Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[CH2:5][CH2:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH3:18])=[O:8]>>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[CH3:18])=[O:8]
Reactant: CNC
Reactant: Cc1[nH]c2ccccc2c1C(=O)CCCl
Product: Cc1[nH]c2ccccc2c1C(=O)CCN(C)C
Reaction time: 0.5 h

Procedure:
A solution of dimethylamine in IMS (33% w/v; 8 ml) was added to 3-chloro-1-(2-methyl-1H-indol-3-yl)-1-propanone (404 mg) and the mixture was left for 30 min. when a solid was precipitated. The mixture was refrigerated for 15 min. and the solid was filtered off and dried to give the title compound (207 mg). The mother liquors were evaporated to leave a solid which was partly dissolved in ethyl acetate (20 ml). Water (20 ml) was added and the solid remaining out of solution dissolved. The organic phase was extracted with 2M hydrochloric acid (3×20 ml) and the combined acidic extracts were brought to pH 10 with 0.88 ammonia solution. The mixture was extracted with ethyl acetate (3×25 ml), and the combined, dried organic extracts were evaporated to leave a solid which was crystallised from ethanol. The crystals were combined to give the title compound (386 mg), m.p. 172°-175°.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>CN(C=O)C>[CH2:13]([NH:17][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11])[CH2:14][CH2:15][CH3:16]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: CCCCN
Solvent: CN(C)C=O
Product: CCCCNc1cc(F)cc(F)c1[N+](=O)[O-]
Yield: 130.3 %

Procedure:
To a stirred solution of 2,4,6-trifluoronitrobenzene (5.31 g, 30 mmol), TEA (8.37 mL, 60 mmol) and DMF (50 mL) was added dropwise a solution of n-butylamine (2.96 mL, 30 mmol) in DMF (20 mL) at rt following General Procedure G1 to obtain crude 2-butylamino-4,6-difluoronitrobenzene (9.0 g). This product was mixed with 3-diethylaminopropanol (11.1 mL, 75 mmol) and anhydrous THF (150 mL), and then powdered KOBut (8.5 g, 75 mmol) was added following General Procedure G2 to afford crude 2-butylamino-4,6-di(3-diethylaminopropoxy)nitrobenzene (15.5 g).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH:3]([CH3:5])[CH3:4].Cl.[CH2:9]([O:13][C:14](=[O:29])[C@H:15]([CH3:28])[NH:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19])[CH:10]([CH3:12])[CH3:11].C(N[C@H](C(O)=O)CC1C=CC=CC=1)(OC(C)(C)C)=O.Cl.C(OC(=O)[C@H](C)N)C(C)C>CO.C(Cl)(Cl)Cl>[CH2:9]([O:13][C:14](=[O:29])[C@H:15]([CH3:28])[NH:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH:19][C:1](=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)COC(=O)[C@H](C)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)CC(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)CC(C)C

Procedure:
Following General Procedure C and using isovaleric acid (Aldrich) and N-(L-phenylalaninyl)-L-alanine iso-butyl ester hydrochloride (prepared from N-BOC-L-phenylalanine (Sigma) and L-alanine iso-butyl ester hydrochloride (prepared as described in Example 83A above) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=135-138° C.). The reaction was monitored by tlc (Rf=0.3 in 3% MeOH/CHCl3) and the product was purified by silica gel chromatography using 3% MeOH/CHCl3 as the eluent.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([F:18])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C(C2(F)CCC3(OCCO3)CC2)=NC=CC=1.N>>[F:18][C:8]1([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]1
Reactant: Fc1cccnc1C1(F)CCC2(CC1)OCCO2
Agent: FC1(c2ncccc2Cl)CCC2(CC1)OCCO2
Agent: N
Product: O=C1CCC(F)(c2ncccc2F)CC1

Procedure:
The title compound was prepared using the procedure as described in Example 1C, except for substituting the product of Example 15B for the product of Example 1B. 1H NMR (300 MHz, DMSO-d6) δ 8.41 (m, 1H), 7.80 (m, 1H), 7.56 (m, 1H), 2.80-2.22 (m, 8H). MS (DCI/NH3) m/e 212 (M+H)+.
Reaction SMILES: N[C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C.[CH2:27]([O:30][C:31](Cl)=[O:32])[CH:28]=[CH2:29]>C(Cl)Cl>[CH2:27]([O:30][C:31]([C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:32])[CH:28]=[CH2:29]
Reactant: C=CCOC(=O)Cl
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)OCC
Reaction time: 4 h
Yield: 60.4 %

Procedure:
A solution of 259A (900 mg, 3.3 mmol) in CH2Cl2 (20 mL) was treated with triethylamine (0.64 mL, 4.62 mmol) and allylchloroformate (0.35 mL, 3.96 mmol) at room temperature. The mixture was stirred for four hours, then washed with 0.1 N HCl (2×10 mL), 1N NaOH (2×10 mL) and brine (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 680 mg (yield: 58%) of Compound 259B as an oil.
Reaction SMILES: [N:1]([C:4]1[CH:25]=[C:24]2[C:7]([CH2:8][CH2:9][C@@H:10]3[CH2:15][S:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:12][C@@:11]32[CH3:26])=[CH:6][CH:5]=1)=[N+]=[N-]>[Pd].CO>[C:19]([O:18][C:17](=[O:23])[NH:16][C:13]1[S:14][CH2:15][C@H:10]2[CH2:9][CH2:8][C:7]3[C:24](=[CH:25][C:4]([NH2:1])=[CH:5][CH:6]=3)[C@@:11]2([CH3:26])[N:12]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N=[N+]=[N-])ccc3CC[C@@H]2CS1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3CC[C@@H]2CS1
Reaction time: 20 h
Yield: 101.8 %

Procedure:
10% Palladium on carbon (54 mg, 0.051 mmol) was added to a flask charged with a solution of tert-butyl rel-((4aS,10bS)-9-azido-10b-methyl-4a,5,6,10b-tetrahydro-4H-naphtho[1,2-d][1,3]thiazin-2-yl)carbamate from step D1 (190 mg, 0.509 mmol) in methanol (40 mL) under dry nitrogen. The vessel was repeatedly flushed with hydrogen gas. The reaction mixture was allowed to stir under a balloon of hydrogen gas for 20 h. The vessel was flushed with nitrogen. The contents were filtered through celite. The celite and vessel were rinsed with methanol. The combined filtrates were concentrated in vacuo. The residue was dried under high vacuum to afford tert-butyl((4aS,10bS)-9-amino-10b-methyl-4a,5,6,10b-tetrahydro-4H-naphtho[1,2-d][1,3]thiazin-2-yl)carbamate (180 mg, 0.518 mmol, 100% yield) as a gray oil. LCMS (M+Na)+=270.1. 1H NMR (500 MHz, chloroform-d) δ 6.89 (d, J=8.1 Hz, 1H), 6.81-6.72 (m, 1H), 6.58 (dd, J=8.1, 2.4 Hz, 1H), 3.66 (br. s, 2H), 3.03 (dd, J=13.0, 3.7 Hz, 1H), 2.92 (dd, J=12.9, 8.3 Hz, 1H), 2.77 (t, J=6.9 Hz, 2H), 2.26 (dt, J=7.2, 3.6 Hz, 1H), 2.11 (dtd, J=14.0, 7.1, 3.6 Hz, 1H), 1.97 (dq, J=13.7, 6.7 Hz, 1H), 1.63 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11](C(OC(C)(C)C)=O)[CH3:12])=[CH:6][CH:5]=1.[ClH:21]>C(OCC)(=O)C>[ClH:21].[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH3:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CN(C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCc1ccc(C(=O)OC)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
To 12.2 g of the compound obtained in step (1-2) above was added 20 ml of an ethyl acetate solution of 4N hydrochloric acid under ice-cooling and after stirring the mixture for one hour, the crystals formed were collected by filtration to provide 6.8 g (yield 90%) of 4-(N-methylaminomethyl)benzoic acid methyl ester hydrochloride. Then, 6.5 g of the crystals thus obtained was dissolved in 30 ml of DMF and 4.2 ml of triethylamine and 5.0 g of (S)-2-methylbutyl bromide were added to the solution under ice-cooling. Then, 1.3 g of 60% sodium hydride was added little by little to the solution and the mixture was heated to 80° C. for from 1 to 2 hours. After cooling, the reaction mixture was diluted with 80 ml of diethyl ether and 5 ml of purified water was added dropwise slowly to the solution. The organic layer formed was collected and, after successively being washed with 20 ml of purified water, 20 ml of a saturated aqueous sodium hydrogen carbonate solution, and then 20 ml of a saturated aqueous sodium chloride solution, dried with magnesium sulfate, and then the solvent was distilled off under reduced pressure.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=O)[C:5]=2[CH:4]=1)[CH3:2].[NH4+].[OH-]>[Zn]>[CH2:1]([C:3]1[CH:16]=[CH:15][C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Product: CCc1ccc2cc3ccccc3cc2c1
Yield: 38 %

Procedure:
To a 5 L 3-neck flask fitted with condenser, thermometer, and overhead stirrer was added 2-ethylanthraquinone (Aldrich, 120 g, 0.51 mol), Zn dust (Mallinckrodt, 300 g, 4.59 mol), CuSO4.5H2O (Mallinckrodt, 3.0 g), and 28% NH4OH (Mallinckrodt, 2.8 mL). The temperature was increased until the initial dark red color had faded (about 6 h). The reaction mixture was then filtered. The filtrate was extracted with EtOAc (5×1 L), and the filter cake washed with EtOAc (2×1 L). The EtOAc solutions were combined and the solvent removed. The residue was refluxed with a mixture of conc. HCl (10 mL) in i-PrOH (1.2 L) for 2 h. Upon cooling, a solid precipitated which was filtered, washed with abs. EtOH (100 mL) and dried to give 40 g (38%) of 2-ethylanthracene mp 140°-142°, (lit. mp 148°-150°, L. H. Klemm et al., J. Org. Chem. 28, 625 (1983), (C, H).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6]C(=O)[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[OH-].[Na+]>OS(O)(=O)=O>[NH2:6][C:5]1[CH:13]=[CH:14][C:2]([CH3:1])=[CH:3][C:4]=1[S:9]([NH2:8])(=[O:10])=[O:11]
Reactant: Cc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 105 °C
Yield: 66.5 %

Procedure:
A mixture of 7-methyl-1,1-dioxo-1,4-dihydro-2-H-benzo[1,2,4]thiadiazin-3-one (7.20 g, 36.36 mmol) in aqueous H2SO4 (50% v/v, 200 mL) was heated at 105° C. for 16 h. The clear solution was then cooled to 0° C. and neutralized using 5N NaOH. The product was extracted with ethyl acetate. The combined extracts were washed with water and concentrated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/hexane (1:1) to afford 4.5 g (85%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[N:11]=2)=[CH:5][CH:4]=1.[C:24](O)(=[O:28])[C:25]([CH3:27])=[CH2:26]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26])=[CH:19][CH:18]=3)[N:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2ccnc(Nc3ccc(N)cc3)n2)cc1
Reactant: C=C(C)C(=O)O
Product: C=C(C)C(=O)Nc1ccc(Nc2nccc(Sc3ccc(OC)cc3)n2)cc1
Yield: 46.5 %

Procedure:
In a procedure analogous to Example 15, reaction of N1-(4-(4-methoxyphenylthio)pyrimidin-2-yl)benzene-1,4-diamine (80 mg, 0.23 mmol) and methacrylic acid (50 mg, 0.46 mmol) furnished the product (42 mg, 47%).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](=[O:24])(=[O:23])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20].[OH-].[Na+]>O1CCOCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:25])=[O:2])(=[O:24])=[O:23])=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:14]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
6,25 g (16.56 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]benzoic acid methyl ester is dissolved in 60 ml of dioxane and combined with 25 ml (50 mmol) of 2N sodium hydroxide solution. The mixture is heated on a water bath until all of the starting material has disappeared. The solution is then concentrated to dryness under vacuum, combined with 2N hydrochloric acid, and the thus-precipitated material is dissolved in ethyl acetate. The organic solution is dried over sodium sulfate, concentrated to dryness, and the residue is crystallized from ethyl acetate/hexane. The title compound melts at 148° C.
Reaction SMILES: O=[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[NH:3]1.O=P(Cl)(Cl)[Cl:16]>CN(C=O)C.C(Cl)Cl>[Cl:16][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[N:3]=1
Reactant: N#Cc1ccc2[nH]c(=O)cnc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(Cl)cnc2c1
Temperature: 100 °C

Procedure:
2-Oxo-1,2-dihydroquinoxaline-6-carbonitrile was suspended in POCl3 (25 mL) and DMF (10 drops) was added. The mixture was heated at 100° C. for 2 h, cooled and concentrated under reduced pressure to leave a black residue. The residue was dissolved in CH2Cl2 (200 mL), washed with satd aq NaHCO3 (25 mL) and brine (25 mL) and dried over Na2SO4. Removal of the solvent left an off white solid (4.50 g). A 0.50-g portion was purified by chromatography on a 40-g silica gel cartridge eluted with a 0-50% EtOAc in hexanes gradient to afford 2-chloroquinoxaline-6-carbonitrile (118 mg). LC-MS Method 1 tR=1.42 min, m/z=190.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[CH3:16][C:17]([S:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>C1COCC1>[C:17]([S:20]([N:22]=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1)=[O:21])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)S(N)=O
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(=NS(=O)C(C)(C)C)CC1
Temperature: 55 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A mixture of tert-butyl 4-oxocyclohexylcarbamate (1.0 g, 4.7 mmol), 2-methylpropane-2-sulfinamide (0.63 g, 5.17 mmol) and Ti(OEt)4 (2.1 g, 9.2 mmol) in 10 mL of THF was stirred at 50-60° C. overnight. The mixture was cooled to room temperature and the residue purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4:1, v/v) to give tert-butyl 4-(tert-butylsulfinylimino)cyclohexylcarbamate (1.0 g, 67%) as an clear oil. MS: (M+H)+=317.3; 1H NMR (300 MHz, CDCl3): δ 4.88-4.86 (m, 1H), 3.83 (brs, 1H), 3.39-3.38 (m, 1H), 2.62-2.15 (m, 5H), 1.68-1.53 (m, 2H), 1.43 (s, 9H), 1.24 (s, 9H).
Reaction SMILES: C([C:11]1[C:18]2[S:17][C:16]3[CH:19]=[C:20]([C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[S:21][C:15]=3[C:14]=2[S:13][CH:12]=1)CCCCCCCCC>[Pt].C(OCC)(=O)C>[CH2:22]([C:20]1[S:21][C:15]2[C:14]3[S:13][CH:12]=[CH:11][C:18]=3[S:17][C:16]=2[C:19]=1[CH2:11][CH2:18][CH2:14][CH2:15][CH2:16][CH2:19][CH2:20][CH2:22][CH2:23][CH3:24])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCC#Cc1cc2sc3c(CCCCCCCCCC)csc3c2s1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCc1sc2c(sc3ccsc32)c1CCCCCCCCCC
Reaction time: 24 h
Yield: 160 %

Procedure:
3-decanyl-6-dec-1-ynyldithieno[3,2-b:2′,3′-d]thiophene (93) (36.0 g, 0.076 mol) was dissolved into ethyl acetate (60 mL). To this solution, 5% Pt/C (9.0 g) was added. The mixture was stirred under a H2 atmosphere (90 psi) for 24 hours. The solution was then filtered. After removal of the ethyl acetate, the residue was purified by chromatography on silica gel eluted with hexane to produce the target compound (29.0 g, 79.9%). 1HNMR: solvent, CD2Cl2 δ 7.29 (d, 1H), 7.27 (d, 1H), 2.80 (t, 2H), 2.67 (t, 2H), 1.68-1.27 (m, 32H), 0.88 (m, 6H). 13CNMR. 142.88, 140.75, 139.82, 131.69, 131.37, 126.69, 125.04, 120.94, 32.16, 29.85 (m, overlap), 22.93, 14.11.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20](Cl)=[O:21])=[CH:9]2)=[O:7])=[CH:4][CH:3]=1.[F:25][C:26]([F:32])([F:31])[S:27]([NH2:30])(=[O:29])=[O:28].C(Cl)Cl.N1C=CC=CC=1>ClCCCl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([NH:30][S:27]([C:26]([F:32])([F:31])[F:25])(=[O:29])=[O:28])=[O:21])=[CH:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CC(=O)Cl)cn2C(=O)c1ccc(Cl)cc1
Reactant: NS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: COc1ccc2c(c1)c(CC(=O)NS(=O)(=O)C(F)(F)F)cn2C(=O)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
80 mg (0.22 mmol) 2-(1-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl)acetyl chloride and 49.4 mg (0.33 mmol) trifluoromethanesulfonamide were dissolved in 1.8 mL 1,2-dichloro ethane (or CH2Cl2) under stirring. Then 17.5 mg (0.22 mmol) pyridine were added and the reaction was allowed to run at ambient temperature until the starting material was consumed (˜4 h). After the addition of 13 μL of AcOH the organic solution was washed with H2O (3×2 mL), dried over Na2SO4, filtered and the concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, ethyl acetate/hexane, 0.5% AcOH gradient) to afford the title compound in 70% yield (73 mg). C19H14ClF3N2O5S, Mr=474.84; 1H NMR (400 MHz, DMSO-d6) d: 3.44 (s, 2H), 3.79 (s, 3H), 6.95 (dd, J=2.6/9.0 Hz, 1H), 7.14 9d, J=2.4 Hz, 1H), 7.23 (s, 1H), 7.64-7.66 (m, 2H), 7.72-7.74 (m, 2H), 8.15 (d, J=8.8 Hz, 1H, C7′-H); 19F NMR (282 MHz, DMSO-d6) d: −75.58 (s, —CF3); LCMS (ESI) tR: 2.37 min (>99%, UV254, ELSD), m/z: 475.0 [M+1]+.
Reaction SMILES: [CH3:1][C@H:2]([NH:9][C@@H:10]([CH3:19])[CH2:11][C:12]([O:14][C:15](C)(C)C)=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>CO>[CH3:15][O:14][C:12](=[O:13])[CH2:11][C@@H:10]([NH:9][C@@H:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:19]
Reactant: C[C@H](N[C@@H](C)CC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: CO
Product: COC(=O)C[C@H](C)N[C@@H](C)c1ccccc1

Procedure:
A solution of compound (29) from Example 14 (1.00 mmol) was stirred in a saturated solution of gaseous hydrogen chloride in methanol for 30 minutes. The solvent was then removed under reduced pressure. This procedure was repeated until no starting material remained. The white solid residue was diluted with ethyl acetate (30 ml), washed with saturated aqueous sodium bicarbonate (2×30 ml), water (20 ml) and brine (20 ml), dried (magnesium sulphate) and filtered, and the solvent was evaporated under reduced pressure to give the title compound (35) as a clear oil. [α]D21 -45.5 (c 1.95, CHCl3); νmax (CHCl3)/cm-1 1736 s (C=O); δH (300 MHz; CDCl3) 7.34-7.20 (5H, m, Ph), 3.88 (1H, q, J=6.5, PhCHCH3), 3.67 (3H, s, OCH3), 2.99 (1H, m, CH3CHCH2), 2.47, 2.38 (2H, ABX system, JAB =14.8, JAX =5.4, JBX =6.5, CH2CO), 1.33 (3H, d, J=6.5 PhCHCH3), 1.06 (3H, d, J=6.4, CH3CHCH2); δC (50 MHz; CDCl3) 173.01 (C=O), 146.29 (Ph:Cipso), 128.63, 126.70 (Ph:Cortho, Cmeta), 127.07 (Ph:Cpara), 55.15, 47.69 (CHN), 51.30 (OCH3), 40.52 (CH2CO), 24.54, 21.34 (NCHCH3); m/z (CI) 222 (MH+, 100%), 206 (15), 148 (10), 118 (5), 105 (10); (Found: C, 70.48; H, 8.80. C13H19NO2 requires C, 70.56; H, 8.65%).
Reaction SMILES: [H-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[F:7][C:8]1[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:9]=1[C:10](O)=[O:11].Cl>CN(C)C=O>[F:7][C:8]1[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:9]=1[C:10](=[O:11])[CH2:6][N+:3]([O-:5])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(F)c(C(=O)C[N+](=O)[O-])c1
Temperature: 0 °C
Yield: 86.5 %

Procedure:
60% Sodium hydride (3.0 g) was suspended in 20 ml of N,N-dimethylformamide, then 8.4 g of nitro-methane was gradually dropped thereinto with ice-cooling and stirring and the mixture was stirred at room temperature for 30 minutes. 2-Fluoro-5-methanesulfonylaminobenzoic acid (8.0 g) and 6.7 g of N,N'-carbonyldiimidazole were dissolved in 30 ml of N,N-dimethylformamide and the solution was made to react at room temperature for 1 hour. The reaction mixture was added, with ice-cooling, to the solution obtained hereinbefore and the mixture was stirred at room temperature for 2 hours. Then, the mixture was poured into ice water, acidified with hydrochloric acid and the crystals separated out therefrom were filtered, washed with small amount of ethanol and dried to give 8.2 g of 4'-fluoro-3'-(2-nitroacetyl)-methanesulfonanilide, m.p. 174°-176 ° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.C(N(CC)CC)C.[C:13]([O:16][CH:17]([CH3:30])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24](O)[N:23]2[N:27]=[CH:28][CH:29]=[C:22]2[N:21]=1)(=[O:15])[CH3:14]>C1(C)C=CC=CC=1>[C:13]([O:16][CH:17]([CH3:30])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([Cl:3])[N:23]2[N:27]=[CH:28][CH:29]=[C:22]2[N:21]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)CCc1cc(O)n2nccc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)CCc1cc(Cl)n2nccc2n1

Procedure:
Phosphorus oxychloride (6.4 ml) and triethylamine (3.5 ml) were added to 40 ml of a toluene suspension containing 4.2 g of the crystals obtained in step (4), and the mixture was refluxed with heating for 6 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was poured into ice water. The mixture was neutralized with sodium acetate and extracted with ethyl acetate. The organic layer was collected, washed with a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane=4:1) to provide 4.3 g of 5-(3-acetoxybutyl)-7-chloropyrazolo[1,5-a]pyrimidine as a light yellow oily compound.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([N:7]1[CH:11]=[C:10]([CH:12]=[O:13])[N:9]=[CH:8]1)=[O:6])[CH3:3].O1CCC[CH2:16]1>>[OH:13][CH:12]([C:10]1[N:9]=[CH:8][N:7]([C:5]([O:4][C:2]([CH3:14])([CH3:1])[CH3:3])=[O:6])[CH:11]=1)[CH3:16]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)n1cnc(C=O)c1
Product: CC(O)c1cn(C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(dimethylethoxycarbonyl)imidazole-4-carboxaldehyde (9.3 g, 47 mmol) in tetrahydrofuran (200 mL) was added a methyl Grignard reagent (6.6 mL, 50 mmol) at ambient temperature. The resulting reaction mixture was stirred overnight at ambient temperature. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to afford 10 g of 4-(1-hydroxyethyl)-1-(dimethylethoxycarbonyl)imidazole as an oil.