Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])=[O:17])[CH2:7][CH2:6]1.[NH2:25][C:26]1[C:34]([Cl:35])=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([O:36][CH3:37])[CH:27]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[ClH:35].[NH2:25][C:26]1[C:34]([Cl:35])=[CH:33][C:29]([C:30]([NH:3][CH2:4][CH:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:24])=[O:17])[CH2:7][CH2:6]2)=[O:31])=[C:28]([O:36][CH3:37])[CH:27]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: NCC1CCN(CCCCCC(=O)c2ccccc2O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccccc2O)CC1
Yield: 107.8 %

Procedure:
4-Aminomethyl-1-(6-(2-hydroxyphenyl)-6-oxohexyl)piperidine dihydrochloride (1.54 g) as a starting compound, 4-amino-5-chloro-2-methoxybenzoic acid (0.82 g), triethylamine (1.7 ml), 1-hydroxybenzotriazole (0.58 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.82 g) were reacted and purified in the same manner as in Example 270 to give 1.15 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(2-hydroxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide hydrochloride, m.p. 143°-145° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)O1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: Cc1nc(OCC(=O)N(C)C2CCN(c3cccnc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine, copper (II) acetate and pyridine in the same manner as in Example 32.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=1)[NH2:5].Cl[S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18].O.[Cl-].[NH4+]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:17]([C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])[CH:6]=[C:7]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=1
Reactant: Nc1cc(F)cc(Oc2cccnc2)c1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1cc(F)cc(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-5-(pyridin-3-yloxy)aniline (1.10 g) in pyridine (22 ml), 1.92 g of methyl 2-(chlorosulfonyl)benzoate was added, and the reaction solution was stirred overnight at room temperature. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a 1N aqueous hydrochloric acid solution and a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel chromatography to yield the title compound as a white solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=2[N:6]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[S:3][C:4]3[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=3[N:6]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1ccc2sc(Br)nc2c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2sc(Nc3ccc(Br)cc3)nc2c1

Procedure:
The mixture containing 2-bromo-5-methoxybenzthiazole (1 eq), 4-Bromoaniline (2 eq) and diisopropylethylamine was subjected to microwave in NMP at 220° C. The resultant mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried. Purification on silica gel gave the desired product. MS: MH+=335
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][C:12]1[C:16]2[C:17](=[O:30])[N:18]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:19][CH2:20][CH2:21][C:15]=2[NH:14][CH:13]=1>ClCCl>[CH3:11][C:12]1[C:16]2[C:17](=[O:30])[N:18]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:19][CH2:20][CH2:21][C:15]=2[NH:14][C:13]=1[CH:3]=[O:4]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
Dichloromethane (36 ml, 559 mmol) and N,N-dimethylformamide (1.637 ml, 20.9 mmol) were stirred for 5 minutes at −15° C. in an ice-salt bath under an argon atmosphere. The solution was added dropwise with phosphorus oxychloride (1.07 ml, 11.5 mmol) and stirred for 15 minutes while maintaining the temperature at −10° C. 3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-on e 32c (1.26 g, 4.58 mmol) was dissolved in 10 ml of dichloromethane, the resulting solution was added dropwise to the above solution. Upon completion of the addition, the ice-salt bath was removed, and the reaction mixture was stirred for 3 hours at room temperature. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was quenched with iced water, adjusted to about pH 10 with sodium hydroxide solution (10 mol/L) and stirred for 30 minutes, extracted with dichloromethane (30 ml×3). The combined organic extracts were washed with saturated brine (30 ml), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d (993 mg, yield 71.4%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:29][NH2:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4[CH:21]=[CH:22][C:23]([C:24](=[O:25])[NH:30][CH3:29])=[CH:27][CH:28]=4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CN
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)cc1
Product: CNC(=O)c1ccc(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)cc1
Yield: 67 %

Procedure:
The product of example 45 (50 mg, 0.128 mmol) in methylamine (40% in water, 3 mL) was heated in a sealed tube at 100° C. for two hours. The resulting precipitate was filtered and washed with small portions of ethyl acetate to afford the title compound (33 mg, 67% yield). 1H NMR (DMSO-d6) δ 13.22 (br s, 1H), 10.41 (s, 1H), 8.58 (m, 1H), 8.52 (s, 1H), 8.00 (m, 6H), 7.75 (d, 1H), 7.56 (d, 1H), 7.36 (t, 2H), 2.79 (m, 3H); ES-MS (m/z) 389 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:12][C@H:13]2[C@H:17]([CH3:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:26][N:27](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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:26]([C:2]1[N:3]=[C:4]([O:12][C@H:13]2[C@H:17]([CH3:18])[CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)#[N:27]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Oc1nc(Cl)cc2ccccc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Oc1nc(C#N)cc2ccccc12
Temperature: 160 °C
Yield: 82 %

Procedure:
A mixture of tert-butyl trans-3-((3-chloroisoquinolin-1-yl)oxy)-4-methylpyrrolidine-1-carboxylate (1 g, 2.76 mmol), zinc cyanide (0.647 g, 5.51 mmol), Pd(PPh3)4 (0.318 g, 0.276 mmol) and DMF (7.83 mL) was heated in a microwave reactor at 160° C. for 20 minutes. The reaction mixture was subsequently taken up in EtOAc (100 mL), washed with brine (50 mL) and water (50 mL), dried over Na2SO4, and concentrated onto silica gel. The crude product was purified by flash column chromatography (SiO2) eluting with a 5-50% gradient of heptane in EtOAc to give title compound as a white solid (0.796 g, 82%). 1H NMR (500 MHz, CDCl3) δ ppm 1.17 (d, 3H), 1.41-1.54 (m, 9H), 2.60 (br s, 1H), 3.26 (br s, 1H), 3.45-3.65 (br s, 1H), 3.74 (br s, 1H), 3.93 (dd, 1H), 5.40 (dt, 1H), 7.67-7.87 (m, 4H), 8.27 (d, 1H); ESI-MS m/z [M+H-tert-butyl]+ 298.6.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=[O:19])[CH2:17][CH3:18])[CH2:8][CH2:9][CH3:10]>O1CCCC1>[CH2:7]([N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]([OH:19])[CH2:17][CH3:18])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCn1cccc1C(=O)CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCn1cccc1C(O)CC
Temperature: 0 °C

Procedure:
To a stirred suspension of 4 g (100 mmol) of lithium aluminum hydride in 300 ml of anhydrous tetrahydrofuran was added dropwise, at room temperature, a solution of 18 g (100 mmol) of 1-butyl-2-propionylpyrrole in 100 ml of anhydrous tetrahydrofuran. The reaction mixture was refluxed for 30 minutes, cooled to 0° C. and the excess reagent destroyed by carefully adding ethyl acetate, saturated sodium sulfate solution and solid anhydrous sodium sulfate. The insoluble material was separated by filtration and the filtrate evaporated in vacuo. The unstable 1-butyl-2-(α-hydroxypropyl)pyrrole thus obtained (20 g, 110 mmol) was dissolved in 250 ml of methanol, the solution cooled to 0° C. and treated with 60 ml of glacial acetic acid and 14 g (220 mmol) of sodium cyanoborohydride. The reaction mixture was stirred at 0° C. for 30 minutes and thereafter for 75 minutes further at room temperature. It was then poured into 1000 ml of saturated sodium carbonate solution and the product extracted with ethyl acetate (3×500 ml). The combined extracts were washed with water (3×250 ml), dried and evaporated under reduced pressure. The residue was purified by column chromatography on 500 g of silica gel, using hexane-methylene chloride (95:5) as eluant, thus obtaining 8.7 g (52%) of the title compound, 1-butyl-2-propylpyrrole, as an oil.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]=[CH2:8])(=[O:4])[NH:2][NH2:3].[CH3:9][C:10]1([CH3:26])[CH2:15][CH:14]([NH:16][C:17](=[O:23])[C:18](OCC)=[O:19])[CH2:13][C:12]([CH3:25])([CH3:24])[NH:11]1>CO>[CH3:9][C:10]1([CH3:26])[CH2:15][CH:14]([NH:16][C:17](=[O:23])[C:18]([NH:3][NH:2][C:1]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4])=[O:19])[CH2:13][C:12]([CH3:25])([CH3:24])[NH:11]1
Reactant: C=CCOC(=O)NN
Reactant: CCOC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Solvent: CO
Product: C=CCOC(=O)NNC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Temperature: 50 °C
Reaction time: 1.33 h
Yield: 85.7 %

Procedure:
Into a 250 ml 3-neck flask was added 9.2 grams (0.079 mole) of allyl carbazate from (A), 34.2 grams (0.08 mole) of a 60% solution of ethyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate and 50 ml of methanol. The flask was equipped with a magnetic stirrer, thermometer and a Dean Stark trap with a reflux The reaction was heated in an oil bath and the methanol was distilled off through the Dean Stark trap. After the methanol distillation ceased, a vacuum was applied to the system to remove any residual methanol and the reaction was cooked for 80 minutes at 90° C. The reaction was cooled to 50° C. and 50 ml of methanol was added and the reaction heated back up to reflux to dissolve the residue. The methanol solution was cooled and concentrated to 25 ml. Upon addition of 25 ml of methyl t-butyl ether, a white solid formed. The solid was filtered off and dried in a vacuum oven over night. The dry powder weighed 22.1 grams (85.7% yield) and assayed 100% by liquid chromatography. The infrared scan of the product contained a weak carbonyl at 1750 cm-1 and a strong carbonyl at 1680 cm-1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:40][N:39]([CH3:41])[CH2:38][CH2:37][NH:36][S:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1)(=[O:34])=[O:35]
Reactant: CN(C)CCNS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)CCNS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 3-bromo-N-(2-dimethylamino-ethyl)-benzenesulfonamide (example B.35) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (200 mg, 34%). MS (ISP) 582.2 [(M+H)+]; mp 146-147° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:12])=[C:5]([CH:7]=[C:8]([F:11])[C:9]=1[Cl:10])N)#[N:2].Cl.O.N([O-])=O.[Na+].O.[BrH:20]>>[C:1]([C:3]1[C:4]([Cl:12])=[C:5]([Br:20])[CH:7]=[C:8]([F:11])[C:9]=1[Cl:10])#[N:2]
Reactant: N#Cc1c(Cl)c(N)cc(F)c1Cl
Reactant: Br
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1c(Cl)c(F)cc(Br)c1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
47.2 g of 3-cyano-2,4-dichloro-5-fluoroaniline (0.23 mol) were added to a solution of 150 ml of hydrochloric acid-water (1:1). The resulting mixture was stirred to be a slurry and then cooled to 0-5° C. A solution of sodium nitrite (16.7 g, 0.242 mol) and water (46 ml) was added thereto over 30 minutes. The resulting solution was added to a solution of cuprous bromide (0.275 mol) in 147 ml of hydrobromic acid. The reaction mixture was stirred for 2 hours and allowed overnight. The resulting mixture was wet-distilled. The distilled fraction was extracted with toluence. The oil layer was washed successively with 10% aqueous solution of NaOH, concentrated sulfuric acid and water, and dried over anhydrous sodium sulfate. After removing the solvent, the residue was crystallized from toluene to give 53.3 g of 3-cyano-2,4-dichloro-5-fluorobromobenzene (0.198 mol) in 86.2% yield.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][O:10][C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19](O)=[O:20])[CH2:15][CH2:14]1)=[O:12].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:11]([O:10][CH3:9])=[O:12])[CH2:18][CH2:17]1)=[O:20]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)ON2C(=O)CCC2=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-hydroxysuccinimide (6.18 g, 0.0537 mol) and trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (10.00 g, 0.05370 mol) in THF (100.00 mL) was charged with (N,N′-dicyclohexylcarbodiimide (11.08 g, 0.0537 mol) in THF (16 mL). This reaction was stirred at rt for an additional 16 h then stirred at 45° C. for 1 h. The reaction mixture was filtered while still warm through a fritted funnel. The cake was washed with 3 more portions of THF and the filtrate was concentrated in vacuo and was crystallized from i-PrOH (300 mL) and filtered through a fritted funnel resulting in 11.8 g, (78% yield) of the title compound as a white crystals. 1H NMR (400 MHz, CDCl3) δ ppm 1.45-1.69 (m, 4H), 2.07-2.16 (m, 2H), 2.18-2.28 (m, 2H), 2.29-2.39 (m, 1H), 2.59-2.71 (m, 1H) 2.84 (br. s., 4H) and 3.68 (s, 3H); MS (ES+): m/z 284.09 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOCC>[Br:27][CH2:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[C:9](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)/C(=C\c1ccc(C)cc1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)/C(=C\c1ccc(CBr)cc1)c1ccccc1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
To a solution of the product of Step B (31 mg, 0.123 mmol) in dry CCl4 (1 mL) under N2 were added NBS (20 mg, 0.9 eq) and a catalytic amount of AIBN. The mixture was stirred at reflux under N2 for 1.5 hours. The mixture was cooled to room temperature, diluted with Et2O and filtered to remove the precipitated succinimide. The filtrate was concentrated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 15:1 hexane/EtOAc to afford 27.4 mg (67%) of the title compound.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=1)[CH2:3][NH2:4].[C:14]([CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](=O)[CH3:29])=[CH:23][CH:22]=1)[CH3:20])([O:16][CH3:17])=[O:15]>>[C:14]([CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=2)[CH3:29])=[CH:23][CH:22]=1)[CH3:20])([O:16][CH3:17])=[O:15]
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Reactant: COC(=O)C=C(C)c1ccc(CC(C)=O)cc1
Product: COC(=O)C=C(C)c1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
Prepared analogously to Example 13 by reaction of 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with 1-[4-(2-carbomethoxy-1-methylethenyl)phenyl]-propan-2-one followed by purification of the base on a silica gel column using chloroform/methanol/methanolic ammonia=9.5/0.4/0.1 as eluant.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Br[CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42]>>[ClH:1].[CH3:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COCCOCCBr
Reactant: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Agent: Cl
Product: COCCOCCOc1cc(F)cc(C[C@H](NC(C)=O)[C@H](O)CNC2(c3cccc(C(C)C)c3)CCCCC2)c1
Yield: 52 %

Procedure:
Using methods analogus to those previously described, compound 11 (0.4 mmol) is reacted with 1-bromo-2-(2-methoxyethoxy)ethane to afford the title compound 60 (0.21 mmol, 52%) as a hygroscopic white solid: 1H NMR (CDCl3) δ 9.4 (br, 1H), 8.5 (br, 1H), 8.32 (br, 1H), 7.54 (s, 1H), 7.38 (m, 2H), 7.26 (m, 1H), 6.56 (s, 1H), 6.47 (m, 2H), 4.34 (v br, water H), 4.1 (m, 4H), 3.83 (m, 2H), 3.70 (m, 2H), 3.58 (m, 2H), 3.38 (s, 3H), 2.96 (hept, J=7 Hz, 1H), 2.8–2.6 (m, 5H), 2.4–2.2 (m, 3H), 2.15 (s, 3H), 1.80 (m, 2H), 1.6 (m, 1H), 1.5–1.3 (m, 3H), 1.27 (d, J=7 Hz, 6H); MS (CI) m/z 559.5 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CC[N:34](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.N>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH2:34])=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol) in dry CH2Cl2:DMF (2.0:0.1 mL), added DIEA (24 μL, 0.14 mmol) and PyBOP® (40 mg, 0.077 mmol). After stirring the mixture at RT for 15 minutes, ammonia was bubbled through the solution for 15 minutes. Added another 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® after stirring the solution for 15 minutes, followed by ammonia bubbling for an additional 15 minutes. The solvent was removed in vacuo and the crude material was purified by prep HPLC (method 10-35_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamide. (27 mg, 0.066 mol, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.[H-].[Na+].[N+]([C:17]1[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=1)([O-])=O.O>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][C:17]3[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(Sc2nc3ccc(Cl)cc3[nH]2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Aldehyde intermediate preparation: 5-Chloro-2-mercaptobenzimidazole (1.5 g, 8.12 mmol) dissolved in 10 ml of anhydrous tetrahydrofuran is added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.325 g, 8.12 mmol) in anhydrous tetrahydrofuran (20 ml) at 10° C. over a 15 minute period. The reaction mixture is stirred for 2 hours at room temperature. Then 5-nitro-2-furaldehyde (1.146 g, 8.12 mmol) dissolved in 20 ml of anhydrous tetrahydrofuran is added dropwise over a 15 minute period and the reaction mixture is stirred at room temperature for an additional 16 hour period. The reaction mixture is then poured into 300 ml of water and extracted twice with 150 ml of ethyl acetate. The combined organic extracts are dried over MgSO4 and concentrated under reduced pressure. The residue is purified on a silica gel column (120 g) eluted with a mixture of cyclohexane and ethyl acetate (80/20, v/v) to yield 1.9 g of 5-(6-chloro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde. Yield=88%. Analytical LC/MS (method B): retention time=3.40 min., m/z=278.95/1Cl (positive ion mode).