Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=O)[N:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH:23]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:24]([OH:28])[C:25]([NH2:27])=[O:26]>ClCCl>[NH2:27][C:25](=[O:26])[CH:24]([OH:28])[CH:23]([NH:22][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][CH:20]=[N:21][C:13]=1[N:10]1[CH:11]=[CH:12][C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[N:9]1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: CN1CCC(c2ccn(-c3ncccc3C(=O)O)n2)CC1
Solvent: ClCCl
Product: CN1CCC(c2ccn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(O)C(N)=O)n2)CC1
Yield: 47 %

Procedure:
Coupling of 2-(3-(1-methylpiperidin-4-yl)-1H-pyrazol-1-yl)nicotinic acid (360 mg, 1.257 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (293 mg, 1.509 mmol) in dichloromethane (50 mL) according to the procedure described for example 1.3 and recrystallization from ethylacetate afforded 273 mg of the title compound; ESI-MS [M+H]+: 463.3.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH3:16])=[N:5][CH:4]=[C:3]1[C:17]([NH2:19])=O>P(Cl)(Cl)(Cl)=O>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH3:16])=[N:5][CH:4]=[C:3]1[C:17]#[N:19]
Reactant: CCOc1ccccc1-c1ncc(C(N)=O)c(=O)[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1ccccc1-c1ncc(C#N)c(=O)[nH]1
Yield: 68 %

Procedure:
A solution of 1,6-dihydro-6-oxo-2-(2-ethoxyphenyl)pyrimidine-5-carboxamide (5.5 g.) in phosphorus oxychloride (160 ml.) was heated under reflux for 3.5 hours. The solution was evaporated under reduced pressure to a thick oil which was treated with water (150 ml.) with vigorous stirring. The mixture was filtered. The collected solid was washed with water, dried, and recrystallized from glacial acetic acid to give the title compound (3.48 g., 68% yield), m.p. 186°-187°.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[NH:7].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[ClH:1].[C:14]1([CH:13]2[N:7]=[C:6]([NH2:8])[C:5]3[C:4](=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:3]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N=C(N)c1ccccc1N
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: NC1=NC(c2ccccc2)Nc2ccccc21
Yield: 52.1 %

Procedure:
A solution of 2-aminobenzamidine dihydrochloride (Example A) (1.0 g, 4.8 mmol) and benzaldehyde (0.48 ml, 5.8 mmol) in ethanol (30 ml) was heated at reflux for 2 hours. The solution was cooled and the solvent evaporated to give an oil which was purified by flash chromatography on aluminium oxide (Brockman 1, activated neutral) using dichloromethane/methanol as eluant to give a solid which was recrystallised from isopropyl alcohol to afford the title compound as a solid (0.65 g), m.p. 212°-214° C.
Reaction SMILES: [CH3:1][C:2]1([C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[NH:26][C:25]3=[O:33])[CH2:20][CH2:19]2)=O)[O:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.CCOCC>[CH3:1][C:2]1([CH2:16][N:18]2[CH2:19][CH2:20][CH:21]([N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[NH:26][C:25]3=[O:33])[CH2:22][CH2:23]2)[O:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12
Reactant: CC1(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)OCc2ccccc2-n2cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(CN2CCC(n3c(=O)[nH]c4ccccc43)CC2)OCc2ccccc2-n2cccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 3.0 g of 1,3-dihydro-1-{1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)carbonyl]-4-piperidinyl}-2H-benzimidazol-2-one in 120 ml of tetrahydrofuran is added 700 mg of lithium aluminum hydride. The reaction mixture is then heated at reflux temperature for 6 hours followed by stirring at room temperature for 18 hours. The reaction mixture is diluted with 150 ml of ether and the excess lithium aluminum hydride destroyed in the usual manner described below. The resulting granular precipitate is removed by filtration. The organic phase is washed with 150 ml of dilute sodium hydroxide and then 150 ml of brine. The organic extracts are then dried over magnesium sulfate, filtered and solvent evaporated under reduced pressure to yield 1,3-dihydro-1-{1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]-benzoxazepin-4-yl)-methyl]-4-piperidinyl}-2H-benzimidazol-2-one, m.p. 199°-201°, the compound of formula II wherein R1 and R5 =H, and R2 =CH3 and n=1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:31])[NH:20][C:21]([CH3:30])=[CH:22][C:23]=2[C:24]2C=CC=[CH:26][CH:25]=2)=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[H][H].CN1CCC(=C2C3C(=CC=CC=3)C=CC3C2=CC=CC=3)CC1>[Pd].CCO.C1COCC1>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[CH:2][CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:31])[NH:20][C:21]([CH3:30])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: [H][H]
Reactant: Cc1cc(-c2ccccc2)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Agent: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cccc2c1cnn2C(C)C
Yield: 34.6 %

Procedure:
6-Bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (70.3 mg, 0.15 mmol) in 3:1 EtOH/THF (4 mL) was hydrogenated using Pd/C (10% wet Degussa type) and a balloon of hydrogen. The reactin mixture was stirred at room temperature overnight. It was filtered through Celite, washed with EtOAc and EtOH and the solvent was evaporated. DMF was added with some water and white solids that crashed out were filtered off, air-dried for 15 min and dried in a vacuum oven for 3 h. The residue was purified by Gilson reversed-phase HPLC (30×100 Varian Polaris C18, 15-80% gradient of MeCN in water with 0.1% TFA over 12 minutes). Most of the solvent was removed and saturated NaHCO3 was added. The solids that crashed out were filtered off, air-dried for 15 min and dried in vacuum oven overnight to give the title compound (19 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (br. s., 1H) 8.63 (br. s., 1H) 8.34 (s, 1H) 7.85 (d, J=8.34 Hz, 1H) 7.39-7.51 (m, 7H) 5.99 (s, 1H) 5.03 (quin, J=6.57 Hz, 1H) 4.22 (d, J=4.29 Hz, 2H) 2.21 (s, 3H) 1.49 (s, 3H) 1.47 (s, 3H). MS(ES) [M+H]+ 367.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:21]3[CH:22]=[CH:17][C:18]([N+:26]([O-:28])=[O:27])=[CH:19][C:20]=3[N+:23]([O-:25])=[O:24])[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCc1c[nH]c2ccc(Nc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 1-chloro-2,4-dinitrobenzene were used. Triethylamine was used as base, tetrahydrofuran was used as solvent, and the reaction was stirred at room temperature for 2 hours. Chromatography afforded the title compound (73%) as a dark red solid: mp, 177.0°-179.0° C.; 13C NMR (DMSO-d6) δ148.2, 135.6, 135.2, 130.1, 129.6, 128.2, 127.9, 124.3, 123.5, 119.6, 116.9. 116.3, 113.3, 112.5, 60.0, 45.2, 23.0; FAB HRMS calculated for C18H19N5O4.[H+ ]370.1517, found 370.1492.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].C(=O)=O.CC(C)=O.[Br:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.FC(F)(F)S(O)(=O)=O.C(N(CC)CC)C>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([O:19][C:2]([CH3:3])([CH3:1])[CH3:4])[CH:16]=[CH:17][CH:18]=1
Reactant: Oc1cccc(Br)c1
Reactant: C=C(C)C
Agent: O=C=O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)Oc1cccc(Br)c1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
Condensed isobutylene (100 ml) was added via a dry ice/acetone cold finger, to dichloromethane (70 ml) at −30° C., followed by a solution of 3-bromophenol (21.5 g, 125 mmol) in dichloromethane (30 ml). Trifluoromethanesulphonic acid (1.5 g, 10.0 mmol) was added dropwise, the reaction cooled to −75° C., and stirred for 2 hours. Triethylamine (1.4 ml, 10.0 mmol) was then added, the solution allowed to warm to room temperature and then concentrated in vacuo to remove the isobutylene. The remaining solution was washed with water, dried (Na2SO4), filtered and evaporated to give the desired product as a pale yellow oil, (33 g, slightly impure).
Reaction SMILES: N[CH:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[NH2:12])[CH2:7][S:8][C@H:3]12.S1C=CC=C1CC(Cl)=O.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34]([NH:36]C1C(=O)N2C(C(O)=O)=C(COC(=O)N)CS[C@H]12)=[O:35]>>[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34]([NH:36][CH:7]1[C:6]([CH2:9][O:10][C:11](=[O:13])[NH2:12])=[C:5]([C:14]([OH:16])=[O:15])[N:4]2[C:17](=[O:18])[CH2:2][C@H:3]2[S:8]1)=[O:35]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Agent: O=C(Cl)Cc1cccs1
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1NC(=O)Cc1cccs1

Procedure:
A third 1 μl portion of the 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid-containing solution, prepared as reported in Example 11, was treated as described in Example 11, except that the acyl halide was 2-thiopheneacetyl chloride, and the resulting product was 7-(2-(2-thienyl)acetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid. It exhibited an RCV value of 0.39.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([N:22]2[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23]2)[CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.C(=O)(OC(C)(C)C)[NH2:30].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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.[Pd].[Pd]>[F:27][C:24]1([F:28])[CH2:25][CH2:26][N:22]([CH:8]([C:4]2[N:3]=[C:2]([NH2:30])[CH:7]=[CH:6][CH:5]=2)[CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:23]1
Reactant: CC(C)(C)OC(N)=O
Reactant: FC1(F)CCN(C(c2cccc(Br)n2)C(c2cccnc2)c2cccnc2)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Nc1cccc(C(C(c2cccnc2)c2cccnc2)N2CCC(F)(F)C2)n1
Temperature: 100 °C

Procedure:
The 2-bromo-6-[1-(3,3-difluoropyrrolidin-1-yl)-2,2-dipyridin-3-ylethyl]pyridine (73 mg, 0.16 mmol), tert-butyl carbamate (23 mg, 0.2 mmol), Cs2CO3 (75 mg, 0.23 mmol), Pd2(dba)3 (3 mg, 0.003 mmol), and xantphos (6 mg, 0.01 mmol) were combined in dry 1,4-dioxane (1.5 mL). The mixture was degassed (3× pump/N2) then heated to 100° C. After 5 hr the mixture was cooled to RT, diluted with EtOAc, filtered through a pad of Celite, and concentrated. The residue was taken up in 1 mL CH2Cl2 to which was added 1 mL TFA at RT. After 90 min the mixture was concentrated. The residue was taken up in saturated NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column (gradient, 0-10% MeOH/CH2Cl2) gave the title compound as a yellow foam. 1H-NMR (500 MHz, CDCl3) δ 8.68 (d, J=2.20 Hz, 1 H), 8.47 (d, J=4.15 Hz, 1 H), 8.37 (d, J=2.19 Hz, 1 H), 8.25 (d, J=3.90 Hz, 1 H), 7.74 (d, J=8.06 Hz, 1 H), 7.41 (d, J=7.81 Hz, 1 H), 7.25 (m, 2 H), 7.02 (m 1 H), 6.27 (m, 2 H), 4.85 (d, J=11.47 Hz, 1 H), 4.39 (s, 2 H), 4.35 (d, J=11.72 Hz, 1 H), 3.10 (m, 1 H), 2.86 (m, 2 H), 2.67 (m, 1 H), 2.0 (m, 2 H); MS (M+H)+ 382.0.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]2[N:17]=[C:18]([CH3:21])[S:19][CH:20]=2)[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:27][CH:28]1[C:38](=[O:39])[N:30]2[C:31]([C:35]([OH:37])=[O:36])=[CH:32][CH2:33][S:34][C@H:29]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OC)(=O)C.O.C(OC(=O)C)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]2[N:17]=[C:18]([CH3:21])[S:19][CH:20]=2)[C:10]([NH:27][CH:28]2[C:38](=[O:39])[N:30]3[C:31]([C:35]([OH:37])=[O:36])=[CH:32][CH2:33][S:34][C@H:29]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: Cc1nc(CON=C(C(=O)O)c2csc(NC=O)n2)cs1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(NC=O)n2)cs1
Yield: 61.8 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-methylthiazol-4-yl-methoxyimino)acetic acid (syn isomer, 0.50 g.), N,N-dimethylformamide (0.123 g.), phosphoryl chloride (0.259 g.) and ethylacetate (6 ml.) were treated in a similar manner to that of Example 1-(1) to give an activated acid solution. The solution and a solution of 7-amino-3-cephem-4-carboxylic acid (0.306 g.), trimethylsilylacetamide (1.03 g.), and bis(trimethylsilyl)acetamide (0.90 ml.) in methyl acetate (3 ml.) were treated in a similar manner to that of Example 1-(1). Water (10 ml.) was added to the resultant mixture, and the ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated in vacuo to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-methylthiazol-4-yl methoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.48 g.)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:10]1[C:14]([CH2:15][CH3:16])=[CH:13][CH:12]=[C:11]1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1)[CH2:8][CH3:9]>O1CCCC1>[CH2:7]([N:10]1[C:14]([CH2:15][CH3:16])=[CH:13][CH:12]=[C:11]1[CH:17]([OH:25])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1)[CH2:8][CH3:9]
Reactant: CCCn1c(CC)ccc1C(=O)c1cccc(N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCn1c(CC)ccc1C(O)c1cccc(N)c1
Temperature: 0 °C
Yield: 93.5 %

Procedure:
To a stirred suspension of 2 g (50 mmol) of lithium aluminum hydride in 100 ml of anhydrous tetrahydrofuran was added dropwise, at room temperature, a solution of 12 g (46 mmol) of 1-propyl-2-(3'-aminobenzoyl)-5-ethylpyrrole in 100 ml of anhydrous tetrahydrofuran. The reaction mixture was refluxed for 15 minutes, cooled to 0° C. and the excess reagent destroyed by carefully adding ethyl acetate, saturated sodium sulfate solution and solid anhydrous sodium sulfate. The insoluble material was separated by filtration and the filtrate evaporated in vacuo, to produce 11.1 g (43 mmol) of 1-propyl-2-(3'-amino-α-hydroxybenzyl)-5-ethylpyrrole. This crude compound was dissolved in 150 ml of methanol, cooled to -10° C. and treated with 23.5 ml of glacial acetic acid and 5.1 g (80 mmol) of sodium cyanoborohydride. The reaction mixture was warmed to room temperature and stirred for 18 additional hours. It was then poured into 500 ml of saturated sodium carbonate solution and the product extracted with ethyl acetate (4×300 ml). The combined extracts were washed with water (3×300 ml), dried and evaporated in vacuo. The residue was purified by column chromatography on 500 g of silica gel, using hexane-acetone (97:3) as eluant, thus obtaining 4.8 g (47%) of the title compound, 1-propyl- 2-(3'-aminobenzyl)-5-ethylpyrrole, as an oil.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:27][C:23]=1[C:24](O)=[O:25].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:27][C:23]=1[C:24]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[NH:8][CH:5]1[CH2:6][CH2:7][C:2]([F:1])([F:20])[CH2:3][CH2:4]1)=[O:25]
Reactant: Nc1cccc2c(NC3CCC(F)(F)CC3)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(NC4CCC(F)(F)CC4)ncnc23)c1
Yield: 21.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(4,4-difluorocyclohexyl)quinazoline-4,8-diamine (Intermediate-9, 60 mg, 0.215 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 116 mg, 0.431 mmol), oxalyl chloride (81 mg, 0.65 mmol), DMF (1 drop) and DIPEA (84 mg, 0.65 mmol) in CH2Cl2 (3 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.13 (s, 1H), 8.71 (d, 1H), 8.49 (s, 1H), 8.19 (m, 2H), 8.05 (d, 1H), 7.57-7.54 (m, 3H), 7.41 (d, 1H), 4.41 (m, 1H), 4.31 (d, 2H), 2.00 (m, 6H), 1.75 (m, 2H), 1.12 (s, 9H); MS (m/z): 530.20 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][O:31]C5CCCCO5)[CH:28]=4)[CH:19]=3)=[C:13]([CH3:38])[N:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C([O-])(O)=O.[Na+]>CC#N.O>[C:1]([C:5]1[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=4)[CH:19]=3)=[C:13]([CH3:38])[N:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(-n2nc(C(C)(C)C)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(CCOC3CCCCO3)c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1nc(-n2nc(C(C)(C)C)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(CCO)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
3-(tert-Butyl)-1-(6-methyl-5-((2-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.18 g, 0.34 mmol) was dissolved in MeCN and treated with a HCl (4 M in dioxane) (0.25 mL, 1.0 mmol). The mixture was stirred at RT for 20 min. Sat. NaHCO3 (aq) (15 mL) was added and the suspension was extracted with EtOAc (5×15 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM). The product was triturated with MeCN (5 mL) and sonicated for 5 min. The solid was isolated by filtration, redissolved in MeCN and water, frozen to −78° C., and lyophilized to afford 3-(tert-butyl)-1-(5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.13 g, 82%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.97 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 7.99 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 6.64 (dd, J=5.7, 2.4 Hz, 1H), 4.89 (t, J=5.3 Hz, 1H), 4.13 (t, J=5.6 Hz, 2H), 3.73 (q, J=5.5 Hz, 2H), 2.33 (s, 3H), 1.27 (s, 9H); MS (ESI) m/z: 436.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)O)c(Cl)c1
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
3.01 g of tert-butyl 4-(bromomethyl)-2-chlorobenzoate was reacted via Procedure O to give tert-butyl 2-chloro-4-(methylsulfonylmethyl)benzoate. 1.2 g of tert-butyl 2-chloro-4-(methylsulfonylmethyl)benzoate was treated with 10 mL of 4N HCl in Dioxane at 45° C. and concentrated upon completion to give crude 2-chloro-4-(methylsulfonylmethyl)benzoic acid. 775 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 1 g of 2-chloro-4-(methylsulfonylmethyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to give pure 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 435 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C1N2CCN(CC2)C1.[CH3:15][N:16]([CH3:21])[S:17](Cl)(=[O:19])=[O:18]>CC#N>[CH3:15][N:16]([CH3:21])[S:17]([N:4]1[CH:3]=[C:2]([Br:1])[CH:6]=[N:5]1)(=[O:19])=[O:18]
Reactant: Brc1cn[nH]c1
Reactant: CN(C)S(=O)(=O)Cl
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CN(C)S(=O)(=O)n1cc(Br)cn1
Reaction time: 20 h

Procedure:
To a solution of 4-bromopyrazole (2.20 g, 15 mmol) and DABCO (1.85 g, 16.5 mmol) in anhydrous MeCN (15 ml) at room temperature was added dimethylsulfamoyl chloride (1.61 ml, 15 mmol). The reaction mixture was stirred for 20 h, then partitioned between 1N HCl(aq) and EtOAc. The aqueous layer was extracted with EtOAc (×2), the organics combined, washed with brine (×1), dried (MgSO4), filtered and the solvent removed in vacuo to afford a colourless liquid. (3.79 g). 1H NMR (400 MHz, CDCl3): 8.00 (1H, s), 7.70 (1H, s), 2.99 (6H, s).
Reaction SMILES: [CH2:1]([N:6]1[C:10](=[O:11])[C:9](=[CH:12][C:13]([O:15]CC)=[O:14])[S:8][CH:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].[OH-].[Na+].Cl>CO>[CH2:1]([N:6]1[C:10](=[O:11])[C:9](=[CH:12][C:13]([OH:15])=[O:14])[S:8][CH:7]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CCOC(=O)C=C1SC(c2ccccc2)N(CCC(C)C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCN1C(=O)C(=CC(=O)O)SC1c1ccccc1
Yield: 36 %

Procedure:
To a solution of ethyl 2-(3-isopentyl-4-oxo-2-phenylthiazolidin-5-ylidene)acetate (0.031 g, 0.1 mmol) and aq. NaOH (0.3 ml of 1 N) in MeOH was stirred at 40° C. for 2 hours. HCl (0.5 ml of 1 N) was added and the MeOH was evaporated. Water and EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc (2×), all organic layers were combined, dried (MgSO4) and evaporated to dryness to give the desired product as an orange oil (11 mg, 36%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.[CH:16]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])OCC>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([F:13])([F:14])[F:15])[C:5]([O:10][CH3:11])=[C:6]([CH:16]([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])[CH:9]=1
Reactant: COc1c(C=O)cc(Br)cc1C(F)(F)F
Reactant: CCOC(OCC)OCC
Solvent: CCCCCC
Product: CCOC(OCC)c1cc(Br)cc(C(F)(F)F)c1OC

Procedure:
5-bromo-2-methoxy-3-trifluoromethylbenzaldehyde (66.19 g) was dissolved in n-hexane (130 mL) and triethyl orthoformate (51 mL), and Amberlyst-15 (6.62 g) was added to the solution, and then the mixture was refluxed for 3 hours. The reaction solution was filtered, and then the solvent was distilled off under reduced pressure to obtain the title compound (82.81 g) as a brown oily substance.