Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]2[CH2:15][NH:14][C:13](=[O:16])[NH:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH:23]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24]1.O>CS(C)=O>[CH:23]1([O:1][C:2]2[CH:3]=[C:4]([CH2:10][CH:11]3[CH2:15][NH:14][C:13](=[O:16])[NH:12]3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(CC2CNC(=O)N2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CC2CNC(=O)N2)cc1OC1CCCC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To the solution of 22.22 g (100 mmoles) of the product obtained in Example 3, step (a) in 220 ml of dimethylsulphoxide, 27 g of powdered anhydrous potassium carbonate are added and the suspension is stirred at 60° C. for 30 minutes, then 12.9 ml (120 mmoles) of cyclopentyl bromide are portionwise added during 60 minutes while the temperature is kept at 60° C. The suspension is further stirred at 60° C. for 20 hours, then cooled to 25° C. and poured into 800 ml of water. The aqueous emulsion is extracted four times with 400 ml of chloroform. The collected organic phases are washed twice with 50 ml of 1 N sodium hydroxide solution, dried over anhydrous magnesium sulphate and evaporated in vacuo. To the oily residue 200 ml of benzene are added and the evaporation is repeated. The residue is triturated with 150 ml of ether and the crystals obtained are filtered after 30 minutes and washed with 50 ml of ether to give 21.30 g (73.4%) of the title compound, m.p. 104°-107° C. After recrystallization from acetone this melting point rises to 115°-116° C. On the basis of its physical properties, this product is identical with the compound obtained in Example 2, step (d).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.CN(C)[CH:10]=[CH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=O>>[CH3:7][C:5]1[N:6]=[C:2]2[N:1]=[CH:10][CH:11]=[C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[N:3]2[N:4]=1
Reactant: CN(C)C=CC(=O)c1cccs1
Reactant: Cc1nc(N)n[nH]1
Product: Cc1nc2nccc(-c3cccs3)n2n1

Procedure:
By the procedure described in Example 5, 3-amino-5-methyl-1,2,4-triazole was reacted with 3-dimethylamino-1-(2-thienyl)-2-propene-1-one to give 1.05 g of the product of the Example as pale yellow needles, mp 184°-185° C.
Reaction SMILES: [H-].[Na+].[C:3]([N:7]1[C:12](=[O:13])[C:11]([CH2:14][CH3:15])=[C:10](Cl)[CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1.O>CN(C)C=O>[C:3]([N:7]1[C:12](=[O:13])[C:11]([CH2:14][CH3:15])=[C:10]([O:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: OCc1ccc(Cl)cc1
Reactant: CCc1c(Cl)cnn(C(C)(C)C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(OCc2ccc(Cl)cc2)cnn(C(C)(C)C)c1=O
Yield: 76.2 %

Procedure:
To 10 ml of dry N,N-dimethylformamide was added 0.75 g of 55% sodium hydride. The resulting mixture was kept at 0° C. and was added dropwise with a solution of 2.2 g of 2-t-butyl-5-chloro-4-ethyl-3(2H)-pyridazinone dissolved in 15 ml of N,N-dimethylformamide. After ten minutes passed, the resulting mixture was added dropwise with a solution of 1.4 g of p-chlorobenzyl alcohol dissolved in 15 ml of N,N-dimethylformamide. After completion of dropwise addition, the resulting mixture was reacted at 80° C. for one hour. The resulting solution was poured into 50 ml of water and extracted twice with 50 ml of diethyl ether. The resulting organic layer was dried over anhydrous sulfate and freed of solvent by distillation under reduced pressure to give a crude product. The crude product was recrystallized from hexane to obtain 2.4 g of 2-t-butyl-5-(p-chlorobenzyloxy)-4-ethyl-3(2H)-pyridazinone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:12][O:13][C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:16]/[C:14]([O:13][CH3:12])=[O:15])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2cc[nH]c2c1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc2cc[nH]c2c1
Yield: 72.4 %

Procedure:
To a solution of indole-6-carboxaldehyde (499 mg) in tetrahydrofuran (20 mL), methyl (triphenylphosphoranylidene) acetate (2.5 g) was added at room temperature, and then the reaction mixture was subjected to microwave irradiation at 200° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the titled compound (501 mg) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11](O)[C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4C(OC(C)(C)C)=O)=[N:8][C:7]=2[CH:32]=1)#[N:2].C[O:34][C:35]([O:39][Si](C)(C)C)=[C:36]([CH3:38])[CH3:37].C([O-])(O)=O.[Na+]>C(Cl)Cl.O.Cl[Ti](Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][NH:16]4)[C:36]([CH3:38])([CH3:37])[C:35]([OH:39])=[O:34])=[N:8][C:7]=2[CH:32]=1)#[N:2]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1nc2cc(C#N)ccc2o1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)c2[nH]ccc2c1C(c1nc2cc(C#N)ccc2o1)C(C)(C)C(=O)O
Reaction time: 0.25 h

Procedure:
A solution of (±)-tert-butyl 4-((5-cyanobenzo[d]oxazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 125-A) (133 mg, 0.31 mmol) in DCM (10 mL) was treated with TiCl4 (1M in DCM, 1 mL, 1 mmol) at 0° C. The reaction mixture was stirred for 15 min, followed by the addition of ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (0.36 g, 2 mmol). The mixture was allowed to reach room temperature over 1 h. The reaction mixture was then poured into aqueous NaHCO3. The organic layer was extracted with ethyl acetate (2×50 mL), and the combined organic layers were dried over Na2SO4, filtered and concentrated to provide a residue. The resulting residue was suspended in water (5 mL) and was treated wtih Dowex ion exchange resin (200% w/w) (washed with water twice). The reaction was stirred at 120° C. overnight in a sealed tube. Reaction was cooled, filtered and directly subjected to purification by FCC1-5% (MeOH:DCM) to obtain the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.05 (br. s., 1H) 7.46-7.61 (m, 1H) 7.23 (t, J=2.78 Hz, 1H) 7.10 (d, J=8.34 Hz, 2H) 6.69 (s, 1H) 6.31-6.51 (m, 1H) 4.19 (s, 1H) 3.72 (s, 3H) 2.45 (s, 3H) 1.60 (s, 3H) 0.93 (s, 3H). HMRS calcd. for C23H21N3O4 (M+H)+ 404.1602. found 404.1595.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1CC#N.Cl.[C:21]([OH:24])(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:22][C:21]([OH:24])=[O:23]
Reactant: COc1c(CC#N)cccc1Oc1cccc(Cl)c1
Reactant: CC(=O)O
Agent: Cl
Product: COc1c(CC(=O)O)cccc1Oc1cccc(Cl)c1

Procedure:
2-[2-Methoxy-3-(3-chlorophenoxy)phenyl]acetonitrile (16.4 g), glacial acetic acid (80 ml) and conc. hydrochloric acid (30 ml) were treated in a similar manner to that of Example 5-(4) to give oily 2-[2-methoxy-3-(3-chlorophenoxy)phenyl]acetic acid (10.1 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH2:12][C:13]2[CH:14]=[C:15]([CH:40]=[CH:41][CH:42]=2)[C:16]([NH:18][CH2:19][C:20]2[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:23]3=[N:24][C:25]=2[CH2:26][CH3:27])=[O:17])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:43][C:44]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([CH2:56][C:57]2[CH:58]=[C:59](B(O)O)[CH:60]=[CH:61][CH:62]=2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])[CH3:45].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH2:31]([N:28]1[C:23]2=[N:24][C:25]([CH2:26][CH3:27])=[C:20]([CH2:19][NH:18][C:16]([C:15]3[CH:14]=[C:13]([CH2:12][N:10]([CH2:9][C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:59]5[CH:60]=[CH:61][CH:62]=[C:57]([CH2:56][N:53]6[CH2:54][CH2:55][N:50]([C:48]([O:47][C:44]([CH3:46])([CH3:45])[CH3:43])=[O:49])[CH2:51][CH2:52]6)[CH:58]=5)[CH:3]=4)[CH3:11])[CH:42]=[CH:41][CH:40]=3)=[O:17])[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]2[CH:30]=[N:29]1)[CH3:32]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CN(C)Cc2ccc(F)c(Br)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CN(C)Cc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Temperature: 150 °C
Yield: 82 %

Procedure:
To a solution of 3-{[[(3-bromo-4-fluorophenyl)methyl](methyl)amino]methyl}-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (0.37 g, 0.58 mmol) in p-dioxane/H2O (4.5/1.5 mL) was added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (0.279 g, 0.87 mmol), Pd(PPh3)4 (33.6 mg, 0.029 mmol), and K2CO3 (0.32 g, 2.32 mmol). The mixture was heated with a microwave at 150° C. for 15 min. The organic layer was separated and concentrated. The residue was redissolved in EtOAc, washed with H2O, brine, dried over Na2SO4, filtered, concentrated and the concentrate purified by CombiFlash chromatograph to afford the title compound 0.396 g (82%). LC-MS m/z 833 (M+H)+.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.O.[NH2:11][NH2:12]>C(O)C>[NH:11]([C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1)[NH2:12]
Reactant: NN
Reactant: COC1=NCCCCC1
Solvent: O
Solvent: CCO
Product: NNC1=NCCCCC1

Procedure:
A 22.5 g portion 7-methoxy-3,4,5,6-tetrahydro-2H-azepine was reacted with 11.3 g of hydrazine hydrate in 200 ml of ethanol by the procedure of Example 9, giving the desired intermediate.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH3:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4](=[O:15])(=[O:14])[N:3]=1.C(NC1C=CC=CC=1)C.[N:25]1([CH2:31][C:32]2[CH:33]=[C:34]([CH:62]=[CH:63][CH:64]=2)[O:35][CH2:36][CH2:37][CH2:38][N:39]([CH2:53][C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=2)C2N(C)C3C=CC=CC=3S(=O)(=O)N=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)(Cl)Cl>[N:25]1([CH2:31][C:32]2[CH:33]=[C:34]([CH:62]=[CH:63][CH:64]=2)[O:35][CH2:36][CH2:37][CH2:38][N:39]([CH2:53][C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=2)[C:2]2[N:7]([CH2:8][CH3:9])[C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[S:4](=[O:15])(=[O:14])[N:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCN1C(Cl)=NS(=O)(=O)c2ccccc21
Reactant: COc1ccc(CN(CCCOc2cccc(CN3CCCCC3)c2)C2=NS(=O)(=O)c3ccccc3N2C)cc1
Solvent: ClC(Cl)Cl
Solvent: CCNc1ccccc1
Product: CCN1C(N(CCCOc2cccc(CN3CCCCC3)c2)Cc2ccc(OC)cc2)=NS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A 0.8 g quantity of 3-chloro-4-ethyl-1,2,4-benzothiadiazine-1,1-dioxide in the form of white crystals prepared in the same manner as in Reference Example 4 with the exception of using N-ethylaniline in place of N-methylaniline was added to a solution of 1.2 g of the N-[3-[3-(piperidinomethyl)phenoxy]propyl]-4'-methoxybenzylamine obtained in Example 1, (iii) in 12 ml of chloroform, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was purified in the same manner as in Example 1, giving 1.67 g of 3-[N-[3-[3-(piperidinomethyl)phenoxy]-propyl]-4'-methoxybenzylamino]-4-ethyl-1,2,4-benzothiadiazine-1,1-dioxide (yield 88% ). This compound was converted to an oxalic acid salt in the same manner as in Example 1 to obtain 1.81 g of a compound 15 in the form of white crystals as listed in Table 1 (yield 92% ). M.p.: 85°~90° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][O:8][C:9]1[C:18]2[C:13](=CC=CC=2)[CH:12]=[CH:11][CH:10]=1)[C:3](O)=[O:4].NC(CCOC1C=CC=CC=1)C(O)=O>>[NH2:1][CH:2]([CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][OH:4]
Reactant: NC(CCOc1cccc2ccccc12)C(=O)O
Agent: NC(CCOc1ccccc1)C(=O)O
Product: NC(CO)CCOc1ccccc1

Procedure:
In the same manner but replacing 2-amino-4-(1-naphthyloxy)butanoic acid with an equivalent amount of 2-amino-4-phenoxy-butanoic acid, described by Y. Knobler, et al., J. Org. Chem., 24, 1794 (1959), 2-amino-4-phenoxy-1-butanol, γmaxCHCl3 3230-3400, is obtained. The hydrochloric acid addition salt of 2-amino-4-phenoxy-1-butanol has mp 136°-138° C, after recrystallization from methanol-diethyl ether.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:21]([O:22]C)=[C:20]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[C:25]=4[CH3:33])[CH:19]=[N:18]3)=[N:15][CH:16]=2)=[O:10])[CH2:5][CH2:4]1)[CH3:2].CC(N(C)C)=O.[Cl-].[Li+]>CS(C)=O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:21]([OH:22])=[C:20]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[C:25]=4[CH3:33])[CH:19]=[N:18]3)=[N:15][CH:16]=2)=[O:10])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3OC)nc2)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)CC1
Yield: 36.5 %

Procedure:
Combined 4-(1-(5-(4-ethylpiperazine-1-carbonyl)pyridin-2-yl)-5-methoxy-1H-pyrazol-4-yl)-2-fluoro-3-methylbenzonitrile (70 mg, 0.156 mmol) and DMA (1561 μl) then added lithium chloride (66.2 mg, 1.561 mmol) and heated at 70° C. overnight. The crude reaction was then diluted with DMSO (500 uL) and purified via preparative HPLC (acetonitrile-water, with TFA) to give the title compound (24.6 mg, 0.057 mmol, 36.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J=7.33 Hz, 3 H) 2.33 (d, J=2.27 Hz, 3 H) 3.16 (t, J=7.20 Hz, 2 H) 3.24-4.06 (m, 8 H) 7.49-7.84 (m, 2 H) 8.04-8.30 (m, 2 H) 8.43 (br. s., 1 H) 8.60 (dd, J=2.15, 0.63 Hz, 1 H). ESI-MS m/z [M+H]+ 435.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[C:20]([C:22](=[O:41])[NH:23][C:24]4[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:25]=4[O:39][CH3:40])[CH:19]=[CH:18][C:17]=3[CH3:42])[CH:15]=2)=[O:10])[CH2:2]1.C=O.[C:45]([BH3-])#N.[Na+]>CO.C(Cl)Cl>[CH3:45][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[C:20]([C:22](=[O:41])[NH:23][C:24]4[CH:29]=[C:28]([C:30]([CH3:31])([CH3:32])[CH3:33])[CH:27]=[C:26]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[C:25]=4[O:39][CH3:40])[CH:19]=[CH:18][C:17]=3[CH3:42])[CH:15]=2)=[O:10])[CH2:2]1
Reactant: COc1c(NC(=O)c2ccc(C)c(-n3cc(C(=O)NCC4CCCNC4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(C(=O)NCC4CCCN(C)C4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.6 %

Procedure:
To a 0° C. suspension of 106 mg (0.268 mmol) of 1-[5-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-[1,2,3]triazole-4-carboxylic acid (piperidin-3-ylmethyl)-amide in 2 mL of MeOH containing 1% HOAc was added 70 μL of aqueous formaldehyde. The suspension was stirred at 0° C. for five minutes then 18 mg (0.281 mmol) of sodium cyanoborohydride was added and the mixture was warmed to rt. After stirring for ˜1 the reaction mixture was diluted with 40 mL of CH2Cl2 and washed with 25 mL of water. The aqueous wash was extracted with CH2Cl2 (2×25 mL), the combined organic extracts were dried (Na2SO4), filtered and evaporated to afford a yellow solid. Chromatography provided 42 mg of product. mp: 209–211. ESI MS (m/z 612, 100, M+H).
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]([O:15][C:16]([NH:18][CH:19]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:20][CH2:21][C:22](O)=[O:23])=[O:17])([CH3:14])([CH3:13])[CH3:12].C1C=CC2N(O)N=NC=2C=1.CNC(N=C=NCC)CCNC>C(Cl)Cl.CCOC(C)=O>[C:11]([O:15][C:16](=[O:17])[NH:18][CH:19]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:20][CH2:21][C:22](=[O:23])[N:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:8][CH2:9][OH:10])([CH3:14])([CH3:12])[CH3:13]
Reactant: OCCNC1CCCCC1
Reactant: CC(C)(C)OC(=O)NC(CCC(=O)O)C1CCCCC1
Agent: CCN=C=NC(CCNC)NC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(CCC(=O)N(CCO)C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of N-cyclohexylethanolamine (0.55 g, 3.9 mmol) and 4-tert-butoxycarbonylamino-4-cyclohexyl-butyric acid (1.0 g, 3.5 mol), in DCM (200 mL), HOBT (0.62 g, 4.5 mmol) and TEA (1.0 mL) were added followed by addition of 1,3-dimethylamino propyl-3-ethylcarbodiimide (EDC, 0.87 g, 4.5 mmol). The reaction mixture was allowed to warm to room temperature and then stirred overnight. EtOAc (300 mL) was added to the reaction mixture. The reaction mixture was then washed with aqueous citric acid solution, saturated NaHCO3 solution, and NaCl solution. The organic layer was collected, dried with MgSO4, and then evaporated to yield {1-cyclohexyl-3-[cyclohexyl-(2-hydroxy-ethyl)-carbamoyl]-propyl}-carbamic acid tert-butyl ester as an oil, which was used in the next step without further purification.
Reaction SMILES: Cl[O-].[Na+].[Cl:4][C:5]1[C:14]([CH:15]=[CH2:16])=[C:13]([Cl:17])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:18][C:19]([CH3:24])([CH3:23])[CH:20]=[N:21][OH:22].Cl[O-]>ClCCl.O>[Cl:4][C:5]1[C:14]([CH:15]2[O:22][N:21]=[C:20]([C:19]([CH3:24])([CH3:23])[CH3:18])[CH2:16]2)=[C:13]([Cl:17])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=Cc1c(Cl)ccc(C(=O)OC)c1Cl
Reactant: CC(C)(C)C=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(Cl)c(C2CC(C(C)(C)C)=NO2)c1Cl
Reaction time: 2 h

Procedure:
At room temperature, 17 ml of a 12% strength aqueous sodium hypochlorite solution were added dropwise with vigorous stirring to a solution of 2.6 g (10 mmol) of methyl 2,4-dichloro-3-ethenylbenzoate and 1 g (10 mmol) of 2,2-dimethylpropionaldoxime in 100 ml of dichloromethane. Twice, in each case after 2 hours of stirring, a further 0.5 g (5 mmol) of the oxime and 9 ml of the hypochlorite solution were added. The reaction mixture was stirred at room temperature for a further 12 hours and then stirred into 350 ml of water. After extraction with dichloromethane, drying and removal of the solvent, the residue was chromatographed.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1.N12CCCN=C1CCCCC2>C1COCC1>[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:9][CH:8]=1
Reactant: c1nc[nH]n1
Reactant: Fc1ccc(CBr)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Fc1ccc(Cn2cncn2)cc1
Yield: 68 %

Procedure:
To a stirred solution of 1,2,4-triazole (0.803 g, 11.6 mmol) in THF (100 mL) at 0° C. was added 4-fluorobenzyl bromide (2.0 g, 10.6 mmol), then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.9 mL, 12.7 mmol) and the mixture was slowly warmed to room temperature. The solution was concentrated in vacuo, then purified by column chromatography (SiO2, MeOH/EtOAc, 5:95) to yield a white solid in 68% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[S-2].[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Agent: [Na+]
Agent: [S-2]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Temperature: 90 °C
Yield: 61.7 %

Procedure:
To a solution of 4-[2-(3-nitrophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-phenyl-2-pyrimidinamine (809 mg, 1.98 mmol) in 1,4-dioxane (16 mL) was added sodium sulfide nonhydrate (1.05 g, 6 mmol) in water (4 mL). The mixture was heated at 90° C. for 5 h, allowed to cool to rt and concentrated in vacuo. The residue was diluted with EtOAc and water. The organic layer was separated and the aqueous layer is extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated to give a dark solid. The crude material was purified by silica gel chromatography (hexanes/EtOAc 30-50%) to afford the titled product (462 mg, 62% yield). 1H NMR (400 MHz, CDCl3): δ 3.75 (brs, 2H), 6.63 (d, 1H, J=5.3 Hz), 6.78 (m, 1H), 6.91 (m, 1H), 6.96-7.00 (m, 2H), 7.06 (m, 1H), 7.16 (m, 1H), 7.22-7.36 (m, 4H), 7.65 (m, 1H), 8.17 (d, 1H, J=5.3 Hz), 8.42 (m, 1H), 8.52 (m, 1H); ES-LC/MS m/z=379 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[N:17]([CH3:18])[CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[N:25][CH:26]=1)#[CH:20]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:20]=[CH:19]\[C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:6]1[CH2:11][C@@H:12]3[N:17]([CH3:18])[C@H:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3
Reactant: C#Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1C
Product: Cc1ccc2c(c1)c1c(n2/C=C\c2ccc(C)nc2)C[C@H]2CCC[C@@H]1N2C

Procedure:
The coupling of 2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110 mg, 0.458 mmol; Example 114A) and 5-ethynyl-2-methylpyridine (107 mg, 0.915 mmol; prepared as described in International Publication No. WO2005090333) was performed according to the procedure described in Example 20 to give the racemic mixture of the title compound as the major of two alkene isomers. The individual enantiomers from the racemic mixture of the major alkene isomer were separated by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine) to afford the title compound as the first-eluting enantiomer: 1H NMR (300 MHz, methanol-d4) δ ppm 1.18-1.30 (m, 1H), 1.30-1.41 (m, 1H), 1.48 (dd, J=13, 2 Hz, 1H), 1.69 (dd, J=13, 2 Hz, 1H), 1.83-2.09 (m, 2H), 2.26 (d, J=17 Hz, 1H), 2.28 (s, 3H), 2.38 (s, 3H), 2.39 (s, 3H), 2.89 (dd, J=18, 7 Hz, 1H), 3.17 (t, J=5 Hz, 1H), 4.13 (s, 1H), 6.64 (d, J=9 Hz, 1H), 6.84-6.90 (m, 1H), 6.92-7.01 (m, 2H), 7.03-7.09 (m, 1H), 7.15-7.22 (m, 2H), 7.96 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 358 (M+H)+.