Azzindani/Open_Reaction_Data huggingface dataset:
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.[OH:25][CH2:26][CH2:27][N:28]([CH2:38][CH2:39][OH:40])[S:29]([C:32]1[S:33][C:34](Br)=[CH:35][CH:36]=1)(=[O:31])=[O:30]>>[OH:25][CH2:26][CH2:27][N:28]([CH2:38][CH2:39][OH:40])[S:29]([C:32]1[S:33][C:34]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)=[CH:35][CH:36]=1)(=[O:31])=[O:30]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(c1ccc(Br)s1)N(CCO)CCO
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1)N(CCO)CCO

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.53) (165 mg, 0.5 mmol) according to general procedure II. Obtained as a light brown solid (78 mg, 27%). MS (ISP) 587.1 [(M+H)+]; mp 122° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][O:25][CH3:26])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28].C(=O)([O-])[O-]>O1CCOCC1.O.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>[CH:27]([C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH2:24][O:25][CH3:26])(=[O:22])=[O:21])[CH2:18][CH2:19]2)[CH:32]=[CH:31][CH:30]=1)=[O:28]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Temperature: 160 °C
Yield: 48.4 %

Procedure:
To a solution of 5-bromo-3-(1-{[2-(methyloxy)ethyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (100 mg, 0.22 mmol) in dioxane (3.0 mL) and water (1.0 ml), (3-formylphenyl)boronic acid (186 mg, 1.25 mmol), Pd(PPh3)4 (25.0 mg, 10%) and cessium carbonate (200 mg, 0.45 mmol) were added. The reaction mixture was heated in a Smith synthesizer microwave at 160° C. for 20 min. All solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate/hexane, 1/1) to yield the desired product (50.0 mg, 48%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:33][CH2:34][CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38]>>[Cl:33][CH2:34][CH2:35][CH2:36][S:37]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:9]=3)[NH:13][CH:12]=2)[CH2:21][CH2:22]1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccc(F)cc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12

Procedure:
3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(4-fluorophenyl)-1H-indole-7-carboxamide was prepared according to the procedure for intermediate 11. 5-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indole-7-carboxamide (20 mg, 0.059 mmol) was reacted with triethyl amine (0.03 mL, 0.236 mmol) and 3-chloropropylsulfonyl chloride (0.03 mL, 0.118 mmol) to give 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(4-fluorophenyl)-1H-indole-7-carboxamide, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.I[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]

Procedure:
A mixture of 5-fluoro-2-nitrophenol (2.5 g, 15.9 mmol), 2-iodopropane (5.4 g, 31.8 mmol), and potassium carbonate (4.2 g, 39.8 mmol) in acetone (40 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum, and the residue was partitioned between ethyl acetate (100 mL) and water (150 mL), and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (3×150 mL), dried (MgSO4), and evaporated, providing 3.2 g, in quantitative yield; 1H NMR (CDCl3) δ 1.42 (d, J=6.0 Hz, 6H), 4.63 (septet, J=6.0 Hz, 6H), 6.64-6.72 (m, 1H), 6.76 (dd, J=9.8 Hz, J=2.5 Hz, 1H), 7.88 (dd, J=8.9 Hz, J=6.1 Hz, 1H).
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7]([N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C:11]([OH:13])=O)=[O:8])[CH3:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC)=O.Cl.[CH3:34][CH:35]1[CH:40]=[C:39]([C:41]([O:43][CH2:44][C:45]([Cl:48])([Cl:47])[Cl:46])=[O:42])[N:38]2[C:49](=[O:52])[CH:50]([NH2:51])[C@H:37]2[S:36]1>CN(C)CC1C=CC=CC=1.ClCCl>[CH3:34][CH:35]1[CH:40]=[C:39]([C:41]([O:43][CH2:44][C:45]([Cl:48])([Cl:46])[Cl:47])=[O:42])[N:38]2[C:49](=[O:52])[CH:50]([NH:51][C:11](=[O:13])[CH2:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]([O:6][CH:4]([CH:1]3[CH2:2][CH2:3]3)[CH3:5])=[O:8])[C@H:37]2[S:36]1
Reactant: CC(OC(=O)N(CC(=O)O)c1ccccc1)C1CC1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Agent: CCOC(=O)Cl
Agent: CN(C)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CN(C(=O)OC(C)C3CC3)c3ccccc3)[C@H]2S1
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A solution of N-(1-cyclopropylethoxycarbonyl)phenylglycine (1.63 g), triethylamine (0.60 g) and dimethylbenzylamine (2 drops) in dried dichloromethane (10 ml) was dropwise added at -10° C. to a solution of ethyl chloroformate (0.67 g) in dried dichloromethane (15 ml), and the mixture was stirred for 1 hour. The mixture was cooled at -10° to 15° C. and to the mixture was dropwise added over 10 minutes a solution of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (2.2 g) and triethylamine (0.55 g) in dried dichloromethane (20 ml), after which the mixture was stirred for 2.5 hours at the same temperature. After the reaction, the reaction mixture was in turn washed with water, 2% hydrochloric acid, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was pulverized by adding isopropyl ether, after which the powder was collected by filtration and dried to give 2,2,2-trichloroethyl 2-methyl-7-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]amino-3-cephem-4-carboxylate (3.0 g), mp 165° to 167.5° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][CH2:26][OH:27])[CH:20]=[CH:19]3)=[N:12][CH:13]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][CH:30]=1>O1CCOCC1.CO>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH2:25][CH2:26][OH:27])[CH:20]=[CH:19]4)=[N:12][CH:13]=2)=[CH:31][CH:30]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: OCCn1ccc2cc(C#Cc3ccc(Br)cn3)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: OCCn1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21
Temperature: 110 °C

Procedure:
Under an N2 atmosphere 56 mL 2 M Na2CO3 solution and 1.29 g (1.1 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 19.0 g (55.7 mmol) 2-[5-(5-bromo-pyridin-2-ylethynyl)-indol-1-yl]-ethanol and 11.55 g (72.4 mmol) 4-chlorophenyl-boric acid in 320 mL 1,4-dioxane and 80 mL MeOH and the reaction mixture is heated to 110° C. for 16 h. The mixture is evaporated down i. vac., the residue is combined with 300 mL water and the suspension is stirred vigorously. The precipitate is filtered off and washed with 200 mL water. The precipitate is suspended three times, each time with 600 mL PE/DCM (5:1), suction filtered and finally dried in the air until a constant weight is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34]C(OC(C)(C)C)=O)=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:42])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:8])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(NC(=O)OC(C)(C)C)cc2)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(N)cc2)nc1
Reaction time: 2.5 h
Yield: 77.7 %

Procedure:
2-[(4-{2-[{4-[(tert-Butoxycarbonyl)amino]benzyl}(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (1.2 g) synthesized in Example 439-1 was dissolved in dichloromethane (20 mL), p-toluenesulfonic acid monohydrate (3.64 g) was added thereto by small portions at room temperature. After 2.5 hr, the mixture was diluted with dichloromethane, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1 to 1:1) to give the title compound (0.78 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][NH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:29][N:30]([CH3:41])[CH2:31][CH2:32][N:33]([C@H:34]1[CH2:35][CH2:36][C@H:37]([CH3:40])[CH2:38][CH2:39]1)[C:6](=[O:8])[CH:5]=[CH:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[F:1]
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN(C(=O)C=Cc1ccccc1F)[C@H]1CC[C@H](C)CC1

Procedure:
Using 1.0 g of 2-fluorocinnamic acid, 1.4 ml of diethyl chlorophosphate, 1.4 ml of triethylamine, 60 ml of methylene chloride, 1.4 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.25 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 1.69 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-2-fluorocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:23]([O:27][C:28]1[N:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])[CH:24]([CH3:26])[CH3:25]>FC(F)(F)C(O)=O>[CH2:23]([O:27][C:28]1[N:36]=[CH:35][C:34]([I:1])=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)COc1ncccc1C(=O)O
Reactant: NC(=O)CCC(=O)NI
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COc1ncc(I)cc1C(=O)O

Procedure:
N-Iodosuccinamide (18.22 g, 0.08 mol), trifluoroacetic acid (100 mL) and trifluoroacetic anhydride (25 mL) were added to 2-isobutoxynicotinic acid (10.55 g, 0.054 mol). The mixture was refluxed for 2.5 h, cooled and the solvents evaporated. The residue was extracted from water with ethyl acetate and the organics washed with water (twice) and brine (twice), dried (MgSO4) and concentrated. The red residue was redissolved in ethyl acetate washed with sodium thiosulfate solution (twice), water (twice), brine (twice), redried (MgSO4) and concentrated to give the desired product as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[OH-].[NH4+:15]>>[NH2:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: [NH4+]
Reactant: O=C(O)CCCCCCCCCBr
Agent: [OH-]
Product: NCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10-bromodecanoic acid (2.51 gr, 10 mmol) was added to a round bottom flask containing 80 mL of aqueous ammonium hydroxide (25% NH3). The resulting mixture was stirred for 24 hours at room temperature, after which the aqueous solution was evaporated under reduced pressure, resulting in 8b as a white solid at quantitative yield. 1H-NMR (200 MHz, CD3OD): 1.25-1.4 (m; 10H), 1.5-1.7 (m; 4H), 2.15 (t; J=7.38 Hz; 2H), 2.89 (t; J=7.48 Hz; 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:12])=[CH:6][C:7]=1[NH:8][CH:9]([CH3:11])[CH3:10].ClC1[N:15]=[N:16]C(Cl)=CC=1NCC>>[CH:9]([NH:8][C:7]1[CH:6]=[C:5]([Cl:12])[N:4]=[N:3][C:2]=1[NH:15][NH2:16])([CH3:11])[CH3:10]
Reactant: CCNc1cc(Cl)nnc1Cl
Reactant: CC(C)Nc1cc(Cl)nnc1Cl
Product: CC(C)Nc1cc(Cl)nnc1NN

Procedure:
When 3,6-dichloro-4-isopropylamino pyridazine is substituted for 3,6-dichloro-4-ethylamino pyridazine in the above process, 4-isopropylamino-6-chloro-3-hydrazino pyridazine (m.p. 132° to 135°C) is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][C:6](=[O:8])[C:5]([C:9](=O)[CH2:10][CH3:11])=[C:4]([OH:13])[CH2:3]1.[Cl:15][C:16]1[S:20][C:19]([CH2:21][O:22][NH2:23])=[CH:18][CH:17]=1>C(O)C.C(Cl)Cl>[Cl:15][C:16]1[S:20][C:19]([CH2:21][O:22][N:23]=[C:9]([C:5]2[C:6](=[O:8])[CH2:7][C:2]([CH3:14])([CH3:1])[CH2:3][C:4]=2[OH:13])[CH2:10][CH3:11])=[CH:18][CH:17]=1
Reactant: CCC(=O)C1=C(O)CC(C)(C)CC1=O
Reactant: NOCc1ccc(Cl)s1
Solvent: ClCCl
Solvent: CCO
Product: CCC(=NOCc1ccc(Cl)s1)C1=C(O)CC(C)(C)CC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.2 %

Procedure:
In this example, a mixture containing 4.0 gms (0.02 mol) of 5,5-dimethyl-3-hydroxy-2-propionylcyclohex-2-en-1-one and 3.6 gms (0.022 mol) of O-[(5-chlorothien-2-yl)methyl]hydroxylamine in 75 mls of ethanol was stirred at room temperature for about 12 hours. The mixture was then evaporated to remove the ethanol, affording a thick syrup. The syrup was then dissolved in methylene chloride and extracted twice with aqueous 5% wt. sodium hydroxide. The aqueous layer was separated and acidified with concentrated hydrochloric acid and then extracted twice with methylene chloride. The methylene chloride layer was separated, dried with magnesium sulfate, and filtered. The filtrate was evaporated under vacuum, affording a viscous liquid which was then purified via column chromatography eluting with tetrahydrofuran-hexane (1:2 vol. ratio) affording 4.8 gms of 2-{1-[(5-chlorothien-2-ylmethoxy)imino]propyl}-3-hydroxy-5,5-dimethylcyclohex-2-en-1-one.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:27]=1[C:28]([NH2:30])=[O:29].CC([O-])(C)C.[Na+]>CN(C=O)C.O.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>[F:25][C:26]1[CH:34]=[C:33]([C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[C:5]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)=[CH:14][CH:13]=3)=[CH:4][CH:3]=2)[CH:32]=[CH:31][C:27]=1[C:28]([NH2:30])=[O:29]
Reactant: CC1(C)OB(c2ccc(C(N)=O)c(F)c2)OC1(C)C
Reactant: CN1CCN(c2ccc(Nc3ccc(Cl)n4ncnc34)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc(Nc3ccc(-c4ccc(C(N)=O)c(F)c4)n4ncnc34)cc2)CC1
Temperature: 110 °C
Yield: 18.4 %

Procedure:
A suspension of (5-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (50 mg, 146 μmol), 2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (97 mg, 360 μmol), Pd(PPh3)4 (51 mg, 40 μmol) and NaOtBu (56 mg, 580 μmol) in 1.2 mL of DMF/water (5:1, degassed) is degassed for 1 min in a sealed tube. The tube is sealed and the reaction mixture heated at 110° C. for forty minutes in the microwave (CEM explorer) and then at the same temperature for thirty minutes in an oil bath. After evaporation of the solvents the residue is taken up in dichloromethane, filtered and evaporated. The crude product is purified by flash chromatography (silica gel, dichloromethane/7N NH3 in methanol 97:3 to 90:10) and triturated (3× with ethyl acetate) affording the title compound (12 mg) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].[N-:16]=[N+]=[N-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([OH:11])[CH:10]([NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Temperature: 60 °C
Yield: 32.6 %

Procedure:
6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (12.1 g, 65.3 mmol) was dissolved in a 8:1 methanol/water mixture (108 mL). Ammonium chloride (15 g) and sodium azide (21.4 g, 329 mmol) was added and the reaction mixturewas heated at 60° C. overnight. After dilution with ether (500 mL), the reaction mixturewas washed with saturated aqueous NaHCO3 (200 mL) and brine (200 mL), dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in methanol (200 mL). 10% Palladium on activated carbon (1.5 g) was added and the reaction mixturewas stirred at ambient temperature under a hydrogen atmosphere until TLC analysis showed the disappearance of the starting material. The reaction mixture was filtered through a pad of Celite and evaporated to dryness under vacuum. The product was purified by flash chromatography on silica gel using 5% methanol in ethyl acetate to 20% methanol, 3% triethylamine in ethyl acetate to give 4.3 g of 3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as yellowish solid.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([C:2]2[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=3)[N:3]=2)=[CH:22]1
Reactant: CC1(C)OB(c2coc3ccccc23)OC1(C)C
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3coc4ccccc34)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 0.67 h
Yield: 57.5 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 150 mg, 0.51 mmol) in 1,4-dioxane (3 mL) was added 2-(benzofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (312 mg, 1.28 mmol), K3PO4 (326 mg, 1.53 mmol), Pd(PPh3)4 (30 mg, 0.03 mmol) and water (3 drops). After stirring 40 min at 95° C. under nitrogen atmosphere, the reaction mixture was dissolved in water (10 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(benzofuran-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (110 mg, 57%).
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]2[CH:34]=[C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)[C:36]3[S:40][C:39]([NH:41][C:42]([NH:44][CH2:45][CH3:46])=[O:43])=[N:38][C:37]=3[CH:47]=2)=[CH:29][N:28]=1>CC(N(C)C)=O>[CH2:45]([NH:44][C:42](=[O:43])[NH:41][C:39]1[S:40][C:36]2[C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)=[CH:34][C:33]([C:30]3[CH:31]=[N:32][C:27]([N:7]4[CH2:6][CH2:5][C:4]([C:3]([F:2])([F:15])[F:16])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8]4)=[N:28][CH:29]=3)=[CH:47][C:37]=2[N:38]=1)[CH3:46]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(Cl)nc3)cc(-c3ccccn3)c2s1
Reactant: CCOC(=O)C1(C(F)(F)F)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C(=O)OCC)(C(F)(F)F)CC4)nc3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
To the solution of ethyl 4-(trifluoromethyl)piperidine-4-carboxylate hydrochloride (0.1 g, 0.44 mmol) in DMA (5.0 mL) was added DIPEA (0.25 mL, 1.46 mmol) at rt and the mixture stirred at rt for 10 min followed by addition of 1-(5-(2-chloropyrimidin-5-yl)-7-(pyridin-2-yl)benzothiazol-2-yl)-3-ethylurea (0.12 g, 0.29 mmol). The reaction was heated up to 80° C. for 16 h and after completion (by TLC), the mixture was poured into 50 mL of ice cold water, extracted with EtOAc (3×50 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 1.50% MeOH: DCM to obtain an off white solid (0.09 g, 51%). 1H NMR (DMSO-d6): δ 1.15 (t, J=7.20 Hz, 3H), 1.20 (t, J=6.80 Hz, 3H), 1.45 (m, 2H), 2.06 (m, 2H), 2.54 (m, 2H), 3.21 (q, J=7.20, 2H), 4.15 (q, J=6.80 Hz, 2H), 4.32 (m, 2H), 6.86 (br s, 1H), 7.44 (m, 1H), 7.99 (m, 2H), 8.23 (s, 1H), 8.47 (m, 1H), 8.80 (m, 1H), 8.92 (s, 2H) and 10.56 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C@H:9]1[CH2:19][OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:10][C@H:9]1[CH2:19][O:20][S:29]([CH3:28])(=[O:31])=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)C[C@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)C[C@H]1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.2 %

Procedure:
To 2.5 g of (2S,4S)-2-Hydroxymethyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester (9.01 mmol) in 70 ml dichloromethane were added 1.92 g of triethylamine (18.02 mmol) and 1.03 g of methanesulfonylchloride (9.01 mmol), dissolved in 5 ml dichloromethane. The reaction was stirred for 16 h at room temperature and yielded 3.4 g of product after standard workup.