Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][N:11]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:10]1=[O:23].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]([N:35]2[CH2:36][CH2:37][N:32]([C:26]3[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:25]=3[CH3:24])[CH2:33][CH2:34]2)=[O:16])[CH2:12][N:11]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:10]1=[O:23]
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Reactant: CC(C)S(=O)(=O)N1CC(C(=O)O)N(c2ccc(F)cc2F)C1=O
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)C(C)C)C(=O)N3c3ccc(F)cc3F)CC2)c1

Procedure:
In analogy to example 1, (RS)-3-(2,4-difluoro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid was coupled with 1-(2,5-dimethylphenyl)piperazine to give the title compound as a colorless solid. MS: 521.5 ([M+H]+)
Reaction SMILES: [OH-].[Na+].CO.[CH3:5][C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:21])[C:16]=2[C:17]([O:19]C)=[O:18])[C:9]([CH3:22])=[CH:8][N:7]=1>O>[CH3:5][C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:21])[C:16]=2[C:17]([OH:19])=[O:18])[C:9]([CH3:22])=[CH:8][N:7]=1
Reactant: COC(=O)c1c(-c2nc(C)ncc2C)cnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ncc(C)c(-c2cnn(C)c2C(=O)O)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
Sodium hydroxide (0.31 g) was added to a mixed solution of methanol (15 ml) and water (15 ml) containing the methyl 4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.9 g) obtained in (Example 3.22) <Step 1>, and the obtained mixture was then stirred at 50° C. for 1 hour. Thereafter, methanol was distilled away from the reaction solution under reduced pressure, and the residue was then adjusted to pH 5-6 by addition of 1 N hydrochloric acid. Thereafter, water was distilled away under reduced pressure. The obtained residue was washed with methylene chloride, and the filtrate was then concentrated under reduced pressure, so as to obtain the title compound (0.94 g) in the form of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:20])[NH:11][CH:12]([C:14]2[S:15][C:16](Br)=[CH:17][CH:18]=2)[CH3:13])=[CH:8][CH:9]=1)=[O:4].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:20])[NH:11][CH:12]([C:14]2[S:15][C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])=[CH:17][CH:18]=2)[CH3:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(C(=O)NC(C)c2ccc(Br)s2)s1
Product: COC(=O)c1ccc(C(=O)NC(C)c2ccc(-c3ccccc3OC)s2)s1

Procedure:
The title compound was prepared in an analogous manner to that described in example 2, step 3 from 5-[1-(5-bromo-thiophen-2-yl)-ethylcarbamoyl]-thiophene-2-carboxylic acid methyl ester and 2-methoxy-benzene-boronic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:34]([C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br)#[N:35].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:34]([C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39][N:32]1[CH:31]=[CH:30][N:29]=[C:28]1[CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=1)#[N:35]
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2cccc(C#N)c2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (80 mg, 0.17 mmol), 3-cyano benzyl bromide (35.0 mg, 0.18 mmol, 1.05 equiv), and potassium carbonate (47.0 mg, 0.34 mmol) were combined in dimethylformamide (1.5 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 85.0 mg (85%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[OH-].[K+]>CO.O>[F:21][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[C:8]3[CH:9]=[N:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]=3[CH:14]=[CH:13]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cncc2c1ccn2-c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cncc2c1ccn2-c1ccc(F)cc1

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid ethyl ester (650 mg, 2.3 mmol) in methanol (25 mL) is added in several portions a solution of 85% KOH (1.2 g, 18.2 mmol) in water (15 mL). The mixture is warmed at reflux for 30 minutes and is then diluted with water (20 mL) and washed with ether (2×15 mL). The aqueous layer is made acidic (pH=4) with concentrated HCl and the resulting precipitate is collected by filtration washing with water to afford the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([OH:30])([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Brc1cccc2ccccc12
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: OC1(c2cccc3ccccc23)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.4 %

Procedure:
A solution of 10.0 gm (42.2 mMol) 1-bromonaphthalene in 180 mL tetrahydrofuran was cooled to −78° C. and then to this solution were added 48.7 mL (63.3 mMol) sec-butyllithium (1.3 M in cyclohexane). After stirring for about 1.5 hours, a solution of 8.2 mL (44.3 mMol) 1-benzylpiperidin-4-one in 60 mL tetrahydrofuran was added dropwise and the resulting mixture was allowed to warm gradually to room temperature. The reaction was then quenched by the addition of 2 N sodium hydroxide. The resulting mixture was extracted with diethyl ether. The organic extracts were combined, washed with saturated aqueous sodium chloride, and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing from 0 to 2% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 4.34 gm (32%) of the desired compound as a white foam.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[NH2:26][CH:27]([C:46]([N:48]([CH3:50])[CH3:49])=[O:47])[CH2:28][C:29]1[CH:30]=[C:31]([CH:43]=[CH:44][CH:45]=1)[O:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1.[NH2:51][C:52]1[N:61]=[C:60]([N:62]2[CH2:67][CH2:66][N:65]([CH3:68])[CH2:64][CH2:63]2)[C:59]2[C:54](=[CH:55][C:56]([C:69](O)=[O:70])=[CH:57][CH:58]=2)[N:53]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:51][C:52]1[N:61]=[C:60]([N:62]2[CH2:63][CH2:64][N:65]([CH3:68])[CH2:66][CH2:67]2)[C:59]2[C:54](=[CH:55][C:56]([C:69]([NH:26][CH:27]([C:46]([N:48]([CH3:50])[CH3:49])=[O:47])[CH2:28][C:29]3[CH:30]=[C:31]([CH:43]=[CH:44][CH:45]=3)[O:32][C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=3)=[O:70])=[CH:57][CH:58]=2)[N:53]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: COC(=O)c1ccc(Oc2cccc(CC(N)C(=O)N(C)C)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cccc(CC(NC(=O)c3ccc4c(N5CCN(C)CC5)nc(N)nc4c3)C(=O)N(C)C)c2)cc1
Reaction time: 1 h

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.030 g, 0.078 mmol) was added to a solution of methyl 4-{3-[2-amino-3-(dimethylamino)-3-oxopropyl]phenoxy}benzoate HCl salt (0.045 g) and 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (0.015 g, 0.052 mmol) in N,N-dimethylformamide (1.0 mL) with N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) at r.t. The reaction was stirred for 1 h. The product was purified with out workup by HPLC (pH=10) to give the desired(0.012 g, 37%) as a white amorphous solid. 1H NMR (400 MHz, DMSO): δ 8.82 (d, 1H), 7.71 (d, 2H), 7.68 (d, 1H), 7.61 (d, 1H), 7.29 (m, 2H), 7.17 (d, 1H), 7.06 (s, 1H), 6.88 (d, 1H), 6.82 (d, 2H), 6.38 (s, 1H), 5.02 (m, 1H), 3.72 (s, 3H), 3.46 (bs, 4H), 3.27 (s, 4H), 2.98 (bs, 5H), 2.77 (s, 3H), 2.17 (s, 3H). Analytical LCMS (M+H)+: m/z=612.0.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:14][C:15]([CH3:31])([CH2:18][N:19]1[CH:27]=[C:26]2[C:21]([C:22]([Cl:30])=[C:23]([Cl:29])[CH:24]=[C:25]2[Cl:28])=[N:20]1)[C:16]#[N:17]>C1COCC1>[C:16]([C:15]([NH:14][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)([CH3:31])[CH2:18][N:19]1[CH:27]=[C:26]2[C:21]([C:22]([Cl:30])=[C:23]([Cl:29])[CH:24]=[C:25]2[Cl:28])=[N:20]1)#[N:17]
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-trifluoromethylbenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=475, RT=0.75 min.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)#[N:2].[OH:19]O.[OH-].[Na+].CO>O>[NH2:2][C:1](=[O:19])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCC#N)CC1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCCC(N)=O)CC1
Yield: 7 %

Procedure:
A stirred mixture of 5.0 g (0.02 mole) of 1-(3-cyanopropyl)-4-(1,1-dimethylethoxycarbonyl)piperazine, 10 ml of 30% hydrogen peroxide solution and 10 ml of 20% NaOH solution warmed spontaneously to 42°. After the initial exothermic reaction had subsided and the temperature returned to room temperature, 50 ml of methanol was added dropwise; a temperature rise to 38° was noted. After heating two hours at 50° the mixture was diluted with 50 ml of water and extracted with CH2Cl2. The organic extracts were dried (Mg SO4), filtered and evaporated on a rotary evaporator. The crude product was recrystallized from ethyl acetatehexane to yield 0.4 g (7%) of 1-(4-amino-4-oxobutyl)-4-(1,1-dimethylethoxycarbonyl)piperazine, 1/4 hydrate, mp-67.5°-71.5°. Calc. for C13H15N3O3. 1/4 H2O (275.87): C, 56.60; H, 9.32; N, 15.23. Found: C, 56.58; H, 9.41; N, 15.23.
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:24])=[N:7]2.ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[Br:1][C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:24])=[N+:7]2[O-:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1Br
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1Br
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of (S)-ethyl 2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (5H) (500 mg, 1.27 mmol) in dichloromethane (13 mL) at 0° C. was added 3-chloroperoxybenzoic acid (269 mg, 77%, 1.21 mmol) and the reaction mixture was allowed to slowly warm to room temperature over 3 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes and methanol/ethyl acetate) to give a yellow oil (497 mg, 95%). LCMS-ESI+ (m/z): [M]+ calcd for C19H2413rNO4: 410.3;
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:33][CH2:32][C:19]3([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl>C(Cl)Cl.CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:33][CH2:32][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cnc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(C(=O)OC(C)(C)C)CC4)n2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1cnc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 197.7 %

Procedure:
To a solution of tert-butyl 9-((5-chloro-2-((1-methyl-1H-imidazol-4-yl)amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (292 mg, 0.6134 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (8 mL, 3 mol/L). The reaction was stirred overnight at rt and concentrated in vacuo to give the title compound as a yellow solid (250 mg, 98.82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[NH2:11])[C:5](O)=[O:6].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[NH2:11])[C:5]([Cl:15])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Nc1c(Cl)cc(C(=O)O)cc1Cl
Product: Nc1c(Cl)cc(C(=O)Cl)cc1Cl
Reaction time: 1 h

Procedure:
The 3,5-dichloro-4-aminobenzoic acid is refluxed with 200 ml. of thionyl chloride. A solution forms in 1 hr. and heating is maintained for 2 additional hours, after which the reaction mixture is permitted to stand overnight. Excess thionyl chloride is removed by evaporation to leave a yellow-brown crystalline mass as a residue. This is recrystallized from a mixture of n-hexane/ethylene chloride (90/10 by volume) to produce a light tan crystalline product, m.p. = 155° C. A portion of this material is recrystallized from methylene chloride as pale yellow needles existing in round clusters. These needles are dissolved in methylene chloride and anhydrous hydrogen chloride is bubbled into the solution. The yellow color is discharged and off-white needles of 3,5-dichloro-4-aminobenzoyl chloride are obtained, m.p. = 165° C.
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[C:11]([Si:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][CH:20]=[O:21])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[C:11]([Si:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[O:16][CH2:17][CH2:18][CH2:19][CH:20]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)[OH:21])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)[Si](OCCCC=O)(c1ccccc1)c1ccccc1
Reactant: Clc1ccc(Br)cc1
Agent: II
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCCC(O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Temperature: 63 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
To a suspension of Mg turnings (145 mg, 6.0 mg-at.) and catalytic amount of iodine in 20 mL THF was added dropwise 1-Bromo-4-chloro-benzene (382 mg, 2.0 mmol) with heating over a period of 30 min. After stirring for an additional 30 min at 63° C. the mixture was cooled to −30° C. and 4-(tert-Butyl-diphenyl-silanyloxy)-butyraldehyde (500 mg, 1.53 mmol) was added slowly as a solution in 5 mL THF. The temperature was maintained at −30° C. for 1 h and slowly raised to room temperature. The excess Grignard reagent was destroyed by careful addition of saturated aqueous NH4Cl (20 mL). The mixture was extracted with ethyl acetate (3×30 mL) and the combined organic layers washed with brine (2×20 mL). After removal of the solvent under reduced pressure the product was isolated by flash column chromatography eluting with 0 to 50% EtOAc/hexanes to afford 330 mg of the title compound as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11]([C:14]([O:16]CC)=[O:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+]>CCO.O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[N:12][C:11]([C:14]([OH:16])=[O:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1ncn(-c2ccc(F)c(F)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncn(-c2ccc(F)c(F)c2)n1
Temperature: 50 °C
Yield: 81.7 %

Procedure:
To a solution of ethyl 1-(3,4-difluorophenyl)-1H-1,2,4-triazole-3-carboxylate (0.30 g, 1.2 mmol, 1 eq) in 5 mL of EtOH/H2O (1.5:1) was added NaOH (0.095 g, 2.4 mmol, 2 eq). The reaction mixture was heated at 50° C. for 1 h then quenched with 0.20 mL of cone. HCl. The contents were filtered and washed with EtOAc then with MeOH and the MeOH filtrate was dried with Na2SO4 and concentrated in vacuo to afford 1-(3,4-difluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (0.22 g, 0.98 mmol, 84%).
Reaction SMILES: [C:1]([C:5]1[S:9][C@@H:8]([C:10]([O:12]CC2C=CC=CC=2)=[O:11])[N:7]([C:20](=[O:33])[C@H:21]([CH3:32])[NH:22][C@H:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:25][CH3:26])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C:5]1[S:9][C@@H:8]([C:10]([OH:12])=[O:11])[N:7]([C:20](=[O:33])[C@H:21]([CH3:32])[NH:22][C@H:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:25][CH3:26])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC[C@H](N[C@@H](C)C(=O)N1N=C(C(C)(C)C)S[C@H]1C(=O)OCc1ccccc1)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCC[C@H](N[C@@H](C)C(=O)N1N=C(C(C)(C)C)S[C@H]1C(=O)O)C(=O)OCC
Yield: 89 %

Procedure:
The S,S,S benzyl ester from step (e) (1.8g) in ethanol (500ml) was hydrogenated over 10% Pd on charcoal (1.8g) at atmospheric pressure and room temperature for 5 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness. The residue was triturated with a 1:1 mixture of ether/petroleum ether 60°-80° to give the required acid as a white solid (1.3g). mp 183°-5°.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][N:40]5[CH:44]=[CH:43][CH:42]=[N:41]5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][N:40]5[CH:44]=[CH:43][CH:42]=[N:41]5)=[O:54])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCn4cccn4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cn4cccn4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(pyrazol-1-ylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (150 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (59.2 mg) in dichloromethane (10 ml) at −78° C. After finishing the dropping, an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was allowed to be at room temperature and stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=1:2→ethyl acetate), and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(pyrazol-1-ylmethyl) sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (80 mg) (Compound 331) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.[NH2:10][NH2:11]>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([NH:10][NH2:11])=[N:6][CH:7]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: NN
Solvent: CC(C)O
Product: NNc1ncc(Cl)cc1F
Temperature: 67.5 °C

Procedure:
A mixture of 5-chloro-2,3-difluoropyridine (10.0 g, 66.9 mmol) and hydrazine (10.0 ml, 319 mmol) in iPrOH (50 mL) was heated to 65-70° C. for 6 hours. The mixture was cooled to 23° C., filtered, and washed with Na2CO3 (satd), and H2O. Product isolated as a white solid. MS (ESI pos. ion) m/z: 162 (MH+). Calc'd exact mass for C5H5ClFN3: 161.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>ClCCl>[CH:19]1([C:22]([O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:23])[CH2:21][CH2:20]1
Reactant: O=C(Cl)C1CC1
Reactant: COCCOCCOCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCCOCCOC(=O)C1CC1
Temperature: 0 °C

Procedure:
Triethylene glycol monomethyl ether (1.1 eq, 5.26 mmol, 0.84 ml) and triethylamine (1.1 eq, 5.26 mmol, 0.73 ml) were taken in a 10 ml round bottom flask and dichloromethane (3 ml) was added. This mixture was cooled to 0° C. and then cyclopropanecarbonyl chloride (4.78 mmol, 0.5 g, 0.43 ml) was added in a dropwise fashion maintaining the temperature at 0° C. with constant stirring.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Br[CH2:25][CH2:26][CH2:27]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]2[O:10][CH2:27][CH2:26][CH2:25][N:11]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)(=[O:13])=[O:14])[C:5]=12)=[O:23]
Reactant: COC(=O)c1cccc(O)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: BrCCCBr
Product: COC(=O)c1cccc2c1N(S(=O)(=O)c1ccc(OC)cc1)CCCO2
Yield: 46.4 %

Procedure:
In the same manner as described in Example 159, 0.300 g (0.890 mmol) of the product of Example 31 and 0.127 mL (1.246 mmol) of 1,3-dibromopropane provided 0.156 g (46%) of the desired product as a colorless oil. Electrospray Mass Spec: 378 (M+H).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH:9]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][O:14][C:10]2[CH:9]=[C:8]([NH:7][S:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])(=[O:34])=[O:33])[CH:13]=[CH:12][CH:11]=2)=[CH:22][CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(CCOc2cccc(N)c2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(CCOc2cccc(NS(=O)(=O)c3ccccc3Cl)c2)cc1
Yield: 36.6 %

Procedure:
Pyridine (0.255 mL; 3.15 mmol) was added to a stirred solution of amino-3-[2-(4-cyanophenyl)ethoxy]benzene (0.15 g; 0.629 mmol; from step (ii) above) and 2-chlorobenzenesulfonyl chloride (0.173 mL; 0.818 mmol) in CH2Cl2 (4 mL). After 45 minutes at room temperature the solvent was removed in vacuo. To remove traces of pyridine, EtOH was added and evaporated. The residue was partitioned between water and EtOAc. The organic layer was washed with 0.1M aqueous HCl and brine, dried (Na2SO4) and the solvent removed in vacuo. Purification by flash chromatography (SiO2; toluene:EtOAc (1:0 to 9:1)) afforded 0.095 g (35%) of the sub-title compound.