Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH2:8]([O:10][C:11](=[O:19])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[CH3:9].Cl>CN(C=O)C.O>[CH2:8]([O:10][C:11](=[O:19])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:7][S:4]([CH3:3])(=[O:6])=[O:5])[CH3:9]
Reactant: CS(N)(=O)=O
Reactant: CCOC(=O)COCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COCCCCNS(C)(=O)=O
Temperature: 100 °C
Yield: 17.1 %

Procedure:
To a mixture of NaH (60% in oil, 167 mg, 4.18 mmol) and DMF (10 mL) was added a solution of methanesulfonamide (398 mg, 4.18 mmol) in DMF (5 mL). The mixture was heated at 100° C. for 1.5 h and was cooled to room temperature. A solution of (4-bromo-butoxy)-acetic acid ethyl ester (1.000 g, 4.182 mmol) in DMF (10 mL) was added and the reaction was heated at 100° C. for 21 h. Water was added to the cooled reaction mixture and the aqueous solution was acidified to pH=2 with concentrated HCl. The aqueous solution was extracted with EtOAc (4×) and the organic solution was dried (MgSO4), filtered, and concentrated. The product was purified by flash chromatography (60% EtOAc/hexanes) to afford the title compound (181 mg). 1H NMR (400 MHz, CDCl3) δ 4.90 (m, 1H), 4.20 (q, 2H), 4.04 (s, 2H), 3.54 (m, 2H), 3.16 (m, 2H), 2.93 (s, 2H), 1.69 (m, 4H), 1.26 (t, 3H); MS 254.1 (M+1).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-:33].[K+].[K+].OO.O>CS(C)=O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([C:27]([CH3:31])([CH3:30])[C:28]([NH2:29])=[O:33])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(C)(C)C#N)C3)ccc1-2
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(C)(C)C(N)=O)C3)ccc1-2
Temperature: 45 °C
Yield: 49.7 %

Procedure:
A solution of 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile (0.26 g, 0.6 mmol) in DMSO (5 mL) was treated with potassium carbonate (16 mg, 0.12 mmol) followed by hydrogen peroxide (30% aq., 0.33 mL) and the mixture was heated at 45° C. for 18 hours then at 50° C. for a few more hours. Further hydrogen peroxide (33 mL, 30% aq.) was added and the mixture heated at 50° C. for 18 hours. After cooling, water was added and the mixture was extracted with EtOAc (×5). The combined organic extracts were dried (Na2SO4), and concentrated in vacuo and the residue purified by flash chromatography (SiO2, first time with 0-10% MeOH in EtOAc then second time with 0-5% MeOH in DCM). Further purification was by reverse-phase preparative HPLC (Gemini C18 column, gradient 30-40% MeOH in H2O+0.1% HCO2H). A solution of the product in a mixture of chloroform and DCM was treated with 0.2M HCl in ether (0.32 mL) and then concentrated in vacuo to give 446 (27 mg, 9%). LCMS: RT=7.41 min, [M+H]+=453. 1H NMR δ (ppm) (DMSO-d6): 10.79 (1 H, s), 8.34-8.28 (1 H, m), 8.06 (1 H, s), 7.82 (1 H, d, J=17.45 Hz), 7.65 (1 H, d, J=4.94 Hz), 7.27-7.16 (1 H, m), 7.07 (1 H, d, J=1.80 Hz), 5.80-5.72 (1 H, m), 4.47 (1 H, td, J=10.76, 4.67 Hz), 4.37-4.26 (3 H, m), 4.20-3.94 (3 H, m), 3.41 (2 H, q, J=4.96 Hz), 1.55-1.45 (12 H, m)
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[ClH:25].Br[C:27]1[CH:45]=[CH:44][C:30]([O:31][C:32]([CH3:43])([CH3:42])[C:33]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[O:34])=[CH:29][CH:28]=1>>[ClH:25].[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:27]2[CH:45]=[CH:44][C:30]([O:31][C:32]([CH3:43])([CH3:42])[C:33]([N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)=[O:34])=[CH:29][CH:28]=2)[C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: CN1CCN(C(=O)C(C)(C)Oc2ccc(Br)cc2)CC1
Agent: Cl
Product: CN1CCN(C(=O)C(C)(C)Oc2ccc(-n3c(C(=O)O)cc4cc(-c5ccc(C(C)(C)C)cc5)ccc43)cc2)CC1

Procedure:
The title compound was prepared in accordance with Example 1 using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 1-(2-(4-bromophenoxy)-2-methylpropanoyl)-4-methylpiperazine hydrochloride (see (a)), followed by precipitation of the hydrochloride salt using HCl (4 M in dioxane).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:42])[NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][C:30]=3[F:36])=[N:23][CH:24]=[N:25]2)=[CH:20][C:19]=1[NH:37][C:38](=[O:41])[CH:39]=[CH2:40])=O)(C)(C)C.[C:43](O)(=O)[CH2:44]C>>[C:38]([NH:37][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:18]=1[O:17][CH2:16][CH2:15][NH:14][C:13]([CH:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6](=[O:5])[CH2:43][CH3:44])=[O:42])[N:25]=[CH:24][N:23]=[C:22]2[NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][C:30]=1[F:36])(=[O:41])[CH:39]=[CH2:40]
Reactant: C=CC(=O)Nc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCNC(=O)C1CCCN1C(=O)OC(C)(C)C
Reactant: CCC(=O)O
Product: C=CC(=O)Nc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCNC(=O)C1CCCN1C(=O)CC
Yield: 83.4 %

Procedure:
The procedure of Example <1-10> was repeated except for using the compound of Example 97 (50 mg, 0.09 mmol) and propionic acid (6.7 mg, 0.09 mmol) to obtain the title compound 45 mg (yield: 82%).
Reaction SMILES: C([O:4][CH2:5][C:6]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([NH:12][C:13](=O)[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:7][O:8]C(=O)C)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:19]([C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([CH2:5][OH:4])[CH2:7][OH:8])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)NC(=O)CCCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCC(CO)(CO)NCCCCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,3-Diacetoxy-2-octadecyl-2-(N-pentanoylamino)propane (400 mg) was dissolved in 30 ml of dry ether and 150 mg of lithium aluminum hydride was added thereto under ice-cooling. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and 20 ml of dry tetrahydrofuran was added thereto. Under ice-cooling, 0.15 ml of water, 0.15 ml of a 15% aqueous sodium hydroxide solution and 0.45 ml of water were added in order and the reaction mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography using chloroform-methanol-acetic acid (19:1:0.1→10:1:0.05) as an eluent to give 153 mg of colorless, powdery 2-octadecyl-2-(N-pentylamino)-1,3-propanediol.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[CH3:19][O:20][C:21]([C@:23]1([CH2:29]O)[CH2:27][CH2:26][CH2:25][N:24]1[CH3:28])=[O:22].CCN(CC)CC>C(Cl)Cl>[CH3:19][O:20][C:21]([C@:23]1([CH2:29][O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH2:27][CH2:26][CH2:25][N:24]1[CH3:28])=[O:22]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COC(=O)[C@]1(CO)CCCN1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@]1(CO[Si](C(C)C)(C(C)C)C(C)C)CCCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (11.7 g, 38.1 mmol) was added to a solution of Intermediate 85e (2.20 g, 12.7 mmol) and Et3N (12.8 g, 127 mmol) in DCM (100 mL) at 0° C., then the mixture stirred at RT for 30 min. The mixture was diluted with DCM and washed with 10% aq. K2CO3 solution, water, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM, to give the title compound as a pale yellow solid (2.51 g, 65%). 1H NMR (400 MHz, CDCl3): 0.97-1.15 (21H, m), 1.72-1.96 (2H, m), 2.23-2.35 (2H, m), 2.46 (3H, s), 2.89-2.99 (2H, m), 3.69 (3H, m), 4.12-4.22 (2H, m).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](C=O)[CH2:10][CH2:9]2)(=[O:5])=[O:4].Cl>CO.C(Cl)(Cl)Cl>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9]2)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CCN2C=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNS(=O)(=O)c1ccc2c(c1)CCN2
Yield: 82.1 %

Procedure:
To a stirred solution of 23.42 g (0.0975 mol) of 5-methylsulfamoyl-N-formylindoline in 500 ml of methanol was added 40 ml of concentrated hydrochloric acid. The solution was heated to reflux for one hour. Thin layer chromatography in chloroform showed the reaction was complete. The solution was allowed to cool, and then the methanol was removed under reduced pressure. The aqueous slurry remaining was dissolved ice water and neutralized by the addition of sodium hydroxide solution. The precipitate was extracted with methylene chloride, washed with water and saturated aqueous sodium chloride solution. The solution was dried over sodium sulfate and then concentrated under reduced pressure. The residue was allowed to air dry to give 17.02 g (0.08 mol) (82% by weight yield) of 5-methylsulfamoylindoline.
Reaction SMILES: [C:1]([CH:4]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:7][CH:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5]1)(=[O:3])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:36])[NH:31][CH2:32][C:33](O)=[O:34])[CH:26]=[CH:27][CH:28]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[C:1]([CH:4]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]([C:33](=[O:34])[CH2:32][NH:31][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=2)=[O:36])[CH:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1CC(C(=O)OC(C)(C)C)NC1c1ccccc1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CC(=O)C1CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C)c2)C1c1ccccc1
Yield: 13.6 %

Procedure:
The reaction is carried out in a way analogous to that described in Example 2B, but from 4.5 g of tert-butyl (2RS,4RS,5SR)-4-acetyl-5-phenylpyrrolidine-2-carboxylate, 3.2 g of 2-[3-(3-methylphenyl)ureido]acetic acid and 3.5 g of N,N'-dicyclohexylcarbodiimide in 50 cm3 of acetonitrile. After treatment, there is obtained 1 g of tert-butyl (2RS,4RS,5SR)-4-acetyl-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylpyrrolidine-2-carboxylate, melting at 100° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].C(N(CC)CC)C.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH:8][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH3:3]
Reactant: CCOC(=O)CCN
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)CCCCNC(=O)OC(C)(C)C
Yield: 59 %

Procedure:
To a suspension of 7.68 g of β-alanine ethyl ester hydrochloride in 50 ml of methylene chloride there was added, with stirring, 5.56 g of triethyl- amine. 10.86 g of N-t-butoxycarbonyl-5-aminovaleric acid, dissolved in 50 ml of methylene chloride, and portionwise 11.35 g of DCC, in that order. After completion of the addition, the reaction mixture was stirred at room temperature overnight and filtered off from separated urea. The filtrate was washed in succession with 250 ml of sodium bicarbonate solution (5%), water, 250 ml of 0.1M citric acid and, finally, with saturated sodium chloride solution. Thereafter, the solvent was evaporated under reduced pressure and the oily residue was purified by column chromatography on silica gel, to obtain N-[5-(1-t-butoxyformamido)valeryl]-β-alanine ethyl ester in 59% yield, melting point 28° (from hexane).
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:10]=1.C(O[C:20]1(O[Si](C)(C)C)[CH2:22][CH2:21]1)C.C([BH3-])#N.[Na+]>CO>[Br:5][C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH:20]3[CH2:22][CH2:21]3)[CH2:13][CH2:12]2)[CH:10]=1
Reactant: Brc1cnn(C2CCNCC2)c1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Brc1cnn(C2CCN(C3CC3)CC2)c1
Temperature: 60 °C

Procedure:
Acetic acid (1.258 ml, 21.98 mmol) is added dropwise, under stirring at RT, to a solution of 4-(4-Bromo-pyrazol-1-yl)-piperidine (as obtained in preparation 89, 1.686 g, 7.327 mmol) and [(1-ethoxy-1-cyclopropyl)oxy]trimethylsilane (2.210 ml, 10.99 mmol) in MeOH (20 ml). Sodium cyanoborohydride (775 mg, 11.7) is then added in one portion at RT. The mixture is then heated at 60° C. for 3 h. After cooling, the reaction mixture is concentrated in vacuo and the residue dissolved in EtOAc and diluted with saturated NaHCO3. After separation, the aqueous phase is re-extracted 3× with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is used without further purification in the next step, and afford the title compound as colorless solid, Rt=0.618 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 270 (M+1, 79Br)+
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(#N)C>[Br:1][C:16]1[CH:15]=[N:14][C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])=[CH:18][C:17]=1[NH2:19]
Reactant: CC(C)(C)c1cc(N)ccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)c1cc(N)c(Br)cn1

Procedure:
Procedure analogous to V. Canibano et al., Synthesis 2001, 14, 2175. 18.7 g (105 mmol) of N-bromosuccinimide are added in portions at 40° C. to a vigorously stirred, light-protected solution of 15.0 g (100 mmol) of 2-tertbutyl-4-aminopyridine [39919-69-2] in 500 ml of acetonitrile, and the mixture is stirred for a further 30 h. The solvent is removed in vacuo, the residue is taken up in 500 ml of dichloromethane, washed five times with 500 ml of water each time and once with 300 ml of sat. sodium chloride solution, the organic phase is dried over sodium sulfate, and the solvent is then removed in vacuo. The crude product is recrystallised from cyclohexane. Yield: 17.9 g (78 mmol), 78%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11](OS(C)(=O)=O)[CH:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:24]>CO>[NH2:24][CH:11]1[CH:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12]1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CC(OCC(F)(F)F)C(OS(C)(=O)=O)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N)C(OCC(F)(F)F)C1
Temperature: 140 °C
Reaction time: 10 h

Procedure:
A mixture of 3.95 g (0.011 mole) of 1-t-butoxycarbonyl-3-(2,2,2-trifluoroethoxy)-4-methylsulfonyloxypyrrolidine [prepared as described in step (a) above] and 100 ml of methanol containing 20% w/v ammonia was transferred to an autoclave and then stirred at 140° C. for 10 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel using a 1:9 by volume mixture of ethanol and ethyl acetate as the eluent, to give 1.61 g of 3-amino-1-t-butoxycarbonyl-4-(2,2,2-trifluoroethoxy)pyrrolidine as a colorless oil. Mass Spectrum (CI): m/e 285 (M+ +1), 229 (M+ +1--CH2 =C(CH3)2).
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH2:9][NH:10][CH2:11]1)[C:7]1[C:2]2=[CH:3][C:4]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([NH:31][CH3:32])(=[O:30])=[O:29])[C:18]([Cl:33])=[CH:17][N:16]=2)=[CH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:40](Br)[C:41]#[CH:42]>CC(C)=O>[Cl:33][C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([NH:31][CH3:32])(=[O:30])=[O:29])=[N:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[CH:8]2[CH2:12][CH2:13][CH:1]3[CH2:11][N:10]([CH2:42][C:41]#[CH:40])[CH2:9]2)=[N:16][CH:17]=1
Reactant: C#CCBr
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CNC2)ncc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)NC)n3)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-[2-(10-Aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide (30 mg, 0.0619 mmol) was placed in acetone (3 mL) and cesium carbonate (60.4 mg, 0.186 mmol, 3.0 eq) was added followed by propargyl bromide (80% in toluene) (7.28 μL, 0.0681 mmol, 1.1 eq). The reaction was stirred at room temperature for 24 hours and was then concentrated under reduced pressure. The residue was taken up in CH2Cl2 (10 mL) and washed with water (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent. Further purification by prep-HPLC using a gradient of 10-90% acetonitrile/water to obtain 2-[5-chloro-2-(10-prop-2-ynyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide as a thin yellow film (6.9 mg, 21%). LCMS (m/e) 523 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.10 (s, 1H), 8.49 (d, 1H, J=8.0 Hz), 8.09 (s, 1H), 7.95 (dd, 1H, J=1.6 and 8.0 Hz), 7.60-7.53 (m, 1H), 7.30-7.20 (m, 3H), 7.01 (d, 1H, J=7.9 Hz), 6.99 (bs, 1H), 4.76-4.67 (m, 1H), 3.36 (d, 2H, J=2.4 Hz), 3.05-3.00 (m, 1H), 2.95-2.84 (m, 3H), 2.63 (d, 3H, J=5.3 Hz), 2.51-2.43 (m, 2H), 2.21-2.15 (m, 2H), 2.14 (t, 1H, J=2.3 Hz), 1.70-1.60 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.[Pd](Cl)Cl.O1CCCC1>[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCCCCCCC
Reactant: Brc1ccc2sccc2c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCC#Cc1ccc2sccc2c1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of 5-bromobenzothiophene (50.0 g), 1-decyne (35.7 g), triethylamine (71.2 g) and dry tetrahydrofuran (150 ml), under nitrogen, was added bis(triphenylphosphine)palladium (11) chloride (1.65 g) followed by copper (1) iodide (0.233 g) with stirring, at room temperature. The reaction mixture was covered with foil and stirred at reflux, under nitrogen, over the weekend. Additional bis-triphenylphosphine)palladium (II) chloride (0.5%) and 0.25% copper (I) iodide were added, and the reaction mixture was stirred at reflux for three days, cooled, filtered through a bed of celite and the filter cake was washed with ether. The residue was flash chromatographed (silica, 1% ethyl acetate-heptane). The appropriate fractions were collected and evaporated to give 56.3 g (89%) of product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(N(CC)CC)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>ClCCl>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH2:10][CH2:9]2)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: Cc1nccc(N2CCN(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nccc(N2CCN(C(=O)N3CCN(S(=O)(=O)c4ccc(Cl)cc4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(tert-butoxycarbonyl)-4-(1-(2-methylpyrimidin-4-yl)piperazin-4-ylcarbonyl)piperazine (700 mg) was stirred in dichloromethane (20 ml) and triethylarnine (1.34 ml) and cooled in an ice-bath. 4-chlorobenzenesulphonylchloride (0.56 g) was added and reaction allowed to warm to room temperature and then stirred overnight. The mixture was evaporated and the residue was purified by chromatography on silica gel using in gradient of dichloromethane to 8% methanol in dichloromethane as eluent to give a foam. This was triturated with diethylether to give 1-(4-chlorophenylsulphonyl)-4-[1-(2-methylpyrimidin-4-yl)piperazin-4-ylcarbonyl]piperazine a colourless solid 1.05 g ;m.p. 183-184° C.; NMR (CDCl3): 8.15 (m, 1H), 7.7 (m, 2H), 7.55 (m, 2H), 6.3 (m, 1H), 3.65 (m, 4H), 3.45 (m, 4H), 3.35 (m, 4H), 3.05 (m, 4H), 2.5 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[C:43]([CH3:45])[N:42]=[CH:41]2)[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH:44]=[C:43]([CH3:45])[N:42]=[CH:41]2)[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Product: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(C#Cc4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)c2)cn1
Yield: 73.7 %

Procedure:
Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G33) (392 mg, 1.2 mmol) and 3-[3-(4-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H7) (300 mg, 1.0 mmol) according to the general procedure K. Obtained as a yellow solid (407 mg).
Reaction SMILES: Cl[C:2](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH:3]([CH3:5])[CH3:4].Cl.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[NH:20][NH2:21].C(N(CC)CC)C>C1COCC1>[NH2:8][C:7]1[N:20]([C:14]2[C:13]([Cl:12])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])[N:21]=[C:2]([CH:3]([CH3:5])[CH3:4])[C:6]=1[C:9]#[N:10]
Reactant: CC(C)C(Cl)=C(C#N)C#N
Reactant: NNc1c(Cl)cccc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1nn(-c2c(Cl)cccc2Cl)c(N)c1C#N
Temperature: 25 °C
Yield: 62.2 %

Procedure:
A solution of (1-chloro-2-methylpropylidene)methane-1,1-dicarbonitrile (9.4 g, 61 mmol) in THF (250 mL) was treated with 2,6-dichlorophenylhydrazine hydrochloride (13.0 g, 61 mmol) followed by triethylamine (12.3 g, 122 mmol). The reaction was then heated to reflux for 18 h. The reaction was then cooled to room temp and partitioned between EtOAc (150 mL) and 1N NaOH (100 mL). The aqueous layer was extracted with EtOAc (2×150 mL) and the combined organic layers were washed with 10% aq. citric acid (150 mL), sat. aq. NaHCO3 (150 mL), and brine (150 mL). The organic layer was dried (MgSO4), filtered, and evaporated. The crude product was recrystallized from EtOAc/hexane to yield the desired pyrazole (11.2 g, 62%).