Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:41][C:38]3[C:39]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Product: COc1ccc2[nH]c(-c3ccc(F)cc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([I:14])[CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20]Br>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:20][CH2:19][CH2:18]2)=[C:4]([I:14])[CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Cl)cc1I
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(Cl)cc2I)CCC1
Reaction time: 0.25 h
Yield: 45.9 %

Procedure:
Ethyl 2-(4-chloro-2-iodophenyl)acetate (3.95 g, 12 mmol) was mixed in DMF (80 mL) in a round bottom flask. NaH (60% dispersion in mineral oil (0.54 g, 13 mmol)) was added, and the reaction mixture was stirred for 15 minutes under a nitrogen atmosphere. 1,3-dibromopropane (1.4 mL, 13 mmol, 1.1 eq) was added via syringe, and the reaction mixture was stirred for 2 hours. An additional 1.10 eq NaH (60% dispersion in mineral oil (0.54 g, 13 mmol)) was added, and the reaction was stirred for 3 hours. The reaction mixture was quenched with water and diluted with EtOAc. The organic layer was separated, washed with water and brine, dried (MgSO4), and concentrated in vacuo to give an orange oil. The crude product was purified by silica flash chromatography (0-30% DCM/hexane) to give the desired compound as a light yellow oil (2.01 g). MS (m/e)=365.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.[CH:25]1([CH2:28][CH2:29]O)[CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1>[CH:25]1([CH2:28][CH2:29][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]3[CH:24]=[CH:23][C:13]4[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=4[CH:11]=3)=[CH:6][CH:7]=2)[CH2:27][CH2:26]1
Reactant: OCCC1CC1
Reactant: CC(=O)NC(C)c1cc2ccc(CCc3ccc(O)cc3)cc2o1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)NC(C)c1cc2ccc(CCc3ccc(OCCC4CC4)cc3)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To a solution of N-(1-{6-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (50.0 mg, 0.154 mmol) obtained in Example 165, 2-cyclopropylethanol (0.0529 mL, 0.616 mmol) and triphenylphosphine (161 mg, 0.616 mmol) in THF (1 mL) were added di(methoxyethyl) azodicarboxylate (144 mg, 0.616 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was directly purified by basic silica gel column chromatography (hexane:ethyl acetate=1:0 to 2:3), and the solvent was evaporated. The residue was triturated with a small amount of diisopropyl ether and hexane to give the title compound (25.9 mg, yield 43%) as a white solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[NH:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10]>>[OH:10][CH2:9][CH2:8][N:7]([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:11][CH2:12][OH:13]
Reactant: OCCNCCO
Reactant: C=CC(=O)OC
Product: COC(=O)CCN(CCO)CCO
Reaction time: 20 h
Yield: 98 %

Procedure:
At 20 to 30° C., 9.01 g of methyl acrylate was added to 10.0 g of diethanolamine. The resulting mixture was allowed to stand for 20 hours. The reaction mixture was concentrated under reduced pressure, whereby N,N-bis(2-hydroxyethyl)-2-(methoxycarbonyl)ethylamine was obtained (yield: 98%).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:16][CH2:15][C:14]4[C:10](=[CH:11][N:12]([CH2:17][CH2:18][N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)[N:13]=4)[C:9]=3[S:26][C:6]=2[N:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[NH2:31].Cl.O1CCOCC1>C(O)(C)C>[Cl:27][C:28]1[CH:29]=[C:30]([NH:31][C:2]2[N:3]=[CH:4][N:5]=[C:6]3[S:26][C:9]4[C:10]5[C:14]([CH2:15][CH2:16][C:8]=4[C:7]=23)=[N:13][N:12]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:11]=5)[CH:32]=[CH:33][C:34]=1[N:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Reactant: CN1CCN(CCn2cc3c(n2)CCc2c-3sc3ncnc(Cl)c23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CN1CCN(CCn2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(N5CCOCC5)c(Cl)c4)c23)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 6-chloro-2-[2-(4-methylpiperazin-1-yl)ethyl]-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazole (50 mg, 0.13 mmol) and 3-chloro-4-morpholinoaniline (82 mg, 0.39 mmol) in isopropanol (3 mL) was added HCl in dioxane (4M, 0.26 mL, 1.03 mmol). The reaction mixture was sealed in a microwave reaction vessel and it was placed in a microwave instrument at 160° C. for 10 min. After it was cooled to room temperature, solvents were evaporated and the residue was dissolved in water/DMF and purified by prep. HPLC. After drying, the TFA salt was neutralized with aq saturated NaHCO3 and extracted with a mixture of CHCl3:isopropanol (3:1). The organic phase was dried over Na2SO4 and concentrated to dryness. The desired product was obtained as a pale solid (40 mg, 55%). 1H-NMR (CD2Cl2) δ 8.43 (s, 1H), 7.84 (d, 1H), 7.53 (m, 2H), 7.08 (m, 2H), 4.20 (t, 2H), 3.86 (m, 4H), 3.37 (t, 2H), 3.11 (t, 2H), 3.04 (m, 4H), 2.80 (t, 2H), 2.53 (m, 4H), 2.43 (m, 4H), 2.26 (s, 3H); LCMS RT=2.29 min; [M+H]+=565.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@@]23C(C)(C)[C@@](C)(CC2)C(=O)O3)=[O:10])=[C:4]([C@@:22]([OH:32])([C:27]#[C:28][CH:29]2[CH2:31][CH2:30]2)[C:23]([F:26])([F:25])[F:24])[CH:3]=1.C(N(CC)CC)C.ClC(OC(Cl)C)=O.C([O-])([O-])=O.[K+].[K+]>O.C(OC)(C)(C)C.CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9](=[O:10])[O:32][C@:22]([C:27]#[C:28][CH:29]3[CH2:31][CH2:30]3)([C:23]([F:24])([F:25])[F:26])[C:4]=2[CH:3]=1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)OC2=O
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A solution of (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10, 30 g, 63.9 mmol), dichloromethane (150 mL) and triethylamine (7.11 g, 70.2 mmol) was stirred at 0-5° C. for 20 minutes, then 1-chloroethyl chloroformate (10.0 g, 70.2 mmol) was added dropwise. The mixture was stirred at 5-10° C. for 1 hour. Then N,N-dimethylformamide (150 mL) was added and further evaporated to 220 mL, then K2CO3 (13.3 g, 95.8 mmol) was added. The reaction mixture was stirred at room temperature overnight. Methyl t-butyl ether (300 mL) and water (200 mL) were added to the mixture, and the resulting layers were separated. The organic layer was washed with brine, and concentrated to 60 mL whereupon petroleum ether (200 mL) was added and stirred. The resulting precipitate was filtered and rinsed with petroleum ether to provide 18.4 g (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-ben zoxazin-2-one (Efavirenz, 1) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:23]([CH:22]=[CH2:21])(=[O:25])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
L-Proline t-butyl ester (6.9 g. 0.04 mol.) and triethylamine (14 ml., 0.1 mol.) are dissolved in 200 ml. of dichloromethane and stirred in an ice bath while 2-chloroethanesulfonyl chloride (8.2 g., 0.05 mol.) in 100 ml. of dichloromethane is added over 20 minutes. After stirring 2 hours, the mixture is washed with 5% potassium bisulfate solution, saturated sodium bicarbonate solution and brine, then evaporated in vacuo. The semi-solid residue is chromatographed on 350 ml. silica gel using 1:1 ethyl acetate/hexane as eluant. The main fraction, comprising N-(vinylsulfonyl)-L-proline t-butyl ester is crystallized from ether/hexane, m.p. 84°-87° (7.1 g., 68%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+]>CN(C=O)C.[OH-].[Na+]>[NH:16]1[C:14]([C:11]2[CH:10]=[N:9][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)=[N:13][CH:12]=2)=[N:15][N:18]=[N:17]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cnc(N2CCC(O)CC2)nc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC1CCN(c2ncc(-c3nnn[nH]3)cn2)CC1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(4-hydroxypiperidin-1-yl)pyrimidine-5-carbonitrile (2 g, 9.79 mmol), sodium azide (0.955 g, 14.69 mmol) and ammonium chloride (1.048 g, 19.59 mmol) in DMF (24.48 mL) was heated at 130° C. for 1 h. The mixture was cooled to RT, diluted with 1N NaOH (5 mL), washed Et2O (2×10) mL. The aqueous layer was acidified to pH about 1 with 2 N HCl and placed in the refrigerator for 1 h. The solid was filtered and washed with water followed by Et2O. The solid was dried under high vacuum to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3I)[C:5]2=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].C[N:40]([CH3:46])[CH2:41][CH2:42][N:43](C)C.N1C=CN=C1>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[N:40]3[CH:41]=[CH:42][N:43]=[CH:46]3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Cl)ccc2I)N1
Reactant: CN(C)CCN(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Cl)ccc2-n2ccnc2)N1
Temperature: 170 °C
Yield: 5.9 %

Procedure:
A solution of racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-chloro-2-iodophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.3 g, 0.5 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added Cs2CO3 (1.2 g, 4 mmol) (Aldrich), CuI (95 mg, 0.5 mmol) (Aldrich), N,N,N′,N′-tetramethylethylenediamine (0.2 mL, 2 mmol), and imidazole (80 mg, 1 mmol). The mixture was heated under nitrogen at 170° C. for 0.5 h. The mixture was cooled to room temperature, partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:MeOH=9: 1) to give a crude product 997 mg), which was further purified by RP-HPLC to give racemic(2′R, 3R, 4′S)-6-chloro-2′-(5-chloro-2-imidazol-1-yl-phenyl)-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 16 mg).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>N1C=CC=CC=1.CN(C)C=O>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][N:17]=[C:16]2[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)C(c1cccc(Br)c1)c1ncnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 17.9 %

Procedure:
To a solvent mixture of pyridine (75 ml) and dimethylformamide (3 ml) at 0(C was added with 11.5 grams of sodium hydride (50% oil suspension). The mixture was stirred for another 20 minutes, added with 25 grams of methyl 3-bromophenylacetate, stirred for another 30 minutes and added with 21 grams of 4-chloro-6,7-dimethoxyquinazoline. The mixture was added with another 50 ml of pyridine and 50 ml of tetrahyudrofuran and stirred at room temperature for 2 hours. The mixture was then poured into 1200 ml of ice water mixture and extracted with ethyl acetate. The ethyl acetate layer was then washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude was then purified on a silica gel column with dichloromethane and methanol as the solvent to provide 7 grams of 6,7-dimethoxy-4-[1-(3-bromophenyl)-1-methoxycarbonylmeth yl] quinazoline as a white solid. M. P. 167-168° C. Alternatively, the reaction can be carried with bases such as sodium amide, lithium diisopropylamide or potassium bis(trimethylsilyl)amide in solvents such as tetrahydrofuran or dimethylforamide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:15]([CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:7]=1)([O:17][CH3:18])=[O:16]
Reactant: CC(=O)CCc1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CCC(C)=O)cc1
Yield: 82.6 %

Procedure:
A solution of 4-(4-hydroxyphenyl) butan-2-one (16.4 g), methyl bromoacetate (15.3 g, 8.5 ml), potassium carbonate (13.8 g) and a trace of potassium iodide in acetone (200 ml) was heated under reflux for 16 hours. The solution was filtered, evaporated and the residue dissolved in ether. The ether solution was shaken successively with 2 N sodium hydroxide solution, water, dried (MgSO4) and evaporated to give the title compound as an oil (19.5 g).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[C:6]1([PH+:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:25](=O)(OC)OC>>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:25][P+:12]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)OC
Agent: F[B-](F)(F)F
Product: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
In a reactor wherein air was replaced by N2, 300.0 g of (1.1 mol) triphenyl phosphine and 500 mL of methanol were added and cooled to 10° C. by a ice-bath. 250.8 g (1.1 mol) of fluoroboric acid aqueous solution (40 wt %) was then added dropwise under strong stirring. After one hour of reaction, the reaction temperature was increased to about 50° C., and the unreacted materials as well as the solvents, including water and methanol, were removed by distillation under vacuum to obtain triphenylphosphonium tetrafluoroborate. The phosphonium salt was then transferred to an autoclave, and 202.0 g (2.2 mol) of dimethyl carbonate was also introduced. After 6 hours of reaction at temperature of 160° C. and at pressure of from 1.4 MPa to 1.5 MPa, the crude product was obtained after distilling off the unreacted materials and solvent. 375.0 g of methyl triphenyl phosphonium tetrafluoroborate was obtained after washing and drying at 60° C. and 0.1 kPa for 4 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[N:31][CH:30]=[N:29]1)[C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:27]([N:28]4[CH:32]=[N:31][CH:30]=[N:29]4)=[C:19]([F:18])[CH:20]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: O=C(O)c1ccc(-n2cncn2)c(F)c1
Product: O=C(c1ccc(-n2cncn2)c(F)c1)N(C1CC1)C1CCN(c2ncc(Cl)cn2)CC1

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 3-fluoro-4-[1,2,4]triazol-1-yl-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.00 min; Mass spectrum (ESI+): m/z=442 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[O:33]1[C:37]([C:38](O)=[O:39])=[CH:36][N:35]=[CH:34]1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:38]([C:37]3[O:33][CH:34]=[N:35][CH:36]=3)=[O:39])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: O=C(O)c1cnco1
Product: Cc1c(N2CCN(C(=O)c3cnco3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure Q using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (40.0 mg, 0.09 mmol) and oxazole-5-carboxylic acid to give (4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazin-1-yl)(oxazol-5-yl)methanone. 1H NMR (DMSO-d6) δ ppm 2.11 (s, 3H), 3.06 (br s, 4H), 3.33-3.39 (m, 4H), 3.69 (br s, 4H), 3.86 (br s, 4H), 6.52 (s, 1H), 7.15-7.20 (m, 1H), 7.28-7.30 (m, 1H), 7.53 (s, 1H), 7.78 (br s, 2H), 8.38 (s, 1H), 8.59 (s, 1H). Mass Spectrum (ESI) m/e=535.9 (M+1).
Reaction SMILES: C(SC1C=CC2N=C(NC(OC)=O)NC=2C=1)CC.[N+:19]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24])([O-:21])=[O:20].[S-:29][C:30]#[N:31].[NH4+].BrBr.[Br-].[Na+].CCCBr.[C-]#N.[Na+]>CO.[Cl-].C[N+](CCCC)(CCCC)CCCC.C(Cl)Cl.C(O)CC>[S:29]([C:27]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([N+:19]([O-:21])=[O:20])[CH:28]=1)[C:30]#[N:31]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: N#C[S-]
Agent: BrBr
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: CCCSc1ccc2nc(NC(=O)OC)[nH]c2c1
Solvent: CCCBr
Solvent: CO
Solvent: ClCCl
Product: N#CSc1ccc(N)c([N+](=O)[O-])c1
Yield: 58 %

Procedure:
Preparation of methyl 5-propylthio-2-benzimidazole carbamate--4-Thiocyano-2-nitroaniline was prepared as described in Example I using 13.8 g of o-nitroaniline and 18.3 g of ammonium thiocyanate dissolved in 80 ml of methanol and adding 17.6 g of bromine in 10 ml of methanol saturated with sodium bromide. After work up and filtering a wet cake of crude product weighing 44 g was obtained. This wet cake along with 32.5 g of n-propanol, 66.4 g of n-propyl bromide, 1.41 g of an aqueous solution of 75% methyl tributyl ammonium chloride, 104.6 g of an aqueous solution of 25% sodium cyanide and 175 ml of methylene chloride was refluxed with moderate agitation for 5 hours as described in Example III. The phases were separated, the volatile components were evaporated and the crude 4-propylthio-2-nitroaniline was added to a flask containing 88.2 g of sodium sulfide nonahydrate and 175 ml of water. The reaction mixture was refluxed for 13 hours as described in Example IV. After work up the methanol solution of crude 4-propylthio-o-phenylenediamine was added to the sodium salt of methyl cyanocarbamate which was prepared as in Example V from 4.35 g of cyanamide, 11.1 g of methyl chloroformate and 14.4 g of 50% aqueous sodium hydroxide. As in Example V, the methanol was removed, the pH was maintained at 4, the product was filtered and washed with water and acetone and allowed to air dry. The weight of crude dry product was 17.2 g which assayed 90% methyl 5-propylthio-2-benzimidazole carbamate, 58% yield from o-nitroaniline.
Reaction SMILES: [CH:1]([C:3]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1)=O.[C:18]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH:5]1[C:4]2[C:3]3([CH2:1][N:27]4[CH2:26][CH2:25][CH:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH2:29][CH2:28]4)[CH2:17][CH:10]([C:11]4[C:16]3=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=CC12CC(c3ccccc31)c1ccccc12
Reactant: c1ccc(C2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(C2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a methanol solution (80 mL) of 9-formyl-9,10-dihydro-9,10-methanoanthracene (described in example 5a) (5.00 g, 22.7 mmol) was added a large excess of freshly activated 3 A molecular sieves (approx. 10 g) under an atmosphere of nitrogen. 4-Phenylpiperidine (4.57 g, 28 mmol, 1.25 eq) was added followed by four portions of sodium cyanoborohydride (1.43 g, 22.7 mmol) over 1.3 h. The resulting suspension of sieves and reagents was stirred for 3 days at room temperature. The reaction was treated with 2.5N NaOH (100 mL) and the aqueous phase was extracted with ethyl acetate (1×400 mL). The organic phase was washed with water (3×100 mL), dried over anhydrous sodium sulfate, filtered and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (300 mL, eluent: 50% methylene chloride in hexane) to recover 1.20 g (15%) of the title compound. TLC analysis (Rf 0.19, 50% methylene chloride in hexane). 1H NMR (CDCl3, 300 MHz) 7.22 (m, 9H), 6.93 (m, 4H), 4.27 (s, 1H), 3.43 (s, 2H), 3.13 (m, 2H), 2.62 (d, J=1.4 Hz, 2H), 2.51 (m, 1H), 2.34 (m, 2H), 1.76 (m, 4H) MS (CI, CH4) m/z 366 (M+1,100), 394 (M+29,16). The free base was dissolved in the minimum of methanol and chloroform, acidified with ethereal HCl and the resulting hydrochloride salt precipitated with ether dilution. The solid was filtered, rinsed with fresh ether, and dried in vacuo (50° C., 10 pascal, 18 h) to yield a solid, mp >300° C.