Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[OH:27]>CC(C)=O>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[O:27][CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: C[C@H](CBr)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C[C@H](COc1c(Cl)cccc1Cl)NC(=O)OC(C)(C)C
Yield: 32.3 %

Procedure:
Intermediate 5A (230 mg, 0.966 mmol), cesium carbonate (409 mg, 1.256 mmol) and 2,6-dichlorophenol (157 mg, 0.966 mmol) were heated in acetone (1 mL) under microwave irradiation at 100° C. for 30 min. The solvents were removed and CH2Cl2 was added. The organic phase was washed with H2O, dried over Na2SO4, filtered and concentrated. The colorless oil was purified by ISCO (hexanes/EtOAc) to give 100 mg of Intermediate 5B (100 mg, 0.312 mmol, 32.3% yield). LC-MS 219.9 (M-Boc+H), RT=2.23 min (Method B).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]([OH:9])=O)=[N:4][NH:5][CH:6]=1.Cl.Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:3]([C:7]([N:24]2[CH2:23][CH2:22][N:21]([CH2:20][C:19]([C:16]3[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=3)=[O:27])[CH2:26][CH2:25]2)=[O:9])=[N:4][NH:5][CH:6]=1
Reactant: O=C(CN1CCNCC1)c1ccc(F)cc1
Reactant: O=C(O)c1n[nH]cc1Cl
Agent: Cl
Product: O=C(CN1CCN(C(=O)c2n[nH]cc2Cl)CC1)c1ccc(F)cc1
Yield: 65.3 %

Procedure:
The title compound was prepared in a similar manner as described in Example 1.2, using 4-chloro-1H-pyrazole-3-carboxylic acid (22.0 mg), and 1-(4-fluorophenyl)-2-(piperazin-1-yl)ethanone dihydrochloride (29.5 mg) as starting materials, to afford the title compound (22.9 mg) as a white solid. Exact mass calculated for C16H16ClFN4O2: 350.1. Found: LCMS m/z (%)=351.3 (M+H+35Cl, 100%), 353.3 (M+H+37Cl, 32%).
Reaction SMILES: C1(C(SC[CH2:10][C:11]([NH:13][CH2:14][C:15](O)=O)=[O:12])=O)SC=CC=1.O1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(OC(Cl)=O)C>C(Cl)Cl>[C:11]([NH:13][C:14]1[CH:15]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:12])[CH3:10]
Reactant: C1CCOC1
Reactant: O=C(O)CNC(=O)CCSC(=O)c1cccs1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1

Procedure:
5.4 grams (0.020 moles) of 2-thenoylmercaptopropionylglycine were added to 50 ml of tetrahydrofurane. The temperature of the resulting mixture was brought to 0° C., then a solution of ethylchloroformate (2.2 grams; 0.020 moles) in 10 ml of anhydrous CH2Cl2 was slowly added. To the resulting solution, the following solution was slowly added:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1)=O.[N:20]1([CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1.[BH4-].[Na+]>CO.C(O)C>[N:20]1([CH2:25][CH2:26][O:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][CH2:1][C:3]3[CH:8]=[CH:7][C:6]([O:9][S:10]([C:13]4[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=4)(=[O:12])=[O:11])=[CH:5][CH:4]=3)=[CH:32][CH:33]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C=O)cc2)cc1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)Oc2ccc(CNc3ccc(OCCN4CCCC4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
A solution of toluene-4-sulfonic acid 4-formyl-phenyl ester (3.28 g, 11.88 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (2.45 g, 11.88 mol) in 40 mL of methanol was stirred at room temperature overnight. The reaction mixture was concentrated to dryness. A portion of the crude residue (1.36 g, ˜2.92 mmol) was dissolved in 35 mL of ethanol and was treated with sodium borohydride (0.687 g, 18.16 mmol), which was added in portions over a period of about 3 hr. The reaction was stirred at room temperature overnight at which time it was concentrated to one-half of its original volume. To this mixture was added 25 mL of water and 25 mL of saturated sodium bicarbonate. The mixture was extracted three times with methylene chloride and the combined organic layers were dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography of the residue (2% methanol/methylene chloride to 10% methanol/methylene chloride) afforded 1.06 g (80%) of the title compound. MS 467.1 (M+1)+
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[CH:17]=[CH2:18])=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:19]>C(O)C.[Pd]>[CH2:17]([C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[C:3](=[O:19])[CH2:4]2)[CH3:18]
Reactant: C=Cc1ccncc1-c1ccc2c(c1)CC(=O)N2C
Agent: [Pd]
Solvent: CCO
Product: CCc1ccncc1-c1ccc2c(c1)CC(=O)N2C
Reaction time: 0.42 h

Procedure:
To a solution of 1-methyl-5-(4-vinyl-pyridin-3-yl)-1,3-dihydro-indol-2-one (30 mg, 0.12 mmol) in ethanol (1 mL) was added 10% palladium on carbon (18 mg, 0.02 mmol). The atmosphere over the reaction mixture was evacuated and the reaction was placed under an atmosphere of hydrogen gas via a balloon. The reaction was stirred for 25 minutes. The reaction mixture was then filtered through a plug of Celite® and the filtrate was then concentrated to dryness. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 6%) to afford 5-(4-ethyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one. The HCl salt of the title compound was prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution was concentrated to furnish the HCl salt of 5-(4-ethyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one. HRMS: (ESI) m/z 253.1335 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.23 (t, J=7.6 Hz, 3H), 2.93 (q, J=7.6 Hz, 2H), 3.28 (s, 3H), 3.66 (s, 2H), 7.16 (d, J=8.6 Hz, 1H), 7.33-7.43 (m, 2H), 8.05 (d, J=6.3 Hz, 1H), 8.65 (s, 1H), 8.71 (d, J=6.1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][S:8](=[O:11])(=[O:10])[N:7]([CH3:12])[C:6]=2[CH:13]=1.C([O-])([O-])=O.[K+].[K+].[CH3:20][Si:21]([CH2:24][CH2:25][O:26][CH2:27]Cl)([CH3:23])[CH3:22]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH2:27][O:26][CH2:25][CH2:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[S:8](=[O:11])(=[O:10])[N:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: CN1c2cc(Br)ccc2NS1(=O)=O
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1c2cc(Br)ccc2N(COCC[Si](C)(C)C)S1(=O)=O
Temperature: 75 °C
Reaction time: 4 h

Procedure:
To a solution of 6-bromo-1-methyl-1,3-dihydrobenzo[c][1,2,5]thiadiazole 2,2-dioxide (557 mmol, 2.10 mmol, as prepared above) in DMF (5 mL), K2CO3 (1.00 g, 7.23 mmol) and SEM-Cl (0.560 mL, 3.20 mmol) were added. The resulting mixture was stirred at 75° C. for 4 h and allowed to cool to rt. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3×20 mL). The combined DCM layers were dried over Na2SO4, filtered, concentrated and the resulting residue was purified by flash column chromatography on silica gel (0-50% hexane/EtOAc) to obtain compound 39a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.12-7.17 (m, 2H), 6.60 (d, J=8.6 Hz, 1H), 5.14 (s, 2H), 3.68-3.74 (m, 2H), 3.25 (s, 3H), 0.93-0.99 (m, 3H), 0.01 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[C:13]3[NH:16]C(=O)C)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>COCCO>[CH:1]1([CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[C:13]3[NH2:16])=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)Nc1cccc2ccc(OCC3CC3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Nc1cccc2ccc(OCC3CC3)cc12
Yield: 73.1 %

Procedure:
A mixture of 13 g (0.05 mol) of N-[7-(cyclopropylmethoxy)naphth-1-yl]acetamide, 35 ml of 10N sodium hydroxide solution and 150 ml of 2-methoxyethanol is heated at reflux for 4 h under a nitrogen atmosphere. The solvent is evaporated under reduced pressure. The residue is taken up in 200 ml of dichloromethane and 200 ml of water, and the mixture is stirred in the presence of carbon black and filtered over kieselguhr. The organic phase obtained is separated, dried over magnesium sulphate and filtered. The solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with dichloromethane. 7.8 g of an oil are obtained which crystallizes on cooling to give a product, melting point: 49°-50° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:24]([O:23][C:19](=[O:22])/[CH:20]=[CH:21]/[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH3:25]
Reactant: C=CC(=O)OCC
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
1-bromo-4-chloro-2-nitrobenzene (5 g), triethylamine (4.42 ml), ethyl acrylate (22.9 ml), palladium (II) acetate (0.048 g) and triphenylphosphine (0.111 g) in DMF (30 ml) was refluxed at 87° C. for 10 h. Toluene was added and the mixture washed with 2M hydrochloric acid and water. The organics were dried and concentrated under reduced pressure to a brown oil which was triturated with isohexane to give a light brown solid. Yield 4.95 g.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].[OH-].[K+].[CH:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].Cl>CN(C=O)C>[CH3:15][C:14]([CH3:17])([CH3:16])[CH:13]([OH:18])[CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CC(C)(C)C=O
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To 153.9 g (1.12 mol) of 2-nitrotoluene in 900 ml of DMF are added, within one hour, 4.5 g (80.2 mmol) of KOH and simultaneously 193.3 g (2.24 mol) of pivalaldehyde. Subsequently, first a further 0.5 equivalent of pivalaldehyde is added and the mixture is stirred at RT for one hour, then another 0.5 equivalent of pivalaldehyde is added and the mixture is stirred at room temperature for a further 2 hours. The mixture is acidified with 40 ml of 10 percent aqueous hydrochloric acid until the color changes (pH 4.5) and a majority of the DMF is distilled off under reduced pressure. After the residue has been distilled at 130° C./0.9 mbar, 136.8 g (yield 54% of theory, purity (GC-MS 98%) of 3,3-dimethyl-1-(2-nitrophenyl)butan-2-ol are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][C:20](=[O:26])[C@@H:21]1[CH2:25][CH2:24][CH2:23][NH:22]1>>[CH3:18][O:19][C:20]([CH:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:11](=[O:13])[CH:10]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:9])[CH:14]([CH3:16])[CH3:15])=[O:26]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Product: COC(=O)C1CCCN1C(=O)C(C(C)C)N(C)C(=O)OC(C)(C)C
Yield: 93.1 %

Procedure:
Using General Procedure I Method A, (2S)-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-butyric acid (0.37 g, 1.6 mmol) is coupled to L-proline methyl ester hydrochloride (0.26 g, 1.6 mmol) to give 1-[2-(tert-butoxycarbonyl-methyl-amino)-3-methyl-butyryl]-pyrrolidine-2-carboxylic acid methyl ester (0.51 g, 93%) as a white solid.
Reaction SMILES: O1CCOCC1.[F:7][C:8]([F:24])([F:23])[C:9]1[C:10]([S:15]([NH:18][C:19](=[O:22])OC)(=[O:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[CH3:25][C:26]1[CH2:30][CH:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:28][N:27]=1>N1C=CC=CC=1>[F:23][C:8]([F:7])([F:24])[C:9]1[C:10]([S:15]([NH:18][C:19]([N:28]2[CH:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:30][C:26]([CH3:25])=[N:27]2)=[O:22])(=[O:16])=[O:17])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)NS(=O)(=O)c1ncccc1C(F)(F)F
Reactant: CC1=NNC(c2ccccc2)C1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC1=NN(C(=O)NS(=O)(=O)c2ncccc2C(F)(F)F)C(c2ccccc2)C1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A dry dioxane (10 ml) solution containing methyl N-(3-trifluoromethylpyridine-2-sulfonyl)carbamate (0.43 g, 1.5 mmol), 3-methyl-5-phenyl-2-pyrazoline (0.48 g, 3.0 mmol) and pyridine (0.45 g) gas refluxed under heating and stirring for one hour. After cooling the mixture, the solvent was distilled off under reduced pressure, and the residue was stirred together with ethyl ether. Precipitated crystals were collected by filtration and then thoroughly washed with ethyl ether, and the crystals were suspended in 20 ml of water. Then, the pH was adjusted to a level of from 1 to 2 with concentrated hydrochloric acid, and the suspension was stirred at room temperature for 5 minutes. Crystals were collected by filtration, thoroughly washed with water and then with ethyl ether and dried to obtain 0.51 g of desired 1-(3-trifluoromethylpyridine-2-sulfonylcarbamoyl)-3-methyl-5-phenyl-2-pyrazoline. Melting point: 185°-187° C.
Reaction SMILES: Cl.C([N+](CCCC)(CCCC)CCCC)CCC.C(N(CC)CC)C.Br[C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1[N:34]([CH2:38][C:39]([CH3:41])=[CH2:40])[C:35](=[O:37])[CH3:36].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:27]=1[C:39]([CH3:41])([CH3:40])[CH2:38][N:34]2[C:35](=[O:37])[CH3:36]
Reactant: C=C(C)CN(C(C)=O)c1cccc(F)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(C)(C)c2c(F)cccc21
Temperature: 100 °C
Yield: 47.9 %

Procedure:
59 mg of palladium acetate, 1.5 g of tetrabutylammonium hydrochloride and 1.8 ml of triethylamine are added to a solution of 1.5 g of N-(2-bromo-3-fluorophenyl)-N-(2-methylallyl)acetamide in 10 ml of N,N-dimethylformamide. The reaction mixture is heated at 100° C. under an argon atmosphere for 16 hours. After cooling, 50 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is then washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of heptane and ethyl acetate (50/50: v/v), so as to give 520 mg of 1-(4-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)ethanone in the form of a yellow oil.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([O:20][CH3:21])(=[O:19])[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH2:13]>S(=O)(=O)(O)O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:13][CH:12]([C:11]([O:20][CH3:21])=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: Sc1nc2ccccc2s1
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: O=S(=O)(O)O
Product: COC(=O)CC(CSc1nc2ccccc2s1)C(=O)OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
16.8 g of finely powdered 2-mercaptobenzothiazole are suspended in 150 ml of 70% sulfuric acid and 16.6 g of dimethyl itaconate are added dropwise at 0°-10° in the course of half an hour, with stirring. After further 16 hours at 0°-10°, the reaction mixture is poured into ice water and extracted with ethyl acetate. The organic phase is separated, dried and the solvent is evapourated. The solid residue is recristallied from cyclohexane yielding dimethyl 3-(benzothiazol-2-ylthio)-propane-1,2-dicarboxylate, melting at 46°-47°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[O:16][CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:37]=[N+:38]=[N-:39].[Na+].O>C(Cl)(Cl)(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:10]([C:11]([F:14])([F:13])[F:12])=[N:39][N:38]=[N:37]2)[CH:5]=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CNC(=O)C(F)(F)F)cc1Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nnnc2C(F)(F)F)cc1Br
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2-bromo-4-(trifluoroacetamido)methylanisole (5 g, 16 mmol) was suspended in carbon tetrachloride (125 ml). Triphenylphosphine (8 g, 30.5 mmol) was added and the mixture stirred at 80° C. for 16 hours. Solvent was removed in vacuo and the residue poured into hexane (100 ml) and stirred at reflux for 30 minutes. The suspension was filtered through Hyflo™ and the filtrate concentrated to an oil. The oil in N,N-dimethylformamide (15 ml) was added to a stirred solution of sodium azide (1 g, 15 mmol) in N,N-dimethylformamide at 0° C. The mixture was stirred at ambient temperature for 2 hours then poured into water (200 ml) and extracted with ethyl acetate (2×100 ml). The combined organics were washed with water (3×200 ml), dried over sodium sulfate and the solvent was removed in vacuo leaving a yellow oil. Chromatography on silica gel, eluting with 10-50% ethyl acetate in hexane, gave the title compound as a yellow oil (230 mg, 5%, δH (360MHz, CDCl3) 4.90 (1H, d, J 7.6Hz, NCHAHBAr), 4.95 (1H, d, J 7.6 Hz, NCHAHBAr), 7.00 (1H, d, J 8.6Hz, 6-H), 7.52 (1H, dd, J 2.2, 8.5Hz, 5-H), 7.80 (1H, d, 2.2Hz, 3-H); m/z (ES+) 337, 339 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=3)[CH:9]=[CH:10][C:4]=2[O:3]1.[CH3:21][O:22][N:23]([CH3:27])[C:24](Cl)=[O:25]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][O:12][C:13]3[CH:19]=[CH:18][C:16]([NH:17][C:24]([N:23]([O:22][CH3:21])[CH3:27])=[O:25])=[CH:15][CH:14]=3)[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)Cc2cc(COc3ccc(N)cc3)ccc2O1
Reactant: CON(C)C(=O)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)Nc1ccc(OCc2ccc3c(c2)CC(C)(C)O3)cc1
Yield: 83.2 %

Procedure:
6.9 g of 4-(2,3-dihydro-2,2-dimethyl-5-benzofuranylmethyloxy)aniline was dissolved into 30 ml of pyridine, and 3.8 g of N-methoxy-N-methylcarbamoyl chloride was slowly added dropwise thereto under cooling with ice. After 2-hours' continuous stirring, pyridine was distilled off under a reduced pressure, and the residual oily matter was dissolved into 100 ml of toluene. After the solution was subsequently washed with water, diluted hydrochloric acid and saturated sodium chloride aqueous solution, toluene was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/3) as a developing solvent (developer) to obtain 7.6 g of Compound No. 2 shown in Table 1.
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([CH:20]=[N:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[CH:64]1[CH2:68][CH2:67][N:66]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:65]1>C1COCC1>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([CH:20]=[N:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:68]4[CH2:64][CH2:65][N:66]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:67]4)=[CH:25][CH:24]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(-c4ccc(O)cc4)ncn23)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(-c4ccc(OC5CCN(C(=O)OC(C)(C)C)C5)cc4)ncn23)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
To a mixture of 4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenol (0.1 g, 0.247 mmol, Prepared using AF from Preparation #AE.1 with (4-tert-butoxyphenyl)magnesium bromide [Novel], AG, J.3 with ethyl formate and L.2 with POCl3) and PPh3 (0.10 g, 0.40 mmol) in THF (1 mL) was added DIAD (0.077 mL, 0.40 mmol). The mixture was stirred at rt for about 20 min and tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.058 g, 0.31 mmol) was added. The mixture was stirred at rt for about 20 h and the mixture was purified directly by silica gel (25 g) chromatography eluting with a gradient of 40 to 90% EtOAc/DCM to afford tert-butyl 3-(4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenoxy)pyrrolidine-1-carboxylate (0.14 g, 100%): LC/MS (Table 2, Method c) Rt=1.51 min; MS m/z 574 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[C:24]([O:28][C:29](=[O:42])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[C:34]([F:41])[CH:33]=1)([CH3:27])([CH3:26])[CH3:25].CCN(CC)CC>ClCCCl>[C:24]([O:28][C:29](=[O:42])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:40])=[C:34]([F:41])[CH:33]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(N=C=O)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CCc1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 9.1) was reacted with 3-(3-fluoro-4-isocyanato-phenyl)-propionic acid tert-butyl ester in 1,2-dichloroethane in the presence of Et3N for 3 days under reflux conditions to give the title compound as brown oil. MS: m/e=591.3 [M+H+].
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:23])([CH3:22])[C:18]([F:21])([F:20])[F:19])[CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][N:4]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[C:32]([F:35])([F:34])[F:33])[CH2:3]1.[N-:36]=[N+:37]=[N-:38].[Na+]>C1(C)C=CC=CC=1>[F:19][C:18]([F:21])([F:20])[C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([S:8]([N:7]2[CH2:6][CH2:5][N:4]([C:24]3[CH:31]=[CH:30][C:27]([C:28]4[NH:38][N:37]=[N:36][N:29]=4)=[CH:26][C:25]=3[C:32]([F:35])([F:33])[F:34])[CH2:3][C@H:2]2[CH3:1])(=[O:9])=[O:10])[CH:12]=1)([OH:23])[CH3:22]
Reactant: C[C@@H]1CN(c2ccc(C#N)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C(C)(O)C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(-c3nnn[nH]3)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C(C)(O)C(F)(F)F)c1
Temperature: 100 °C

Procedure:
The compound of Example 29U, 4-((3R)-3-methyl-4-{[3-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl]sulfonyl}piperazin-1-yl)-3-(trifluoromethyl)benzonitrile, was used as starting material to make the title compound. A mixture of 4-((3R)-3-methyl-4-{[3-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl]sulfonyl}piperazin-1-yl)-3-(trifluoromethyl)benzonitrile (300 mg, 0.58 mmol), NaN3 (112.5 mg, 1.73 mmol), Et3NHCl (238.1 mg, 1.73 mmol) were charged to a microwave vial. Toluene (3 mL) was introduced under nitrogen atmosphere and the reaction mixture was heated at 100° C. over night in an oil bath. Reaction was complete as determined by TLC. Reaction mixtures was diluted with EtoAc, washed with 10% HCl until pH=6-7. The organic layer was dried over Na2SO4 and concentrated. The crude product was purified via prep HPLC under acidic condition to yield 1,1,1-trifluoro-2-[3-({(2R)-2-methyl-4-[4-(1H-tetrazol-5-yl)-2-(trifluoromethyl)phenyl]piperazin-1-yl}sulfonyl)phenyl]propan-2-ol as a white solid (111.2 mg, 34.3 yield %). HRMS: calcd for C22H22F6N6O3S+H+, 565.14510. found (ESI-FTMS, [M+H]1+), 565.14524.