Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([CH:5]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:7]([C:21]#[N:22])[CH2:6]1)=[O:4].[NH2:23][NH2:24].[Cl-].[Na+].C(Cl)Cl>C(Cl)(Cl)Cl>[C:21]([N:7]1[C@H:8]2[C:18]([C:17]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:20]=3[C:10]([CH2:9]2)=[CH:11][NH:12]4)=[CH:19][CH:5]([C:3]([NH:23][NH2:24])=[O:4])[CH2:6]1)#[N:22]
Reactant: NN
Reactant: COC(=O)C1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C#N)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: N#CN1CC(C(=O)NN)C=C2c3cccc4[nH]cc(c34)C[C@H]21

Procedure:
950 mg of 6-cyano-9,10-didehydroergolinecarboxylic acid methyl ester (3.2 mmol) is dissolved in 100 ml of chloroform and 18 ml of anhydrous hydrazine and stirred for one hour in an ice bath and for 3 hours at room temperature. The mixture is distributed between saturated sodium chloride solution and methylene chloride; the organic phase is washed with water, dried with magnesium sulfate, and evaporated (crude product 739 mg). The product is chromatographed on silica gel with methylene chloride, ethyl acetate, and methanol, yielding the pure 6-cyano-9,10-didehydroergolinecarboxylic acid hydrazide. A solution of 950 mg (3.2 mmol) of this hydrazide in 100 ml of tetrahydrofuran is cooled in an ice bath and combined in succession with 11 ml of a saturated solution of hydrogen chloride in toluene (about 0.7N), 3.5 ml of a 1N lithium nitrite solution in tetrahydrofuran, and 22 ml of the above hydrogen chloride solution. Under ice cooling, the mixture is agitated for 20 minutes, then diluted with 140 ml of dioxane, and heated for 30 minutes in an oil bath preheated to 80° C. After cooling in an ice bath, 20 ml of 0.2N hydrochloric acid is added thereto, the mixture is allowed to stand for 20 minutes and evaporated to dryness. The residue is made into a solution with a small amount of methanol, distributed between chloroform and sodium bicarbonate, the aqueous phase is washed with chloroform, the organic phase respectively several times with water, dried with magnesium sulfate, and evaporated. 1.0 g of the crude 8-amino-6-cyano-9,10-didehydroergoline is dissolved in 15 ml of pyridine, combined with 0.6 ml of acetyl chloride, and ice is added after one hour; the mixture is distributed between saturated bicarbonate solution and methylene chloride; the organic phase is dried and evaporated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=O)=[CH:4][CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[CH:12]1([NH:15][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=C(O)Cc1ccc(F)cc1
Product: Fc1ccc(CCNC2CC2)cc1

Procedure:
Synthesized according to typical procedures C and D from (4-fluorophenyl)acetic acid and cyclopropylamine.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[N:14]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)N[C@@H]2CCCC[C@H]2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@@H]2CCCC[C@H]2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
To a solution of 1.146 g (3.1 mmol) of the product from Example 3 in 31 mL of DMF was added 0.137 g (3.42 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 min at 25° C. and then 0.42 mL (3.50 mmol) of benzyl bromide was added all at once. This reaction mixture was stirred for 10 hr at 55° C. and then poured into water and extracted with ether. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide a white solid which was recrystallized from EtOAc/Hexanes to provide 1.364 g (95%) of the desired product. 1H NMR(CDCl3): 7.7 ppm (dd, 2H, Ar), 7.1-7.4 (m, 5H, Ar), 6.9 ppm (dd, 2H, Ar), 4.5-4.7 ppm (AB quartet, 2H, CH2 --Ar), 3.9 ppm (s, 3H, OMe), 4.0 ppm (m, 1H, N--CH), 2.9 ppm (m, 1H, CH--CO2 --), 1.0-2.3 ppm (m, 17H, hydrocarbon protons).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]([NH:18][C:19]2[NH:23][N:22]=[C:21]([CH:24]3[CH2:26][CH2:25]3)[CH:20]=2)[N:12]=1.[F:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35]([C@:37]2([CH3:42])[CH2:41][CH2:40][CH2:39][NH:38]2)=[O:36])=[CH:30][CH:29]=1>C1COCC1>[Cl:17][C:15]1[N:14]=[C:13]([NH:18][C:19]2[NH:23][N:22]=[C:21]([CH:24]3[CH2:26][CH2:25]3)[CH:20]=2)[N:12]=[C:11]([N:38]2[CH2:39][CH2:40][CH2:41][C@@:37]2([CH3:42])[C:35]([NH:34][C:31]2[CH:32]=[N:33][C:28]([F:27])=[CH:29][CH:30]=2)=[O:36])[N:16]=1
Reactant: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
Diisopropylethylamine (0.77 mL, 4.42 mmol) was added to a mixture of 4,6-dichloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-1,3,5-triazin-2-amine (800 mg, 2.95 mmol) and (S)—N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide (625 mg, 2.8 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature overnight and the product was separated by preparative HPLC. Removal of the solvents furnished 1C (860 mg, 64%) as a TFA salt. LC/MS [M+H]+: 458; Ret time (Method F): 2.70 min.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:9](=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12].N1C=CN=C1.[OH-].[Na+]>CN(C=O)C.C1CCCCC1.CC(=O)OCC>[Si:1]([O:12][C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[CH:9]=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1C=O
Temperature: 25 °C

Procedure:
13.58 g (90.07 mmol) of t-butyidimethylsilyl chloride (TBDMSCl) were added to a solution of 10.00 g (81.89 mmol) of salicylaldehyde and 6.13 g (90.07 mmol) of imidazole in 82 ml of DMF. The mixture was stirred at room temperature and the reaction was monitored by thin-layer chromatography (cyclohexane/EA 10:1). 1 N NaOH was added, and the mixture was extracted with petroleum ether. The combined organic phases were dried over Na2SO4, the solvent was removed and the product was purified chromatographically (silica gel, cyclohexane/EA 10:1). This gave 16.94 g (87.5%) of a clear liquid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([CH:22]([CH3:24])[CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH:22]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](=[O:14])[CH2:12][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=1)=[O:34])([CH3:24])[CH3:23]
Reactant: CC(C)N(C(=O)CN(C(=O)CN)c1ccccc1)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(c2ccccc2)C(C)C)c2ccccc2)c1
Yield: 36.3 %

Procedure:
The procedure is analogous to that described in Example 81, but 0.6 g of 2-(2-amino-N-phenylacetamido)-N-isopropyl-N-phenylacetamide and 0.24 g of 3-methylphenyl isocyanate are used as the starting material. The crude product obtained is purified by chromatography on 30 g of silica (0.065-0.200 mm) contained in a column 1.5 cm in diameter [eluent: dichloromethane/ethyl acetate (80/20 by volume)], collecting 20 cm3 fractions. Fractions 6 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from diethyl ether, 0.3 g of N-isopropyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}-N-phenylacetamide melting at 170° C is obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[S:12]([OH:15])(=O)=[O:13].P(Cl)(Cl)(Cl)(Cl)[Cl:17].Cl>>[Br:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[S:12]([Cl:17])(=[O:15])=[O:13]
Reactant: O=S(=O)(O)c1c(F)c(F)c(F)c(F)c1Br
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Product: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1Br
Reaction time: 0.33 h
Yield: 88.1 %

Procedure:
1-Bromo-2,3,4,5-tetrafluorobenzene (5.0 g, 21.8 mmol) was mixed at ambient temperature with 20% fuming sulfuric acid (20 mL). The mixture was heated at 40° C. for 3 h and at 110° C. for 2 h. The reaction mixture was allowed to cool to ambient temperature and poured onto 12 g of crushed ice. The mixture was acidified dropwise with concentrated HCl (2 mL) until a solid, consisting mostly of 2-bromo-3,4,5,6-tetrafluorophenylsulfonic acid was formed. The solid was filtered, washed with 12N HCl, and dried under-high vacuum to afford 5.3 g of 2-bromo-3,4,5,6-tetrafluorophenylsulfonic acid as a white hygroscopic solid that was used without further purification. To the sulfonic acid (3.0 g, 9.7 mmol) was then added phosphorous pentachloride (8.0 g, 38.4 mmol) in small portions, at ambient temperature (Caution: exothermic reaction with significant evolution of HCl). The reaction was allowed to stir for 20 minutes after the final addition of phosphorous pentachloride. The reaction mixture was then poured onto crushed ice and the white solid that formed was filtered and dried to afford 2.8 g of the title compound, which was used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])C=CC=CC=1.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[CH:38]=O>C1(C)C=CC=CC=1>[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[CH:38]=[CH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C=Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a suspension of tert-butyl triphenylphosphoranediylacetate (8.82 g, 23.4 mmol) in toluene (15 mL) was added a solution of 2-naphthaldehyde (2.82 g, 18.0 mmol) in toluene (15 mL). The mixture was stirred at room temperature for 18 hr and filtered. The filtrate was concentrated, subjected to silica gel column chromatography (ethyl acetate/hexane=1/30) and recrystallized (acetonitrile/water=1/2) to give the title compound as a colorless paste (4.1 g, yield 91%), melting point: 74-75° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][C:13](=O)[C:12](=[CH:17]N(C)C)[CH2:11]2)[CH:5]=1.[C:22](=O)(O)O.[NH2:26][C:27]([NH2:29])=[NH:28].O.O.O.C([O-])(=O)C.[Na+]>CCO>[CH2:1]([O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][C:13]3[N:28]=[C:27]([NH2:29])[N:26]=[CH:17][C:12]=3[CH2:11]2)[CH:5]=1)[CH3:22]
Reactant: O=C(O)O
Reactant: N=C(N)N
Reactant: COC(=O)c1cccc(N2CCC(=O)C(=CN(C)C)C2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cccc(N2CCc3nc(N)ncc3C2)c1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
A solution of methyl-3-(3-dimethylaminomethylene-4-oxopiperidin-1-yl)-benzoate (1.52 g, 5.27 mmol) in EtOH (100 mL) was treated with guanidine carbonate (3.80 g, 21.08 mmol), followed by addition of sodium acetate trihydrate (5.74 g, 42.16 mmol). The reaction mixture was refluxed for 15 hours and the solvent was removed in vacuo. The residue was partitioned between water and ethyl acetate and the mixture was vigorously stirred at ambient temperature for several minutes. The yellow, amorphous precipitate was collected, washed with water, ethyl acetate, and dried to give 776 mg of the title compound. The ethyl acetate layer was dried (MgSO4), filtered, and concentrated. The residue obtained was triturated with diethyl ether to give an additional 182 mg of the title compound (958 mg total, 61%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].Cl.[NH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:16])=[C:5]2[OH:20]
Reactant: CCOC(=O)C1=C(O)c2cc(F)ccc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(F)ccc2C(C)(C)C1=O
Temperature: 95 °C
Reaction time: 15 h
Yield: 77.7 %

Procedure:
A mixture of ethyl 6-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (1.1 g, 4.0 mmol), tert-butyl 2-aminoacetate hydrochloride (0.99 g, 5.9 mmol) in 10 mL dioxane, was treated with N-ethyl-N-isopropylpropan-2-amine (1.5 g, 12 mmol). The mixture was warmed to 95° C. and stirred for 15 hours. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 1.13 g of the title compound as a white solid. MS m/e=364 (M+Na)+.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.CCCCCC.[N+](C1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:25](=[CH2:32])[C:24]2[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=2C1)#[C-].C([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[N+:4]([C:5]1([CH3:7])[C:23]2[CH:36]=[CH:35][CH:34]=[CH:33][C:24]=2[C:25](=[CH2:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[CH2:6]1)#[C-:1]
Reactant: [C-]#[N+]C1Cc2ccccc2C(=C)c2ccccc21
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: [C-]#[N+]C1(C)Cc2ccccc2C(=C)c2ccccc21
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
Diisoproylamine (1.1 g, 10.9 mmole) in 25 ml of dry tetrahydrofuran was stirred in a dry ice/acetone bath. Under a nitrogen blanket, this solution was treated with n-butyllithium/hexane (5.0 ml of 2.2 M solution) added dropwise over 10 minutes. After 5 minutes, a solution of 10-isocyano-5-methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.4 g, 10.4 mmole) in 25 ml of dry tetrahydrofuran was added dropwise (over 45 minutes) to the lithium diisopropylamide solution. The resulting deep red solution was stirred in the cold for 15 minutes then treated with methyliodide (4.56 g, 32 mmole) added all at once. The mixture was stirred 2 hours in the cold and an additional 1 hour at room temperature. The solvent was removed in vacuo and the residue chromatographed on 75 g of silica gel, eluted with methylene chloride. The combined product fractions were evaporated in vacuo to give 2.2 g (86%) solid. Recrystallization from ether gave, m.p. 146°-147.5° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]3=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1.[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25][C:24]=2[C:23]([C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)=[CH:22][CH:21]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25][C:24]=2[C:23]([C:33]2[CH:34]=[C:35]([C:2]3[CH:11]=[N:10][C:9]4[C:4](=[C:5]5[CH:19]=[CH:18][CH:17]=[CH:16][C:6]5=[C:7]5[CH:15]=[CH:14][CH:13]=[CH:12][C:8]5=4)[N:3]=3)[CH:36]=[CH:37][CH:38]=2)=[CH:22][CH:21]=1
Reactant: Clc1cnc2c3ccccc3c3ccccc3c2n1
Reactant: OB(O)c1cccc(-c2cccc3c2sc2ccccc23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1cc(-c2cnc3c4ccccc4c4ccccc4c3n2)cc(-c2cccc3c2sc2ccccc23)c1
Temperature: 25 °C

Procedure:
First, 5.3 g (20 mmol) of 2-chlorodibenzo[f,h]quinoxaline, 6.1 g (20 mmol) of 3-(dibenzothiophen-4-yl)phenylboronic acid, 460 mg (0.4 mmol) of tetrakis(triphenylphosphine)palladium(0), 300 mL of toluene, 20 mL of ethanol, and 20 mL of a 2M aqueous solution of potassium carbonate were put in a 2-L three-neck flask. The mixture was degassed by being stirred under reduced pressure, and the air in the three-neck flask was replaced with nitrogen. This mixture was stirred under a nitrogen stream at 100° C. for 7.5 hours. After cooled to room temperature, the obtained mixture was filtered to give a white residue. The obtained residue was washed with water and ethanol in this order, and then dried. The obtained solid was dissolved in about 600 mL of hot toluene, followed by suction filtration through Celite and Florisil, whereby a clear colorless filtrate was obtained. The obtained filtrate was concentrated and purified by silica gel column chromatography using about 700 mL of silica gel. The chromatography was carried out using hot toluene as a developing solvent. Acetone and ethanol were added to the solid obtained here, followed by irradiation with ultrasonic waves. Then, the generated suspended solid was collected by filtration and the obtained solid was dried, so that 7.85 g of white powder was obtained in 80% yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CS([C:19]1[N:24]=[CH:23][C:22]2=[CH:25][CH:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=3)[N:21]2[N:20]=1)=O.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:37][S:34]([C:30]1[CH:29]=[C:28]([C:27]2[N:21]3[C:22]([CH:23]=[N:24][C:19]([NH:15][C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[N:14]=4)=[N:20]3)=[CH:25][CH:26]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:35])=[O:36]
Reactant: CN1CCN(Cc2cccc(N)n2)CC1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(C)(=O)=O)c3)n2n1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2cccc(Nc3ncc4ccc(-c5cccc(S(C)(=O)=O)c5)n4n3)n2)CC1

Procedure:
Into a microwave vial, 6-(4-Methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (0.149 g, 0.722 mmol), 2-Methanesulfinyl-7-(3-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.110 g, 0.328 mmol), N,N-Diisopropylethylamine (0.126 mL, 0.722 mmol), and 1-Methoxy-2-propanol (0.5 mL, 5 mmol) were added. The reaction was microwaved on 300 watts, 180° C. for 4 hours. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give [7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[6-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amine a yellow solid (20 mg, 10%). LCMS (E/I+) 478.8 (M+H). NMR 1H (DMSO-d6)-9.16 (s, 1H), 8.81 (d, 1H, J=7.82), 8.78 (s, 1H), 8.46 (dd, 1H, JJ=1.89, 5.36 Hz), 7.83-7.95 (m, 2H), 7.78 (t, 1H, J=7.57 Hz), 7.58 (d, 1H, J=5.05 Hz), 7.19 (dd, 1H, JJ=5.05, 6.94 Hz), 7.15 (d, 1H, J=5.05 Hz), 3.80 (s, 2H), 3.40-3.51 (m, 2H), 2.93-3.11 (m, 4H), 2.81 (s, 3H), 2.34-2.60 (m, 5H).
Reaction SMILES: [P:1]([O-])([O:5]CC)[O:2][CH2:3][CH3:4].O.[CH2:10]([NH2:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(O)C>[CH2:3]([O:2][P:1]=[O:5])[CH3:4].[CH2:10]([NH3+:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCOP([O-])OCC
Reactant: CCCCCCCCCCCCCCN
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCC[NH3+]
Product: CCOP=O
Yield: 105.3 %

Procedure:
To a mixture of 34.6 g. (0.25 moles) of diethyl phosphite, 50 ml. of water and 50 ml. of ethanol a mixture of 53.4 g. (0.25 moles) of tetradecylamine and 70 ml. of ethanol is added. The reaction mixture is refluxed for 4 hours, whereupon the solvent is distilled off in vacuo. 80.7 g (99.8%) of tetradecyl-ammoniumethyl phosphanate are obtained, melting at 45° to 46° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](Cl)(Cl)Cl)[C:5]([CH3:13])=[CH:4][C:3]=1[F:14].[CH3:15][O-:16].[Na+].S(=O)(=O)(O)[OH:19]>CO>[CH3:15][O:16][C:9](=[O:19])[CH2:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([F:14])=[CH:4][C:5]=1[CH3:13]
Reactant: O=S(=O)(O)O
Reactant: C[O-]
Reactant: Cc1cc(F)c(Br)cc1CC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1cc(Br)c(F)cc1C
Temperature: 5 °C

Procedure:
To a solution of 1-bromo-2-fluoro-4-methyl-5-(2,2,2-trichloro-ethyl)-benzene (29.2 g) in methanol (100 ml) is added a sodium methoxide solution (30% in methanol, 78.2 ml) dropwise. The reaction mixture is stirred at reflux for 24 hours, cooled to 5° C. and treated with concentrated sulfuric acid (13.2 ml) dropwise. After further warming to reflux for 21 hours, the mixture is concentrated and the residue diluted with water/ethyl acetate. The aqueous layer is extracted with ethyl acetate, the combined organic layers are washed with brine, dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel (ethyl acetate/cyclohexane 1:3). Yield: 18.76 g of (5-bromo-4-fluoro-2-methyl-phenyl)-acetic acid methyl ester as an oil.
Reaction SMILES: Cl.[CH2:2]([O:4][CH:5]([O:11][CH2:12][CH3:13])[C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[CH3:3].[CH2:14]([O:21][C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26](O)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.CCOCC>[CH2:12]([O:11][CH:5]([O:4][CH2:2][CH3:3])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:26](=[O:27])[C@@H:25]1[CH2:29][CH2:30][CH2:31][N:24]1[C:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23])[CH3:13]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(OCC)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(OCC)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of L-prolinal diethyl acetal hydrochloride (898 mg) and benzyloxycarbonyl-L-proline (1.2 g, 4.82 mmol) in dichloromethane (15 ml) are added successively, under ice-cooling and agitation, 1-hydroxy-benzotriazole (645 mg), triethylamine (0.68 ml, 4.88 mmol) and N,N-dicyclohexylcarbodiimide (1.0 g, 4.90 mmol). After the addition, stirring is further continued for 2 hours under ice-cooling, and then for 45 minutes at room temperature. Ether (40 ml) is added to the reaction mixture and the mixture is filtered for removal of insolubles. The filtrate is washed successively with water (10 ml), a saturated aqueous solution of sodium hydrogen carbonate (10 ml) and a saturated aqueous solution of edible salt (10 ml), dried over magnesium sulfate and filtered. The filtrate is concentrated to dryness under reduced pressure. The residue is purified by column chromatography on silica gel (benzene-ether-ethanol, 20:20:1) to give 1.125 g (69%) of the title compound as pale yellow crystals.