Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH2:19][C:20](=O)[CH2:21][C:22](OC)=[O:23]>>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH2:19][C:20]1[CH:21]=[C:22]([OH:23])[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: COC(=O)CC(=O)Cc1ccc(F)cc1F
Product: N#Cc1ccnc(-n2nc(Cc3ccc(F)cc3F)cc2O)c1

Procedure:
The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl 4-(2,4-difluorophenyl)-3-oxobutanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@H:12](C(C)C)[C:13]([O:15][CH3:16])=[O:14])[CH2:5]2.BrC1C=CC(C(OC)=O)=C(CBr)C=1.Cl.COC(=O)CN>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:5]2
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O
Agent: COC(=O)CN
Agent: COC(=O)c1ccc(Br)cc1CBr
Agent: Cl
Product: COC(=O)CN1Cc2cc(Br)ccc2C1=O

Procedure:
The compound of example 362 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and glycine methyl ester hydrochloride.
Reaction SMILES: CCN(CC)CC.[C:8]([C:10]1[CH:15]=[N:14][CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[N:11]=1)#[CH:9].[OH:28][N:29]=[C:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C.CCOC(C)=O.O>[CH:25]([S:22]([C:19]1[CH:20]=[CH:21][C:16]([C:12]2[N:11]=[C:10]([C:8]3[O:28][N:29]=[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:9]=3)[CH:15]=[N:14][CH:13]=2)=[CH:17][CH:18]=1)(=[O:24])=[O:23])([CH3:27])[CH3:26]
Reactant: ON=C(Cl)c1ccccc1
Reactant: C#Cc1cncc(-c2ccc(S(=O)(=O)C(C)C)cc2)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)c1ccc(-c2cncc(-c3cc(-c4ccccc4)no3)n2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 32.6 %

Procedure:
Et3N (27.56 mg, 37.96 μL, 0.2724 mmol) was added to a stirred solution of 2-ethynyl-6-(4-isopropylsulfonylphenyl)pyrazine (65 mg, 0.2270 mmol) and N-hydroxybenzimidoyl chloride (35.32 mg, 0.2270 mmol) in DMF (2 mL) and the reaction was stirred at ambient temperature for 45 minutes then heated to 65° C. for 1 hour. The mixture was cooled to ambient temperature and diluted with EtOAc and water and the layers separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic extracts washed with water (×3), brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 12 g column, eluting with 0 to 40% EtOAc/Petroleum Ether) and the relevant fractions concentrated in vacuo. The residue was triturated from methanol and the precipitate isolated by filtration to give the title product as a cream solid (30 mg, 33% Yield). 1H NMR (400.0 MHz, DMSO) H NMR (400.0 MHz, DMSO) d 9.53 (s, 1H), 9.32 (s, 1H), 8.58 (d, 2H), 8.09-8.07 (m, 3H), 8.04-8.02 (m, 2H), 7.61-7.57 (m, 3H), 3.55 (sept, 1H) and 1.21 (d, 6H) ppm; MS (ES+) 406.1; LCMS Retention time 1.72 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:13]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[NH:14][C:15](=[O:26])[C:16]2[CH:21]=[C:20]([OH:22])[C:19]([N+:23]([O-])=O)=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].O.NN.CCOC(C)=O>CO.CCCCCC.[Ni]>[NH2:23][C:19]1[C:20]([OH:22])=[CH:21][C:16]([C:15]([NH:14][C@@H:13]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:10])[F:12])=[C:2]([F:1])[CH:3]=2)[C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:26])=[N:17][CH:18]=1
Reactant: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1cc(O)c([N+](=O)[O-])cn1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1cnc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1O
Reaction time: 3 h

Procedure:
To a stirred solution of (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-4-hydroxy-5-nitropicolinamide (0.35 g, 0.0007 mol) in MeOH (10 mL) was added Raney Ni (0.3 g, Monarch), followed by hydrazine hydrate (2 mL, Aldrich) added in a drop-wise fashion at rt. The reaction mixture was stirred for 3 h. After completion of the reaction (monitored by TLC, 50% EtOAc in hexane), the reaction mixture was filtered through Celite® brand filter agent and concentrated providing a residue. The residue was triturated with Et2O, filtered dried under vacuum to give the title compound as a brown solid. 1H NMR (DMSO-d6) δ: 9.41 (d, J=7.5 Hz, 1H), 8.55 (d, J=4.2 Hz, 1H), 7.83-7.78 (m, 2H), 7.54-7.44 (m, 3H), 7.27 (d, J=9.9 Hz, 2H), 6.46 (d, J=6.9 Hz, 1H), 5.29 (s, 2H).
Reaction SMILES: Cl.N[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=2)[C:6]([Br:18])=[CH:5][CH:4]=1.Cl.N([O-])=O.[Na+].[I-:24].[K+]>O.ClCCl>[Br:18][C:6]1[CH:5]=[CH:4][C:3]([I:24])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11]2
Reactant: [I-]
Reactant: CS(=O)(=O)Oc1ccc2c(Br)ccc(N)c2c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)Oc1ccc2c(Br)ccc(I)c2c1
Reaction time: 0.25 h

Procedure:
To a solution of the product from Step D (1.50 g, 4.25 mmol) in 16 mL of 1:1THF/3M HCl solution at 0° C. was added NaNO2 as a 40 wt % solution in water (0.626 mL, 4.68 mmol). After 15 minutes, a solution of potassium iodide (2.12 g, 12.76 mmol) in 5 mL of water was added, and the solution was stirred for 3 hours. The reaction was poured into dichloromethane and water, the aqueous layer was extracted with dichloromethane, and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (20-30% EtOAc/hexane) to yield the desired product as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([CH2:14][OH:15])[N:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1)=[CH2:2].[CH2:16]([Zn]CC)C.ICI>C1(C)C=CC=CC=1.CCCCCC>[CH:1]1([C:3]2[CH:4]=[C:5]([N:9]3[CH:13]=[C:12]([CH2:14][OH:15])[N:11]=[CH:10]3)[CH:6]=[CH:7][CH:8]=2)[CH2:16][CH2:2]1
Reactant: CC[Zn]CC
Reactant: C=Cc1cccc(-n2cnc(CO)c2)c1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: ICI
Product: OCc1cn(-c2cccc(C3CC3)c2)cn1
Temperature: 20 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
Under an Ar atmosphere, a mixture of [1-(3-vinyl-phenyl)-1H-imidazol-4-yl]-methanol (0.10 g, 0.5 mmol) in toluene (20 ml) was successively treated with diethylzinc (3.8 ml of a 1.1 M solution in hexane, 4.2 mmol) and diiodomethane (6.6 g, 25 mmol). The resulting mixture was stirred at 20° C. for 12 h. The preciptate was filtered and stirred for 30 min with AcOEt and saturated aqueous NH4Cl solution. The organic phase was separated, dried (Na2SO4) and concentrated to yield the title compound as a yellow oil (0.10 g, 93%). MS: m/e=215 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[N:12]=[C:13]([NH:20][CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[C:14]4[CH:19]=[CH:18][NH:17][C:15]=4[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1>C(O)(C(F)(F)F)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[N:12]=[C:13]([NH:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:14]4[CH:19]=[CH:18][NH:17][C:15]=4[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Nc3ccc4cn[nH]c4c3)nc3[nH]ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c(NC3CCNCC3)nc(Nc3ccc4cn[nH]c4c3)nc2[nH]1
Yield: 31.9 %

Procedure:
A solution of tert-butyl 4-(2-(1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (4 mg, 0.009 mmol) in TFA (1 mL) was stirred at room temperature for 2 h. It was concentrated in vacuo. The residue was purified by reverse phase HPLC using a gradient of 3-30% CH3CN in water over 10 min. as eluents to give a powder (1 mg). MS 349.0 (M+H); UV 201.4, 242.6, 306.7 nm.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([O:17][C:18]2[CH:26]=[C:25]3[C:21]([C:22]([CH3:29])([CH3:28])[C:23](=[O:27])[NH:24]3)=[CH:20][CH:19]=2)[CH3:16])[CH:10]=1.O.[OH-].[Na+].Cl>C1COCC1.CO.CCOC(C)=O>[CH3:16][CH:15]([O:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH3:28])([CH3:29])[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1)[C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CCCCCc1cccc(C(C)Oc2ccc3c(c2)NC(=O)C3(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(Oc1ccc2c(c1)NC(=O)C2(C)C)c1cccc(CCCCCC(=O)O)c1
Temperature: 5 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
To a solution of 6-[3-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yloxymethyl)-phenyl]-hexanoic acid methyl ester (110 mg, 0.27 mmol) in (1:1) THF/CH3OH (1 mL) is added 250 μL water and 10N NaOH soln (270 μL). The mixture is stirred for 16 hrs, cooled to 5° C., adjusted to pH 4 with 2N HCl soln. and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 50% ethyl acetate/5% methanol/hexanes) to give 67 mg of title compound. 1H NMR (300 MHz, CDCl3) δ 7.29 (m, 3H), 7.14 (d, 1H), 7.09 (d, 1H), 6.63 (dd, 1H), 6.52 (d, 1H), 5.04 (s, 2H), 3.18 (s, 3H), 2.64 (t, 2H), 2.36 (t, 2H), 1.66 (m, 4H), 1.40 (m, 2H), 1.34 (s, 6H). MS (ESI) 396 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1C=CN=C1)=[O:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2C=CN=C(NN)[C:21]=2[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:16][CH:15]=1.O>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:11]=[CH:12][N:8]3[C:1](=[O:2])[NH:3][N:10]=[C:9]3[C:21]=2[C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)=[CH:18][CH:19]=1
Reactant: NNc1nccc(-c2ccc(Cl)cc2)c1-c1ccncc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To a stirring solution of 1,1′-carbonyldiimidazole (2.5 g, 15.4 mmol) in THF (15 mL) at room temperature under argon was added 4-(4-chlorophenyl)-2-hydrazinyl-3,4′-bipyridine (0.92 g, 3.1 mmol). The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was then concentrated under vacuum to produce a yellow solid. This solid was stirred in an ice bath and water (25 mL) was added. Solid was collected by filtration and further washed with water (15 mL×2). After drying in an oven at 50° C. under reduced pressure overnight, 960 mg of the title compound was obtained as a yellow solid. HPLC/MS: retention time=1.985 min, [M+H]+=323. 1H NMR (DMSO-d6, 500 MHz): δ 12.61 (s, 1H), 8.50 (d, J=6.05 Hz, 2H), 7.94 (d, J=7.15 Hz, 1H), 7.36 (d, J=8.2 Hz, 2H), 7.23 (d, J=6.05 Hz, 2H), 7.18 (d, J=8.2 Hz, 2H), 6.68 (d, J=7.15 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.CC1C=C(C)N2N=C(C=O)N=C2N=1.[CH:26]1([C:31]2([CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([CH:47]([OH:49])[CH3:48])=[C:43]([F:50])[CH:42]=3)[O:36][C:35](=[O:37])[CH2:34][C:33](=[O:38])[CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:34]3[C:35](=[O:37])[O:36][C:31]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)([CH2:39][CH2:40][C:41]4[CH:46]=[CH:45][C:44]([CH:47]([OH:49])[CH3:48])=[C:43]([F:50])[CH:42]=4)[CH2:32][C:33]=3[OH:38])[N:10]=2)[CH:7]=1
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Reactant: CC(O)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Agent: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: CC(O)c1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(Cl)cn4n3)C(=O)O2)cc1F

Procedure:
The title compound was prepared analogously to Example B(97) where where 6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-Cyclopentyl-6-{2-[3-fluoro-4-(1-hydroxy-ethyl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione (Example B(115) (was substituted in place of 6-[2-(3-Chloro-5-ethyl-4-methoxy-phenyl)-ethyl]6-cyclopentyl-dihydro-pyran-2,4-dione of that example. 1H NMR (400 MHz, DMSO-d6): δ 1.13 (d, J=6.4 Hz, 3H), 1.23-1.60 (m, 8H), 1.81-1.91 (m, 2H), 2.21-2.25 (m, 1H), 2.40-2.46 (m 3H), 2.6 (d, J=16 Hz, 1H), 3.14 (s, 1H), 3.58 (d, J=16 Hz, 1H), 3.68 (d, J=16 Hz, 1H), 4.78-4.80 (m, 1H), 5.02 (d, J=5 Hz, 1H), 6.75 (d, J=10 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H), 7.23 (t, J=7.70 Hz, 1H), 8.70 (d, J=2.5 Hz, 1H), 9.4 (d, J=2.5 Hz, 1H). Anal. Calcd. For C26H28ClFN4O4.0.5H2O: C, 59.60; H, 5.58; N, 10.69. Found: C, 59.67; H, 5.44; N, 10.65. MS (ESI): 515.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[Cl:12].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5]([Cl:12])=[CH:6][C:7]([Br:11])=[CH:8][C:9]=1[CH2:10][Br:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cc(Br)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(Cl)cc(Br)cc1CBr

Procedure:
A mixture of 4-bromo-2-chloro-6-methyl-benzoic acid methyl ester (2.447 g, 9.27 mmol,), N-bromosuccinimide (1.815 g, 10.2 mmol), and benzoyl peroxide (0.051 g, 0.22 mmol) in carbon tetrachloride (30 mL) was refluxed until most of the starting materials were consumed (as analyzed by GC/MS). The resulting mixture was filtered and the filtrate concentrated to afford 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester. The product was used without further purification.
Reaction SMILES: Cl.[NH2:2][OH:3].O.C(=O)([O-])O.[Na+].[CH3:10][C:11]([S:16][C:17]#[N:18])([CH3:15])[C:12](=O)[CH3:13]>C(O)C>[N:2](=[C:17]1[N:18]=[C:12]([CH3:13])[C:11]([CH3:15])([CH3:10])[S:16]1)[OH:3]
Reactant: NO
Reactant: CC(=O)C(C)(C)SC#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1=NC(=NO)SC1(C)C
Temperature: 25 °C

Procedure:
8.3 g. (0.12 mol) of hydroxylamine hydrochloride were dissolved in 50 ml. of water and treated with 10.1 g. (0.12 mol) of sodium hydrogen carbonate. This solution (pH 6-7) was added with stirring at room temperature to a solution of 14.3 g. (0.1 mol) of 3-methyl-3-thiocyanato-2-butanone in 100 ml. of ethanol. The temperature of the mixture rose rapidly to 37° C. The mixture was then stirred for 1 hour, 120 ml. of the solvent were then distilled off at 50° C. in vacuo. The residue was extracted three times with 100 ml. of ether each time. The organic phase was washed with a small amount of water, dried over sodium sulfate and concentrated until crystallization began. After cooling, the crystal sludge was treated with 10 ml. of hexane. The crystals were filtered off under suction, washed with ether/hexane (2:1) and dried to yield 2-oxo-4,5,5-trimethyl-3-thiazoline-oxime, m.p. 151°-153° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH:25]=[CH:24][C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][CH2:22][NH2:23])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:26]([C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=1)=O>>[C:1]1([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:21][CH2:22][NH:23][CH2:26][C:28]3[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])=[CH:30][CH:29]=3)=[CH:24][CH:25]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Reactant: NCCc1ccccc1OCc1ccc(CCc2ccccc2)cc1
Product: CC(C)(C)OC(=O)c1ccc(CNCCc2ccccc2OCc2ccc(CCc3ccccc3)cc2)cc1

Procedure:
This compound was prepared analogously to Ex. 1.1 from 2-(2-{[4-(2-phenylethyl)-benzyl]oxy}phenyl)ethylamine and tert-butyl 4-formylbenzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:24]([N:27]1[C:35](=[O:36])[N:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]2=[N:28]1)[C:25]#[CH:26].C#C>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][N:27]3[C:35](=[O:36])[N:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]4=[N:28]3)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Reactant: C#CCn1nc2ccccn2c1=O
Agent: C#C
Solvent: O
Product: Cc1nnc2n1-c1ccc(C#CCn3nc4ccccn4c3=O)cc1C(c1ccccc1F)=NC2

Procedure:
This compound was obtained as described in example 17 by coupling of 6-(2-fluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with 2-(2-propynyl)-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one. The product was purified by chromatography in the usual fashion and crystallized from ethyl acetate/ethanol. Recrystallization from ethanol gave light yellow crystals with m.p. 170°-173° C. They contained 0.66 molar amounts of water. The synthesis of the required acetylene is described in Example 27.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([CH3:19])[C:17]=1[OH:18])=[O:12])[CH3:9].[OH-].[Na+]>O>[CH3:5][O:18][C:17]1[C:16]([CH3:19])=[CH:15][NH:14][C:13]=1[C:11]([O:10][CH2:8][CH3:9])=[O:12]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1[nH]cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1[nH]cc(C)c1OC
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Add dimethyl sulfate (3 mL, 3.99 g, 31.63 mmoles) to a mixture of 3-hydroxy-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (3.5 g, 20.69 mmoles) and 2M sodium hydroxide (75 mL, 1500 mmoles) and stir the reaction mixture vigorously for 30 mins at room temp (water cooling bath applied). Collect the resultant precipitate and wash with water. Add more dimethyl sulfate (3 mL, 3.99 g, 31.63 mmoles) to the filtrate and stir for 30 minutes. Collect the resultant precipitate and wash with water. Add more dimethyl sulfate (3 mL, 3.99 g, 31.63 mmoles) to the filtrate and stir for 1 h. Combine the isolated precipitates and dry in a vacuum oven at 50° C. for 30 minutes to give ethyl 3-methoxy-4-methyl-1H-pyrrole-2-carboxylate (3.221 g, 84.98% yield). MS (m/z): 184.09 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([O:23]CC)=[O:22])[CH2:14][CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].O.[OH-].[Li+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([OH:23])=[O:22])[CH2:14][CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc([C@H]2CC[C@@H](NC(=O)c3nc(Cl)c(CC)[nH]3)CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCc1[nH]c(C(=O)N[C@H]2CC[C@@H](c3cccc(C(=O)O)c3)CC2)nc1Cl
Yield: 49.4 %

Procedure:
The same operation as in Example (1i) was performed using ethyl cis-3-{4-[(4-chloro-5-ethyl-1H-imidazole-2-carbonyl)amino]cyclohexyl}benzoate obtained in Example (194b) (50 mg, 0.124 mmol) and lithium hydroxide monohydrate (44 mg, 0.124 mmol), to obtain 23 mg of the title compound as a white solid (49%).
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C@H:41]2[CH2:46][CH2:45][C@H:44]([CH:47]=O)[CH2:43][CH2:42]2)=[CH:35][CH:34]=1)#[N:32]>C1COCC1>[F:2][CH2:3][CH2:4][CH:5]=[CH:47][C@H:44]1[CH2:45][CH2:46][C@H:41]([CH2:40][CH2:39][C:36]2[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)[CH2:42][CH2:43]1
Reactant: FCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(CC[C@H]2CC[C@H](C=O)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(CC[C@H]2CC[C@H](C=CCCF)CC2)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A mixture of (3-fluoropropyl)triphenylphosphonium bromide (14.7 g, 36.5 millimols) with THF (60 ml) was cooled down to -20° C., followed by adding t-BuOK (4.1 g, 36.5 millimols) to the mixture, stirring for one hour, dropwise adding to the mixture, a THF (50 ml) solution of trans-4-(2-(4-cyanophenyl)ethyl)cyclohexanecarbaldehyde (9.0 g, 30.2 millimols so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, and treating the product in the same manner as in Example 1 except that the quantity used for extraction was made 200 ml, to obtain raw 4-(2-(trans-4-(4-fluorobutenyl)cyclohexyl)ethyl)benzonitrile (8.1 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:30][O:29][C:28]1[CH:27]=[CH:26][NH:25][C:24]=1/[CH:23]=[C:12]1\[C:13](=[O:22])[NH:14][C:15]2[C:11]\1=[C:10]([C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=2
Reactant: C#Cc1cccnc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(C#Cc3cccnc3)c21

Procedure:
Using Method D above, 3-ethynyl pyridine (0.14 g, 1.38 mmol) (see Example 64) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (0.2 g, 0.55 mmol) (Starting Material 3) using (Ph3P)4Pd (31.8 mg) (Aldrich) and CuI (5.3 mg) (Aldrich) as catalyst in DMF (6 mL) and Et3N (6 mL) as solvent and at 85° C. for 18 h, yielding (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-4-[(3-pyridinyl)ethynyl]-2H-indol-2-one. (Yield 0.16 g, 71%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([N+]([O-])=O)[C:14]=1[C:15]#[N:16])([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][C:5]2=[O:9])[C:14]=1[C:15]#[N:16])([O-:12])=[O:11]
Reactant: O=C1CCCN1CCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(OCCN2CCCC2=O)cccc1[N+](=O)[O-]
Yield: 74 %

Procedure:
Prepared as in Example 160d from 1-(2-hydroxyethyl)pyrrolidin-2-one and 2,6-dinitrobenzonitrile in 74% yield. MS 276 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[CH:16]=2)[NH:11][N:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:51]1[CH:56]=[CH:55][CH:54]=[N:53][C:52]=1[N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([C:21]([N:60]4[CH2:61][CH2:62][N:57]([C:52]5[N:51]=[CH:56][CH:55]=[CH:54][N:53]=5)[CH2:58][CH2:59]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(=O)N4CCN(c5ncccn5)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.3 %

Procedure:
To a solution of 3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid (18 mg, 0.05 mmol) in DMF (1 mL) was added HATU (20 mg, 0.05 mmol) and 1-(2-pyrimidyl)piperazine (11 uL, 0.08 mmol). The reaction solution was stirred for 16 hours at ambient temperature. The crude product was extracted into ethyl acetate and washed with H2O. The organic layer was dried over Na2SO4, filtered, and adsorbed onto silica gel. Purification by flash chromatography with a gradient of ethyl acetate (containing 10% MeOH) and hexanes afforded the title compound as a white powder (7.2 mg, 28% yield). 1H NMR (500 MHz, CD3OD) δ 8.85 (d, J=2 Hz, 1H), 8.42 (d, J=2 Hz, 1H), 8.35 (d, J=4.5 Hz, 2H), 7.83 (d, J=8 Hz, 1H), 7.79 (s, 1H), 7.64 (m, 2H), 7.50 (m, 2H), 7.20 (d, J=8.5 Hz, 1H), 7.11 (t, J=8 Hz, 1H), 6.64 (t, J=4.5 Hz, 1H), 3.96 (br s, 2H), 3.89 (s, 3H), 3.86 (br s, 4H), 3.60 (br s, 2H). MS: m/z 492.1 (M+H+).