Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].[K+].[NH4+].[Cl-]>CC(N(C)C)=O.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>[C:19]1([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:30]=[N:25][CH:26]=[N:27][CH:28]=3)=[CH:3][CH:4]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cncnc1
Reactant: O/N=C(\CC(c1ccccc1)c1ccc(Br)cc1)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O/N=C(\CC(c1ccccc1)c1ccc(-c2cncnc2)cc1)c1ccncc1
Yield: 451 %

Procedure:
To a stirred solution of (E)-3-(4-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 5, 10 mg) and pyrimidine-5-boronic acid (49 mg) in a mixture of DMA/H2O (2.1 mL, 20:1) tetrakis(triphenylphosphine)palladium (0) (36 mg), triphenylphosphine (17 mg) and potassium fluoride (31 mg) were added. The mixture was irradiated in the microwave at 140° C. for 15 min. A saturated aqueous solution of NH4Cl was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on an ISOLUTE Flash NH2 cartridge (EtOAc) to yield the title compound (45 mg, 45%) as a white foam, MS (ESI+): m/z=381.1 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH3:12]>C(O)(=O)C.C(O)C.[Fe]>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([Cl:11])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(Cl)ccc(N)c1Cl
Yield: 96 %

Procedure:
To a solution of 2,6-dichloro-3-nitrotoluene (50 g) in acetic acid (400 ml) and ethanol (200 ml) was added iron (67.8 g) and the mixture was refluxed for 1.5 hours under nitrogen atmosphere. The insoluble material was filtered off and the filtrate was concentrated. To the residue was added a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate three times. The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate three times and brine, dried over magnesium sulfate, and concentrated in vacuo to give 2,4-dichloro-3-methylaniline (41 g).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][N:25]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(S(C)(=O)=O)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (34.2 mg, 0.059 mmol) and triethylamine (0.025 mL, 0.178 mmol) in DCM (0.5 mL) was added methanesulfonyl chloride (6.9 μL, 0.089 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (14.7 mg, 41.6%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.6 Hz, 6H), 1.82-1.93 (m, 2H), 2.02-2.08 (m, 2H), 2.77 (t, J=5.7 Hz, 2H), 2.84-2.93 (m, 2H), 2.98 (s, 3H), 3.24-3.32 (m, 2H), 3.45 (t, J=5.9 Hz, 2H), 4.10-4.18 (m, 3H), 4.50-4.55 (m, 1H), 5.67 (br s, 1H), 6.99-7.04 (m, 1H), 7.26-7.35 (m, 2H); ESI-MS m/z [M+H]+ 482.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([C:17](=[O:22])N(OC)C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][C:29](=[O:38])[C:30]1[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:37])([CH3:27])([CH3:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:17](=[O:22])[CH2:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[C:29](=[O:38])[NH:28][C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Reactant: Cc1cccc(Cl)c1C(=O)NC(C)(C)C
Product: CC(C)(C)NC(=O)c1c(Cl)cccc1CC(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-2-(2-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (1.5 g, 4.6 mmol) and N-tert-butyl-2-chloro-6-methyl-benzamide (1.5 g, 4.6 mmol), followed by purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:17](OCOCCOC)=[O:18].[OH-].[Na+]>O1CCCC1>[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[CH3:29])[CH:17]=[O:18]
Reactant: COCCOCOC(=O)c1ccc(C)c(OCOCCOC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOCOc1cc(C=O)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
Lithium aluminum hydride (0.35 g) was added by small portions over 12 minutes to an ice-cooled solution of (2-methoxyethoxy)methyl 3-[(2-methoxyethoxy)methoxy]-4-methylbenzoate (3.5 g) in tetrahydrofuran (20 ml) below 5° C. under nitrogen atmosphere. After the mixture was stirred at the same temperature for 30 minutes, 2N sodium hydroxide (0.5 ml) was added to the mixture. After the mixture was stirred for 30 minutes, the insoluble materials were removed by filtration and washed with tetrahydrofuran. The filtrate and the washing were combined, and evaporated under reduced pressure. The residue was dissolved into ethyl acetate, and manganese (IV) oxide (3.5 g) was added to the solution. After being stirred under reflux for 2 hours, the reaction mixture was filtered through Celite® and the insoluble mass was washed with ethyl acetate. The filtrate and the washing were combined and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using mixed solvents of hexane and ethyl acetate (10:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give 3-[(2-methoxyethoxy)methoxy]-4-methylbenzaldehyde (1.7 g) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[O:9])[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)c1ccccn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccccn3)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use pyridine-2-carboxylic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (70% yield). 1H NMR (300 MHz, CDCl3) δ 8.60-8.58, 8.03, 7.98, 7.86-7.79, 7.73-7.71, 7.39-7.35, 6.98, 3.96-3.83, 3.54, 1.50, 0.78-0.69, 0.47-0.41, 0.08-0.05. MS (ES+) m/z 381.2 (M+1).
Reaction SMILES: [F:1][CH:2]([F:40])[C:3]1[N:7]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:22][CH2:21][N:20]([S:23]([CH:26]=[CH2:27])(=[O:25])=[O:24])[CH2:19][CH2:18]4)[N:15]=[CH:16][C:11]3=[C:10]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1.[CH3:41][NH:42][CH3:43]>C1COCC1.O>[F:40][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:18][CH2:19][N:20]([S:23]([CH2:26][CH2:27][N:42]([CH3:43])[CH3:41])(=[O:24])=[O:25])[CH2:21][CH2:22]4)[N:15]=[CH:16][C:11]3=[C:10]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCC(n2ncc3c(N4CCOCC4)nc(-n4c(C(F)F)nc5c(OC)cccc54)nc32)CC1
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2cnn(C3CCN(S(=O)(=O)CCN(C)C)CC3)c2n1
Reaction time: 0.17 h
Yield: 93 %

Procedure:
A suspension of the above vinylsulfonamide (140 mg, 0.243 mmol) in 100 mL THF was treated with 10 mL of 40% aq. dimethylamine to give a clear solution. After 10 min, the mixture was diluted with water and the THF was removed under vacuum to give 140 mg (93% yield) of N-[2-({4-[6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylamine as a white solid: 1H NMR (CDCl3) δ 7.99 (s, 1H), 7.82 (dd, J=8.4, 0.6 Hz, 1H), 7.45 (t, JHF=53.6 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 4.85 (tt, J=11.1, 4.1 Hz, 1H), 4.07 (s, 3H), 4.06 (m, 4H), 4.02 (m, 1H), 3.98 (m, 1H), 3.91 (m, 4H), 3.18-3.07 (m, 4H), 2.80 (dd, J=8.3, 6.4 Hz, 2H), 2.41 (dq, J=11.7, 4.2 Hz, 2H), 2.29 (s, 6H), 2.14 (dd, J=12.5, 2.5 Hz, 2H).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][C@H:13]([CH2:20][OH:21])[NH:14][CH2:15]2.N1C=CN=C1.[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.ClCCl.C(OC)(C)(C)C.CN(C)C=O>[Br:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][C@H:13]([CH2:20][O:21][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[NH:14][CH2:15]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H]1Cc2c(Br)cccc2CN1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1Cc2c(Br)cccc2CN1
Temperature: 10 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
Add tert-butyldimethylchlorosilane (193.7 g, 1.29 mol) to a mixture of [(3R)-5-bromo-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol (148.9 g, 0.58 mol), 1H-imidazole (202.9 g, 2.92 mol), 4-dimethylaminopyridine (0.72 g, 5.84 mmol) and N,N-dimethylformamide (1.04 L) in dichlormethane (2.61 L) at 20° C. and stir in an appropriate vessel. After 3 hours, cool the mixture to 10° C. and add saturated aqueous ammonium chloride solution (1.3 L). Extract the aqueous with dichloromethane and wash the combined organic extracts with brine (2×2 L), dry over anhydrous sodium sulfate and concentrate under reduced pressure to give a residue. Dissolve the residue in methyl tert-butyl ether (1.5 L) and wash with brine (2×1 L). Dilute the organic phase with toluene (5 L) and concentrate under reduced pressure to give a residue. Add toluene (2.6 L) to the residue and concentrate under reduced pressure to give the title compound (210 g, 0.53 mol). MS (m/z). 356(M+1 (79Br)), 358(M+1 (81Br)).
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:25]([CH:28]1[S:32][CH:31]([C:33](O)=[O:34])[CH2:30][CH2:29]1)[CH2:26][CH3:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:25]([CH:28]1[S:32][CH:31]([C:33]([O:24][C:21]2[CH:20]=[CH:19][C:18]([C:15]3[N:16]=[CH:17][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:13][N:14]=3)=[CH:23][CH:22]=2)=[O:34])[CH2:30][CH2:29]1)[CH2:26][CH3:27]
Reactant: CCCC1CCC(C(=O)O)S1
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCc1cnc(-c2ccc(OC(=O)C3CCC(CCC)S3)cc2)nc1

Procedure:
4.9 g of 4-(5-undecyl-pyrimidin-2-yl)phenol, 2.6 g of 5-propyl-tetrahydrothiophene-2-carboxylic acid (prepared as shown in Scheme 1) and 3.1 g of dicyclohexylcarbodiimide are stirred for 24 h in 50 ml of dichloromethane at room temperature. Filtration, removal of the dichloromethane by distillation, purification by chromatography (silica gel; dichloromethane/heptane) and recrystallization from acetonitrile affords the target compound as colorless crystals.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:15](=[O:18])[N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:13](=[O:25])[N:12]([CH2:26][C:27]4[O:31][N:30]=[C:29]([CH2:32][O:33][CH3:34])[N:28]=4)[C:11]=3[CH:10]=2)=[C:5]([O:35][CH3:36])[CH:4]=1.[CH2:37]([O:39][C:40]1[C:49]([O:50][CH3:51])=[CH:48][C:47]2[C:46]([C:52]3[CH:60]=[CH:59][C:55]([C:56](O)=[O:57])=[CH:54][CH:53]=3)=[N:45][C@@H:44]3[CH2:61][CH2:62][S:63][CH2:64][C@@H:43]3[C:42]=2[CH:41]=1)[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:37]([O:39][C:40]1[C:49]([O:50][CH3:51])=[CH:48][C:47]2[C:46]([C:52]3[CH:53]=[CH:54][C:55]([C:56]([N:22]4[CH2:23][CH2:24][CH:19]([N:14]5[C:15](=[O:18])[C:16]6[S:17][C:9]([C:6]7[CH:7]=[CH:8][C:3]([F:2])=[CH:4][C:5]=7[O:35][CH3:36])=[CH:10][C:11]=6[N:12]([CH2:26][C:27]6[O:31][N:30]=[C:29]([CH2:32][O:33][CH3:34])[N:28]=6)[C:13]5=[O:25])[CH2:20][CH2:21]4)=[O:57])=[CH:59][CH:60]=3)=[N:45][C@@H:44]3[CH2:61][CH2:62][S:63][CH2:64][C@@H:43]3[C:42]=2[CH:41]=1)[CH3:38]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: COCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6OC)cc5n(Cc5nc(COC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
6-(4-fluoro-2-methoxyphenyl)-1-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (415 mg; compound B84) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (383 mg; compound C10) and HBTU (322 mg) in DCM (10 ml) in the presence of DIPEA (498 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc, 100/0/to 0/100 (v/v)] and by preparative HPLC as a solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([CH2:15][N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].FC(F)(F)C(O)=O>ClCCl>[CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([CH2:15][N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(c2)N(S(C)(=O)=O)CCO3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1CCOc2ccc(CN3CCNCC3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.2 %

Procedure:
tert-Butyl 4-(4-methanesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)piperazine-1-carboxylate (2.5 g, 6.1 mmol) was dissolved in dichloromethane (50 mL) and treated with trifluoroacetic acid (182 mmol). The resulting mixture was stirred at ambient temperature for 3 h then evaporated to dryness under reduced pressure. The residue was extracted with hot ethanol and the combined extracts evaporated to dryness under reduced pressure. Chromatography on SiO2, eluting with 0.880 ammonia/methanol/dichloromethane (1:9:90), gave the title compound (1.2 g, 63%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Br[CH2:12][CH2:13][CH2:14][Cl:15].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:12][CH2:13][CH2:14][Cl:15])[N:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: ClCCCn1ncc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.2 %

Procedure:
To a solution of 5-bromo-1H-indazole (3.0 g, 15 mmol) in DMSO (15 mL) was added 1-bromo-3-chloropropane (2.0 mL, 20 mmol) and K2CO3 (6.33 g, 45.9 mmol). The reaction was stirred at room temperature for 72 h; then the reaction was diluted with methylene chloride (100 mL) and washed with a 5% LiCl solution (4×). The organics were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (40 g ISCO column, hexanes/EtOAc, 95:5 to 65:35) gave the title compound (2.14 g, 51%) as a white powder: 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J=0.5, 1H), 7.87 (d, J=1.5 Hz, 1H), 7.48-7.45 (dd, J=8.9, 1.8 Hz, 1H), 7.38 (d, J=8.9 Hz, 1H), 4.54 (t, J=6.4 Hz, 2H) 3.47 (t, J=6.0 Hz, 2H) 2.42-2.37 (m, 2H); ESI MS m/z 273 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[C:24]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[C:18]([O:25][CH3:26])=[CH:17][CH:16]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+].O.O.Cl>C(O)C>[C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[C:24]3[O:23][CH2:22][CH2:21][O:20][C:19]=3[C:18]([O:25][CH3:26])=[CH:17][CH:16]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cccc(NC(=O)c2ccc(OC)c3c2OCCO3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)Nc2cccc(C(=O)O)c2)c2c1OCCO2
Yield: 80 %

Procedure:
Compound 185 (0.19 g) obtained in Example 185 was suspended in ethanol (1 ml), mixed with a 24% aqueous sodium hydroxide solution (1.3 ml), and heat-refluxed for 2 hours. The resultant was allowed to stand for cooling, mixed with water, and adjusted to PH 2 by adding 2N hydrochloric acid water. The precipitated solid was collected by filtration to give Compound 186(0.14 g, 80%) as colorless crystals.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[C:15]([O:23][CH3:24])[CH:14]=2)[N:5]=1)[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O.C(Cl)Cl>C(Cl)Cl.CO>[CH2:1]([S:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:21])=[O:20])=[C:15]([O:23][CH3:24])[CH:14]=2)[N:5]=1)[CH3:2]
Reactant: C1CCNCC1
Reactant: CCSc1nc(-c2ccc(S(=O)(=O)Cl)c(OC)c2)cc2nccn12
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCSc1nc(-c2ccc(S(=O)(=O)N3CCCCC3)c(OC)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(5-Ethylsulfanyl-imidazo[1,2-c]pyrimidin-7yl)-2-methoxy-benzenesulfonylchloride (200 mg, 0.52 mmol) and piperidine (89 mg, 1.04 mmol) in CH2Cl2: MeOH (2:1, 5 ml). was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was carried out with CH2Cl2. The combined organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated to give the crude product of 5-Ethylsulfanyl-7-[3-methoxy-4-(piperidine-1-sulfonyl)-phenyl]imidazo[1,2-c]pyrimidine which was purified by preparative thin layer chromatography (45 mg, 20%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:11]([CH2:12][CH3:13])[C:10]([CH3:14])=[N:9][C:8]=1[CH3:15])=O.C(=O)(O)O.[C:21]1([NH:27][C:28]([NH2:30])=[NH:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C[O-].[Na+].O>CC(N(C)C)=O>[NH:27]([C:28]1[N:30]=[C:5]([C:7]2[N:11]([CH2:12][CH3:13])[C:10]([CH3:14])=[N:9][C:8]=2[CH3:15])[CH:4]=[CH:3][N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: CCn1c(C)nc(C)c1C(=O)C=CN(C)C
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCn1c(C)nc(C)c1-c1ccnc(Nc2ccccc2)n1
Temperature: 150 °C
Yield: 69.2 %

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-ethyl-2,4-dimethylimidazole (Method 10; 5.65 g, 25.6 mmol), phenylguanidine hydrogen carbonate (6.05, 30.7 mmol) and sodium methoxide (3.47 g, 64.2 mmol) were suspended in anhydrous DMA (80 ml) and the mixture heated at 150° C. for 18 hours. The reaction mixture was allowed to cool to ambient temperature and poured into water (50 ml). The solution was extracted EtOAc (2×50 ml). The combined extracts were washed with water (2×50 ml) and then brine (2×50 ml), dried and the volatiles removed by evaporation. The residue purified by flash silica chromatography DCM:MeOH (increasing in polarity from 100:0 to 96:4) to give the title compound (5.2 g, 70%) as an orange oil. NMR: 1.06 (t, 3H), 2.22 (s, 3H), 2.34 (s, 3H), 4.32 (q, 2H), 6.83 (d, 1H), 6.97 (t, 1H), 7.28 (t, 2H), 7.70 (d, 2H), 8.43 (d, 2H), 9.40 (s, 1H); m/z 294.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:33][CH2:32][N:24]2[C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=3[CH:31]=[C:23]2[C:22]1=[O:34])(=[O:3])[CH3:2].Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:49]=[C:48]([CH2:50][O:51][CH3:52])[N:47]([CH3:53])[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:33][CH2:32][N:24]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=[C:23]3[C:22]2=[O:34])=[CH:8][CH:9]=[CH:10][C:11]=1[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:49]=[C:48]([CH2:50][O:51][CH3:52])[N:47]([CH3:53])[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1)(=[O:3])[CH3:2]
Reactant: COCc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Product: COCc1cc(Nc2cc(-c3cccc(N4CCn5c(cc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)nn1C
Yield: 71.9 %

Procedure:
Following Example 148b, 557 mg of 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a and 327 mg of 5-bromo-3-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one 176c were reacted to give 176d as a yellow solid (420 mg, 72%). LCMS: [M+H]+ 585