Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1)[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:35]=[C:36]([O:38][CH3:39])[CH:37]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(OC)cc(OCCCCCCl)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(OC)cc(OCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.0 g) as starting compound and 5-(3,5-dimethoxyphenoxy)pentyl chloride (1.4 g) were reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(5-(3,5-dimethoxyphenoxy)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:24]12([CH2:34][NH2:35])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>CN(C)C=O>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:35][CH2:34][C:24]12[CH2:33][CH:28]3[CH2:27][CH:26]([CH2:32][CH:30]([CH2:29]3)[CH2:31]1)[CH2:25]2)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc(F)c1Cl
Reaction time: 8 h

Procedure:
A solution of 2-chloro-3-fluorobenzoic acid (0.098 g) and carbonyldiimidazole (0.091 g), in N,N-dimethylformamide (3.0 ml) was stirred for 2.5 hours at room temperature. 1-Adamantanemethylamine (0.1 ml) was then added and stirring continued overnight. The reaction mixture was partitioned between ethyl acetate and 2N hydrochloric acid and the organic layer was separated, washed with 10% aqueous sodium hydroxide, water and brine and then dried over sodium sulphate (Na2SO4). The organic layer was subsequently concentrated under reduced pressure to yield the tire compound as a white solid (0.138 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:21])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[CH3:23][O:24][NH2:25]>>[CH3:23][O:24][N:25]=[C:18]([CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH3:21])[CH3:19]
Reactant: CON
Reactant: CC(=O)CCCn1c(C)nc2c(N)nc3ccccc3c21
Agent: Cl
Product: CON=C(C)CCCn1c(C)nc2c(N)nc3ccccc3c21

Procedure:
By the general method described in Part F of Example 30, 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one was reacted with O-methylhydroxylamine hydrochloride to provide 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one O-methyloxime in about a 5.25 to 1 mixture of E and Z isomers as white needles after recrystallization from toluene, mp 158-161° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:17][C@H:18]1[CH2:23][NH:22][CH2:21][CH2:20][NH:19]1.O(C(C)(C)C)[Na]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:17][C@@H:18]1[NH:19][CH2:20][CH2:21][N:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[S:16][N:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:23]1
Reactant: C[C@H]1CNCCN1
Reactant: O=S(=O)(Nc1ncns1)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H]1CN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CCN1
Yield: 18.8 %

Procedure:
Synthesized according to general procedure 8. The reaction was set up with 4-bromo-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (4.7 mmol), (S)-2-methylpiperazine (4.7 mmol), Pd2(dba)3 (0.12 mmol) 2-(di-t-butylphosphino)biphenyl (0.50 mmol), NaO-tBu (10 mmol), and toluene (12 mL). For the purification, 10% MeOH in CH2Cl2 with the addition of 1% triethylamine was used as a solvent system to obtain the desired amine as a white solid (300 mg, 19% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=340.2; tR=1.40 min.
Reaction SMILES: Cl.NCCCC[N:7]1[C:11](=[O:12])[CH2:10][C:9]([CH2:14][CH3:15])([CH3:13])[C:8]1=[O:16].C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CN=C1.CCCCN(C(SC(N(CCCC)CCCC)=S)=S)CCCC.[OH-].[Na+].C(O)C(N)(CO)CO>CN(C=O)C.O.C(N(CC)CC)C>[CH3:15][CH2:14][C:9]1([CH3:13])[C:8](=[O:16])[NH:7][C:11](=[O:12])[CH2:10]1
Reactant: CCC1(C)CC(=O)N(CCCCN)C1=O
Agent: CCCCN(CCCC)C(=S)SC(=S)N(CCCC)CCCC
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCC1(C)CC(=O)NC1=O
Reaction time: 0.25 h

Procedure:
To a slurry of 92.1 milligrams (mg) of the HCl salt of N-(4-aminobutyl)2-ethyl-2-methylsuccinimide in 0.6 mL of dry DMF at room temperature under argon was added 107 microliters (μL) of triethylamine. The suspension was stirred 15 min; then a solution of 180.2 mg of carbonyldiimidazole (CDI) in 0.6 mL of DMF was added via syringe in one portion. The resulting suspension was stirred at room temperature for 50 min to complete formation of the imidazole. It was then added dropwise, over 8 min, to a stirring solution of 250 mg of Miles Pentex® crystalline bovine serum albumin (BSA) (Miles Laboratories, Inc., Elkhart, IN, USA) in 108 mL of water at pH 4.5 and 5° C. The pH was maintained at 4.5 during and after the addition by an automatic titrator (HCl). After 18 hrs at pH 4.5 and 5° C., the clear, translucent reaction was adjusted to pH 8 with sodium hydroxide solution, and applied to a 3.0×62 cm column of Sephadex G-25F gel (Pharmacia, Piscataway, NJ, USA) in 50 millimolar (mM) TRIS buffer [tris(hydroxymethyl)aminomethane], pH 8.2. The column was eluted with this buffer at a flow rate of 1 mL/min and 10 mL fractions were collected.
Reaction SMILES: C(N(CC)CC)C.C(Cl)(Cl)[Cl:9].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1NC(=O)CC1C=CC(OC2C=CC(O[C@H]3CC[C@@H](N)CC3)=CC=2)=CC=1>>[C:14]([Cl:9])(=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClC(Cl)Cl
Reactant: COC(=O)c1ccccc1NC(=O)Cc1ccc(Oc2ccc(O[C@H]3CC[C@@H](N)CC3)cc2)cc1
Solvent: CCN(CC)CC
Product: O=C(Cl)c1ccccc1
Yield: 149.1 %

Procedure:
A reactor was charged with 358 μl (1.7 eq, 179 μmol) of 0.5M triethylamine-chloroform solution containing 420 μl (105 μmol, 50 mg) of 2-(2-(4-(4-(cis-4-aminocyclohexyloxy)phenoxy)phenyl)acetylamino)benzoic acid methyl ester (0.25M-CHCl3) obtained by the Example 17, benzoyl chloride (1.5 eq, 22 mg) was added thereto and the mixture was stirred for 2.5 hours. After completing the reaction, 139 mg (157.5 μmol) of an aminomethylated polystyrene resin (product of Novabiochem) was added to the system and stirred for 12 hours. The solution was put on a Silica cartridge (product of Waters) and developed with a hexane/ethyl acetate mixture (1/2) and the obtained solution was distilled to remove the solvent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.C(N(CC)CC)C.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35](Cl)=[O:36].[OH-].[Na+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:36]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc5ccccc5c4)cc23)CC1
Yield: 82 %

Procedure:
To a solution of 0.989 gm (4.31 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 20 mL tetrahydrofuran and 10 mL dimethylformamide were added 0.721 mL (5.2 mMol) triethylamine followed by 0.904 gm (4.74 mMol) 2-naphthoyl chloride. After 18 hours the reaction mixture was cooled in an ice bath and then diluted with 100 mL ethyl acetate followed by 50 mL 2N sodium hydroxide. The phases were separated and the aqueous extracted with ethyl acetate. The organic extracts were combined then washed sequentially with 2N sodium hydroxide, water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash chromatography, eluting with 100:10:1 dichloromethane:methanol:ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure. The residue was precipitated from ethyl acetate/hexane to give 1.355 gm (82.1%) of the title compound as a tan powder.
Reaction SMILES: I[N:2]1[C:7]([OH:8])=[C:6]2[CH:9]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:5]2[N:4]=[CH:3]1.[CH2:19]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[C:20]#[CH:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Pd](Cl)Cl.C(#N)C>[O:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[O:22][CH2:19][C:20]#[C:21][N:2]1[C:7]([OH:8])=[C:6]2[CH:9]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:5]2[N:4]=[CH:3]1
Reactant: C#CCOC1CCCCO1
Reactant: CC(C)(C)C(=O)Nc1cc2c(O)n(I)cnc-2n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1cc2c(O)n(C#CCOC3CCCCO3)cnc-2n1
Reaction time: 12 h

Procedure:
A mixture of 14.6 g of 3-iodo-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine, 7.6 g of 2-(2-propynyloxy)-tetrahydropyran, 798 mg (10%) of palladium chloride, 2.36 g (20%) of triphenyl phosphine, 428 mg (5%) of cuprous iodide, 45 ml of triethyl amine and 700 ml of acetonitrile is heated at reflux under nitrogen for 12 hours. There then are added to the hot reaction mixture 3.2 g of 2-(2-propynyloxy)-tetrahydropyran and reflux is continued for an additional 12 hours. After heating for a total of 24 hours under reflux, the solvent is removed under reduced pressure, and the residue filtered through silica gel using 2% methanol in methylene chloride. This filtrate is concentrated and chromatographed on silica gel eluting with 20:1 ethyl acetate:hexane mixture to give 3-(3-tetrahydropyr-2-yloxyprop-1-yn-1-yl)-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine which is further purified by recrystallization with ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][CH:8]([CH2:10][C:11](=[O:35])[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[S:27][C:26]3[C:25]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:24][C:23](Cl)=[N:22][C:21]=3[CH:20]=2)[CH:14]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:45]2[CH:53]=[CH:52][CH:51]=[C:50]3[C:46]=2[CH:47]=[N:48][NH:49]3)O1>>[C:1]([O:5][C:6](=[O:36])[NH:7][CH:8]([CH2:10][C:11](=[O:35])[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[S:27][C:26]3[C:25]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:24][C:23]([C:45]4[CH:53]=[CH:52][CH:51]=[C:50]5[C:46]=4[CH:47]=[N:48][NH:49]5)=[N:22][C:21]=3[CH:20]=2)[CH:14]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CC(=O)Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1)NC(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CC(CC(=O)Nc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1)NC(=O)OC(C)(C)C

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (50 mg) was reacted with Boc-2-aminoisobutric acid via General Procedure I to give tert-butyl(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)propan-2-ylcarbamate. 75 mg of the crude tert-butyl(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)propan-2-ylcarbamate was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield tert-butyl(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylcarbamoyl)propan-2-ylcarbamate.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].O=[C:16]([NH:22][CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)(Cl)Cl>[C:25]1([C:24]2[S:2][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:22][CH:23]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(=O)NCC(=O)c1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ncc(-c2ccccc2)s1
Yield: 74.7 %

Procedure:
P2S5 (25.5 g, 114.7 mmol) was added to a solution of ethyl 2-oxo-2-((2-oxo-2-phenylethyl)amino)acetate (13.5 g, 57.39 mmol) in dry CHCl3 (150 mL), and the resulting reaction mixture was heated to reflux for 5 h. The reaction mixture was quenched with water and the organic product was extracted with CHCl3. The combined extracts were washed with H2O and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10-15% EtOAc in petroleum ether) to afford ethyl 5-phenylthiazole-2-carboxylate (10 g, yield 75%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.64-7.62 (m, 2H), 7.48-7.39 (m, 3H), 4.53-4.47 (q, J=7.0 Hz, 2H), 1.49-1.45 (t, J=7.2 Hz, 3H). MS (ESI) m/z: Calculated for C12H11NO2S: 233.05. found: 234.0 (M+H)+.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:17][CH2:16][CH2:15][CH2:14][S:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: ClCCCBr
Reactant: O=C(O)c1ccccc1S
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1SCCCCl
Temperature: 25 °C
Yield: 39.1 %

Procedure:
With stirring at room temperature, 15.4 g (99.9 mmols) of thiosalicylic acid was added by small portions to 50 ml of a solution of 2.44 g (101.7 mmols) of sodium hydride in dimethylformamide. The solution was dropwise added to 100 ml of a solution of 15.7 g (99.7 mmols) of 1-bromo-3-chloropropane in dimethylformamide with stirring under ice cooling. The mixture was stirred under ice cooling for further an hour and a half. After the reaction, an aqueous saturated sodium bicarbonate solution was added to the mixture followed by extraction of the solution with ethyl acetate 10 times. The ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol =50/1) to afford 9.0 g (yield: 39%) of 1-chloro-3-(2-hydroxycarbonylphenylthio)propane.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]1([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)(=O)C.B(F)(F)F.CCOCC>O>[C:6]1([C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:1][CH2:2][C:3]([OH:5])=[O:4])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)CS
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 64574.2 %

Procedure:
A mixture of distilled mercaptoacetic acid (20.87 g, 0.23 mmol), triphenylmethanol (60.0 g, 0.23 mol) and glacial acetic acid (200 ml) was heated to 70° C. Boron trifluoride etherate (32 ml, 0.25 mol) was added and the resulting brown mixture was stirred for 45 minutes at room temperature. The reaction mixture was then poured into water (500 ml), depositing a buff, granular solid which was filtered off, washed well with water then ether, and dried to give compound (V) (49.67 g, 67%). A further crop (12.27 g, 16%) was recovered from the ether washings, purified by recrystallization from benzene/hexanes. Both crops were homogeneous by TLC, mp 158.5°-160°.
Reaction SMILES: CO[C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[N:7]([CH3:24])[N:6]=1)=[O:4].[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:3]([C:5]2[CH:9]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[N:7]([CH3:24])[N:6]=2)=[O:4])[CH2:27][CH2:28]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)n(C)n1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NC2CCOCC2)nn1C
Yield: 90 %

Procedure:
As described for example 115, 1-methyl-5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-1H-pyrazole-3-carboxylic acid methyl ester (70 mg, 0.21 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (76 mg, 90%) which was obtained as a colorless oil. MS: m/e=398.2 [M+H]+.
Reaction SMILES: [Na].Br[C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][NH2:12])[CH:6]=[C:5]([CH3:13])[CH:4]=1.[CH3:14][OH:15]>>[CH3:14][O:15][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][NH2:12])[CH:6]=[C:5]([CH3:13])[CH:4]=1
Reactant: Cc1cc(Br)nc(NCCN)c1
Reactant: CO
Agent: [Na]
Product: COc1cc(C)cc(NCCN)n1
Temperature: 140 °C

Procedure:
Sodium (45 mg, 1.96 mmol) was dissolved in methanol (1.5 ml), N-(6-bromo-4-methyl-2-pyridyl)ethane-1,2-diamine (69 mg, 0.3 mmol) was added and the resulting mixture was stirred under microwave heating at 140° C. for three hours. The mixture was concentrated under reduced pressure and the residue was washed several times with ethyl acetate and acetonitrile. The washing solutions were decanted from the solid, the combined washing solutions were evaporated to dryness under reduced pressure to yield 58 mg. MS(ESI) m/z=182.0 [M+1]+.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([CH3:39])[S:37][CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([CH3:39])[S:37][CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3csc(C)n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3csc(C)n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(2-methyl-thiazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][C@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[CH3:9])=[N:6][CH:7]=1
Reactant: C[C@H]1CCCN1
Reactant: Clc1ncc(Br)cn1
Solvent: ClCCl
Product: C[C@H]1CCCN1c1ncc(Br)cn1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
Solid 5-bromo-2-chloropyrimidine (27.5 g, 142 mmol) was added in three portions to a 500 mL flask containing (S)-2-methylpyrrolidine (20.24 ml, 213 mmol) stirred at room temperature. After 1 hr the resulting solids were dissolved in warm DCM, washed with water, brine, dried over MgSO4 and concentrated onto silica in vacuo. Column purified by silica gel chromatography to afford white crystalline solids (30.7 g, 89%), ESI-MS (EI+, m/z): 241.02, 1H NMR (Chloroform-d) δ: 8.31 (d, J=5.0 Hz, 2H), 4.33-4.14 (m, 1H), 3.61 (tt, J=7.6, 3.0 Hz, 1H), 3.56-3.41 (m, 1H), 2.23-1.88 (m, 3H), 1.88-1.63 (m, 1H), 1.25 (t, J=5.5 Hz, 3H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][CH2:21][CH2:22][NH:23][S:24]([NH:27]C(=O)OCC(Cl)(Cl)Cl)(=[O:26])=[O:25])=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(=O)C>O1CCCC1.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:16]([NH:20][CH2:21][CH2:22][NH:23][S:24]([NH2:27])(=[O:25])=[O:26])=[N:17][O:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
A solution of 2,2,2-trichloroethyl ({[2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl]amino}sulfonyl)carbamate (320 mg, 0.50 mmol; from Step Q, Method D) in tetrahydrofuran (THF, 4.0 mL) was stirred at room temperature. Acetic acid (0.30 mL, 5.3 mmol) and zinc flakes (160 mg, 2.5 mmol, 5.0 equiv.) were sequentially added. This reaction mixture was stirred at room temperature for 3 h. HPLC indicated reaction completion. The reaction mixture was filtered through Celite and the Celite was washed with THF. The combined filtrate was concentrated in vacuum and the resulting residue was dissolved in ethyl acetate (20 mL). The ethyl acetate solution was washed with saturated sodium carbonate and brine, dried over sodium sulfate and concentrated. The crude material was crystallized from ethyl acetate and diethyl ether to give the desired product (147 mg, 63%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:27]1[CH2:31][CH2:30][O:29][CH:28]1[C:32]1[O:36][C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:34][CH:33]=1>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:35]4[O:36][C:32]([CH:28]5[O:29][CH2:30][CH2:31][O:27]5)=[CH:33][CH:34]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5ccc(C6OCCO6)o5)cc34)cc2)cc1
Yield: 62.1 %

Procedure:
Prepared according to Procedure B from (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (1.5 g, 3.7 mmol) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl) -furan (1.9 g, 4.42 mmol) dissolved in dioxan (30 ml) and heated at reflux under nitrogen for 6 hr. The solvent was removed from the cooled reaction under vacuum, and the residual oil was triturated with iso-hexane/ethyl acetate to give the product (1.07 g, 62%) as a pale yellow solid; δH [2H6]-DMSO 9.96 (1H, b, NH), 8.80 (1H, s, 5-H), 8.51 (1H, s, 2-H), 8.18 (1H, d, 7-H), 7.80 (1H, d, 8-H), 7.70 (2H, d, 2′-H, 6′-H), 7.58–7.30 (5H, m, 5×Ph-H), 7.10 (3H, m, 3′-H, 5′-H, furan 3-H), 6.78 (1H, d, furan 4-H), 6.12 (1H, s, CH02), 5.18 (2H, s, PhCH2), 4.22-3.94 (4H, m, 2×CH2); m/z 466 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH2:13](N(CC)CC)[CH3:14]>C(O)C>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([CH:13]=[CH2:14])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1ccc2cccc(Br)c2n1
Reactant: CCN(CC)CC
Solvent: CCO
Product: C=Cc1cccc2ccc(C)nc12
Yield: 73.3 %

Procedure:
A suspension of 4.80 g (21.60 mmol) 8-bromo-2-methylquinoline (commercially available from ACB Block Ltd, Moscow, Russia), 0.89 g (1.10 mmol) PdCl2dppfCH2Cl2, 4.48 g (32.40 mmol) potassium vinyl tetrafluoroborate and 3.10 ml (22.10 mmol) triethylamine in 150 ml ethanol was heated at reflux for 3 h. The resulting yellow suspension was filtered and the filtrate evaporated to dryness. The residue was suspended in ethyl acetate, filtered and the filtrate extracted with water. The organic layer was evaporated to dryness and the isolated crude product purified by silica gel chromatography (CH2Cl2/ethyl acetate 98:2) to yield 2.68 g (73%) of the title compound as a colorless oil. MS: 169.1 (M+). 1H-NMR (300 MHz, CDCl3): 2.74 (s, 1H); 5.47 (dd, J=11.1, 1.6 Hz, 1H); 5.97 (dd, 17.9, 1.6 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H); 7.43 (t, J=7.7 Hz, 1H); 7.66 (dd, J=8.1, 1.2 Hz, 1H); 7.87 (dd, J=7.3, 1.2 Hz, 1H); 7.97 (d, J=8.4 Hz, 1H); 8.05 (dd, J=17.9, 11.1 Hz, 1H).