Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([OH:35])[C:33]#[CH:34].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[F:10][C:9]([F:12])([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:34]#[C:33][CH2:32][OH:35])=[CH:3][CH:4]=1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: OCC#Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of 1-iodo-4-(trifluoromethoxy)benzene (5.00 g), copper(I) iodide (66.3 mg), triphenylphosphine (228 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (360 mg), propargyl alcohol (1.13 ml), diisopropylethylamine (12.1 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 21 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.46 g) as a brown oil.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:12][CH:11]=1)#[N:2].Cl.[NH2:43][OH:44].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[NH2:2][C:1](=[N:43][OH:44])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:18]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][N:21]3[C:29]([C:32]([NH:34][CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[CH:30][CH:31]=[C:20]3[CH2:19]2)=[O:17])=[CH:14][CH:15]=1
Reactant: NO
Reactant: N#CCc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1)=NO
Yield: 22.3 %

Procedure:
A mixture of 0.806 g (0015 mol) of 10-{[2′-(cyanomethyl)-1,1′-biphenyl-4-yl]carbonyl}-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 17, 0.52 g (0.0075 mol) of hydroxylamine hydrochloride and 1.03 g (0.0075 mol) of potassium carbonate in 100 mL of ethanol and 25 mL of water was heated under reflux for 2 hours. An additional 1.04 g (0.015 mol) of hydroxylamine hydrochloride and 2.06 g (0.015 mol) of potassium carbonate was added to the and refluxing was allowed to continue until LC/MS indicated that all the starting nitrile was consumed. The solvents were removed in vacuo and the residue was washed with water and purified by chromatography to provide the title compound (0.191 g), m.p. 131-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH:16](C(OCC)=O)C(OCC)=O)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:27][CH3:28])=[CH:10]1)=[N:5]2>O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:16])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:27][CH3:28])=[CH:10]1)=[N:5]2
Reactant: CCOC(=O)C(C(=O)OCC)c1c2ccc(Cl)cc2nc2ccc(OC)cc12
Agent: Cl
Solvent: O
Product: COc1ccc2nc3cc(Cl)ccc3c(C)c2c1

Procedure:
A solution of the compound of Example 19 (a) (2.2 g, 5.5 mmol) in water (5 mL) and concentrated hydrochloric acid was heated to reflux for 4 h and filtered to give the title compound. MS(ES) m/e 258.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[I:19]C1C=C(C=CC=1)N.N1C=CC=CC=1C=O>>[I:19][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Reactant: Nc1cccc(I)c1
Agent: O=Cc1ccccn1
Product: Ic1cccc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-iodoaniline (263 mg, 1.2 mmol) and pyridine-2-carboxaldehyde (128 mg, 1.2 mmol) were employed to obtain 2-[2-(3-iodophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].Cl.[NH2:14][OH:15]>C(O)C>[NH2:1][C:2]1[C:3]([C:8]([NH2:9])=[N:14][OH:15])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: N#Cc1ncccc1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=NO)c1ncccc1N
Yield: 54.4 %

Procedure:
A suspension of 3-amino-2-cyanopyridine (1.18 g, 9.9 mmol), sodium methoxide (0.64 g, 12 mmol) and hydroxylamine hydrochloride (0.83 g, 12 mmol) in ethanol (10 ml) was heated under reflux for 1 h. The mixture was filtered and the filtrate concentrated to an oil, which was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (50:1 to 10:1) as eluent to afford the product as a yellow solid (0.82 g), MS (+CI) m/z 153 [M+H]+; 1H NMR (d6-DMSO) 9.80 (1H, br. s), 7.80 (1H, dd), 7.10 (1H, d), 7.08 (1H, d), 6.62 (2H, s), 5.90 (1H, s).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[NH2:14][OH:15].C([O-])(=O)C.[Na+].O>C(O)C>[C:1](=[N:14]/[OH:15])(\[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][N:5]=1)/[CH3:2]
Reactant: NO
Reactant: CC(=O)c1cc(C(F)(F)F)ccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C/C(=N\O)c1cc(C(F)(F)F)ccn1
Yield: 77.2 %

Procedure:
A solution of 2-acetyl-4-trifluoromethylpyridine (1.2 g), hydroxylamine (0.495 g) and sodium acetate (2.2 g) in a mixture of ethanol:water (20:10 ml) was heated under reflux for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (×2). The combined extracts were washed with water, dried and concentrated to give a solid which was washed with hexane to give (E)-2-acetyl-4-trifluoromethylpyridine oxime (1.0 g, 77% yield) as a pale pink solid; 1H NMR (270 MHz): δ2.39(3H,s), 7.47(1H,d), 7.89(1H,brs), 8.12(1H,s), 8.12(1H,s), 8.78(1H,d); ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:24]([N:27](CC3C=CC(OC)=CC=3)[C:28]3[S:29][CH:30]=[CH:31][N:32]=3)(=[O:26])=[O:25])=[CH:20][C:21]=2[CH3:23])[N:16]=[CH:15][CH:14]=1>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:24]([NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)(=[O:25])=[O:26])=[CH:20][C:21]=2[CH3:23])[N:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc(C)c3c(-c4ccc(C(F)(F)F)cc4OC)ccnc3c2)cc1
Solvent: O
Solvent: CO
Product: COc1cc(C(F)(F)F)ccc1-c1ccnc2cc(S(=O)(=O)Nc3nccs3)cc(C)c12
Reaction time: 1 h
Yield: 32 %

Procedure:
To a microwave vial charged with (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (3.16 mg, 0.014 mmol), 4-chloro-N-(4-methoxybenzyl)-5-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide (6 mg, 0.013 mmol), potassium phosphate tribasic (3.24 μl, 0.039 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (0.924 mg, 1.304 μmol) was added dioxane (52.3 μl) and water (17.44 μl). The mixture was irradiated at 100° C. for 30 min affording conversion to desired product according to LC-MS, 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-5-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide. m/z (ESI) 600.2 (M+H)+. The mixture was dried under reduced pressure. To the crude oil was added DCM (0.9 ml) and TFA (0.3 ml) was added at room temperature. After 1 hr of stirring, LC/MS indicated complete PMB cleavage. The mixture was dried under reduced pressure and purified with a 25 g (15 μm spherical silica) column ramping EtOAc in heptane (0 to 100%, 10% DCM throughout) providing product, obtained as a film. The material was lyophilized from MeOH/H2O providing 4-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide (2 mg, 4.17 μmol, 32.0% yield) as a yellow film. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.75 (s, 3H) 6.86 (d, J=4.59 Hz, 1H) 7.28 (d, J=4.59 Hz, 1H) 7.38 (d, J=4.27 Hz, 1H) 7.41-7.48 (m, 2H) 7.49 (s, 1H) 7.63 (s, 1H) 8.32-8.39 (m, 1H) 8.99 (d, J=4.27 Hz, 1H). m/z (ESI) 480.2 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.Cl.Cl.[F:38][C:39]([F:62])([F:61])[C:40]1[CH:41]=[C:42]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][C@@H:54]3[CH2:59][CH2:58][C@H:57]([NH2:60])[CH2:56][CH2:55]3)[CH2:48][CH2:47]2)[CH:43]=[CH:44][CH:45]=1>ClCCl>[C:1]([CH2:3][C:4]([NH:60][CH:57]1[CH2:58][CH2:59][CH:54]([CH2:53][CH2:52][N:49]2[CH2:48][CH2:47][N:46]([C:42]3[CH:43]=[CH:44][CH:45]=[C:40]([C:39]([F:62])([F:61])[F:38])[CH:41]=3)[CH2:51][CH2:50]2)[CH2:55][CH2:56]1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: N[C@H]1CC[C@@H](CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCC(=O)NC1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Reaction time: 0.25 h

Procedure:
To a solution of 43 mg (0.5 mmol) of cyanoacetic acid in 5 mL of dichloromethane stabilized on amylene are successively added 68 mg (0.5 mmol) of 1-hydroxybenzotriazole, 96 mg (0.5 mmol) of 3-ethyl-1-(3-dimethylaminopropyl)-carbodiimide hydrochloride and 0.21 mL (1.5 mmol) of triethylamine. The mixture is stirred for 15 minutes then 214 mg (0.5 mmol) of the 80%/20% trans/cis 4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylamine dihydrochloride is added. The mixture is stirred overnight at room temperature.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[CH:6][CH:5]=1.CO>[OH-].[K+]>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:16])=[O:2])=[CH:5][CH:6]=1)#[CH:11]
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc(C(=O)O)cc1
Yield: 95.1 %

Procedure:
4-(Trimethylsilyl)ethynyl-benzoic acid methyl ester (714 mg, 3.07 mmol) was dissolved in 4% KOH:MeOH (w:v, 30 mL) and allowed to reflux overnight. The reaction was quenched with 6N HCl to pH 2-3 (as indicated by pH paper) and extracted 2× with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and evaporated to afford 4-ethynylbenzoic acid (427 mg, 2.92 mmol, 95%) as a brown solid. H-NMR (d6-acetone, 500 MHz) δ (ppm): 7.62 (d, J=16.2 Hz, 2H); 8.03 (d, J=16.3 Hz, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.C1(P(=[CH:30]/[CH:31]=[CH:32]/[CH:33]=[O:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[O:34]=[CH:33]/[CH:32]=[CH:31]/[CH:30]=[CH:1]/[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: O=C/C=C/C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: N#Cc1ccc(/C=C/C=C/C=O)cc1

Procedure:
A solution of 13.1 g (99 mmol) of 4-formylbenzonitrile (commercially available) and 40 g (120 mmol) of (triphenylphosphoranylidene)crotonaldehyde [prepared as described in Tetrahedron Lett., 493 (1971)] in 200 ml of dichloromethane was stirred at ambient temperature overnight. At the end of this time, the reaction mixture was concentrated to dryness in vacuo. The resulting residue was purified by chromatography on a silica gel (250 g) column using ethyl acetate as the eluant to give a mixture of the desired compound and a geometrical isomer thereof. A solution of the mixture of the two isomers in 150 ml of toluene was heated at reflux under irradiation with a tungsten lamp (300 W) for 12 hours. The reaction mixture was then concentrated in vacuo. The resulting residue was purified by chromatography on a silica gel (1.2 kg) column using a 1:9 mixture of ethyl acetate and toluene as the eluant to afford 3.46 g (yield 19%) of the title compound as pale brown needle-like crystals which were collected by filtration.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14](=[O:17])[NH:13][CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:18][O:19][CH:20]([O:25][CH3:26])[CH2:21][CH2:22][CH2:23]Br>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]([CH2:23][CH2:22][CH2:21][CH:20]([O:25][CH3:26])[O:19][CH3:18])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Reactant: COC(CCCBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(CCCN1CCN(C(=O)OC(C)(C)C)CCC1=O)OC
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 51.8 %

Procedure:
To a suspension of 60% sodium hydride in mineral oil (0.2 g, 5 mmole) in N,N-dimethylformamide (6 mL) was added 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.0 g, 4.67 mmole). The reaction mixture was warmed at 50° C. for 5 minutes, and then at room temperature for 15 minutes. To the resulting solution was added 4-bromobutyraldehyde dimethyl acetal (0.99 g, 5 mmole). After the reaction mixture was stirred at room temperature for 16 hours, the solvent was removed, and the residue was partitioned between water and ethyl acetate. The organic phase was washed with water, dried (magnesium sulfate), and concentrated. The residue was dissolved in diethyl ether, and the suspension was filtered, and the filtrate was concentrated. Purification by silica gel chromatography, eluting with 2% methanol in chloroform, gave 4-(4,4-dimethoxybutyl)-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.8 g,) as a heavy syrup. Nmr: (chloroform-d) δ (ppm) 1.49, s, (9H); 2.64, m, 3H, 3.32, s (3H); 4.37, m, (1H).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:35])([CH3:34])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:33])([CH3:32])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][C:19]=2[F:31])[N:8](S(N(C)C)(=O)=O)[CH:9]=1>CO>[CH3:2][C:3]([CH3:35])([CH3:34])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:33])([CH3:32])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][C:19]=2[F:31])[NH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(-c2ccc(F)cn2)cc1F
Agent: Cl
Solvent: CO
Product: CC(C)(C)Cc1c[nH]c(C(C)(O)Cc2ccc(-c3ccc(F)cn3)cc2F)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (1 mL, 4 mmol) was added to an ambient temperature solution of 4-(2,2-dimethylpropyl)-2-{2-[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (20 mg, 0.04 mmol) in methanol (2 mL). After stirring at 70° C. for 1 h, volatiles were removed. The residue was partitioned between methanol/ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride then with 0-100% acetone/methylene chloride afforded the title compound. (M+H) found: 386.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([CH2:10][O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1)[NH2:22].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([CH2:10][O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:3]=2)[CH:23]=[CH:24][C:25]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1
Reactant: CNc1cc(COCC(F)(F)F)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNc1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 120 °C
Yield: 51.1 %

Procedure:
2-Chloro-N-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-amine (161 mg, 0.63 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (256 mg, 1.26 mmol), cesium carbonate (410 mg, 1.26 mmol), palladium(II) acetate (21 mg, 0.09 mmol) and 2-(dicyclohexylphosphino)biphenyl (33 mg, 0.09 mmol) were mixed in dioxane (10 mL) under an atmosphere of nitrogen. The vial was heated in microwave reactor at 120° C. for 90 min. The mixture was filtered through a plug of diatomeous earth which was eluted with MeOH. The mixture was partitioned between EtOAc and sodium hydroxide (1 M, aq). The organic layer was dried over sodium sulfate and concentrated in vacuum. The residue was purified by preparative HPLC to give the title compound as a solid 136 mg (51%).
Reaction SMILES: [C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=4)=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[C:13](O)=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.CC(=O)OCC>[C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][CH:34]=4)=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[C:13]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)O)cc3)nc2)cc1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)NS(C)(=O)=O)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid Compound 85 (78.0 mg, 0.13 mmol), methanesulfonamide (20.0 mg, 0.21 mmol), and DMAP (16.1 mg, 0.13 mmol) in DMF (1.5 mL) was added EDC (40.3 mg, 0.21 mmol) and the solution stirred overnight at room temperature. The reaction mixture was diluted in EA (50 mL), washed with aqueous saturated sodium bicarbonate (2×20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude product was purified by chromatography (hexane/EA) to afford 36 mg (40%) of (S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)benzamide, Compound 299 as a colorless solid. LCMS-ESI (m/z) calculated for C38H46N4O5S: 670.3. found 671.3 [M+H]+, tR=11.01 min (Method 10).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([N:17]3[CH2:21][CH2:20][C@H:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[ClH:32]>O1CCOCC1>[F:31][C:2]([F:1])([F:30])[C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][CH:12]([C:15]([N:17]3[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18]3)=[O:16])[CH2:13][CH2:14]2)[CH:6]=[CH:5][CH:4]=1.[ClH:32]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C2CCN(c3cccc(C(F)(F)F)n3)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCN(C(=O)C2CCN(c3cccc(C(F)(F)F)n3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl [(3S)-1-({1-[6-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}carbonyl)pyrrolidin-3-yl]carbamate (1.3 g, 2.9 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (10 mL). After being stirred at room temperature for 1 hr, the solution was concentrated to give the desired product as HCl salt (0.6 g). MS (M+H) 343.1.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C(O)(=O)C.[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21]>O.C(OCC)(=O)C>[C:20]([C:22](=[C:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21]
Reactant: CCOC(=O)CC#N
Reactant: O=C1CCCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C#N)=C1CCCC1
Temperature: 70 °C

Procedure:
To an ambient solution of hexamethyldisilazane (17.7 mL, 84.0 mmol) m acetic acid (56 mL) was added sequentially cyclopentanone (5.0 mL, 56.3 mmol) and ethyl 2-cyanoacetate (12.0 mL, 113 mmol). The solution was heated to 70° C. for 15 hours. The reaction was cooled to room temperature and diluted with water (100 mL) and ethyl acetate (100 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×100 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 100% hexane to 5% ethyl acetate in hexane, to give the title product as a white, solid. MS (ESI) m/z 180 [M+H]+.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([C:29](=O)[CH2:30][CH2:31][CH2:32][CH3:33])[C:25](OC)=[O:26])=[C:19]([F:35])[CH:18]=1)#[N:10].O>CO>[CH2:30]([C:29]1[N:4]=[C:2]([CH3:3])[NH:5][C:25](=[O:26])[C:24]=1[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:12]2[C:11]([C:9]#[N:10])=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:18][C:19]=1[F:35])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OC
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Yield: 68.9 %

Procedure:
To a suspension of acetamidine hydrochloride (6.7 g) in methanol (50 mL) were added sodium methoxide (28% methanol solution, 20.5 mL) and then methyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (13.0 g), and the mixture was stirred for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was triturated with diisopropyl ether to give the title compound (9.15 g, 69%) as pale-yellow crystals.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[CH3:34])[CH2:29]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([CH3:34])=[C:26]([CH3:25])[CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Cc1ccc(CCl)cc1C
Product: Cc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1C

Procedure:
The title compound (0.003 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 3,4-dimethylbenzyl chloride (0.6 mL) in place of benzyl chloride. MS (ESI): exact mass calculated for C22H24ClN3, 365.17. found, m/z 366.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.40-7.38 (m, 2H), 7.35-7.32 (m, 2H), 6.98-6.96 (m, 1H), 6.90-6.86 (m, 1H), 6.72-6.69 (m, 1H), 5.30 (s, 1H), 5.19 (s, 1H), 2.90-2.87 (m, 2H), 2.86-2.82 (m, 2H), 2.77-2.73 (m, 2H), 2.72-2.68 (m, 2H), 2.21 (s, 3H), 2.17 (s, 3H).