Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH2:15]([S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:16][CH3:17]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([S:18]([CH2:15][CH2:16][CH3:17])(=[O:20])=[O:19])=[CH:29][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CCCS(=O)(=O)c1ccc(C(=O)O)cc1
Product: CCCS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
1 g of 4-fluorobenzonitrile was used in Procedure Q with 1-propanethiol to afford 4-(propylthio)benzonitrile. 860 mg of 4-(propylthio)benzonitrile was reacted via Procedure T to give 4-(propylthio)benzoic acid. 700 mg of 4-(propylthio)benzoic acid was reacted via Procedure R to give 4-(propylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(propylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(propylsulfonyl)benzamide. MS (Q1) 415.0 (M)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1.S(OC)(O[CH3:27])(=O)=O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]([C:13]2[N:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[N:18]=2)([CH3:27])[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1cc(OC)nc(C(C#N)c2cccc(Cl)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(C(C)(C#N)c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
Sodium hydride (0.83 g of 80% in oil) was added to a stirred solution of the product of Example 48 (8.0 g) in dimethylformamide at room temperature. Dimethyl sulphate (3.5 g) was then added, and the mixture was stirred at room temperature for 4 hours. The mixture was poured onto water (250 ml), and the oil was extracted into ethyl acetate. The combined extracts were dried over magnesium sulphate, and evaporated to give an orange liquid, which was purified by chromatography to give 5.2 g of the desired product as a white solid, mp 89°-93° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].C1(C)C=CC=CC=1.[C:15]([CH:17]1[CH2:19][NH:18]1)#[N:16].C>C(OCC)(=O)C>[Cl:1][CH2:2][C:3]([NH:5][C:6]([N:18]1[CH2:19][CH:17]1[C:15]#[N:16])=[O:7])=[O:4]
Reactant: O=C=NC(=O)CCl
Reactant: N#CC1CN1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#CC1CN1C(=O)NC(=O)CCl

Procedure:
A solution of 36 g. chloroacetyl isocyanate in 100 ml. toluene is added dropwise, while stirring and cooling, at a temperature of 20° to 30° C. to 20.4 g. 2-cyanoaziridine dissolved in 200 ml. toluene. The resulting suspension is further stirred for 1 hour at ambient temperature, then filtered with suction. The solid material obtained is washed with toluene and triturated with diethyl ether to give 62 g. of crude product. This is introduced into about 2.5 to 3 liters ethyl acetate at a temperature of 60° C., boiled for a short time and the clear solution treated with active charcoal. After filtration, the clear and still hot filtrate is evaporated in a vacuum and the evaporation residue is triturated with anhydrous diethyl ether and dried for 1 hour at 70° C. There are obtained 39.3 g. of product with a melting point of 152°-155° C. After further purification by stirring for 5 minutes with 200 ml. ethyl acetate at 60° C. and trituration of the crystals obtained with diethyl ether, there are obtained, after drying in a vacuum at 70° C. 28.9 g. 1-(N-chloroacetyl-carbamoyl)-2-cyanoaziridine; m.p. 152°-155° C.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:38])C(=O)C1>CN(C=O)C>[Br:38][CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC/C=C/CCCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCC/C=C/CCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of trans-dec-4-en-1-ol (1.52 g, 9.74 mmol) in DMF (25 mL) was added triphenylphosphine (2.81 g, 10.7 mmol). The solution was cooled to 0° C. and NBS (1.85 g, 10.4 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (1 mL). The solution was diluted with ether (100 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford trans-1-bromo-dec-4-ene (1.60 g, 75%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.49 (1H, m), 5.35 (1H, m), 3.42 (2H, t, J=6.6 Hz), 2.15 (2H, m), 1.96 (4H, m), 1.29 (6H, m), 0.90 (3H, t, J=7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 132.36, 127.89, 33.61, 32.80, 32.73, 31.65, 31.14, 29.45, 22.82, 14.36.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:9]=[C:10]([CH3:20])[N:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:12]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:11]2[CH:12]=[C:8]([CH2:7][OH:6])[N:9]=[C:10]2[CH3:20])=[CH:18][CH:17]=1
Reactant: Cc1nc(C(C)(C)O[SiH2]C(C)(C)C)cn1-c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(CO)cn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole (14.7 g, 45.7 mmol) was dissolved in 200 mL THF. Tetrabutyl ammoniumfluoride (91 mL, 1M in THF, 91 mmol) was added and the reaction mixture was stirred at RT overnight. The solvent was evaporated. The residue was taken up in 200 mL water and extracted three times with ethyl acetate (200 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was suspended in 150 mL ethyl acetate, filtered and dried. The desired compound was obtained as a white solid (7.16 g, 76%), MS: m/e=207.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(=O)([O-])O.[Na+].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37](ON3C(=O)CCC3=O)=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]([OH:15])=[O:14])[C:37]([O:36][CH2:35][CH:33]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:34]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:38])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)NCCNCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCN(CC(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 20 h

Procedure:
10.9 g (50 mmol) of N-(2-tert-butoxycarbonylaminoethyl)aminoacetic acid are stirred together with 50 ml of water, 11.3 g (135 mmol) of sodium hydrogen carbonate and 50 ml of tetrahydrofuran. Subsequently, 24.3 g (72 mmol) of N-(9-fluorenylmethoxycarbonyloxy)succinimide are added. The mixture is stirred at room tmeperature for 20 h and the salt removed by filtration; the filtrate is acidified and the phases separated, and the organic phase is then concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].C([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH:33]1[CH3:38])(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:35]2[CH2:36][CH2:37][NH:32][CH:33]([CH3:38])[CH2:34]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27]
Reactant: CC(C)N1CCNCC1C
Reactant: O=Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Product: CC1CN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CCN1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carbaldehyde (INTERMEDIATE AAA 1) and 1-isopropyl-2-methylpiperazine as described in EXAMPLE AAA1, STEP A. 1H NMR (CDCl3, 500 MHz): δ 0.90 (brs, 3H), 0.93 (brs, 3H), 0.98 (brs, 3H), 1.92 (brs, 1H), 2.16 (brs, 1H), 2.31 (brs, 1H), 2.57 (m, 2H), 2.67 (brs, 1H), 3.21 (brs, 1H), 3.40 (s, 2H), 4.22-4.485 (m, 2H), 5.05 (s, 1H), 6.17 (s, 1H), 6.85 (d, 1H, J=3.7 Hz), 7.30-7.60 (m, 7H). MS (API-ES+): 559 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CCOC(=O)Cc1ccc(C)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(C)c(O)c1
Temperature: -78 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
step 3—To a solution of 4c (2.2 g; 8.0 mmol) and 250 mL CH2Cl2 cooled to −78° C. was added dropwise via syringe BBr3 (9.8 mL; 0.104 mol). After 1 h at −78° C. the reaction was stirred for 4 h in an ice-water bath. The reaction mixture was recooled to −78° C. and the reaction quenched aqueous NaHCO3 then warmed to rt and the organic phase washed with water, saturated NaHCO3 and brine. The organic phase was dried (MgSO4) and the solvent evaporated to afford 1.4 g of ethyl 3-hydroxy-4-methylphenylacetate (6).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][C:15]([CH3:17])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(O)(C(F)(F)F)=O>[CH3:14][C:15]1([CH3:17])[O:1][C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4](=[O:6])[O:5]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)c2cc([N+](=O)[O-])ccc2O1
Reaction time: 1 h
Yield: 89.3 %

Procedure:
A mixture of 2-hydroxy-5-nitrobenzoic acid (50.0 g. 0.27 mol), acetone (40 mL, 0.54 mol) and trifluoroacetic anhydride (100 mL, 0.71 mol) in TFA (300 mL) was heated at reflux. After 1 hour, a supplementary amount of acetone (60 mL, 0.82 mol) was added and the reaction mixture was refluxed for 48 hours. The solvents were evaporated under reduced pressure. The residual brown solid was dissolved in DCM (800 mL) and washed with a mixture of saturated aqueous NaHCO3 (400 mL) and water (400 mL). The aqueous layer was extracted with DCM (2×400 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The residual brown oil was taken up in cold pentane (300 mL, 0° C.) and a yellow solid precipitated off. Filtration and washing with pentane gave 53.8 g (88%) of the title compound as a yellow solid. HPLC, Rt: 2.9 min (purity: 99.8%). 1H NMR (CDCl3) δ: 8.88 (d, J=2.8 Hz, 1H), 8.44 (dd, J=9.0, 2.8 Hz, 1H), 7.14 (d, J=9.0 Hz, 1H), 1.80 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([O:10]C)=O.[OH-].[Na+].Cl.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1>CO.O>[NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH:44][CH2:43][C:42]1[CH:45]=[CH:46][C:39]([O:38][CH3:37])=[CH:40][CH:41]=1)=[O:10]
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1sc(Br)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CO
Product: COc1ccc(CNC(=O)c2sc(Br)cc2N)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 84.2 %

Procedure:
To a solution of methyl 3-amino-5-bromothiophene-2-carboxylate (1.2 g, 5.08 mmol) in MeOH (15 mL) was added sodium hydroxide (0.61 g, 15.2 mmol) and water (5 mL). After stirring at 60° C. for 5 h, 6 M HCl (1.58 mL) was added to the mixture to adjust the pH to 10. After removal of the solvent at reduced pressure, the residue was dissolved in DMF (35 mL). Then, 1-hydroxybenzotriazole (4.1 g, 30.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.7 g, 30.5 mmol) and 4-methoxybenzyl amine (3.76 mL, 25.4 mmol) were added. After stirring at room temperature for 17 h, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 90:10 hexane/EtOAc to 50:50 hexane/EtOAc) to give the title compound (1.46 g, 84%) as a yellow gum:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Na+].[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.CCN(CC)CC.[NH4+].[OH-]>O1CCOCC1.CS(C)=O.[Cl-].[Na+].O.CC([O-])=O.CC([O-])=O.[Cu+2].CCOC(C)=O>[F:15][C:16]([F:27])([F:28])[O:17][C:18]1[CH:23]=[C:22]([S:11]([C:8]2[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=2)(=[O:13])=[O:12])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)Nc1ccc(S(=O)[O-])cc1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)c2cccc(OC(F)(F)F)c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 57.9 %

Procedure:
To a solution of sodium 4-acetamidobenzenesulfinate dehydrate (128 mg, 0.5 mmol), 3-trifluoromethoxy-phenylboronic acid (144 mg, 0.75 mmol) and Et3N (0.313 mL, 2.25 mmol) in 1,4-dioxane (4 mL) and DMSO (4 mL) is added Cu(OAc)2 (114 mg, 0.625 mmol). The mixture is heated at 60° C. for 16 h then cooled to ambient temperature. EtOAc (12 ml) and brine (6 ml) is added followed by concentrated NH4OH (0.6 mL) and the mixture is stirred at ambient temperature for 15 min. The layers are separated and the aqueous layer is extracted with EtOAc (6 mL). The combined extracts are dried (Na2SO4) and evaporated. The residue is purified by preparative TLC with 2:1 EtOAc/hexanes to give 104 mg (57%) white solid.
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=O)[CH3:2].CO.C[O-].[Na+].I[CH2:26]CC>C1COCC1.CO>[CH2:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:2][CH3:26]
Reactant: CC(=O)SC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CCCI
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCSC1CCN(c2ccc(N)cc2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-acetylthiopiperidin-1-yl)nitrobenzene (3.34 g) in a mixture of THF (30 ml) and methanol (30 ml) was added 28% sodium methoxide methanol solution (2.67 ml) at 0-5° C. and stirred at the same temperature for 30 minutes. To the mixture was added iodopropane (1.51 ml) at the same temperature and stirred at ambient temperature for 2 hours. The reaction mixture was evaporated in vacuo and dissolved in ethyl acetate (100 ml). The solution was washed three times with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. A solution of the resulting residue, ammonium chloride (1.0 g) and iron powder (4.0 g) in a mixture of ethanol (60 ml) and water (30 ml) was refluxed for 2 hours. The reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (300 ml) eluting with ethyl acetate. The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-(4-propylthiopiperidin-1-yl)aniline (2.47 g).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH3:36])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[CH:28][C:29]([S:32]([NH:35][CH3:36])(=[O:33])=[O:34])=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 4-bromo-N-methyl-benzenesulfonamide (example B.27) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (300 mg, 58%). MS (ISP) 508.3 [(M+H)+]; mp 202-203° C.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]2[N:7]([CH2:15][CH2:16][NH:17][C:18](=O)[CH3:19])[CH:6]=[CH:5][C:4]=2[CH2:3]1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:1][CH:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]2[N:7]3[CH2:15][CH2:16][N:17]=[C:18]([CH3:19])[C:6]3=[CH:5][C:4]=2[CH2:3]1
Reactant: CC(=O)NCCn1ccc2c1-c1ccccc1C(C)C2
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CC1=NCCn2c1cc1c2-c2ccccc2C(C)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
N-[2-(4,5-Dihydro-5-methyl-1H-benzo[g]indol-1-yl)ethyl]acetamide (5.0 g) was treated with 20 ml of phosphorus oxychloride under argon and the mixture was stirred at 100° C. for 30 minutes. The cooled mixture was added to 2000 ml of ice-water and treated with 200 ml of 28% sodium hydroxide solution. The mixture was extracted once with 300 ml of methylene chloride and twice with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. 4.6 g of residue were chromatographed on 200 g of silica gel with methylene chloride/methanol mixtures (49:1 to 9:1) as the eluent. Of the crude product, 3.9 g of brown oil, 1.9 g were dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. After concentration to 10 ml and addition of 10 ml of ethanol and 70 ml of ethyl acetate there separated ochre-yellow crystals which were recrystallized from an ethanol/ethyl acetate mixture (1:2, 30-fold amount). There were obtained 1.7 g (43%) of 5,6,10,11-tetrahydro-5,8-dimethylbenzo[g]pyrazino[1,2-a]indole fumarate (2:3); m.pt.: 156°-157° C. (dec.).
Reaction SMILES: I[C:2](=[CH:7][O:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11].C(N(CC)CC)C>CN(C=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:9][O:8][CH:7]=[C:2]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C#C[Si](C)(C)C
Reactant: COC=C(I)C(=O)OC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC=C(C#C[Si](C)(C)C)C(=O)OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of compound 37-g (30 g, 124 mmol), ethynyltrimethylsilane (24.3 g, 248 mmol), triethylamine (37.6 g, 372 mmol), copper(I) iodide (2.35 g, 6.2 mmol), Pd(dppf)Cl2 (2.50 g) in DMF (300 mL) was stirred overnight at 80° C. The reaction mixture was cooled to room temperature, poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (PE:EA=1:5) to afford compound 37-h (15 g, 57%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.671 (s, 1H), 3.977 (s, 3H), 3.763 (s, 3H), 0.234 (s, 9H); LC-MS (ESI): 213 [M+H]+.
Reaction SMILES: [F:1][CH2:2][CH:3]1[N:8]([CH3:9])[CH2:7][CH2:6][N:5]([C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=2)[CH2:4]1.Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:24][C:22]1[CH:23]=[C:18]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([N:5]3[CH2:6][CH2:7][N:8]([CH3:9])[CH:3]([CH2:2][F:1])[CH2:4]3)=[CH:15][N:14]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CN1CCN(c2ccc(N)nc2)CC1CF
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1CF
Temperature: 25 °C
Yield: 53.6 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (60 mL), 336f (crude, 14.1 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (4.5 g, 16.9 mmol), and cesium carbonate (11.5 g, 35.2 mmol). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (820 mg, 1.41 mmol) and tris(dibenzylideneacetone)dipalladium(0) (645 mg, 0.7 mmol) were added. After three cycles of vacuum/argon flash, the reaction mixture was heated at reflux for 15 h. The reaction was cooled to room temperature, filtered and concentrated to afford a black solid, which was purified by column chromatography eluting with methylene chloride/methanol (from 100:1 to 50:1) to afford 336g as a yellow solid (3.1 g, 50%). MS: [M+H]+ 410.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[C:5]([C:4]1[CH:7]=[CH:8][N:9]=[C:2]([NH:1][S:11]([CH3:10])(=[O:13])=[O:12])[CH:3]=1)#[N:6]
Reactant: N#Cc1ccnc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(C#N)ccn1
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
A solution of 2-amino-isonicotinonitrile (1 g, 8.4 mmol) and methanesulfonyl chloride (0.716 mL, 9.2 mmol) in pyridine (10 mL) is stirred at room temperature for 12 hours. The mixture is poured onto ice and stirred for 20 min. The mixture is filtered and washed with water (100 mL), followed by diethyl ether (100 mL). The solid is dried in vacuo to afford N-(4-cyanopyridin-2-yl)-methanesulfonamide (1.1 g, 66%). MS: 198 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 3.32 (s, 3H), 7.27 (s, 1H), 7.48 (d, J=5.1 Hz, 1H), 8.53 (d, J=5.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17]O)[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)=[C:4]([I:9])[CH:3]=1
Reactant: CN1CCC(CO)CC1
Reactant: Oc1ccc(Cl)cc1I
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCC(COc2ccc(Cl)cc2I)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a stirred solution of 4-chloro-2-iodophenol (1.72 g, 6.75 mmol) in anhydrous THF (10.0 mL) were sequentially added (1-methylpiperidin-4-yl)methanol (1.31 g, 10.14 mmol) and triphenyl phosphine (2.66 g, 10.14 mmoL). The reaction mixture was cooled to 0° C., and to it diisopropyl-azodicarboxylate (1.96 mL, 10.14 mmol) was added in drop wise manner. After the addition was over, stirring continued for another 0.5 h at 0° C. and then for 12 h at room temperature. Solvents were removed in vacuum and the residue was purified by silica gel column chromatography, providing Compound 173 (1.85 g, 75%).