Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]1[CH:35]=[CH:34][C:12]([O:13][C:14]2[C:22]3[N:21]=[C:20](S(C)(=O)=O)[NH:19][C:18]=3[CH:17]=[C:16]([O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH:15]=2)=[CH:11][CH:10]=1.[NH:36]1[CH:40]=[N:39][CH:38]=[N:37]1>C(OCC)(=O)C>[F:8][C:9]1[CH:35]=[CH:34][C:12]([O:13][C:14]2[C:22]3[N:21]=[C:20]([N:36]4[CH:40]=[N:39][CH:38]=[N:37]4)[NH:19][C:18]=3[CH:17]=[C:16]([O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[CH:15]=2)=[CH:11][CH:10]=1
Reactant: c1nc[nH]n1
Reactant: CS(=O)(=O)c1nc2c(Oc3ccc(F)cc3)cc(Oc3cccnc3)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(Oc2cc(Oc3cccnc3)cc3[nH]c(-n4cncn4)nc23)cc1
Temperature: 160 °C
Reaction time: 8 h

Procedure:
5.0 mg of sodium hydride was added to a dimethylformamide (0.5 ml) solution of 16 mg of 4-(4-fluoro-phenoxy)-2-methanesulfonyl-6-(pyridin-3-yloxy)-1H-benzimidazole, and then 10.4 mg of [1,2,4]triazole was added to it, and the reaction liquid was stirred overnight at 160° C. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), ethyl acetate) to obtain the entitled compound.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][CH:7]=[CH:6]1)(=[O:3])[CH3:2].ClC1C=CC=CC=1.[OH-].CC(C)=O>CO>[C:1]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C=CCC1
Agent: [OH-]
Solvent: CC(C)=O
Solvent: Clc1ccccc1
Solvent: CO
Product: CC(=O)OC1CCCC1
Temperature: 56 °C
Yield: 96 %

Procedure:
A solution of 1.80 g (0.014 mol) of 2-cyclopentenyl acetate in 3.80 g (0.12 mol) of methanol and 0.700 g of chlorobenzene (the internal standard for chromatographic analysis) was slowly passed through a jacketed column containing 20 ml of Dowex 1-X4 (an anion exchange resin of the quaternary ammonium type) in the hydroxide form in methanol. The column was maintained at 56° C by refluxing acetone in the jacket. The resin was then rinsed with methanol, and the combined effluent and rinsings were analyzed by gas chromatography using a 6ft. OV-17 column programmed from 80° to 220° C. The analysis showed that 2-cyclopentenol had beend formed in 96% yield and essentially 100% efficiency. No byproducts were observed.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[CH2:11][C:10](=O)[CH2:9][C:8](=[O:13])[CH2:7]2)=[CH:2]1.C([O-])(=O)C.[NH4+:18]>C(O)C>[NH2:18][C:10]1[CH2:11][CH:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH2:7][C:8](=[O:13])[CH:9]=1
Reactant: [NH4+]
Reactant: O=C1CC(=O)CC(c2ccsc2)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1=CC(=O)CC(c2ccsc2)C1
Yield: 95.7 %

Procedure:
A mixture of 5-(3-thienyl)cyclohexane-1,3-dione (10.5 g) and ammonium acetate (13.1 g) in ethanol (200 ml) was refluxed for 16 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added water (50 ml). The resulting crystals were filtered, washed with water and toluene, and dried to give 1-amino-5-(3-thienyl)cyclohexen-3-one (10 g) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[N:10]([CH2:19][CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH3:23])[C:9]([O:31]C)=[N:8][C:7]=1[CH2:33][O:34][CH2:35][CH2:36][N:37]=[N+:38]=[N-:39])=[O:5])[CH3:2]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[N:10]([CH2:19][CH2:20][CH2:21][NH:22][CH3:23])[C:9](=[O:31])[NH:8][C:7]=1[CH2:33][O:34][CH2:35][CH2:36][N:37]=[N+:38]=[N-:39])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(COCCN=[N+]=[N-])N=C(OC)N(CCCN(C)C(=O)OC(C)(C)C)C1c1ccccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=C(COCCN=[N+]=[N-])NC(=O)N(CCCNC)C1c1ccccc1Cl
Reaction time: 2 h

Procedure:
A solution of racemic 4-(2-azido-ethoxymethyl)-1-[3-(tert-butoxycarbonyl-methyl-amino)-propyl]-6-(2-chloro-phenyl)-2-methoxy-1,6-dihydro-pyrimidine-5-carboxylic acid ethyl ester (200 mg, 0.354 mmol) in CH2Cl2 (3 mL) and trifluoroacetic acid (1.5 mL) was stirred at RT under N2 to remove the BOC protecting group. After 2 h, 1N aqueous HCl (1 mL) and THF (3 mL) was added to the mixture. The mixture was left to stir overnight. The mixture was taken up in EtOAc (50 mL) and basicified with saturated NaHCO3 solution. The organic extract was washed with brine (25 mL), dried (Na2SO4), filtered, concentrated and dried in vacuo 150 mg (93% crude yield) of thick yellowish oil as crude product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12]1([N:18]2[C:30]3[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:1]([C:5]1[CH:10]=[C:9]([C:27]2[CH:28]=[CH:29][C:30]3[N:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:19]4[C:24]([C:25]=3[CH:26]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: CC(C)(C)c1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cc(-c2ccc3c(c2)c2ccccc2n3-c2ccccc2)ncn1
Yield: 95 %

Procedure:
Next, in a recovery flask equipped with a reflux pipe were put 1.00 g of 4-tert-butyl-6-chloropyrimidine obtained in Step 2, 3.44 g of 9-phenyl-9H-carbazol-3-ylboronic acid, 1.32 g of sodium carbonate, 0.050 g of bis(triphenylphosphine)palladium(II) dichloride (abbreviation: PdCl2(PPh3)2), 20 mL of water, and 20 mL of DMIF, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes to be heated. Then, water was added to this solution and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and a saturated aqueous solution of sodium chloride, and was dried with magnesium sulfate. The solution obtained by the drying was filtered. The solvent of this solution was distilled off, and then the given residue was purified by flash column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 2:1 to give HtBupczpm (white powder, yield of 95%). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). Synthesis Scheme (a-3) of Step 3 is shown below.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([Cl:34])[CH:33]=1)[NH:30][C:29](=[O:35])[CH:28]=[C:27]2[OH:36].Cl>O>[C:1]([C:28]1[C:29](=[O:35])[NH:30][C:31]2[C:26]([C:27]=1[OH:36])=[CH:25][C:24]([Cl:23])=[CH:33][C:32]=2[Cl:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(O)c2cc(Cl)cc(Cl)c2[nH]1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: O=C(c1ccccc1)c1c(O)c2cc(Cl)cc(Cl)c2[nH]c1=O
Temperature: 25 °C
Yield: 65.6 %

Procedure:
Benzoyl chloride (0.93 gram) is added to a mixture of 1.5 grams of anhydrous aluminum chloride and 10 ml of nitrobenzene, the mixture is stirred at room temperature until it becomes uniform, stirred at 105° to 110° C. for eight hours with 1.26 grams of 6,8-dichloro-4-hydroxy-2-quinolone, decomposed with concentrated hydrochloric acid, small amount of water is added thereto, and crystals separated out therefrom are collected by filtration. The crystals are washed with water and then washed with methanol and ether to give 1.2 grams of 3-benzoyl-6,8-dichloro-4-hydroxy-2-quinolone, pale yellow powder, melting point 258° to 259° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([C:23]([F:26])([F:25])[F:24])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:27][OH:28])=[CH:4][CH:3]=1.CC1(C)N([O])C(C)(C)CCC1.[N+]([O-])([O-])=O.[Na+].O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:27]=[O:28])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([C:23]([F:25])([F:24])[F:26])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(CO)c23)c(C(F)(F)F)n1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 64 h
Yield: 67.8 %

Procedure:
A mixture of {9-chloro-1-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}methanol (500 mg, 1.21 mmol), 2,2,6,6-tetramethylpiperidine 1-oxyl (18.9 mg, 0.12 mmol) and sodium nitrate (33.4 mg, 0.484 mmol) in acetic acid (10 mL) was stirred at room temperature and ambient pressure for 64 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-80% ethyl acetate/n-hexane gradient mixture to give the title compound (336.3 mg, 0.82 mmol, 68%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[Cl:12].CCN(C(C)C)C(C)C.[O:22]1[CH2:26][CH2:25][CH:24]([C:27](Cl)=[O:28])[CH2:23]1>C(Cl)Cl>[Cl:12][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:1][C:27]([CH:24]1[CH2:25][CH2:26][O:22][CH2:23]1)=[O:28]
Reactant: Nc1c(Cl)cc(O)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1c(Cl)cc(O)cc1[N+](=O)[O-])C1CCOC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.40 g (2.12 mmol) 4-amino-3-chloro-5-nitrophenol were placed in 5 mL DCM. 0.44 mL DIPEA and 0.34 g tetrahydrofuran-3-carbonyl chloride were added and the mixture was stirred for 2 h at RT. A further 0.34 g tetrahydrofuran-3-carbonyl chloride was added and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and washed with water. The organic phase was evaporated down i.vac.
Reaction SMILES: Br[C:2]1[C:3]([F:15])=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[F:8].CCN(C(C)C)C(C)C.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.[C:67]1([CH2:73][SH:74])[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>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]>[CH2:73]([S:74][C:2]1[C:3]([F:15])=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[F:8])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: SCc1ccccc1
Reactant: O=C1CCCN1c1ccc(F)c(Br)c1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C1CCCN1c1ccc(F)c(SCc2ccccc2)c1F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Intermediate 93 (1 g, 3.62 mmol) in dioxane (30 ml) was stirred under argon. DIPEA (1.26 ml, 7.24 mmol), xantphos (0.126 g, 0.22 mmol) and Pd2(dba)3 (0.099 g, 0.11 mmol) were added and the reaction was heated to 100° C. Phenyl-methanethiol (0.41 ml, 3.44 mmol) was slowly added and the reaction stirred for 3 h. The reaction was quenched by the addition of 150 ml of H2O. After extraction with ethyl acetate (three times), the combined organic layers were washed with water, dried with Na2SO4, evaporated to dryness and the product was purified by silica gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18]Cl)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>COCCOCCOC>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(OCCCCl)cc1
Reactant: c1c[nH]cn1
Solvent: COCCOCCOC
Product: Cl
Product: O=C(c1ccc(Cl)cc1)c1ccc(OCCCn2ccnc2)cc1
Yield: 65.6 %

Procedure:
A solution of the 4'-chloro-4-chloropropoxybenzophenone (3.0 g, 9.7 mmol) and imidazole (1.3 g, 19 mmol) in 2-methoxyethyl ether (20 mL) was heated to 120° C. for 24 hours. The solvent was removed by distillation and the resulting residue was chromatographed (flash, SiGel, 9:1 CH2Cl2 -MeOH). The hydrochloride salt was made in HCl/MeOH and recrystallized from acetone to give 1.2 g (36%) of the title compound as a white solid. m.p. 210°-212° C. IR (KBr): 1645, 1601cm-1. MS: 341 (MH) . 1H NMR (CD3OD): δ9.00(s,1H), 7.89-6.87(m,10H), 4.11(t,2H), 3.45(t,2H), 2.11(m,2H).
Reaction SMILES: COC1C=CC([C:9]2(C)[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([C:24]4[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=4)[C:22]#[N:23])=[N:16]3)=[CH:11][CH2:10]2)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+].CN([CH:41]=[O:42])C>O>[CH3:41][O:42][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]([C:27]3[CH:26]=[CH:25][C:24]([CH3:21])=[CH:29][CH:28]=3)=[CH:18][C:17]([CH2:20][CH:21]([C:22]3[NH:23][N:34]=[N:33][N:32]=3)[C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16]2)=[CH:13][CH:14]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(C2(C)C=CC(n3ccc(CC(C#N)c4cccc(C)c4)n3)=CC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: COc1ccc(-n2nc(CC(c3cccc(C)c3)c3nnn[nH]3)cc2-c2ccc(C)cc2)cc1
Temperature: 100 °C
Yield: 20 %

Procedure:
3-[1-(4-Methoxy-phenyl)-p-tolyl-1H-pyrazol-3-yl]-2-m-tolyl-propionitrile (Example 73, 0.10 g, 0.24 mmol), sodium azide (32 mg, 0.50 mmol) and ammonium chloride (26 mg, 0.50 mmol) were mixed in DMF (3.0 mL) and heated at 100° C. for 4 days. The reaction mixture was cooled, diluted with water (25 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (1×25 mL) and dried with Na2SO4, and the solvent was removed under reduced pressure yielding 21 mg (20%) of 5-{2-[1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-1-m-tolyl-ethyl}-1H-tetrazole. HPLC: Rt=3.16 (Method B). MS (ES+): mass calculated for C27H26N6O, 450.22; m/z found 451.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.25-7.17 (m, 3H), 7.12 (d, J=7.9 Hz, 2H), 7.07 (d, J=7.4 Hz, 1H), 7.04 (d, J=9.0 Hz, 2H), 6.99 (d, J=8.1 Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 6.23 (s, 1H), 4.85 (dd, J=6.7, 9.2 Hz, 1H), 3.75 (s, 3H), 3.60 (dd, J=9.3, 14.8 Hz, 1H), 3.34 (dd, J=6.4, 14.4 Hz, 1H), 2.28 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH:14][NH:15][C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:10][C:9]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1.C(O)(=O)C>C(O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:10][C:11]2[N:12]([C:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:15][N:14]=2)[N:13]=1
Reactant: O=C(Cc1ccc(C(F)(F)F)cc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)nn23)cc1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetohydrazide (124 mg, 0.24 mmol) and acetic acid (69 μL, 1.2 mmol) in ethanol (2.5 mL) in a vial was heated in a microwave oven at 180° C. for 30 min. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-70%) in hexanes to obtain 100 mg of the desired product with 96% purity. The product was crystallized from methanol (2 mL) to yield 42 mg of the pure product as a white solid. The mother liquid was concentrated. The obtained residue was purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 70% to 100% B, 10 min gradient, 100% B hold for 4 min, (A=90% H2O, 10% MeOH and B=10% H2O, 90% MeOH); Flow rate at 20 mL/min, UV detection at 220 nm) to afford additional 48 mg of the title compound as a white powder (90 mg in total, 75% yield). HPLC/MS (method A): retention time=4.08 min, (M+H)+=499.3.
Reaction SMILES: [C:1]1([S@@:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[NH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:21]=[CH:20][O:19][C:18]=1[C:22]([NH:24][C:25]1[CH:26]=[C:27]([C:31]#[C:32][C:33]2[CH:34]=[N:35][CH:36]=[C:37]([CH:41]=2)[C:38](O)=[O:39])[CH:28]=[CH:29][CH:30]=1)=[O:23].Cl.CN(C)CCCN=C=NCC.Cl>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:16][C:17]1[CH:21]=[CH:20][O:19][C:18]=1[C:22]([NH:24][C:25]1[CH:26]=[C:27]([C:31]#[C:32][C:33]2[CH:41]=[C:37]([C:38]([N:9]=[S@:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])=[O:39])[CH:36]=[N:35][CH:34]=2)[CH:28]=[CH:29][CH:30]=1)=[O:23]
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)O)c2)c1
Reactant: CCOC(=O)C[S@](=N)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To a solution of ethyl (S)-(S-phenylsulfonimidoyl)acetate (139 mg, 0.61 mmol) in anhydrous DMF (3 mL) at room temperature was added 5-{3-[(3-Methyl-furan-2-carbonyl)-amino]-phenylethynyl}-nicotinic acid (233 mg), catalytic amount of 4-(dimethylamino)pyridine, and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (141 mg). The reaction mixture was stirred at room temperature for 30 min. The reaction was then poured into aqueous HCl (0.5%) and extracted with EtOAc. After the aqueous layer was separated, solid sodium chloride was added and the resulting aqueous mixture was extracted again with EtOAc. The organic layers were combined, washed with brine (1×), saturated aqueous NaHCO3 (1×), then brine (1×), and finally dried with sodium sulfate. The upper solution was decanted, concentrated, and the yellow oily residue was subject to a column chromatography (silica gel, gradient elution EtOAc-Hex from 1:5 to 1:1.5) to give the title compound as a white foam (147 mg, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:29]=[C:12]3[CH:13]=[C:14]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[CH:22][C:21]=4[C:26]([OH:28])=O)=[O:19])[CH:15]=[CH:16][N:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=[CH:42][CH:43]=[N:44][C:39]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N1CCC1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:29]=[C:12]3[CH:13]=[C:14]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[CH:22][C:21]=4[C:26]([N:44]4[CH2:43][CH2:42][CH2:39]4)=[O:28])=[O:19])[CH:15]=[CH:16][N:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cccc(-c2nc3cc(NC(=O)c4c(C(=O)O)cnn4C)ccn3n2)c1
Agent: C1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc3cc(NC(=O)c4c(C(=O)N5CCC5)cnn4C)ccn3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
To a solution of 5-[2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid (4.0 g, 10.2 mmol) in DMF (50 ml) were added HATU (8.5 g, 22 mmol), azetidine hydrochloride (1.05 g, 93.5 mmol) and DIPEA (7.5 ml, 40 mmol) at 0° C. The resultant reaction mixture was stirred at 25° C. for 16 h. The mixture was diluted with water (100 ml) and stirred for 15 min. The resultant precipitated solid was filtered, washed thoroughly with water, and dried azeotropically with toluene followed by vacuum to yield 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide as off-white solid (1.9 g, 44%). LC-MS: m/z=432.4 [M+H]+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[N:9]=2)[NH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1.O>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[CH:15][CH:16]=3)[N:9]=2)[N:4]([S:38]([C:35]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:40])=[O:39])[CH:3]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(I)c3n2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of 7-iodo-2-(4-isopropylsulfonylphenyl)-5H-pyrrolo[2,3-b]pyrazine (5.0 g, 11.70 mmol) and DIPEA (3.024 g, 4.075 mL, 23.40 mmol) in DMF (25.00 mL) was added p-toluenesulfonyl chloride (2.454 g, 12.87 mmol). The resulting solution was stirred at room temperature for 2 hours. Water was added and the resultant precipitate collected, dried in vacuo at 40° C. to give the sub-title compound as an off-white solid (6.61 g, 97.16%). 1H NMR (400.0 MHz, DMSO) δ 9.18 (s, 1H), 8.64 (s, 1H), 8.42 (d, 2H), 8.05 (q, 4H), 7.48 (d, 2H), 3.50-3.45 (m, 1H), 2.36 (s, 3H) and 1.22-1.19 (m, 6H) ppm; MS (ES+) 581.9.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([OH:22])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[CH3:34][C:35]1([C:40](Cl)=[O:41])[CH2:38][CH:37]([CH3:39])[CH2:36]1>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[CH2:17][CH:18]([CH3:19])[CH3:20])=[C:11]([O:22][C:40]([C:35]2([CH3:34])[CH2:38][CH:37]([CH3:39])[CH2:36]2)=[O:41])[CH:10]=1)=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)CC(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1O
Reactant: CC1CC(C)(C(=O)Cl)C1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CC(C)CC(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1OC(=O)C1(C)CC(C)C1

Procedure:
Following a procedure similar to that described in Example 13A above, when 3-hydroxy-4-(isovaleryloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with 1,3-dimethylcyclobutanecarbonyl chloride there is obtained 3-(1,3-dimethylcyclobutanecarbonyloxy)-4-(isovaleryloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 13B, there is obtained 3-(1,3-dimethylcyclobutanecarbonyloxy)-4-(isovaleryloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.