Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([NH:11][C:12](=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=1[O:26][CH2:27][C@H:28]([NH:41][C:42](=[O:56])[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]2[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=2)[CH:44]=1)[CH2:29][CH2:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])[CH3:9].Cl.Cl[C:59]([NH2:61])=[NH:60].CS(C)(=O)=O>O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([NH:11][C:12](=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=1[O:26][CH2:27][C@H:28]([NH:41][C:42](=[O:56])[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]2[CH:54]=[CH:53][C:52]([NH:55][C:59]([NH2:61])=[NH:60])=[CH:51][CH:50]=2)[CH:44]=1)[CH2:29][CH2:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])[CH3:9]
Reactant: COC(=O)C(=Cc1ccc(C#N)cc1OC[C@@H](CCC(=O)OCc1ccccc1)NC(=O)c1cccc(-c2ccc(N)cc2)c1)NC(C)=O
Reactant: N=C(N)Cl
Agent: CS(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(=Cc1ccc(C#N)cc1OC[C@@H](CCC(=O)OCc1ccccc1)NC(=O)c1cccc(-c2ccc(NC(=N)N)cc2)c1)NC(C)=O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 340 mg (0.52 mmol) of methyl 2-acetamido-3-[2-[(2R)-2-[[3-(4-aminophenyl)benzoyl]amino]-4-benzyloxycarbonylbutoxy]-4-cyanophenyl]acrylate trifluoroacetate, 430 mg (3.74 mmol) of chloroformamidine hydrochloride and 2.0 g of dimethyl sulfone was stirred at 120° C. for 2 hours. Water was added to the reaction mixture. After washing with ethyl acetate, the aqueous layer was freeze-dried and purified by the reversed phase HPLC in the same manner as that in step 5 in Example 1 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[C:10](C(=O)C)[N:9]=2)=[CH:4][CH:3]=1.FC1C=CC(B(O)O)=CC=1.[Br:26]C1N=C(Cl)SN=1>>[Br:26][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[S:12][N:11]=1
Reactant: Clc1nc(Br)ns1
Reactant: CC(=O)c1nsc(-c2ccc(F)cc2)n1
Agent: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2nc(Br)ns2)cc1

Procedure:
In another embodiment, 1-(5-(4-fluorophenyl)-1,2,4-thiadiazol-3-yl)ethanone is prepared according to the methodology and reagents of Scheme 17A. Specifically, 4-fluorophenyl boronic acid is reacted with 3-bromo-5-chloro-1,2,4-thiadiazole to provide 3-bromo-5-(4-fluorophenyl)-1,2,4-thiadiazole. 3-Bromo-5-(4-fluorophenyl)-1,2,4-thiadiazole is then reacted with a tin reagent such as tributyl(1-ethoxyvinyl)-stannane to convert the bromide moiety of 3-bromo-5-(4-fluorophenyl)-1,2,4-thiadiazole to an acetyl group. In one embodiment, this reaction is performed in the presence of a catalyst such as PdCl2(PPh3)4. In another embodiment, the reaction is performed in DMF at elevated temperatures overnight. 1-(5-(4-Fluorophenyl)-1,2,4-thiadiazol-3-yl)-ethanone may then converted to a compound of Formula (I-A) by the methods described herein, such as Scheme 1.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([C@H:40]3[CH2:45][CH2:44][C@H:43]([CH2:46][CH2:47][CH2:48]O)[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)(=[O:19])[CH:17]=[CH2:18].N1C(C)=CC=CC=1C.O>ClCCl>[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:35]=[CH:36][C:37]([C@H:40]3[CH2:45][CH2:44][C@H:43]([CH2:46][CH2:47][CH2:48][O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH2:42][CH2:41]3)=[CH:38][CH:39]=2)=[CH:32][CH:33]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C=CC(=O)OCCCCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCCO)CC3)cc2)cc1
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCCOS(=O)(=O)C(F)(F)F)CC3)cc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3.47 g of trifluoromethanesulphonic anhydride dissolved in 10ml of dichloromethane were added dropwise at 0° C. to a solution of 4.77 g of 6-[4'-[trans-4-(3-hydroxy-propyl)-cyclohexyl]-biphenyl-4-yloxy]-hexyl acrylate and 1.32 g of lutidine in 100 ml of dichloromethane. The reaction mixture was stirred at 0° C. for 90 minutes and subsequently poured into 100 ml of water and extracted twice with 50 ml of dichloromethane. The combined organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate and concentrated. Chromatographic purification of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) gave 5.09 g of [4'-[trans-4-[3-(trifluoromethanesulphonyloxy)-propyl]-cyclohexyl]-biphenyl-4-yloxy]-hexyl acrylate.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][CH:4]([O:6][C:7]2[C:8]3[C:22]([C:23]#[N:24])=[CH:21][N:20]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)[N:12]=2)[CH2:3]1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:23]([C:22]1[C:8]2[C:7]([O:6][CH:4]3[CH2:3][CH:2]([NH:1][C:33](=[O:36])[CH:34]=[CH2:35])[CH2:5]3)=[N:12][C:11]([NH:13][C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)=[N:10][C:9]=2[N:20]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:21]=1)#[N:24]
Reactant: C=CC(=O)Cl
Reactant: Cn1cc(Nc2nc(OC3CC(N)C3)c3c(C#N)cn(COCC[Si](C)(C)C)c3n2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)NC1CC(Oc2nc(Nc3cnn(C)c3)nc3c2c(C#N)cn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
To a solution of 4-[(3-aminocyclobutyl)oxy]-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (cis:trans 1:1) (380 mg, 0.84 mmol) in DCM (10 mL) was added acryloyl chloride (68 μL, 0.84 mmol) and DIPEA (146 μL, 0.84 mmol). The reaction solution was stirred at rt for 10 min. The reaction mixture was partitioned between DCM (50 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was separated, dried over Na2SO4 and evaporated. The product was purified via flash chromatography eluting with a gradient of 0%-100% EtOAc in heptanes to give the title compound (317 mg, 75% yield) as a 1:1 cis:trans isomeric mixture. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.43 (s, 1H) 8.42-8.63 (m, 1H) 8.11 (s, 1H) 7.96 (br. s., 1H) 7.43-7.62 (m, 1H) 6.00-6.31 (m, 2H) 5.61 (ddd, J=9.69, 7.05, 2.64 Hz, 3H) 4.07-5.26 (m, 2H) 3.81 (d, J=5.79 Hz, 3H) 3.56 (t, J=7.93 Hz, 2H) 2.84-2.99 (m, 1H) 2.51-2.58 (m, 2H) 2.08-2.20 (m, 1H) 0.84 (t, J=8.06 Hz, 2H) −0.12 (br. s., 9H). m/z (APCI+) for C24H32N8O3Si 509.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([Cl:34])[C:24]([S:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].Cl.O1CCOCC1>CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:22]=[C:23]([Cl:34])[C:24]([S:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(SCc4ccccc4)c(Cl)cc3n2COCCOC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc3cc(SCc4ccccc4)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a mixture of 1-[5-benzylsulfanyl-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (96.0 mg, 0.192 mmol) and EtOH (5 mL) was added 4M HCl in dioxane (5 mL, 20 mmol). The mixture was stirred for 18 h at 23° C. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated in Et2O. The resultant suspension was filtered and washed with Et2O to yield the titled compound (69.0 mg, 87%). MS (ESI/CI): mass calcd. for C20H17ClN4O2S, 412.1; m/z found, 413.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.53 (d, J=12.3 Hz, 1H), 8.95 (s, 1H), 8.35 (s, 1H), 7.78 (s, 0.5H), 7.65 (s, 0.5H), 7.55 (s, 0.5H), 7.44 (s, 0.5H), 7.38 (d, J=7.2 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 7.25 (s, 1H), 4.32-4.26 (m, 4H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([NH:33][CH3:34])=[O:32])=[CH:27][CH:26]=1)=[C:8]2[C:12]([O:14]CC1C=CC([N+]([O-])=O)=CC=1)=[O:13])[CH3:3].O.C(=O)([O-])O.[Na+:40]>C1COCC1.[Pd]>[Na+:40].[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:25]1[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH3:34])=[O:32])=[CH:29][CH:30]=1)=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3]
Reactant: CNC(=O)c1ccc(C2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Reaction time: 0.5 h

Procedure:
4-Nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[(methylamino)carbonyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (60 mg) obained in the above Step b) was dissolved in THF (6 ml) and ion-exchange water (4.7 ml), and thereto was added 0.1 N aqueous sodium hydrogen carbonate solution (1.3 ml). To the mixture was added 10% palladium on carbon (120 mg), and the mixture was subjected to hydrogenolysis for 30 minutes under atmospheric pressure at room temperature. The catalyst was removed by filtration, and washed with water, and chloroform was added to the filtrate, and extracted and separated (three times). The organic solvent in the aqueous layer was removed under reduced pressure, and the resultant was purified by polymer chromatography (CHP-20P). The fractions eluted with 0–2% aqueous THF solution were combined and lyophilized to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[(methylamino)carbonyl]-phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt (18 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]=2[S:5](=[O:17])(=[O:16])[NH:4][C:3]=1[C:18]([NH2:20])=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3.[CH:21]([Cl:24])(Cl)Cl.[H][H]>[Pd].CO>[Cl:24][C:21]1[CH:18]=[C:3]([NH:20][C:18]([C:3]2[NH:4][S:5](=[O:17])(=[O:16])[C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:19])[CH:2]=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: NC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Reactant: ClC(Cl)Cl
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1cccc(Cl)c1)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Yield: 57 %

Procedure:
A solution of 490 mgm (1 millimol) of 2-benzyl-N-3-chloro-phenyl)-4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide in 100 ml of a mixture of chloroform and methanol (2:1) was hydrogenated in the presence of 500 mgm of a palladium-on-charcoal catalyst (10%) at a hydrogen pressure of 3 atmospheres for 10 hours. The reaction mixture was then filtered, and the catalyst left on the filter was copiously washed with hot chloroform. The combined filtrates were evaporated, and the residue was purified by columnchromatography (silicagel particle size 0.2-0.5 mm), using chloroform/methanol (20:1) as the eluant. 230 mgm (57% of theory) of N-(3-chloro-phenyl)-4-hydroxy-2H-naphtho[2,1-e]1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 262° C (decomp.), were obtained.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C(OC(=O)C)(=O)C.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:8]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CCCCCCC
Reactant: CCO[SiH](OCC)OCC
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCC[Si](OCC)(OCC)OCC
Temperature: 50 °C
Yield: 14.3 %

Procedure:
224 mg Of octene-1, 328 mg of triethoxysilane, and 56 mg of toluene were placed in a glass reaction tube and 0.01 ml of acetic anhydride was added to this mixture. Then, 0.001 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 wt %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of octene-1 was 16.5%, and n-octyltriethoxysilane was produced at a yield of 14.3%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH:15]2[CH:17]([CH:18]=[O:19])[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.O.C(OO)(=O)C1C(=CC=CC=1)C(O)=[O:30].[Mg]>CCO.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:17]([C:18]([OH:30])=[O:19])[CH:15]([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccccc1C(=O)OO
Reactant: CC(C)(C)OC(=O)N1CC2CCCCC(C1)C2C=O
Agent: [Mg]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CCCCC(C1)C2C(=O)O

Procedure:
2.86 g of 10-formyl-8-aza-bicyclo[4.3.1]decane-8-carboxylic acid tert-butyl ester and 5.8 g of magnesium monoperoxyphthalic acid hexahydrate in 170 ml of EtOH/H2O (1:1) are stirred at RT. The mixture obtained is diluted with EtAc. The mixture obtained is extracted with aqueous 1M HCl and brine. The organic layer obtained is dried, solvent is evaporated and the evaporation residue is crystallized from MeOH/H2O. 8-aza-bicyclo[4.3.1]decane-8,10-dicarboxylic acid 8-tert-butyl ester is obtained. m.p.: 218-222°; 13C-NMR: 179.88, 155.31, 80.00, 52.43, 50.98, 47.63, 33.14, 32.31, 28.91, 27.06.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC.C[Si]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37](Br)[CH:36]=1)(C)C.[C:42]1([C:48]#[CH:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[OH:34][C:35]1[CH:36]=[C:37]([C:49]#[C:48][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: C[Si](C)(C)Oc1cccc(Br)c1
Reactant: C#Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Product: Oc1cccc(C#Cc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
Palladium acetate (0.20 g, 8.9×10-4 mol) and tri-o-tolylphosphine (0.40 g, 1.31×10-3 mol) as well as 60 ml of NEt3 were placed in a 3-necked 100 ml round-bottomed flask equipped with a reflux condensor, a thermometer and a nitrogen adaptor. The resultant yellow mixture was then heated to reflux under N2. At about 70° C., the mixture turned deep-red but still maintained its homogeneity. While the mixture was still refluxing, 3-bromophenyl trimethylsilyl ether (7.10 g, 28.95 mmol) was introduced via the reflux column, allowing it to flow slowly along the wall of the column, into the reaction mixture. After about 15 minutes, degased phenylacetylene (3.11 g, 30.45 mmol) was added to the reaction mixture in a similar manner. As soon as the reactants were in contact, sudden rise in temperature and concomitant precipitation of white solids occurred. The color of reaction mixture became lighter as the reaction progressed. After about 3 hours, the reaction mixture was dark brown and no further change in color was observed even after 17 hours at 80° C. The cooled reaction mixture was poured into about 300 ml of water and extracted with ethyl ether (100 ml, 3×50 ml). The dark ethereal extract was subjected to rotary evaporation to afford a dark oil. About 20 ml of water was added to the dark oil and the mixture was rota-evaporated, in a 70° C-water bath for about 15 minutes. Then, 150 ml of methanol was added and rotary evaporation was resumed until all solvent was removed at 70° C. The resultant dark oil was then dried in vacuo at room temperature for 24 hrs and solidified into dark brown crude product (about 5.0g). Proton NMR (CDCl3): 5.18 (singlet, --OH), 6.71-7.67 (complex, aromatic H). The hydroxyl proton is readily exchanging with deuterium of D2O. IR(KBr): δ (OH) at 3350 cm-1 (strong and broad); δ (C≡C) at 2210 cm-1 (W). The crude product was used in the subsequent reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1.[Cl-].[Li+].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].C1(C)C=CC=CC=1>CCOC(C)=O.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>[CH2:15]([C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1)[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc2nonc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc2nonc2c1
Temperature: 110 °C

Procedure:
To a 250 mL flask charged with 5-Bromo-2,1,3-benzoxadiazole (5.0 g, 25 mmol), Palladium Tetrakis (0.87 g, 0.75 mmol), and lithium chloride (2.1 g, 50 mmol) was added Allyl Tri-n-butyltin (10 g, 30 mmol) and toluene (100 mL). The mixture was attached to a reflux condenser, sealed and purged with nitrogen. The reaction was heated to 110° C. for 2 hours. TLC showed good and complete reaction. The reaction was diluted with EtOAc, washed with brine, concentrated and purified by silica gel chromatography.
Reaction SMILES: CC1(C)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC=2C(C2C=CC=CC=2)=CC1.[CH3:30][C:31]1([CH3:58])[C:40]2[CH:39]=[C:38]([C:41]#[C:42][C:43]3[CH:53]=[CH:52][C:46]([C:47]([O:49]CC)=[O:48])=[CH:45][CH:44]=3)[CH:37]=[CH:36][C:35]=2[C:34]([C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:33][CH2:32]1>>[CH3:30][C:31]1([CH3:58])[C:40]2[CH:39]=[C:38]([C:41]#[C:42][C:43]3[CH:44]=[CH:45][C:46]([C:47]([OH:49])=[O:48])=[CH:52][CH:53]=3)[CH:37]=[CH:36][C:35]=2[C:34]([C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:33][CH2:32]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3C(C)(C)C)cc1
Agent: CC1(C)CC=C(c2ccccc2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC(C)(C)C1=CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 51 mg (0.13 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-2-yl)ethynyl]benzoate (Compound 96) was converted to the title compound (white solid) using 28 mg (1.3 ml, 0.66 mmol) of LiOH (0.5 M aqueous solution).
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)[C:2]#[CH:3].[CH2:20]=O.[NH:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:20][C:3]#[C:2][CH2:1][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCCNCC1
Reactant: C=O
Reactant: C#CCN1c2ccccc2C(=O)Nc2cccnc21
Product: O=C1Nc2cccnc2N(CC#CCN2CCCCCC2)c2ccccc21
Yield: 35 %

Procedure:
Prepared analogously to Example lb) from 5,11-dihydro-11-(2-propynyl)-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, paraformaldehyde and hexahydro-1H-azepine in a yield of 35% of theory. Colourless crystals m.p. 157° C. (ethyl acetate).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([SH:17])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC=CC=1>C(O)C.[OH-].[K+].CN(C)C(=O)C>[CH2:18]([S:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: Sc1nnc(-c2ccccc2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: c1ccccc1
Solvent: CCO
Product: c1ccc(CSc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 4-phenylphthalazine-1-thiol (238 mg; 1 mmol) in ethanol (30 ml), aqueous KOH (1 molar, 1 ml) and N,N-dimethylacetamide (30 ml) are added. After 10 minutes, benzylchloride (126 mg, 1 mmol) is added, and the mixture is stirred at room temperature overnight. The solution is concentrated, and water (20 ml) is added to the residual to give a precipitate. Filtration gives a light yellow solid (R1=phenyl, R2=phenyl, A=benzene, Y1=CH2, m=0, n=1, p=0, q=0).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC2C(=C(OS(C(F)(F)F)(=O)=O)N(C3C=CC=C(Cl)C=3)N=2)CC1)=O)(C)(C)C.ClC1C=C(NN)C=CC=1.C1(B(O)O)C=CC=CC=1>>[Cl:24][C:20]1[CH:19]=[C:18]([N:13]2[C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3cccc(Cl)c3)c(-c3ccccc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(-c3cccc(Cl)c3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Agent: NNc1cccc(Cl)c1
Agent: OB(O)c1ccccc1
Product: Clc1cccc(-n2nc3c(c2-c2ccccc2)CCNCC3)c1

Procedure:
2-(3-Chloro-phenyl)-3-phenyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. The desired compound (53.9 mg) was prepared from 142.7 mg of 2-(3-chloro-phenyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (made as in Example 176, Steps A and B) replacing phenylhydrazine with (3-chloro-phenyl)-hydrazine, as described in Example 43, Step D, using 102.1 mg of phenylboronic acid. MS (ESI): exact mass calculated for C24H26ClN3O2, 423.17. found, m/z 424.1 [M+H]+.
Reaction SMILES: [Br:1]Br.[CH2:3]([N:5]([CH2:8][C:9]1[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[S:22][CH:23]=2)=[O:17])[CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])[CH3:4]>CO>[Br:1][C:23]1[S:22][C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:20][C:19]=1[NH:18][C:16]([NH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][N:5]([CH2:6][CH3:7])[CH2:3][CH3:4])[N:14]=1)=[O:17]
Reactant: CCN(CC)Cc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Reactant: BrBr
Solvent: CO
Product: CCN(CC)Cc1cccc(NC(=O)Nc2nc(-c3ccncc3)sc2Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (46 μL, 0.90 mmol) was added to a solution of 1-(6-diethylaminomethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea (190 mg, 0.45 mmol, Example 117) in MeOH (8 mL) and the resulting solution was stirred at RT for 1 h. The reaction was quenched with saturated sodium bisulfite solution and concentrated in vacuo. The residue was dissolved in CHCl3/IpOH (3/1, 10 mL) and washed with H2O (3×10 mL) followed by 1N NaOH solution (10 mL). The organics were combined, dried over Na2SO4, and concentrated in vacuo to give a yellow solid. MS m/z: 461.1 (M+H). Calc'd for C19H21BrN6OS-461.39.
Reaction SMILES: IC.[CH3:3][O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([C:14]2[CH:18]=[N:17][NH:16][N:15]=2)[N:6]=1.[C:19](=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:3][O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([C:14]2[CH:18]=[N:17][N:16]([CH3:19])[N:15]=2)[N:6]=1
Reactant: O=C([O-])[O-]
Reactant: COc1nc(-c2cn[nH]n2)ccc1[N+](=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1nc(-c2cnn(C)n2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 19.2 %

Procedure:
Iodomethane (330 μL, 5.31 mmol) was added to a solution of 2-methoxy-3-nitro-6-(2H-1,2,3-triazol-4-yl)pyridine (Preparation 199, 235 mg, 1.063 mmol) and potassium carbonate (294 mg, 2.125 mmol) in THF (5.1 mL). The reaction mixture was stirred at room temperature for 72 hours. The solid was filtered and the filtrate concentrated in vacuo. The residue was purified using Biotage silica gel column chromatography eluting with cyclohexane/EtOAc 80/20 to 40/60 to afford the title compound as a beige solid (48 mg, 19%).