCC[C@H]1OCc1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: O=S(=O)(O)CCCN[C@@H]1CCC[C@H]1OCc1ccccc1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To a solution of (1R,2R)-2-benzyloxycyclopentylamine (1.0 g, 5.2 mmol) in tetrahydrofuran (12 mL) was slowly added 1,3-propanesultone (601 mg, 5.0 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×15 mL). The product was suspended in EtOH and the solvent was evaporated (to remove THF residue). The solid was dried in vacuo, affording the title compound (717 mg, 46%). 1H NMR (D2O, 500 MHz) δ ppm 7.32 (m, 5H), 4.53 (d, 1H, J=11.2 Hz), 4.42 (d, 1H, J=11.2 Hz), 4.02 (m, 1H), 3.36 (m, 1H), 3.01 (t, 2H, J=7.8 Hz), 2.81 (t, 2H, J=7.8 Hz), 2.01 (m, 4H), 1.65 (m, 3H), 1.49 (m, 1H). 13C NMR (D2O, 125 MHz) δ ppm 137.00, 129.07, 129.01, 128.77, 81.78, 71.81, 63.89, 48.02, 45.34, 29.93, 27.43, 21.61, 20.94. [α]D=−38.8° (c=0.00122 in water). ES-MS 314 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]2[C:14]3([CH2:19][CH2:18][N:17](C(OCCCC)=O)[CH2:16][CH2:15]3)[CH:13]=[N:12][C:9]2=[CH:10][CH:11]=1)[CH3:2].[CH:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]2[C:14]3([CH2:19][CH2:18][N:17]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:16][CH2:15]3)[CH2:13][NH:12][C:9]2=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC(C)(C)OC=O
Reactant: CCCCOC(=O)N1CCC2(C=Nc3ccc(CC(=O)OCC)cc32)CC1
Product: CCOC(=O)Cc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)CC1)CN2

Procedure:
tert-butyl 5-(2-ethoxy-2-oxoethyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate was prepared by the procedures described in Example 1, Step 2, substituting tert-butyl 5-chlorospiro[indole-3,4′-piperidine]-1′-carboxylate with butyl 5-(2-ethoxy-2-oxoethyl)spiro[indole-3,4′-piperidine]-1′-carboxylate. LCMS (APCI+) m/z 275.2 [M+H−Boc]+; Rt=3.58 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[CH2:19]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[F:1])[CH3:20]
Reactant: CCO
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of 2-fluoro-4-nitro-benzoic acid (1.0 g, 5.4 mmol) in ethanol (10 ml) was treated with concentrated sulphuric acid (0.3 ml) and stirred at reflux overnight. Upon cooling to room temperature, a crystalline precipitate started to form. Precipitation was completed at 0° C., the solid was filtered, washing with ethanol/water 2:1, and dried under high vacuum, yielding 750 mg (65% yield) 2-fluoro-4-nitro-benzoic acid ethyl ester as a white solid. This was used as such in the following reaction.
Reaction SMILES: [C:1]([CH:3]([C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[N:21][CH:20]=1)[N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1)#[N:2].C([NH+](CC)CC)C.C(=O)([O-])[O-]>ClCCl.FC(F)(F)C(O)=O>[NH2:11][CH2:10][CH:7]1[CH2:6][CH2:5][N:4]([CH:3]([C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:21][CH:20]=2)[C:1]#[N:2])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(C(C#N)c2cnc(-c3ccccn3)s2)CC1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC(c1cnc(-c2ccccn2)s1)N1CCC(CN)CC1
Reaction time: 1 h

Procedure:
The compound prepared in Example 235 (0.14 g) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.4 mL). The reaction was stirred for 1 hour and then concentrated and pumped to dryness. The amine salt was dissolved in tetrahydrofuran (5 mL) and Macroporous triethylammonium methylpolystyrene carbonate (MP-carbonate: Argonaut Technologies catalog number 80,026-9; 0.65 g) (2.5-3.5 mmol/g) 1.6-2.2 mmol was added. After 2 hours of stirring the reaction was filtered, washed with tetrahydrofuran, concentrated and used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=1[CH2:23][C:24]([NH:26][CH:27]1[C:44](=[O:45])[N:29]2[C:30]([C:41]([OH:43])=[O:42])=[C:31]([CH2:34][S:35][C:36]3[N:37]=[N:38][NH:39][CH:40]=3)[CH2:32][S:33][C@H:28]12)=[O:25])=O)(C)(C)C>CCOCC>[NH2:15][CH2:16][C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=1[CH2:23][C:24]([NH:26][CH:27]1[C:44](=[O:45])[N:29]2[C:30]([C:41]([OH:43])=[O:42])=[C:31]([CH2:34][S:35][C:36]3[N:37]=[N:38][NH:39][CH:40]=3)[CH2:32][S:33][C@H:28]12)=[O:25]
Reactant: CC(C)(C)OC(=O)NCC1=C(CC(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4c[nH]nn4)CS[C@H]23)CCCC1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: NCC1=C(CC(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4c[nH]nn4)CS[C@H]23)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of trifluoroacetic acid (1 ml.) and 5h (0.55 g., 0.98 mmoles) was stirred for 30 min. at room temperature and diluted with ether (50 ml.) to give the precipitate which was collected by filtration and slurried in a small amount of water (2 ml.). The mixture was adjusted to pH 6 with ammonium hydroxide and diluted with acetonitrile (200 ml.) to precipitate 6h which was washed with acetonitrile (50 ml.). Yield 0.36 g. (80%). M.p. 203° - 215° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:11]=O)[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.O1CCC[CH2:14]1>>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2([CH:11]=[CH2:14])[CH2:10][CH2:9]2)[CH:3]=1
Reactant: C1CCOC1
Reactant: O=CC1(c2cncc(Br)c2)CC1
Product: C=CC1(c2cncc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyltriphenylphosphonium bromide-sodium amide complex (510 mg, 01.22 mmol) in tetrahydrofuran (2.0 mL) was added a solution of the title compound from Example 73 Step B (97 mg, 0.43 mmol) in tetrahydrofuran (1.0 mL) The reaction stirred at room temperature for 16 hours. It was then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic extracts were combined, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-100% ethyl acetate in hexanes) provided the title compound: LCMS m/z 225.77 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 8.54 (s, 1H), 8.47 (s, 1H), 7.50 (s, 1H), 5.68 (dd, J=10.4, 17.1, 1 H), 4.98 (d, J=10.4, 1 H), 4.62 (d, J=17.1, 1 H), 1.12-1.05 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:9]2[CH:10]=[CH:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)=[CH:16][CH:15]=1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(Cn2ccc(-c3ccccc3)n2)cc1
Yield: 88.9 %

Procedure:
A mixture of 3-phenyl-1H-pyrazole (1.35 g, 9.36 mmol), 4-methoxybenzyl chloride (1.5 g, 9.7 mmol) and K2CO3 (3.3 g, 24.2 mmol) in methyl ethyl ketone was refluxed for 24 h. The salts were filtered off, and the solvent was removed in vacuo. The residue was purified by a column chromatography on silica gel to yield the title compound (2.2 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:9]=3[C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:9]2[C:8](=[O:17])[NH:7][C:6]3[CH:18]=[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])[CH:3]=[CH:4][C:5]=3[NH:11][C:10]=2[CH:12]=1
Reactant: Nc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2

Procedure:
A mixture of Example 7C (30 mg, 0.11 mmol) and CH3SO2Cl (13 mg, 0.112 mmol) in pyridine (4 mL) was stirred overnight at room temperature. The excess pyridine was removed under reduced pressure and the residue was washed with hexanes and filtered. The filter cake was dried in a vacuum oven to provide the desired product. MS (DCI) m/e 338 (M+H)+, 355 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:27])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]=[O:24])=[C:17]([CH3:25])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:26]=1.[CH:28]([Mg]Br)=[CH2:29]>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:27])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]([OH:24])[CH:28]=[CH2:29])=[C:17]([CH3:25])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:26]=1
Reactant: Cc1c(C=O)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Temperature: -78 °C

Procedure:
A suspension of 2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (2) (100 mg, 0.25 mmol) in THF (3 ml) was cooled to −78° C. Vinylmagnesium bromide (1M in THF, 2.0 mmol) was added dropwise, and the brown suspension was warmed gradually to −10° C. over 2 h. The solution was quenched with saturated ammonium chloride and extracted with ethyl acetate, and concentrated in vacuo to provide the title compound, which was used in the next step without purification, mp 235-236° C., MS (ES) 429 (MH+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH2:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[Cl:26])[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N+]=[N-].[CH:27]([O-])=[O:28].[NH4+]>C(O)C>[CH:27]([NH:1][CH2:4][C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH2:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[Cl:26])[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:28]
Reactant: [N-]=[N+]=NCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Reactant: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=CNCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
Reduction of this azide to the corresponding amine was carried out according to a published procedure of Gartiser et al., Tetrahedron Lett., 1983, 24:1609. A suspension of 3-azidomethyl-9-(2,5-dichlorobenzyl)-9H-β-carboline (4.60 g, 12 mmol), ammonium formate (3.90 g, 61.7 mmol), and 10% Pd-on-carbon (2.0 g, 20mol %) in ethanol (200 mL) was stirred at room temperature under nitrogen for 15 hours. The reaction mixture was filtered to remove the solids, and the filtrate concentrated and diluted with CH2Cl2 (100 mL). The resulting solution was washed with water (2×25 mL) and brine (25 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was recrystallized from ethyl acetate, affording 3.0 grams (65%) of N-formyl-[9-(2,5-dichlorobenzyl)-9H-β-carbolin-3-yl]methylamine as a pale-yellow solid. 1H NMR (CDCl3) 6 8.65 (s, 1H), 8.30 (s, 1H), 8.24 (d, 1H), 7.95 (s, 1H), 7.58 (t, 7.40 (m, 3H), 7.20 (dd, 1H), 6.51 (s, 1H), 5.60 (s, 2H), 4.78 (d, 1H); MS monoisotopic mass (calculated) 383.1, MH+ (observed) 384.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:9]#[N:10])=[C:4]([CH3:20])[CH:3]=1.[NH4+].[OH-]>C(O)C.O.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:9][NH2:10])=[C:4]([CH3:20])[CH:3]=1
Reactant: Cc1cc(F)ccc1C(C#N)CCOC1CCCCO1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(F)ccc1C(CN)CCOC1CCCCO1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
2-(4-Fluoro-2-methylphenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile (4.5 g, 16 mmol) was dissolved in ethanol (40 mL) and concentrated NH4OH aq (20 mL). Raney® nickel suspended in water (one teaspoonful) was added and the mixture was alternately evacuated and flushed with H2. The mixture was then stirred under H2 at room temperature until the consumption of gas ceased. The catalyst was removed with a magnet and the mixture was then filtrated and the solvent was evaporated. There was obtained 4.1 g (90%) of [2-(4-fluoro-2-methylphenyl)-4(tetrahydro-2H-pyran-2-yloxy)butyl]amine as a pale blue oil. 1H NMR (500 MHz, CDCl3): 1.4-2.0 (m, 8H), 2.4 (d, 3H), 3.2-3.8 (m, 6H), 4.4-4.6 (d, 1H), 6.9 (d, 2H), 7.1-7.2 (b, 1H).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].C(N(CC)CC)C>C(#N)C>[CH2:9]([CH2:8][CH2:7][CH2:6][O:14][S:1]([NH2:2])(=[O:4])=[O:3])[CH2:10][CH2:11][CH2:12][O:13][S:1]([NH2:2])(=[O:4])=[O:3]
Reactant: OCCCCCCCO
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)OCCCCCCCOS(N)(=O)=O
Yield: 37 %

Procedure:
The title compound was obtained using the following procedure: The sulfamoyl chloride in acetonitrile solution prepared in (a) was reacted as in Example 11 with 10.5 g (0.0755 mole) of 1,7-heptanediol (95%), 30.3 g (0.300 mole) of triethylamine in 100 ml additional acetonitrile followed by using extracting, washing and concentration procedures of Example 11 through the first evaporation. The viscous residue which solidified on standing was purified by high pressure liquid chromatography using the Waters Associates® Prep LC/System 500A with PrepPAK® 500 silica. Eluting solvent used was 10:1 mixture methylene chloride-acetone at a flow rate of 200 ml/min. Fractions containing the title compound were combined and the solvents were evaporated under reduced pressure to give a viscous oil which solidified on standing. The solid was recrystallized from wet methylene chloride to give 8.2 g (37% yield) of title compound as white solid, mp 88.5°-90.5° C.