Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH:30]1([S:36]C2CCCCC2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.[Na]>CN(C)C=O>[CH:30]1([S:36][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)=[CH:19][C:17]=4[CH:18]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C1CCC(SC2CCCCC2)CC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSC4CCCCC4)cc2)CCO3)cc1
Yield: 108.7 %

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.2 g) and sodium cyclohexylsulfide (0.08 g) in dimethylformamide (10 ml) was stirred at room temperature for 2.5 hours. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4-(cyclohexylthiomethyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 53) (0.19 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])=[CH:22][CH:21]=1>>[ClH:1].[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([NH:30][CH2:29][CH2:28][CH2:27][CH2:26][C:23]3[CH:22]=[CH:21][N:20]=[CH:25][CH:24]=3)=[O:12])[C:4]=2[CH:3]=1
Reactant: NCCCCc1ccncc1
Reactant: O=C(Cl)N1Cc2ccccc2Sc2ccc(Cl)cc21
Product: Cl
Product: O=C(NCCCCc1ccncc1)N1Cc2ccccc2Sc2ccc(Cl)cc21

Procedure:
The title compound of Example 49 is reacted with the product of Example 23 by the method described in Example 18 to produce the free base of the title product. This material is converted to the title compound by the method described in Example 16.
Reaction SMILES: [C:1]([NH:4][C:5]([CH:26]1[CH2:31][CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28][CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].C(OCC)(=O)C>CO.CCCCCCC.[Pd]>[C:1]([NH:4][C:5]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:18][C:19]([CH3:24])([CH3:25])[C:20]([CH3:23])([CH3:22])[O:21]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CO
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCNCC1
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
In a 100 mL round bottom flask while under an argon atmosphere, benzyl 4-(2-acetamido-1-(tert-butylamino)-1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexan-2-yl)piperidine-1-carboxylate (3.0 g, 5.25 mmol) in methanol (40 mL) was degassed with argon (bubbled through solution) and subsequently treated with palladium (25 mg, 10 wt % on active carbon, wet, Degussa type E101 NE/W). After continued bubbling for 10 min the argon was replaced with a slow stream of hydrogen. After 1.5 h the reaction was complete (reaction monitored by TLC for the disappearance of starting material (50% ethyl acetate in heptane, Rf 0.3) and solution was purged with argon, filtered through the Celite 545 and the filter cake washed with methanol. The methanol solution was concentrated and collected solvents evaporated to give crude 2-acetamido-N-tert-butyl-2-(piperidin-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (2.20 g 96%) which was used without further purification (contained approximately 10% product with loss of boronic acid protecting group). 1H NMR (CDCl3, 300 MHz) δ 6.95 (s, 1H), 5.53 (s, 1H), 3.09 (bt, J=11.1 Hz, 2H), 2.80 (ddd, J1=14.1 Hz, J2=13.5 Hz, J3=4.5 Hz, 1H), 2.65-2.48 (m, 2H), 2.26 (dddd, J1=12.0 Hz, J2=12.0 Hz, J3=3.0 Hz, J4=2.7 Hz, 1H), 2.00-1.90 (m, 1H), 1.98 (s, 3H), 1.78-1.63 (m, 2H), 1.45-1.00 (m, 5H), 1.36 (s, 9H), 1.21 (s, 8H), 0.73 (t, J=7.5 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[OH:15].[C:16]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:16][O:15][C:3]1[CH:4]=[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: Oc1cc(Oc2ccccc2)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of 2-bromo-5-phenoxyphenol (0.38 g, 1.4 mmol) in 6 ml acetone was added K2CO3 (0.58 g, 4.2 mmol) and iodomethane (0.26 ml, 4.2 mmol). The-reaction mixture was heated to reflux for 8 h, cooled to ambient temperature and filtered. The solvent was removed under reduced pressure and the residue was taken up in EtOAc. The organic phase was washed with 1N NaOH, water and brine. Drying over Na2SO4 afforded 0.36 g (92%) of 2-methoxy-4-phenoxybromobenzene.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:22]=1.[Cl:23][C:24]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:25]=1[C:26]([NH2:28])=[O:27]>>[C:26]([C:25]1[CH:29]=[CH:30][C:31]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:22]=2)=[CH:32][C:24]=1[Cl:23])(=[O:27])[NH2:28]
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Reactant: CC1(C)OB(c2ccc(C(N)=O)c(Cl)c2)OC1(C)C
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)c(Cl)c4)ccc3o2)CC1
Yield: 16.6 %

Procedure:
Following the General Procedure-2, the titled compound (30 mg) was prepared from Intermediate 13 (150 mg, 0.41 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (110 mg, 0.41 mmol) as a pale-yellow solid. M.P.: 178-181° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.04 (d, J 1.7, 1H), 7.88 (bs, 1H), 7.80 (d, J 1.7, 1H), 7.77 (d, J 8.5, 1H), 7.73-7.68 (m, 2H), 7.62-7.58 (m, 1H), 7.52 (d, J 8, 1H), 4.78 (septet, J 6.2, 1H), 3.97 (d, J 13.2, 2H), 3.34-3.24 (m, 1H), 3.10-3.00 (m, 2H), 2.15-2.05 (m, 2H), 1.75-1.65 (m, 2H), 1.19 (d, J 6.2, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[NH2:18].[C:20](OC(OCC)OCC)(=O)C.[OH-].[Na+]>O>[CH3:1][CH:2]([CH3:19])[CH2:3][N:4]1[C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]3[N:15]=[N:16][N:17]=[C:7]3[C:6]=2[N:18]=[CH:20]1
Reactant: CCOC(OCC)OC(C)=O
Reactant: CC(C)CNc1c(N)c2nnnn2c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)Cn1cnc2c1c1ccccc1n1nnnc21

Procedure:
N5-(2-Methylpropyl)tetrazolo[1,5-a]quinoline-4,5-diamine (0.2 g, 0.78 mmole, Example 16) was combined with diethoxymethyl acetate (2 mL) and heated on a steam bath for 3 hours. Water (10 mL) and 10% sodium hydroxide (2 mL) were added and the reaction mixture was heated on a steam bath for 1 hour. A solid was isolated by filtration then recrystallized from methanol/ethyl acetate to provide 0.16 g of 6-(2-methylpropyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as a white crystalline solid, m.p. 210-212° C. Analysis: Calculated for C14H14N6: % C, 63.14; % H, 5.30; % N, 31.56; Found: % C, 63.12; % H, 5.32; % N, 31.61.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][CH2:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.S(Cl)([Cl:38])=O.O>C(Cl)(Cl)Cl>[Cl:38][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][CH2:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CO)cc2)CCC3)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.2 %

Procedure:
To a solution of N-(4-hydroxymethylphenyl)-2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (10.0 g, 26.1 mmol) and pyridine (0.1 ml) in chloroform (150 ml) was dropwise added a solution of thionyl chloride (3.4 ml, 39.2 mmol)in chloroform (90 ml), and the mixture was stirred under nitrogen atmosphere at room temperature for 17 hours. After the reaction completed, water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the resulting powder was washed with hexane to give N-(4-chloromethylphenyl)-2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (10.2 g, 97%) as colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:19][CH:18]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCCCCCCc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCCc1ccc(C=Nc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 5.9 g. of p-aminobenzonitrile and 10.2 g. of p-n-heptylbenzaldehyde in 100 ml. of benzene is treated with 150 mg. of p-toluenesulfonic acid and reacted as described in Example 1. After evaporation, there remain 15.4 g. of a yellow oil which crystallizes with cooling. Purification is carried out by several recrystallizations from isopropanol as described in Example 1. The p-[(p-n-heptylbenzyliden)amino]benzonitrile which is obtained has a melting point of 32.7°-33.0° C. and a clearing point of 72.3° C. UV (ethanol): ε281 = 24100 (shoulder at 310 nm). The nuclear magnetic resonance, mass spectrum, infrared and microanalysis data confirm the structure.
Reaction SMILES: CCC([O-])(C)C.[K+].[C:8]1([CH2:14][C:15]#[N:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O:19][C:20](=O)[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=1)C>C1COCC1>[CH3:27][C:23]1[CH:22]=[C:21]([C:20](=[O:19])[CH:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:15]#[N:16])[CH:26]=[CH:25][N:24]=1
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)c1ccnc(C)c1
Agent: CCC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)C(C#N)c2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Potassium tert-pentylate (25% in toluene, 11.3 mL, 20 mmol) was added dropwise to a solution of phenylacteonitrile (590 mg, 5.0 mmol, [CAS Reg. No. 140-29-4]) in THF (8 mL). After 45 min, 2-methyl-isonicotinic acid ethyl ester (998 mg, 6.0 mmol, [CAS Reg. No. 25635-17-0]) was added drop wise, and the mixture was stirred for 3 h at r.t. The solvent was evaporated, and the residue was taken up in ethyl acetate, and washed with 1N aqueous HCl. The combined water layers were saturated with NaCl, and the crude title compound (as an orange precipitate) was collected by filtration. Evaporation of the organic layer gave an additional small crop of crude product. The combined material (1.02 g, 85%) was used in the next step without further purification. 1H NMR (300 MHz, DMSO-D6) □ 8.81 (1H, d), 7.94 (1H, s), 7.86 (1H, d), 7.78 (2H, d), 7.44 (2H, dd), 7.33 (1H, d), 2.71 (3H, s); MS (m/e)=237.1 [MH+].
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[C:6]([NH:10][C:11]1[C:12]([NH2:18])=[CH:13][CH:14]=[CH:15][C:16]=1[Cl:17])([CH3:9])([CH3:8])[CH3:7].C(N(C(C)C)CC)(C)C.[I-].[Na+]>C1COCC1.C(#N)C>[C:6]([N:10]1[C:11]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[Cl:17])[NH:18][C:3](=[O:4])[CH2:2]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)Nc1c(N)cccc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)N1CC(=O)Nc2cccc(Cl)c21
Temperature: -78 °C

Procedure:
Bromoacetyl bromide (2.8 ml, 32 mmol) was added drop wise to a solution of N*2*-tert-butyl-3-chlorobenzene-1,2-diamine from Example 12B (4.1 g, 21 mmol) and diisopropylethylamine (11 ml, 63 mmol) in THF (75 ml) while cooling to −78° C. The mixture was allowed to warm to room temperature over 18 h and the solvent was evaporated. Chloroform was added and the mixture was washed with sodium hydrogen carbonate, dried and evaporated. To the residue were added acetonitrile (90 ml), diisopropylethylamine (5.6 ml, 32 mmol) and sodium iodide (3.2 g, 21 mmol). The mixture was heated at reflux for 18 h, cooled and evaporated. The residue was taken up in chloroform, washed with water, dried and evaporated. The residue was purified by flash chromatography on silica (eluant pet.ether:EtOAc 100:0 to 50:50) to give an orange solid; yield 1.5 g, 29%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:13]O)[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:6]=2[CH:28]=1.[C:29](O)(=O)[CH3:30].C(=O)C.C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:29]([CH3:30])=[N:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[C:10]3[CH2:9][N:8]=[C:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:6]=2[CH:28]=1
Reactant: CC(=O)O
Reactant: ON=C(C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1)N1CCOCC1
Agent: CC=O
Solvent: ClCCl
Solvent: CCO
Product: Cc1nc(N2CCOCC2)c2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
A mixture of 0.4 g of 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-N-hydroxy-α-(4-morpholinyl)-1H-1,4-benzodiazepine-2-methanimine, 5 ml of glacial acetic acid and 0.4 ml of acetaldehyde was heated to reflux for 5 minutes. The usual workup and chromatography of the crude reaction mixture on 5 g of silica gel using 5% (v/v) of ethanol in methylene chloride gave yellow crystalline product identical with that described above.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.ClCCl.[CH2:15](Br)[C:16]#[CH:17]>CO>[CH3:8][N:6]1[CH:7]=[C:2]([NH:1][CH2:17][C:16]#[CH:15])[C:3](=[O:11])[N:4]([CH3:10])[C:5]1=[O:9]
Reactant: C#CCBr
Reactant: Cn1cc(N)c(=O)n(C)c1=O
Solvent: ClCCl
Solvent: CO
Product: C#CCNc1cn(C)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of Step 1 intermediate (1.4 g, 9.023 mmol) in 1:1 mixture of dichloromethane and methanol (28 mL) was added propargyl bromide (1.4 mL) and the mixture was stirred at room temperature for 2 h. Reaction mixture was filtered through celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to give 500 mg of the product.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[C:6]([O:21][CH3:22])[CH:5]=1)(=[O:3])[CH3:2].[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CCCCCCC.C(Cl)Cl>[C:23]([C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=1[O:21][CH3:22])#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C#CCCCCC
Reactant: COc1cc(C(C)=O)ccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCCCCC#Cc1ccc(C(C)=O)cc1OC

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-acetyl-2-methoxy-phenyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/DCM 1:1; yield (110 mg, 90%); 1H NMR δ (CDCl3): 7.50-7.41 (m, 3H), 3.91 (s, 3H), 2.59 (s, 3H), 2.47 (t, J=7.14 Hz, 2H), 1.63 (p, J=7.22 Hz, 2H), 1.5-1.29 (m, 4H), 0.91 (t, J=7.13 Hz, 3H); LCMS m/z: 244.
Reaction SMILES: I[C:2]1[C:10]2[N:9]=[N:8][N:7]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]4)[N:12]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1[C:30](B(O)O)=[CH:31][S:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>CCO>[CH3:27][S:24]([N:21]1[CH2:22][CH2:23][CH:18]([NH:17][C:13]2[N:12]=[C:11]([N:7]3[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([C:30]5[C:29]([CH3:28])=[CH:33][S:32][CH:31]=5)[C:10]=4[N:9]=[N:8]3)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20]1)(=[O:26])=[O:25]
Reactant: Cc1cscc1B(O)O
Reactant: CS(=O)(=O)N1CCC(Nc2nccc(-n3nnc4c(I)cccc43)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cscc1-c1cccc2c1nnn2-c1ccnc(NC2CCN(S(C)(=O)=O)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
A mixture of [4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-yl]-(1-methanesulfonyl-piperidin-4-yl)-amine (364 mg), 4-methyl-3-thiopheneboronic acid (109 mg) and Na2CO3 (2 M aq, 1.1 mL, degassed), toluene (13 mL, degassed) and EtOH (1 mL), was bubbled with argon and stirred at RT for 10 min in a screw cap pressure flask. To this was added Pd(PPh3)4 (25 mg), the flask sealed, and the mixture stirred overnight at 110° C. The reaction mixture was then cooled to RT, diluted in water, extracted in DCM, washed with water and brine, dried over Na2SO4, and the solvent stripped to yield a solid. The solid was chromatographed on silica, eluting with 0-30% Magic Base/DCM, then chromatographed again on silica using 0-100% EtOAc/hexanes. The product was titurated with Et2O, filtered, and evaporated in vacuo overnight to provide (1-methanesulfonyl-piperidin-4-yl)-{4-[4-(4-methyl-thiophen-3-yl)-benzotriazol-1-yl]-pyrimidin-2-yl}-amine (Compound 5, 219 mg). Mp=244.0-245.0° C.; M+H=470.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:15](=[O:16])[CH:14]2[CH2:17][CH:11]1[CH2:12][CH2:13]2)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.O>[C:3]([O:7][C:8](=[O:9])[NH:10][C@H:11]1[CH2:12][CH2:13][C@@H:14]([CH2:15][OH:16])[CH2:17]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2CCC1C2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
In a round-bottomed flask, 3-oxo-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (crude from Step 2, 1.87 g) was dissolved in THF (20 ml) and water (2 ml). The reaction mixture was cooled to 0° C. and sodium borohydride (301 mg, 7.97 mmol) was added. The reaction was stirred at 0° C. for 30 min then a second portion of sodium borohydride (301 mg, 7.97 mmol) was added. The reaction mixture was stirred at 0° C. for 7.5 h then a third portion of sodium borohydride (602 mg, 15.94 mmol) was added. The reaction mixture was stirred at room temperature overnight then a fourth portion of sodium borohydride (602 mg, 15.94 mmol) was added. The reaction mixture was stirred at room temperature overnight then cooled to 0° C. and carefully quenched with 1M HCl. When gas evolution had ceased (pH=˜6) the mixture was extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-60% EtOAc) to afford 1.73 g (95%, 2 steps) of (cis-3-hydroxymethyl-cyclopentyl)-carbamic acid tert-butyl ester as an off-white solid.
Reaction SMILES: [N:1]([C:4]1[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=O)=[N+]=[N-].O=S(Cl)[Cl:26]>>[Br:23][C:21]1[CH:20]=[CH:19][C:5]2[C:4]([CH:22]=1)=[N:1][N:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[C:6]=2[Cl:26]
Reactant: [N-]=[N+]=Nc1cc(Br)ccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Product: FC(F)(F)c1ccc(-n2nc3cc(Br)ccc3c2Cl)cc1
Yield: 85 %

Procedure:
A solution of the product of Step 2 (3 g, 0.0078 mol) in SOCl2 (15 mL) was heated at reflux for 24 h. The mixture was then concentrated and the residue partitioned between ether (3×20 mL) and Na2CO3 solution (10 mL). The organic phase was separated, dried (MgSO4) and concentrated to give 2.5 g (85% yield) of product as a tan powder. 1H NMR (360 MHz, CDCl3): 7.25 (1H, d, J 8.9 Hz), 7.37 (1H, d, 8.9 Hz), 7.80-7.95 (5H, m).
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5](CO)[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[C:14]([CH3:20])=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[C:14]=1[CH3:20]
Reactant: CN(C)c1cccc(CO)c1
Reactant: Cc1c(O)cccc1Br
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Cc1c(Br)cccc1OC1CCCCC1

Procedure:
The title compound was prepared by substituting cyclohexanol for (3-(dimethylamino)phenyl)methanol and 3-bromo-2-methylphenol for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: [CH3:1][N:2]([CH2:40][C@@H:41]1[CH2:43][C@H:42]1[CH3:44])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[N:33]=1)[C:6]([NH:8][NH:9][C:10]([C@H:12]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O)=O)=[O:7].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.Cl>ClCCCl.CCOC(C)=O>[CH3:39][N:34]([C:32]1[CH:31]=[C:5]([C:6]2[O:7][C:10]([C@H:12]3[C@@H:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][N:8]=2)[CH:4]=[C:3]([N:2]([CH3:1])[CH2:40][C@@H:41]2[CH2:43][C@H:42]2[CH3:44])[N:33]=1)[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: C[C@@H]1C[C@H]1CN(C)c1cc(C(=O)NNC(=O)[C@H]2[C@@H](c3ccccc3)CCCN2C(=O)OC(C)(C)C)cc(N(C)S(C)(=O)=O)n1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: C[C@@H]1C[C@H]1CN(C)c1cc(-c2nnc([C@@H]3NCCC[C@@H]3c3ccccc3)o2)cc(N(C)S(C)(=O)=O)n1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl cis-2-[(2-{2-(methyl[(trans-2-methylcyclopropyl)methyl]amino)-6-[methyl(methylsulfonyl)amino]isonicotinoyl}hydrazino)carbonyl]-3-phenylpiperidine-1-carboxylate (93.7 mg, 0.15 mmol) in 1,2-dichloroethane (1.5 ml) was added Burgess reagent (162 mg, 0.60 mmol). The reaction vessel was sealed and heated to 120° C. for 10 min in an Emry's Optimizer microwave reactor. The reaction was concentrated in vacuo and purified via reverse phase HPLC to yield the cyclodehydration product. A solution of the material in EtOAc (15 ml) at 0° C. was saturated with HCl gas and allowed to stir for 1 h. The reaction was concentrated in vacuo and purified via reverse phase HPLC to yield title example N-methyl-N-(6-(methyl[(trans-2-methylcyclopropyl)methyl]amino)-4-[5-(cis-3-phenylpiperidin-2-yl)-1,3,4-oxadiazol-2-yl]pyridin-2-yl)methanesulfonamide. HRMS (ES, M+H), cal'd for C26H34N6O3S: 511.2486. found: 511.2475. 1H NMR (400 MHz, CD3OD) δ 7.32 (m, 3H), 7.19 (d, J=7.3 Hz, 2H), 6.78 (m, 1H), 6.55 (m, 1H), 5.45 (d, J=5.1 Hz, 1H), 3.99 (m, 1H), 3.62 (m, 1H), 3.54 (m, 2H), 3.38 (m, 1H), 3.34 (s, 3H), 3.14 (s, 3H), 3.10 (s, 3H), 2.43-2.27 (m, 2H), 2.03 (m, 2H), 1.04 (d, J=5.7 Hz, 3H), 0.73 (m, 2H), 0.46 (m, 1H), 0.26 (m, 1H).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11]1)=[O:7])(C)(C)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33](C(O)=O)=[C:32]([O:40][CH3:41])[CH:31]=1>>[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH2:11]2)=[O:7])=[C:32]([O:40][CH3:41])[CH:31]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCN)C1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNC(=O)c2ccc(Cl)cc2)C1

Procedure:
3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propylamine (1.00 g) as starting compound was reacted and treated in the same manner as in Example 1 using 4-chlorobenzoyl chloride (0.54 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.86 g) to give 4-amino-5-chloro-N-(1-(3-(4-chlorobenzoylamino)propyl)pyrrolidin-3-ylmethyl)-2-methoxybenzamide.