Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:24])[CH2:15][C:16]2[C:21]([Br:22])=[CH:20][N:19]=[C:18]([Cl:23])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Mg]Br>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([OH:24])([CH3:25])[CH2:15][C:16]2[C:21]([Br:22])=[CH:20][N:19]=[C:18]([Cl:23])[CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2cc(Cl)ncc2Br)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(C)(O)Cc2cc(Cl)ncc2Br)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[2-(5-bromo-2-chloro-pyridin-4-yl)-acetyl]-piperidine-1-carboxylic acid tert-butyl ester (9.80 g) in tetrahydrofuran (6 mL) is added dropwise to an ice-cold solution of methyl magnesium bromide (1.4 mol/L in toluene/tetrahydrofuran 75:25; 74.0 mL). The reaction mixture is stirred for 30 min before the cooling bath is removed. After stirring the mixture at room temperature for 1 h, the mixture is poured into aqueous NH4Cl solution. The resulting mixture is extracted with ethyl acetate, and the combined extracts are dried (MgSO4) and concentrated. The residue containing significant amounts of starting material is azeotropically dried using toluene and resubmitted to the reaction conditions and work-up procedure described. The crude product is purified by preparative HPLC (column: Waters X-Bridge C18; mobile phase: water+0.125% NH4OH/methanol 90:10→100:0) to give the title compound. Mass spectrum (ESI+): m/z=433/435/437 (Cl+Br) [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[S:20][C:21]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:22]=2[N:23]=1.[H-].[Na+]>CN(C=O)C.[Cu]I>[CH3:18][C:19]1[S:20][C:21]2[CH:27]=[CH:26][C:25]([O:28][C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[CH:5]=[CH:4][N:3]=3)=[CH:24][C:22]=2[N:23]=1
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: FC(F)(F)c1ccc(-c2ccnc(Cl)c2)cc1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ccn3)ccc2s1

Procedure:
This material was prepared according to the method described in Example 413 using 2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine (Example 410 (c), 0.16 g, 0.6 mmol), 2-methyl-5-benzothiazolol (0.12 g, 0.7 mmol), sodium hydride (38 mg, 1.0 mmol) and copper (I) iodide (12 mg, 0.06 mmol) in DMF (3 mL). Purification on a Biotage 40S column (3:1 hexanes: EtOAc), provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 367 (M+1). Mp: 160.5-163.5° C. Anal. Calcd for C20H13F3N2OS. 0.25 H2O: C, 61.45; H, 3.48; N, 7.17; S, 8.20.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH:4]([NH:16][C:17]([CH3:27])=[CH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14]Br)=[CH:8][CH:7]=1.[CH:29]1[C:41]2[NH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1.[OH-].[Na+]>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:27][C:17]([NH:16][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:38]2[C:39]3[NH:40][C:41]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:34]=3[CH:35]=[CH:36][CH:37]=2)=[CH:8][CH:7]=1)[C:3]([OH:2])=[O:28])=[CH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C(Cc1ccc(OCCBr)cc1)NC(C)=CC(=O)c1ccccc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=CC(=O)c1ccccc1)NC(Cc1ccc(OCCc2cccc3c2[nH]c2ccccc23)cc1)C(=O)O
Yield: 19.7 %

Procedure:
To a solution of 2-(1-methyl-3-oxo-3-phenyl-propenylamino)-3-[4-(2-bromoethoxy)-phenyl]-propionic acid methyl ester (0.22 g, 0.49 mmol) and carbazole (0.082 g, 0.49 mmol) in benzene (10 ml) is added tetrabutyl ammonium bromide (0.08 g) and 50% NaOH aqueous solution (0.084 g, 1.08 mmol), then the mixture is heated to reflux for 10 h. After cooled, benzene (30 ml) is added, and the mixture is washed with water(3×30 ml). Then the solvent is evaporated under a vacuum. The crude product is purified by silica gel chromatography using CHCl3/MeOH (4:1) as eluent to give the title compound (0.05 g, 20%). HRMS calcd for C33H30N2O4: 518.6123. Found: 518.6125. MA calcd for C33H30N2O4: C, 76.43%; H, 5.83%; N, 5.40%. Found: C, 76.21%; H, 5.85%; N, 5.39%.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[N:22]=[C:23](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[CH:15][CH:14]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Yield: 87.6 %

Procedure:
In an argon atmosphere, 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (218 mg) and 65% oily sodium hydride (39 mg) were dissolved in DMF (5 ml) added thereto. With stirring under ice cooling, 4-(chloromethyl)-2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazole (250 mg) was added, followed by stirring at room temperature for 3 hours. After water was added, the reaction mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over sodium sulfate, after which it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-ethanol=24:1), after which it was recrystallized from ethyl acetate to yield the titled compound (368 mg) as colorless crystals.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([OH:24])=O)[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:28][CH:25]4[CH2:27][CH2:26]4)=[O:24])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: COc1nccc2c1c(-c1csc(C(=O)O)c1)nn2C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1csc(C(=O)NC3CC3)c1)nn2C1CCCC1

Procedure:
A solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (75.0 mg) obtained in Step A of Example 155, cyclopropylamine (0.023 mL), EDCI hydrochloride (62.8 mg) and HOBt (44.3 mg) in DMF (10 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (78.0 mg).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[C:8](/[N+:17]([O-:19])=[O:18])\[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:3][CH:2]=1.[CH:20]1[CH2:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:9]([C@:8]1([N+:17]([O-:19])=[O:18])[C@H:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C@@H:22]2[CH2:23][C@H:24]1[CH:20]=[CH:21]2)(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(/C(=C\c1ccccc1)[N+](=O)[O-])c1ccccc1
Reactant: C1=CCC=C1
Solvent: ClCCl
Product: O=C(c1ccccc1)[C@@]1([N+](=O)[O-])[C@@H]2C=C[C@@H](C2)[C@H]1c1ccccc1
Temperature: 45 °C
Reaction time: 24 h
Yield: 80.9 %

Procedure:
A solution of (E)α-nitrochalcone [Dornow et al., Ann., 588:40 (1954); Yamamura et al., Bull. Chem. Soc., Jpn. 44:2440 (1971)] (Compound 7, 5.35 g, 21.1 mmol) in a minimum amount of CH2Cl2 (2-3 mL) was treated with freshly cracked cyclopentadiene (15.7 mL, 190 mmol, 9.0 equiv. ). The reaction mixture was stirred at 45° C. for 24 hours before the mixture was partitioned between CH2Cl2 (200 mL) and H2O (200 mL). The CH2Cl2 layer was dried (Na2SO4) and concentrated under reduced pressure. Chromatography (SiO2, 5×15 cm, 5 percent Et2O-hexane eluant) afforded Compound 9 (5.45 g, 6.73 g theoretical, 81 percent) as a white crystalline solid: mp 119°-120° C. (Et2O-hexane, colorless needles); 1H NMR (CDCl3, 250 MHz) δ 7.33 (d, 2H, J=8.0 Hz), 7.25-6.97 (m, 8H), 6.72 (m, 1H, C6-H), 5.99 (m, 1H, C5-H), 4.24 (d, 1H, J=2.7 Hz, C3-H), 3.84 (s, 1H, C1-H), 2.93 (s, 1H, C4-H), 2.65 (d, 1H, J=9.8 Hz, C7-H syn to ketone), 1.86 (d, 1H, J=9.9 Hz, C7-H anti to ketone); 13C NMR (CDCl3, 62.5 MHz) δ192.5, 144.3, 137.9, 134.2, 133.7, 133.0, 129.0, 128.6, 128.4, 127.9, 127.5, 105.4, 54.8, 53.5, 51.1, 48.5; IR (neat) vmax 3004, 2970, 1685, 1540, 1465, 1354, 1240 cm-1 ; FABHRMS (NBA-NaI) m/e 342.1101 (C20H17NO3 +Na+ requires 342.1106). A mixture of minor diastereomers (<3 percent) was isolated in trace amounts. Anal. Calcd for C20H17NO3 : C, 75.22; H, 5.37; N, 4.39. Found: C, 74.85; H, 5.29; N, 4.55.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].[O:21]1CCOCC1>O>[NH2:3][C:4]1[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:21])=[O:1]
Reactant: O=C1Cc2cccc(Nc3ccc(Cl)cc3)c2N1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)O)cccc1Nc1ccc(Cl)cc1

Procedure:
A mixture of 2-oxo-7-(4-chloroanilino)indoline (3.2 g.), sodium hydroxide (1.2 g.), dioxane (20 ml.) and water (40 ml.) was refluxed under heating for 118 hours with stirring. After cooling, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in water and washed with ethyl acetate, adjusted to pH 2 to 3 with 5% sulfuric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with benzene to give 2-[2-amino-3-(4-chloroanilino)phenyl]acetic acid (2.7 g.). mp 190° to 192° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([OH:22])=O)[CH2:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([Cl:25])=[O:22])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)nc2)C1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1=NN(c2ccccc2Cl)C(c2ccc(Br)nc2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5-(6-Bromo-pyridin-3-yl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (450.0 mg, 1.2 mmol) prepared in Step 3 was added to thionyl chloride (5.0 mL). The reaction mixture was stirred at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 5-(6-bromo-pyridin-3-yl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride as a dark brown liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=2)[N:9]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccc(C(F)(F)F)cc3c2=O)cc1C
Reactant: BrCc1ccccn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ccccn3)c3ccc(C(F)(F)F)cc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 55 mg (0.16 mmol) of 3-(3,4-dimethyl-benzoyl)-6-trifluoromethyl-1H-quinolin-4-one, 18 mg of 60% sodium hydride, 52 mg of 2-bromomethylpyridine hydrobromide and 1 mL of N,N-dimethylformamide. Yield: 49 mg of a white solid: LC-MSD, m/z for C25H19F2N2O2 [M+H]+=437.5; HPLC retention time: 2.6 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].S(OC)(O[CH3:18])(=O)=O.[OH-].[Na+].S(=O)(=O)(O)O>>[CH3:18][O:1][C:2]1[C:11]([OH:12])=[C:10]([OH:13])[CH:9]=[C:4]([CH:3]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(O)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
In 2.95 l of a 5% aqueous solution of borax was dissolved 36.8 g of methyl 3,4,5-trihydroxybenzoate, and the solution was stirred at room temperature for 5 hours. Then, 110.5 ml of dimethyl sulfate and a solution of sodium hydroxide were dropped into the solution and the reaction mixture was further stirred for 5 hours. After cooling, the mixture was made acidic by concentrated sulfuric acid and extracted with ethyl acetate. The solvent was removed from the extract to obtain 25.5 g of methyl 5-methoxy-3,4-dihydroxybenzoate (the yield was 64.5%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[OH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[OH:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2cccc(O)c2)cc1
Yield: 70 %

Procedure:
Prepared in a similar manner to example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and 3-hydroxyphenylboronic acid. Yield: 70%. MS (M+H, 312).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6](O)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(Cl)([Cl:17])=O>>[Cl:17][CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OC(CCCCCl)Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: ClCCCCC(Cl)Cc1ccccc1
Yield: 99.5 %

Procedure:
By operating as in Preparation 7 and starting from 12.3 g of 6-chloro-1-phenyl-hexan-2-ol and 12.9 g of thionyl chloride, 13.3 g of expected product is recovered.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH:15]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)[CH2:16][O:17][CH2:18][CH2:19][CH3:20]>>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:15]([CH3:14])[CH2:16][O:17][CH2:18][CH2:19][CH3:20])=[CH:29][CH:28]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Reactant: CCCOCC(C)Oc1ccc(CBr)cc1
Product: CCCOCC(C)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Yield: 35.4 %

Procedure:
Procedures similar to those in Preparation Example 8 were carried out by using 2.0 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 3.1 g of 4-(1-methyl-2-propoxyethoxy)-benzyl bromide to obtain 1.43 g of the aimed compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14](O)=[O:15])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:19][CH:18]=3)[C:9]=2[CH3:27])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:39][NH:40][CH3:41].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([N:40]([CH3:41])[CH3:39])=[O:15])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:19][CH:18]=3)[C:9]=2[CH3:27])=[CH:6][CH:7]=1
Reactant: CNC
Reactant: Cc1c(-c2ccc(S(N)(=O)=O)cc2)c(C(=O)O)n(C)c1-c1ccc(Cl)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1c(-c2ccc(S(N)(=O)=O)cc2)c(C(=O)N(C)C)n(C)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-1,4-dimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxylic acid (49ε, 1.00 g, 2.47 mmol) in DMF (15 ml) was added HOBT (0.41 g, 2.72 mmol) at room temperature, which was then followed by the addition of dimethylamine hydrochloride (0.40 g, 4.94 mmol). the reaction mixture was cooled to 0° C. and to the cooled reaction mixture was then added EDC (0.71 g, 3.70 mmol) and triethylamine (1.00 g, 1.37 ml, 9.88 mmol). The reaction mixture was then stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. Ethyl acetate (100 ml) was added to the residue so obtained. The mixture so obtained was then washed with saturated sodium bicarbonate solution (20 ml) followed by washing with brine (20 ml). The organic layer obtained was dried over anhydrous sodium sulphate. The dried organic layer was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography over silica gel (100-200 mesh) using 90% ethyl acetate in hexanes as an eluent to obtain the title compound (0.94 g, 88.1%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25](Br)[CH:24]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([NH2:22])=[N:14]2)[CH:8]=1)(=[O:5])=[O:4].[N:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35][CH:34]=1.C([O-])(=O)C.[K+].COC=COC>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[F:1][C:2]([F:32])([F:31])[S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:37]4[CH:38]=[N:33][CH:34]=[N:35][CH:36]=4)[CH:24]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([NH2:22])=[N:14]2)[CH:8]=1)(=[O:5])=[O:4]
Reactant: OB(O)c1cncnc1
Reactant: NC1=NC(c2cccc(OS(=O)(=O)C(F)(F)F)c2)(c2ccc(F)c(Br)c2)c2ccccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: O
Product: NC1=NC(c2cccc(OS(=O)(=O)C(F)(F)F)c2)(c2ccc(F)c(-c3cncnc3)c2)c2ccccc21
Temperature: 25 °C
Yield: 36.7 %

Procedure:
3-(3-Amino-1-(3-bromo-4-fluorophenyl)-1H-isoindol-1-yl)phenyl trifluoromethane-sulfonate (Scheme #20, H, 0.083 g, 0.16 mmol), 5-pyrimidinylboronic acid (0.019 g, 0.16 mmol), potassium acetate (0.031 g, 0.31 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane (0.006 g, 7.84 μmol) and solvent (2 mL of a mixture of dimethoxyethene and water in a ratio of 4:1) was irradiated under argon atmosphere in a microwave at 130° C. for 20 minutes. When cooled to ambient temperature the mixture was partitioned between ethylacetate and water, the organic phase was dried over magnesium sulfate and evaporated. Purification by preparative HPLC afforded 0.031 g (37%) of the title compound. 1H NMR (CDCl3) δ 9.18 (s, 1 H), 8.86 (d, J=1.26 Hz, 2 H), 7.58-7.45 (m, 4 H), 7.43-7.31 (m, 4 H), 7.30-7.25 (m, 1 H), 7.19-7.10 (m, 2 H), 5.43 (br s, 2 H); MS (ES) m/z 529 [M+1]+.
Reaction SMILES: CC(C)([O-])C.[K+].[SH:7][CH2:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13].Cl[C:22](Cl)=[CH:23][N+:24]([O-:26])=[O:25].Cl.[Cl-].[Na+]>C(O)(C)(C)C>[C:15]1([S:12]([N:11]2[CH2:10][CH2:9][CH2:8][S:7][C:22]2=[CH:23][N+:24]([O-:26])=[O:25])(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])C=C(Cl)Cl
Reactant: O=S(=O)(NCCCS)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CC(C)(C)O
Product: O=[N+]([O-])C=C1SCCCN1S(=O)(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
0.22 g of potassium t-butoxide was added drop-by-drop over 10 minutes to a solution of 0.23 g of 3 in 5 ml of t-butanol, under nitrogen. The resulting mixture was added drop-by-drop over 20 minutes to 0.30 g of 13A. After 20 minutes at room temperature, the mixture was poured into 2% hydrochloric acid saturated with sodium chloride, the resulting mixture was extracted with methylene chloride, the solvent was evaporated from the extract and the residue was purified over silica gel, using methylene chloride as eluent, to give 25, m.p.: 106°-107° C.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]2[CH2:13][C@H:12]([CH:14]([CH3:16])[CH3:15])[N:11]([C:17]3[CH:22]=[CH:21][N:20]4[N:23]=[CH:24][C:25]([C:26]5[CH:31]=[CH:30][C:29]([C:32]6[N:36]=[CH:35][N:34](COCC[Si](C)(C)C)[N:33]=6)=[CH:28][CH:27]=5)=[C:19]4[N:18]=3)[C:10]2=[O:45])[CH2:3]1.FC(F)(F)C(O)=O>>[NH:34]1[CH:35]=[N:36][C:32]([C:29]2[CH:30]=[CH:31][C:26]([C:25]3[CH:24]=[N:23][N:20]4[CH:21]=[CH:22][C:17]([N:11]5[C@@H:12]([CH:14]([CH3:15])[CH3:16])[CH2:13][N:9]([CH2:8][CH2:7][N:4]6[CH2:5][CH2:6][C@@H:2]([F:1])[CH2:3]6)[C:10]5=[O:45])=[N:18][C:19]=34)=[CH:27][CH:28]=2)=[N:33]1
Reactant: CC(C)[C@H]1CN(CCN2CC[C@@H](F)C2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1CN(CCN2CC[C@@H](F)C2)C(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To (S)-1-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (0.025 g, 0.0394 mmol) was added trifluoroacetic acid (5 mL) and the reaction stirred for 2 hours at ambient temperature. The reaction was concentrated in vacuo and the material purified by reverse preparative HPLC to give (S)-3-(3-(4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropylimidazolidin-2-one (0.0143 g, 0.0284 mmol, 72.0% yield) as the bis TFA salt. LCMS (APCI+) m/z 504 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH2:1]([NH:8][C:9]1[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Br)cc1NCc1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of N-benzyl-5-bromo-2-nitroaniline (700 mg, 2.28 mmol) in EtOH (8 mL) and water (8 mL) was added iron powder (766 mg, 13.7 mmol) and NH4Cl (733 mg, 13.7 mmol). The mixture was stirred at 60° C. for 4 h. The reaction solution was filtered with the filtrate concentrated to remove EtOH. The residue was diluted with water and extracted with EtOAc with the organic layer concentrated to give the crude N1-benzyl-5-bromobenzene-1,2-diamine. The crude product was used in next step without further purification. LCMS (m/z): 277.1/278.1 [M+H]+/[M+2H]+