Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CC1CCCCN1
Reactant: N#Cc1ccc(F)c2ccccc12
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1CCCCN1c1ccc(C#N)c2ccccc12
Temperature: 60 °C
Reaction time: 72 h
Yield: 18.9 %

Procedure:
1-Cyano-4-fluoronaphthalene (100 mg, 0.58 mmol), 2-methylpiperidine (0.28 mL, 2.3 mmol) and DBU (0.01 mL, 59 μmol) were dissolved in pyridine (2 mL) and stirred at 60° C. for 3 days. The temperature was raised to 110° C. and the stirring was continued for 10 days. The reaction was worked up in the same way as for 198RL60. The crude compound was purified by preparative TLC followed by preparative HPLC to give the title compound (27.4 mg, 19%) as a colourless oil, which was stored under argon atmosphere.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH2:8]P(OCC)(OCC)=O)=[O:7].[CH:17]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][C:19](=O)[CH2:18]2.O>COCCOC>[CH:17]12[CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][C:19](=[CH:8][C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH2:18]2
Reactant: O=C1CC2CCC(C1)C2
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C=C1CC2CCC(C1)C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (1.55 g, 38.7 mmol, 60% dispersion in oil) in 1,2-dimethoxy ethane (70 mL) at 0° C., triethyl phosphono acetate (8.38 mL, 41.9 mmol) was added. The resulting mixture was stirred 15 minutes at 0° C., 15 minutes at room temperature, and cooled to 0° C. Then, a solution of bicyclo[3.2.1]octan-3-one (Biogene, 4.0 g, 32.2 mmol) in 1,2-dimethoxy ethane (20 mL) was added and the resulting solution was stirred for 5 minutes at 0° C. and then stirred at room temperature overnight. Water was added and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with H2O (50 mL), brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using an Analogix® Intelliflash280™ (Hex-EtOAc, 0 to 25%) to give the title compound. MS (DCI/NH3) m/z 212 (M+NH4)+
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]1[O:16][C:15]2[C:10](=[N:11][C:12]([CH3:17])=[CH:13][CH:14]=2)[CH:9]=1.[CH2:18]=O>C(O)=O.Cl>[ClH:1].[ClH:1].[CH3:18][N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]1[O:16][C:15]2[C:10](=[N:11][C:12]([CH3:17])=[CH:13][CH:14]=2)[CH:9]=1
Reactant: Cc1ccc2oc([C@@H]3CCCN3)cc2n1
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: Cc1ccc2oc([C@@H]3CCCN3C)cc2n1

Procedure:
A 315 mg (1.04 mmol) sample of 2-(2-(S)-pyrrolidinyl)-5-methylfuro[3,2-b]pyridine dihydrochloride, from Example 5b above, was dissolved in 5 mL of 88% formic acid and 10 mL of 37% aqueous formaldehyde and heated at reflux for 0.5 hours. The reaction mixture was cooled, diluted with 2 N HCl and extracted with ether. The aqueous solution was adjusted to pH 10 with K2CO3 and extracted with CH2Cl2. The CH2Cl2 extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on silica gel, eluting with 100:0 to 95:5 CHCl3 :EtOH The residue was converted to the salt by treatment with HCl/ether, and the salt was recrystallized from EtOH/EtOAc to give 332 mg of title compound: 1H NMR (DMSO, 300 MHz) δ 2.13-2.23 (m, 2H), 2.35-2.60 (m, 3H), 2.71 (s, 3H), 2.88 (s, 2H), 3.33 (br s, 1H), 3.70 (br s, 1H), 4.88 (m, 1H), 7.54 (d, 1H, J=8.8 Hz), 7.61 (s, 1H), 8.36 (d, 1H, J=8.5 Hz); MS m/z: 217 (M+H)+, 234 (M+NH4)+ ; Anal. Calcd for C13H16N2O.2.0 HCl.1.0 H2O: C, 50.82; H, 6.55; N, 9.12. Found: C, 50.47; H, 6.77; N, 8.92.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]#[N:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].[N:42]([Sn](C)(C)C)=[N+:43]=[N-:44]>C1(C)C=CC=CC=1>[NH:9]1[CH:10]=[C:6]([C:2]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:40]4[NH:41][N:44]=[N:43][N:42]=4)[CH:36]=3)[CH:31]=2)([OH:1])[CH:3]([CH3:5])[CH3:4])[N:7]=[CH:8]1
Reactant: CC(C)C(O)(c1ccc2cc(C#N)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CC(C)C(O)(c1ccc2cc(-c3nnn[nH]3)ccc2c1)c1c[nH]cn1
Yield: 74.9 %

Procedure:
A solution of 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthonitrile (1.0 g) and azidotrimethyltin (770 mg) in toluene (10 mL) was refluxed for 48 h. The precipitate was collected by filtration, dissolved in THF-methanol (1:1) and concentrated. The residue was diluted with water and extracted with a mixed solution of ethyl acetate-THF (1:1). The extract was dried and concentrated. The residue was purified by column chromatography (eluent; hexane:THF=1:3) and crystallized from ethyl acetate to give the titled compound (469 mg) as a pale yellow powder.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[CH:4][C:3]=1[F:29].C([Sn](CCCC)(CCCC)[C:35]1[O:36][CH:37]=[CH:38][CH:39]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:29])=[C:2]([C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)[N:11]=2)[C:6](=[O:28])[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(Cl)c(F)cc2c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(-c3ccco3)c(F)cc2c1=O

Procedure:
A solution of Example 7F (210 mg), 2-(tributylstannyl)furan (220 μL) and dichlorobis(triphenyl-phosphine)palladium (II) (10.5 mg) in toluene (8 mL) was heated at 80° C. for 3 hours then cooled and filtered through diatomaceous earth (Celite®) with ethyl acetate. The filtrate was dried (Na2SO4), filtered, and concentrated; and the concentrate was flash chromatographed on silica gel with heptane then dichloromethane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[F:19]C1C(F)=CC=CC=1B(O)O>>[F:1][C:2]1[C:7]([F:19])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: OB(O)c1cccc(F)c1F
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: O=C(O)c1csc(-c2cccc(F)c2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (2,3-difluorophenyl)boronic acid gave the title compound.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[S:10][C:9]([C:11]([OH:13])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][C@@H:48]([CH2:62][C:63]1[CH:68]=[C:67]([F:69])[CH:66]=[C:65]([F:70])[CH:64]=1)[C@H:49]([OH:61])[CH2:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH3:60])[CH:54]=1>C(Cl)Cl>[F:69][C:67]1[CH:68]=[C:63]([CH:64]=[C:65]([F:70])[CH:66]=1)[CH2:62][C@H:48]([NH:47][C:11]([C:9]1[S:10][C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][CH:8]=1)=[O:13])[C@H:49]([OH:61])[CH2:50][NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH3:60])[CH:54]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)O)s1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc(CS(C)(=O)=O)s2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.1 %

Procedure:
To a solution of acid from step 5 (115 mg, 0.52 mmol) and N,N-diisopropylethylamine (540 μL, 3.12 mmol) in methylene chloride (6.5 mL) was added HBTU (200 mg, 0.52 mmol) and the reaction mixture was stirred for 0.5 h. (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (211 mg, 0.52 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 1–5% methanol in chloroform) gave the title compound (45 mg): mp 128–131° C.; ESI MS m/z 537 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13])=[CH:4][CH:3]=1
Reactant: C[C@H](CCl)CBr
Reactant: Oc1ccc(Cl)cc1
Product: C[C@H](CCl)COc1ccc(Cl)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-chlorophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[S:7][C:8]([C:10]([NH2:12])=O)=[CH:9][C:5]=2[CH:4]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[S:7][C:8]([C:10]#[N:12])=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1cc2cc(C(N)=O)sc2cc1OC
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COc1cc2cc(C#N)sc2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
5,6-Dimethoxy-benzo[b]thiophene-2-carboxamide (65 g) was suspended in pyridine (325 ml). The solution was cooled to 0° C. and treated dropwise with trifluoro acetic anhydride (185 ml) whilst maintaining the internal reaction temperature below 10° C. The mixture was then stirred at room temperature for 30 min. then cooled and treated dropwise with water (170 ml) whilst maintaining the internal temperature below 30° C. The reaction mixture was diluted with more water (800 ml), stirred and the brown solid was filtered and dried under vacuum over calcium chloride at 60° C. Recrystallisation from acetone/ether afforded 5,6-dimethoxy-benzo[b]thiophene-2-carbonitrile as a white solid (47 g), m.p. 125° C.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5]1)[CH:2]=C.I([O-])(=O)(=O)=[O:29].[Na+]>C(OCC)C.O.[Os](=O)(=O)(=O)=O>[Si:11]([O:10][C@@H:6]1[CH2:7][CH2:8][CH2:9][C@H:4]([CH2:1][CH:2]=[O:29])[CH2:5]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@@H]1CCC[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](O[C@@H]1CCC[C@H](CC=O)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5.5 g of (cis-3-allylcyclohexyloxy)-tert-butyl-diphenylsilane are dissolved in 100 ml of diethyl ether, and 9.4 g of sodium periodate, dissolved in 100 ml of water, are added. At 0° C., 15 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) are added, and the mixture is stirred vigorously at room temperature. After 5 hours, a further 5 g of sodium periodate are added, and the mixture is stirred at room temperature for another 3 hours. The reaction mixture is then diluted by addition of 300 ml of methyl tert-buthyl ether and washed with saturated sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 6 g of [cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde as a yellow-brown oil. C24H32O2Si (380.61), MS(ESI): 381 (M+H+), Rf(n-heptane:ethyl acetate=5:1)=0.44.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:12])=[CH:6][C:7]=1[NH:8][CH:9]([CH3:11])[CH3:10].ClC1[N:15]=[N:16]C(Cl)=CC=1NCC>>[CH:9]([NH:8][C:7]1[CH:6]=[C:5]([Cl:12])[N:4]=[N:3][C:2]=1[NH:15][NH2:16])([CH3:11])[CH3:10]
Reactant: CC(C)Nc1cc(Cl)nnc1Cl
Reactant: CCNc1cc(Cl)nnc1Cl
Product: CC(C)Nc1cc(Cl)nnc1NN

Procedure:
When 3,6-dichloro-4-isopropylamino pyridazine is substituted for 3,6-dichloro-4-ethylamino pyridazine in the above process, 4-isopropylamino-6-chloro-3-hydrazino pyridazine (m.p. 132° to 135°C) is obtained.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[C:35]([CH3:37])([CH3:36])[CH2:34][C:33]4[C:32]([C:38](O)=[O:39])=[C:31]([F:41])[CH:30]=[CH:29][C:28]=4[NH:27]3)[CH:21]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[C:35]([CH3:37])([CH3:36])[CH2:34][C:33]4[C:32]([C:38]([NH:9][S:6]([CH:3]5[CH2:5][CH2:4]5)(=[O:8])=[O:7])=[O:39])=[C:31]([F:41])[CH:30]=[CH:29][C:28]=4[NH:27]3)[CH:21]=2)=[CH:18][CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(-c2cccc(C3Nc4ccc(F)c(C(=O)O)c4CC3(C)C)c2)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2cccc(C3Nc4ccc(F)c(C(=O)NS(=O)(=O)C5CC5)c4CC3(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.7 %

Procedure:
To a suspension of 60% sodium hydride (75 mg, 1.86 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (242 mg, 1.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(4′-tert-butyl-biphenyl-3-yl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (80 mg, 0.19 mmol) and 1,1′-carbonyldiimidazole (65 mg, 0.38 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(4′-tert-butyl-biphenyl-3-yl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carbonyl]-amide (21 mg, 20%) as a white solid: LC/MS m/e calcd for C31H35FN2O3S (M+H)+: 535.70, observed: 535.1.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:33]4[CH:41]=[CH:42][CH:43]=[CH:44][C:32]=4[N:31]=3)[CH:12]=[C:13]([C:15]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]4[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=4[N:16]=3)[CH:14]=2)O1.Br[C:47]1[CH:60]=[CH:59][C:50]2[O:51][C:52]3[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][C:53]=3[C:49]=2[CH:48]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>[Pd].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.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.O>[Br:58][C:55]1[CH:56]=[CH:57][C:52]2[O:51][C:50]3[CH:59]=[CH:60][C:47]([C:9]4[CH:14]=[C:13]([C:15]5[N:19]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)[C:18]6[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=6[N:16]=5)[CH:12]=[C:11]([C:30]5[N:34]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:33]6[CH:41]=[CH:42][CH:43]=[CH:44][C:32]=6[N:31]=5)[CH:10]=4)=[CH:48][C:49]=3[C:53]=2[CH:54]=1
Reactant: Brc1ccc2oc3ccc(Br)cc3c2c1
Reactant: CC1(C)OB(c2cc(-c3nc4ccccc4n3-c3ccccc3)cc(-c3nc4ccccc4n3-c3ccccc3)c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc2oc3ccc(-c4cc(-c5nc6ccccc6n5-c5ccccc5)cc(-c5nc6ccccc6n5-c5ccccc5)c4)cc3c2c1
Temperature: 80 °C
Reaction time: 16.5 h
Yield: 55.4 %

Procedure:
A mixture of 2,2′-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-phenylene)bis(1-phenyl-1H-benzo[d]imidazole) (3.00 g, 5.10 mmol), 2,8-dibromodibenzo[b,d]furan (1.83 g, 5.61 mmol), tetrakis(triphenylphosphine) palladium(0) (0.30 g, 0.26 mmol), potassium carbonate (2.11 g, 15.30 mmol), 1,4-dioxane (90.00 mL), and water (18.00 mL) was degassed with bubbling argon for 50 min. The reaction mixture was then heated to 80° C. and was stirred overnight (16.5 hours), maintaining an argon atmosphere. Consumption of the starting material was confirmed by thin-layer chromatography and the reaction was cooled to room temperature. The product was extracted with dichloromethane, dried, and purified by silica gel column chromatography with ethyl acetate in dichloromethane as the eluent. The product fractions were then dried and the product was collected to yield Compound 14 (2.00 g, 56%). Confirmed by LCMS (APCI): calculated for C44H27BrN4O (M+H): 707. Found: 707.
Reaction SMILES: [NH2:1][C:2]1[C:3](C(O)=O)=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[N:7]=1.CC(C)=O>ClC1C=CC=CC=1Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Br:14])[C:5]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[N:4][CH:3]=1
Reactant: CC(C)n1nc(-c2nc(C(=O)O)c(N)nc2-c2ccccc2Br)ccc1=O
Solvent: Clc1ccccc1Cl
Solvent: CC(C)=O
Product: CC(C)n1nc(-c2ncc(N)nc2-c2ccccc2Br)ccc1=O
Yield: 102.7 %

Procedure:
A mixture of 3-amino-5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarboxylic acid (601 mg) in 1,2-dichlorobenzene (3 ml) was refluxed for 2 hours. After cooling, the mixture was purified by column chromatography on silica gel (EtOAc only) to give a solid. The solid was suspended with acetone and collected by filtration to give 6-[5-amino-3-(2-bromophenyl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone as a solid (554 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](Cl)=[O:11])=[CH:2]1.[N:13]12[CH2:20][CH2:19][C:16]([CH2:21][OH:22])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:22][CH2:21][C:16]23[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]2)[CH2:14][CH2:15]3)=[O:11])=[CH:2]1
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Reactant: OCC12CCN(CC1)CC2
Solvent: ClCCl
Product: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.3 %

Procedure:
To a solution of 1H-indole-3-carbonyl chloride (45 mg, 0.25 mmol) in 3 mL of methylene chloride at 0° C. was added (quinuclidin-4-yl)methanol (36 mg, 0.25 mmol) in 2 mL of methylene chloride. The mixture was stirred at room temperature overnight. The solvent was evaporated and water (10 mL) was added. The water layer was basified to pH 12 using 10% aqueous potassium hydroxide and extracted three times with 25 mL each of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to yield 8 mg of desired product. 1HNMR: 12.02 (bs, 1H); 8.13 (d, 1H); 7.9 (m, 1H); 7.42 (m, 1H); 7.18 (m, 2H); 4.3 (bs, 2H); 3.03 (m, 6H); 1.75 (m, 6H). MS (m/e): 285.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11])[CH3:8].[Cl:19][C:20]1[CH:21]=[C:22]([C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH2:41]Cl)=[CH:37][CH:36]=3)[N:31]=2)[CH:23]=[CH:24][C:25]=1[CH2:26][CH:27]([CH3:29])[CH3:28]>CN(C)C=O>[CH2:7]([O:9][C:10]([C:12]1([CH3:18])[CH2:17][CH2:16][N:15]([CH2:41][C:38]2[CH:37]=[CH:36][C:35]([C:32]3[N:31]=[C:30]([C:22]4[CH:23]=[CH:24][C:25]([CH2:26][CH:27]([CH3:28])[CH3:29])=[C:20]([Cl:19])[CH:21]=4)[O:34][N:33]=3)=[CH:40][CH:39]=2)[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C1(C)CCNCC1
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CCl)cc3)no2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)CCN(Cc2ccc(-c3noc(-c4ccc(CC(C)C)c(Cl)c4)n3)cc2)CC1
Temperature: 67.5 °C

Procedure:
Potassium carbonate (0.29 g, 0.0021 mol) and 4-methylpiperidine-4-carboxylic acid ethyl ester (0.36 g, 0.0021 mol) are added to a solution of 5-(3-chloro-4-isobutylphenyl)-3-(4-chloromethylphenyl)-[1,2,4]-oxadiazole (0.5 g, 0.0014 mol) in N,N-dimethylformamide (10 mL). The reaction mixture is heated at 65-70° C. for 2 hours. Removal of solvent gives a crude residue which is purified by column chromatography (silica gel 230-400 mesh, toluene:ethyl acetate 4:1) to give 1-{4-[5-(3-chloro-4-isobutylphenyl)-[1,2,4]-oxadiazol-3-yl]-benzyl}-4-methylpiperidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=[O:13])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CC(C)=O.C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([F:15])[C:3](=[O:13])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(/C=C/c1ccc(O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COc1ccc(/C=C/C(=O)C(F)(F)F)cc1
Temperature: 22 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
A solution of (E)-1,1,1-trifluoro-4-(4-hydroxyphenyl) 3-buten-2-one (0.105 g, 0.49 mmol) in acetone (6 ml) was treated with powdered potassium carbonate (0.3 g) and tert-butyl bromoacetate (0.20 g, 1.02 mmol) and stirred at 22° C. for 3 h. The reaction mixture was then diluted with toluene, washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was chromatographed on silica gel (elution toluene-ethyl acetate 2%) and gave 0.150 g (94%) of the title material as yellow needles: mp 112-113° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:13]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1)#[N:14]
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(C#N)cc1C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of methyl 4-bromo-2-methylbenzoate (26.6 g, 0.116 mol) in DMF (300 mL) was added zinc cyanide (8.1 g, 0.07 mol) followed by tetrakis(triphenylphosphine)palladium(0) (6.7 g, 0.0058 mol). The reaction mixture was placed in a 100° C. oil bath and stirred for 2 h, at which time it was filtered through a bed of celite and the filter cake rinsed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (10% ethyl acetate in hexanes) to afford methyl 4-cyano-2-methylbenzoate (18.1 g, 89%) as a white powder. 1H NMR (400 MHz, CDCl3): 7.97 (d, 1H), 7.55 (s, 1H), 7.53 (br m, 1H), 3.93 (s, 3H), 2.62 (s, 3H).