Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([CH3:24])[N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].[CH2:27]1[O:29][C@@H:28]1[CH2:30]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:17]=[C:16]([CH3:24])[N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[O:26][CH2:30][C@@H:28]1[CH2:27][O:29]1)[CH3:2]
Reactant: OC[C@@H]1CO1
Reactant: CCc1cc(-c2noc(-c3cc(CC(C)C)cc(C)n3)n2)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1cc(-c2noc(-c3cc(CC(C)C)cc(C)n3)n2)cc(C)c1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
To a solution of 2-ethyl-4-[5-(4-isobutyl-6-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (79 mg, 0.224 mmol) in THF (6 mL), (R)-(+)-glycidol (25 mg, 0.335 mmol) and triphenyl phosphine (88 mg, 0.335 mmol) are added. The mixture is stirred and cooled to 0° C. before DEAD (58 mg, 0.335 mmol, as a 40% solution in toluene) is added. The mixture is warmed to rt and stirring is continued for 4 h. Another portion of (R)-(+)-glycidol (8 mg, 0.112 mmol), triphenyl phosphine (30 mg, 0.112 mmol) and DEAD (19 mg, 0.112 mmol) is added. Stirring is continued for 4 h before the solvent is evaporated. The crude product is purified on prep. TLC using heptane:EA 7:3 to give 2-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-4-isobutyl-6-methyl-pyridine (46 mg) as a yellow oil; LC-MS: tR=1.17 min, [M+H]+=408.19.
Reaction SMILES: O[C:2]1[C:7]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[C:6]=2[C:5](=[O:17])[N:4]([CH3:18])[N:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:2]1[C:7]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[C:6]=2[C:5](=[O:17])[N:4]([CH3:18])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1nc(O)c2scc(-c3ccncc3)c2c1=O
Product: Cn1nc(Cl)c2scc(-c3ccncc3)c2c1=O
Temperature: 120 °C
Reaction time: 18 h

Procedure:
The mixture of 7-hydroxy-5-methyl-3-(pyridin-4-yl)thieno[2,3-d]pyridazin-4(5H)-one and 4-hydroxy-6-methyl-3-(pyridin-4-yl)thieno[2,3-d]pyridazin-7(5H)-one (2.0 g, 7.71 mmol) was dissolved in POCl3 (15 mL) and stirred at 120° C. for about 18 h. Following this, most of the solvent was removed under reduced pressure. Water was added in caution until the POCl3 was consumed. MeOH was added, basified with K2CO3. The suspension was filtered through a Büchner funnel. The filtrate was concentrated to dryness under reduced pressure. The resulting brown oil was purified by preparative HPLC to give the title compound as white solid. Preparative HPLC was performed using a 2767 PHW003 HPLC-system (Waters) equipped with a C18 preparative column (10 um 21*250 mm, Boston). Mobile Phase: A: water (10 mM NH4HCO3), B: CH3CN; Gradient: 30-43% B in 8 min, stop at 14 min; Flow Rate: 30 mL/min; Detective Wavelength: 214\254 nm; Rt: 5.77 mM. LC-MS (Method B): m/z 278 (M+H)+, Rt: 1.79 min. 1H NMR (400 MHz, CDCl3): δ=8.69-7.68 (m, 2H), 7.67 (s, 1H), 7.49-7.48 (m, 2H), 3.82 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]1[O:13][CH3:14].[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[CH:21]1([NH:26][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]2[O:13][CH3:14])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(Cl)ncnc21
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(NC3CCCC3)ncnc21

Procedure:
To 1.5 g of 6-chloro-9-(2′-O-methyl-β-D-ribofuranosyl)-9H-purine and 510 mg of cyclopentylamine, 1.5 ml of triethylamine and 70 ml of ethanol were added. The solution was refluxed with heating for several ten minutes to 8 hours. After washing the residue with water, methanol was added and the solution was concentrated to dryness again. The residue was recrystallized with ethyl acetate to give N6-cyclopentyl-2′-O-methyladenosine (Compound 1). yield: 80%
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH:10][C:11]2[C:16]([C:17]([O:19]CC3C=CC=CC=3)=[O:18])=[CH:15][N:14]=[C:13]3[NH:27][CH:28]=[CH:29][C:12]=23)[CH2:5]1)(=[O:3])[NH2:2]>O1CCOCC1.CO.[Pd]>[C:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=[C:13]3[NH:27][CH:28]=[CH:29][C:12]=23)[CH2:5]1)(=[O:3])[NH2:2]
Reactant: NC(=O)[C@H]1CCC[C@H](Nc2c(C(=O)OCc3ccccc3)cnc3[nH]ccc23)C1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)[C@H]1CCC[C@H](Nc2c(C(=O)O)cnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
To a solution of benzyl 4-{[trans-3-carbamoylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (36 mg) in dioxane (7 ml) and methanol (7 ml) was added 10% Pd—C (50% wet) (10 mg) and stirred at ambient temperature for 3 hours under hydrogen atmosphere. After filtration the filtrate was evaporated in vacuo to give 4-{[trans-3-carbamoylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (28 mg).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[N:28]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[C:37]([O:36][C:34]([N:28]1[CH2:33][CH2:32][N:31]([CH2:12][C:9]2[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:6]=[C:7]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)[CH:8]=2)[CH2:30][CH2:29]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)cc(COS(C)(=O)=O)c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Yield: 75.9 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 75.9%).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]3[C:11]([CH:15]=2)=[N:12][O:13][N:14]=3)[CH:5]=1.Cl[CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1>>[S:21]1[CH:22]=[C:18]([CH2:17][N:6]([C:7]2[CH:8]=[CH:9][C:10]3[C:11]([CH:15]=2)=[N:12][O:13][N:14]=3)[N:4]2[CH:5]=[N:1][N:2]=[CH:3]2)[N:19]=[CH:20]1
Reactant: ClCc1cscn1
Reactant: c1cc2nonc2cc1Nn1cnnc1
Product: c1nc(CN(c2ccc3nonc3c2)n2cnnc2)cs1

Procedure:
Starting Compounds: 5-[N-(4H-1,2,4-triazol-4-yl)-amino]benzofurazan and 4-chloromethylthiazole
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>C1COCC1>[CH:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH:7][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[C:19]([F:18])([F:29])[F:30])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(N)c1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(NC(=O)c2ccccc2C(F)(F)F)c1
Temperature: 0 °C

Procedure:
One gram of 3-isopropylaniline and 0.8 gram of triethylamine were dissolved in 50 ml of THF, cooled to 0° C. and agitated. A solution prepared by dissolving 1.54 grams of 2-trifluoromethylbenzoyl chloride in 20 ml of THF were dropwisely added. After agitating for 30 minutes, the reaction mixture was filtered and THF in the filtrate was distilled off under reduced pressure. The residue was extracted by benzene, and rinsed with 3N-HCl, a saturated sodium bicarbonate solution and water successively in this order. The benzene layer was dried by adding anhydrous magnesium sulfate and then benzene was distilled off under reduced pressure to obtain the desired product. The yield was 1.98 grams (87%), and the product had a melting point of 87.5° to 88.5° C. and an IR absorption peak at 1655 cm-1 (c=b 0).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([N:14]1[CH2:19][C@@H:18]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:17][CH2:16][C@H:15]1[CH3:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[CH2:20]([C@@H:18]1[CH2:19][N:14]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:15]([CH3:27])[CH2:16][N:17]1[C:29]([O:31][CH3:32])=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cl
Reactant: C[C@@H]1CN[C@H](Cc2ccccc2)CN1Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N1C[C@@H](C)N(Cc2ccccc2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
Pyridine (0.3 mL, 3.7 mmol) was added to a stirring solution of (2R,5R)-1,5-dibenzyl-2-methylpiperazine (0.28 g, 1.0 mmol) and methyl chloroformate (0.10 g, 0.087 ml, 1.1 mmol) in CH2Cl2 (11 ml). After stirring at ambient temperature for 1 day, the reaction was evaporated in vacuo and the residue purified by flash chromatography (SiO2, 5% MeOH in CH2Cl2) to afford pure product (0.17 g, 49% yield over the two steps). MS (ESI) 339 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[N+:18]([CH3:21])([O-:20])=[O:19].C(NCC)C>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[CH2:9][CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:21][N+:18]([O-:20])=[O:19])=[CH:6][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: O=C(/C=C/c1ccccc1)c1ccc(F)cc1
Solvent: CO
Solvent: CCNCC
Product: O=C(CC(C[N+](=O)[O-])c1ccccc1)c1ccc(F)cc1
Yield: 95.1 %

Procedure:
In a 1 L flask, 138.8 g (613 mmol) of (2E)-1-(4-fluorophenyl)-3-phenylprop-2-en-1-one were dissolved in 825 g of methanol, admixed with 187.0 g (3.06 mol) of nitromethane and 224.1 g (3.06 mol) of diethylamine and refluxed for 16 h. The solvent was half distilled off in vacuo and the precipitated solid was separated off and dried to constant weight in vacuo to obtain 167.7 g (583 mmol) of 1-(4-fluorophenyl)-4-nitro-3-phenylbutan-1-one.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.Cl>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 4-bromobenzaldehyde, 1 (110 g, 0.59 mol), malonic acid (112.5 g, 1.189 mol), piperidine (11 mL) in pyridine (350 mL) was heated to 80° C. for 1 h, then refluxed for 3 h. Then the reaction mixture was cooled to room temperature, poured into a large beaker filled with cold water, and then acidified (pH<3) by slowly adding 25 mL of concentrated hydrochloric acid. The resulting precipitate was filtered and washed with cold water. The crude product was dissolved in aqueous sodium hydroxide, acidified (pH<3) (1:1 hydrochloric acid/water), filtered, and washed (cold water). The solid was dried in vacuo (60-70° C.) to give 2 (118.8 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][C:23]([O:26][C:27]4[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=4)([CH:24]=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[F:36][C:37]([Si](C)(C)C)([F:39])[F:38].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1.C(=O)([O-])O.[Na+]>[F:36][C:37]([F:39])([F:38])[CH:24]([C:23]1([O:26][C:27]2[CH:28]=[C:29]([F:35])[C:30]([F:34])=[C:31]([F:33])[CH:32]=2)[CH2:22][CH2:21][CH2:20][N:19]2[C:15]([C:5]3[CH:6]=[CH:7][C:8]([C:9]4[O:13][C:12]([CH3:14])=[N:11][CH:10]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16][N:17]=[C:18]12)[OH:25]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1cc(-c2nnc3n2CCCC3(C=O)Oc2cc(F)c(F)c(F)c2)ccc1-c1cnc(C)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COc1cc(-c2nnc3n2CCCC3(Oc2cc(F)c(F)c(F)c2)C(O)C(F)(F)F)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-(3,4,5-trifluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carbaldehyde (150 mg) and (trifluoromethyl)trimethylsilane (0.137 mL) in THF (1.5 mL) was added TBAF (1M THF solution, 0.062 mL) under an argon atmosphere at room temperature. The reaction mixture was stirred at room temperature for 2 hr, 1N hydrochloric acid (3 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and further recrystallized from ethyl acetate/hexane to give the title compound (38.8 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)(=O)=O)=CC=1.[C:20]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([N+:33]([O-:35])=[O:34])=[CH:28][CH:27]=2)([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:20]([C:24]1[N:25]([CH2:12][C@@H:13]2[CH2:17][O:16][C:15]([CH3:18])([CH3:19])[O:14]2)[C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([N+:33]([O-:35])=[O:34])=[CH:28][CH:27]=2)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](Cn2c(C(C)(C)C)cc3cc([N+](=O)[O-])ccc32)O1
Temperature: 80 °C
Reaction time: 20 h
Yield: 65.7 %

Procedure:
To a stirred solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (1.58 g, 5.50 mmol) in anhydrous DMF (10 mL) under nitrogen gas was added 2-tert-butyl-5-nitro-1H-indole (1.00 g, 4.58 mmol) followed by Cs2CO3 (2.99 g, 9.16 mol). The mixture was stirred and heated at 80° C. under nitrogen gas. After 20 hours, 50% conversion was observed by LCMS. The reaction mixture was re-treated with Cs2CO3 (2.99 g, 9.16 mol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (1.58 g, 5.50 mmol) and heated at 80° C. for 24 hours. The reaction mixture was cooled to room temperature. The solids were filtered and washed with ethyl acetate and hexane (1:1). The layers were separated and the organic layer was washed with water (2×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/hexane=1.5/1) to give (R)-2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-nitro-1H-indole (1.0 g, 66%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=2.2 Hz, 1H), 8.08 (dd, J=2.2, 9.1 Hz, 1H), 7.49 (d, J=9.1 Hz, 1H), 6.00 (s, 1H), 4.52-4.45 (m, 3H), 4.12 (dd, J=6.0, 8.6 Hz, 1H), 3.78 (dd, J=6.0, 8.6 Hz, 1H), 1.53 (s, 3H), 1.51 (s, 9H), 1.33 (s, 3H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N+:11]([C:14]1[CH:38]=[CH:37][C:17]([CH2:18][O:19][C:20]([N:22]2[CH2:26][CH:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][CH:23]2[CH2:35][OH:36])=[O:21])=[CH:16][CH:15]=1)([O-:13])=[O:12].CCN(CC)CC>C(Cl)Cl>[O:27]([C@H:25]1[CH2:26][N:22]([C:20]([O:19][CH2:18][C:17]2[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:38][CH:37]=2)=[O:21])[C@H:23]([CH:35]=[O:36])[CH2:24]1)[Si:28]([C:31]([CH3:34])([CH3:32])[CH3:33])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
To a stirred mixture of molecular sieves dried DMSO (15.0 ml, 212 mmol) and dichloromethane (1.24l ) at -78° C. was added oxalyl chloride (10.0 ml, 114 mmol) dropwise over 5 minutes and stirring was continued for additional 10 minutes. To this solution was added a mixture of 1-(4-nitrobenzyloxycarbonyl) -2-hydroxymethyl-4-(tertbutyldimethylsiloxy) pyrrolidine (31.0 g, 75.6 mmol) and CH2Cl2 (155 ml) dropwise over 15 minutes and the stirring was continued for 30 minutes at the same temperature. After addition of Et3N (52.5 ml, 377 mmol), removing of cold bath to warm to room temperature, washed with aqueous saturated NaHCO3 (300 ml), dried (MgSO4) of organic portion and concentrated in vacuo to afford the oily product which became solid after storage at room temperature. This crystalline product was washed with diethyl ether-hexane (1:10), collected by filtration and dried to give (2S, 4R)-4-tert-butyl-dimethylsiloxy-2-formyl-N-(4-nitrobenzyloxycarbonyl)pyrrolidine (29.7 g, 96% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]([CH3:15])([CH3:14])[C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2].[I:16]N1C(=O)CCC1=O.FC(F)(F)C(O)=O>C(#N)C.C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]([CH3:14])([CH3:15])[C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[I:16])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOc1cccc(C(C)(C)C(C)=O)c1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOc1cc(C(C)(C)C(C)=O)ccc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of 3-(3-ethoxy-phenyl)-3-methyl-butan-2-one (3.720 g, 18.03 mmol) in acetonitrile (40 mL) was added N-iodosuccinimide (5.679 g, 25.24 mmol) and trifluoroacetic acid (0.7 mL, 9.02 mmol) with stirring under argon. The reaction mixture was stirred at room temperature for 10 min then at 50° C. for 1 h. Upon cooling to room temperature, it was diluted with 10% ethyl acetate in hexane and filtered through a bed of Celite and silica gel. The filtrate was washed with water (1×), saturated solution of sodium bicarbonate (1×), 5% solution of sodium thiosulfate (1×), brine (1×), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the crude residue by flash chromatography (330 g of silica gel, eluting with 30% ethyl acetate in hexane over 30 min) gave 4.83 g of 3-(3-ethoxy-4-iodo-phenyl)-3-methyl-butan-2-one as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[C:8]([CH2:15][CH:16]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18][CH2:17]3)=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=[C:6]2[CH:5]=[C:4]([C:24]([OH:26])=O)[CH:3]=1.CCN=C=NCCCN(C)C.Cl.[CH:39]1[CH:40]=[CH:41][C:42]2N(O)N=[N:45][C:43]=2[CH:44]=1.O.NC1C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[N:7]2[C:8]([CH2:15][CH:16]3[CH2:21][CH2:20][C:19]([F:22])([F:23])[CH2:18][CH2:17]3)=[C:9]([C:11]([F:14])([F:12])[F:13])[N:10]=[C:6]2[CH:5]=[C:4]([C:24]([NH:45][C:43]2[CH:44]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:26])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)n2c(CC3CCC(F)(F)CC3)c(C(F)(F)F)nc2c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: Nc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cc(Cl)n2c(CC3CCC(F)(F)CC3)c(C(F)(F)F)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A part of the crude product of 5-chloro-3-(4,4-difluorocyclohexylmethyl)-2-trifluoromethylimidazo[1,2-a]pyridine-7-carboxylic acid obtained in step 3 (28 mg) was dissolved in DMF (2.0 mL), and the solution was stirred overnight at room temperature after adding EDC.HCl (27 mg, 0.141 mmol), HOBt.H2O (22 mg, 0.141 mmol), and aniline (13 mg, 0.141 mmol). The reaction mixture was extracted with ethyl acetate after adding a sodium hydrogen carbonate aqueous solution. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=9/1) to give 5-chloro-3-(4,4-difluorocyclohexylmethyl)-N-phenyl-2-trifluoromethylimidazo[1,2-a]pyridine-7-carboxamide (18.0 mg, two-step yield 62%).
Reaction SMILES: Cl.[C:2]1([C:8]2[S:12][C:11]3=[N:13][C:14]([NH:16][C:17]([C@@H:19]4[CH2:24][O:23][CH2:22][CH2:21][NH:20]4)=[O:18])=[CH:15][N:10]3[CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C:26]([O:29][C:30]([NH:32][C@@H:33]([C:40](O)=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])([CH3:28])[CH3:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:26]([O:29][C:30](=[O:31])[NH:32][C@@H:33]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:40](=[O:41])[N:20]1[CH2:21][CH2:22][O:23][CH2:24][C@@H:19]1[C:17](=[O:18])[NH:16][C:14]1[N:13]=[C:11]2[N:10]([CH:15]=1)[CH:9]=[C:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[S:12]2)([CH3:28])([CH3:25])[CH3:27]
Reactant: O=C(Nc1cn2cc(-c3ccccc3)sc2n1)[C@@H]1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCOC[C@@H]1C(=O)Nc1cn2cc(-c3ccccc3)sc2n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
Compound 16 (0.063 mmol), Boc-D-α-phenylglycine (0.126 mmol), and BOP (0.126) were added to dichloromethane (1.9 mL). Triethylamine (3.15 mmol) was added dropwise and the reaction mixture was stirred at room temperature overnight. The mixture was diluted in dichloromethane, washed sequentially with saturated solution of NaHCO3, water, and brine. The organic layers were gathered, dried, filtered, and concentrated under reduced pressure. The residue was purified by semi-preparative HPLC to give compound A22 as a white solid in 6% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.41 (s, 2H), 1.44 (s, 7H), 1.83-2.09 (m, 1H), 2.64-3.90 (m, 4H), 4.33-4.68 (m, 1H), 5.19-6.09 (m, 2H), 7.29-7.45 (m, 9H), 7.50-7.582 (m, 2H), 7.60-7.64 (m, 1H); MS (ESI, EI+) m/z=562.29 (MH+).
Reaction SMILES: I[C:2]1[C:3]([CH3:18])=[N:4][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C:6]=1[CH3:7].C([Mg]Cl)(C)C.CN([CH:27]=[O:28])C>C1COCC1>[CH3:18][C:3]1[C:2]([CH:27]=[O:28])=[C:6]([CH3:7])[N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[N:4]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c(I)c2C)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2nc(C)c(C=O)c2C)cc1
Temperature: -73 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
In a reaction vessel under inert atmosphere, 4-iodo-3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole x53 (1.44 g, 3.8 mmol) is dissolved in dry THF (10 ml) and cooled down to −73° C. A 2M solution of isopropylmagnesiumchloride in THF (9.6 mmol, 4.8 ml) is added dropwise and the mixture is stirred at −73° C. for 1 h. Then 0.44 ml of DMF (5.7 mmol) are added and the solution stirred at room temperature overnight. DMF (1.9 mmol) is further added and stirring is continued for 16 h. The reaction mixture is quenched with a saturated solution of NH4Cl, extracted three times with CH2Cl2, the organic phase is washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 0.88 g of crude 3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-carbaldehyde x56, which is used in the next step without any further purification.