Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-:35])=[O:34])[CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccc(Cl)cc2)CC1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-[(4-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-[(4-chlorophenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: ClC(N(C)C)=C(C)C.[F:9][CH:10]([F:25])[O:11][C:12]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([NH2:24])=[CH:17][C:13]=1[C:14]([OH:16])=O.[F:26][C:27]([F:36])([F:35])[C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1.N1C=CC=CC=1>C(Cl)Cl.C1COCC1>[F:26][C:27]([F:35])([F:36])[C@H:28]1[CH2:29][CH2:30][C@H:31]([NH:34][C:14](=[O:16])[C:13]2[CH:17]=[C:18]([NH2:24])[C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:12]=2[O:11][CH:10]([F:9])[F:25])[CH2:32][CH2:33]1
Reactant: N[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: Nc1cc(C(=O)O)c(OC(F)F)cc1[N+](=O)[O-]
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OC(F)F)cc1[N+](=O)[O-]
Reaction time: 5 h

Procedure:
(1-Chloro-2-methyl-propenyl)-dimethylamine (102 μl) is added to a mixture of 2-(difluoro-methoxy)-5-amino-4-nitro-benzoic acid (175 mg, 0.705 mmol, prepared in analogy to WO2010/034797), 5 mL THF and 10 mL DCM and it is stirred for 5 h. Then trans-4-trifluoromethyl-cyclohexylamine (158 mg, 0.776 mmol) and pyridine (139 μL, 1.77 mmol) are added and it is stirred overnight. The solvent is removed i. vac., half-saturated aq. NaHCO3— solution is added and it is extracted with DCM. The organic layers are dried with Na2SO4, filtered, concentrated and purified via preparative HPLC (Method F).
Reaction SMILES: [CH2:1]([C:3]1[S:44][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:27][C:26]=3[F:43])[C:8](=[O:23])[N:9]([CH2:12][CH:13]([OH:22])[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[C:45](OC(=O)C)(=[O:47])[CH3:46].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:45]([O:22][CH:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:12][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:44][C:6]=2[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][C:26]=2[F:43])[C:8]1=[O:23])(=[O:47])[CH3:46]
Reactant: CCc1cc2c(=O)n(CC(O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3F)c2s1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc2c(=O)n(CC(OC(C)=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of 6-ethyl-1-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[2-hydroxy-2-(4-methoxyphenyl)ethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.3 g), acetic anhydride (0.07 mL), triethylamine (0.1 mL), N,N-dimethylpyridin-4-amine (0.006 g) and methylene chloride (20 mL) was stirred at room temperature for 16 hr. The reaction mixture was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.23 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[C:21]([O:32][CH3:33])=[C:22]([N:27]([CH3:31])[C:28](=[O:30])[CH3:29])[CH:23]=[C:24]([F:26])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:26][C:24]1[CH:25]=[C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)[C:21]([O:32][CH3:33])=[C:22]([N:27]([CH3:31])[C:28](=[O:30])[CH3:29])[CH:23]=1
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: COc1c(C(=O)C=CN(C)C)cc(F)cc1N(C)C(C)=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1c(-c2ccnc3c(C(=O)c4cccs4)cnn23)cc(F)cc1N(C)C(C)=O
Yield: 40.5 %

Procedure:
A mixture of 0.180 g (0.93 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.275 g (0.93 mmol) of N-[3-(3-dimethylamino-acryloyl)-5-fluoro-2-methoxy-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 160 mg of N-{5-fluoro-2-methoxy-3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 40%).
Reaction SMILES: [C:1]([CH:3]1[CH2:13][C:12]2[C:14]3[C:9]([N:10]([CH2:15][C:16]4[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=4)[N:11]=2)=[N:8][C:7]([N:26](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:6][C:5]=3[S:4]1)#[N:2].C[O:42]C1C(C)=CN=C(CN2C3C4C(CC(C)SC=4N=C(N)N=3)=N2)C=1C.Cl.C(=O)(O)[O-].[Na+]>O>[NH2:26][C:7]1[N:8]=[C:9]2[C:14]3[C:12]([CH2:13][CH:3]([C:1]([NH2:2])=[O:42])[S:4][C:5]=3[N:6]=1)=[N:11][N:10]2[CH2:15][C:16]1[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=1
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc42)SC(C#N)C3)c1C
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C)C3)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(N)=O)C3)c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
A mixture composed of di-tert-butyl {7-cyano-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylen-4-yl}imidodicarbonate of Step 4) of Example 3 (30 mg) and concentrated hydrochloric acid (1 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water and neutralized with a saturated sodium bicarbonate solution. The precipitate was collected by filtration and sequentially washed with a saturated sodium bicarbonate solution and water. Then, the resulting solid was dried to obtain the title compound (18.5 mg, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]2[C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])=[CH:5][CH:4]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:44])C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>O1CCCC1.O.C(OCC)(=O)C>[OH:44][C@H:12]([CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:13]([N:15]1[C@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][O:17][C:16]1=[O:26])=[O:14]
Reactant: COc1ccc(CCCCC(=O)N2C(=O)OC[C@H]2c2ccccc2)cc1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CCC[C@@H](O)C(=O)N2C(=O)OC[C@H]2c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
(4R)-3-[5-(4-Methoxyphenyl)pentanoyl]-4-phenyl-1,3-oxazolidin-2-one (Reference Example 20) (1.0 g) was dissolved in tetrahydrofuran (10 ml) and the resulting solution was cooled to −78° C., followed by adding thereto sodium hexamethyldisilazide (1M, 3.4 ml). After 30 minutes, a solution of Davis reagent (0.9 g) in tetrahydrofuran (5 ml) was added dropwise thereto. After stirring for 1 hour, a solution of camphorsulfonic acid (1.5 g) in tetrahydrofuran (5 ml) was added thereto and stirred for 30 minutes. Ethyl acetate and water were added to the reaction mixture to effect separation and extraction. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution, dried, concentrated, and then the residue was purified by a silica gel chromatography (100 g, ethyl acetate:hexane=1:3) to obtain (4R)-3-[(2R)-2-hydroxy-5-(4-methoxyphenyl)pentanoyl]-4-phenyl-1,3-oxazolidin-2-one (0.75 g).
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18]([S:24]([N:27](CC1C=CC(OC)=CC=1OC)[C:28]1[S:29][CH:30]=[CH:31][N:32]=1)(=[O:26])=[O:25])=[CH:19]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18]([S:24]([NH:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1)(=[O:26])=[O:25])=[CH:19]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4C(=O)c4ccccc4)cccc3c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccccc1)N1CCCC1c1cccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-(1-benzoylpyrrolidin-2-yl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (0.040 g, 0.065 mmol) was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred for 15 minutes at room temperature. The reaction was diluted with methanol and concentrated. The material was triturated in diethyl ether, filtered, and the solids were washed with diethyl ether. The solids were collected and vacuum dried overnight to afford 5-(1-benzoylpyrrolidin-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=12.79 (br. s., 1H), 8.48 (s, 1H), 8.38 (d, J=8.8 Hz, 1H), 8.11-7.95 (m, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.75-7.57 (m, 4H), 7.49 (br. s., 3H), 7.26 (br. s., 1H), 7.17-6.96 (m, 1H), 6.84 (d, J=4.2 Hz, 1H), 5.94 (br. s., 1H), 3.90 (br. s., 1H), 3.58 (br. s., 1H), 2.70-2.58 (m, 1H), 1.89 (br. s., 2H), 1.74 (br. s., 1H). m/z (ESI) 464.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:13](=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=2)[CH3:10])[C:5]([I:36])=[CH:4][N:3]=1.[OH-].[NH4+:38]>O1CCOCC1>[NH2:38][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:13](=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=2)[CH3:10])[C:5]([I:36])=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: COc1ncc(-c2cccc3cc([C@H](C)Nc4nc(Cl)ncc4I)n(-c4ccccc4)c(=O)c23)cn1
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ncc(-c2cccc3cc([C@H](C)Nc4nc(N)ncc4I)n(-c4ccccc4)c(=O)c23)cn1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
To a solution of (S)-3-(1-((2-chloro-5-iodopyrimidin-4-yl)amino)ethyl)-8-(2-methoxypyrimidin-5-yl)-2-phenylisoquinolin-1(2H)-one 3 (800 mg, 1.31 mmol) in anhydrous 1,4-dioxane (4 mL) in a sealed tube, ammonium hydroxide (7 mL) was added and the resulting mixture was stirred at 110° C. for 20 h. The mixture was allowed to cool to RT, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography using a silica gel cartridge and eluting with 0-8% MeOH-DCM to afford the product, (S)-3-(1-((2-amino-5-iodopyrimidin-4-yl)amino)ethyl)-8-(2-methoxypyrimidin-5-yl)-2-phenylisoquinolin-1(2H)-one 4.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:24])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32]>C1(C)C=CC=CC=1.CCO.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:31]([C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:24])[N:8]3[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:19])=[O:20])=[CH:14][CH:13]=3)=[CH:4][CH:3]=2)=[CH:35][CH:34]=1)#[N:32]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CN(C)S(=O)(=O)c1ccc(CN2C(=O)Cc3ccc(Br)cc32)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-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)c1ccc(CN2C(=O)Cc3ccc(-c4ccc(C#N)cc4)cc32)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
4-(6-Bromo-2-oxo-2,3-dihydro-indol-1-ylmethyl)-N,N-dimethyl-benzenesulfonamide (1.60 g, 4.24 mmol) and tetrakis(triphenylphosphine)palladium (0) (195 mg, 0.17 mmol) were dissolved in a solution of 25 ml of toluene and 4 ml of EtOH under an atmosphere of dry N2. To the reaction mixture was added a solution of aqueous sodium carbonate (Na2CO3) (1.03 g, 9.75 mmol) dissolved in 6 ml of water followed by 4-cyanobenzene boronic acid (1.55 g, 10.6 mmol). The reaction mixture was heated to 100° C. and stirred at this temperature overnight. The reaction mixture was concentrated under vacuum and then partitioned between DCM and saturated aqueous NaHCO3. The DCM layer was dried over MgSO4, filtered and concentrated under vacuum to give a brown oil. The brown oil was chromatographed on silica gel eluting with a gradient from DCM to DCM/MeOH (98:2) to give 1.15 g of the titled compound as an orange solid in 63% yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][NH2:21])[CH3:17]>C(OCC)(=O)C>[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][NH:21][C:4]1[N:5]=[N:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([CH3:1])[N:3]=1)[CH3:17]
Reactant: CCN(CC)CCN
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Solvent: CCOC(C)=O
Product: CCN(CC)CCNc1nnc(-c2ccccc2)c(C)n1
Yield: 64.2 %

Procedure:
A mixture of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (2.17 g) and N,N-diethylethylenediamine (2.99 g) was heated at 150° C. to 160° C. for 17 hours. The reaction mixture was dissolved in ethyl acetate, washed with water and brine, and then dried over sodium sulfate, which was treated with silical gel and filtered by suction. The filtrate was evaporated to dryness and the resulting residue was crystallized with diisopropyl ether under ice cooling. The resultant crystals were collected by filtration, washed with diisopropyl ether and dried to give 3-(2-diethylaminoethylamino)-5-methyl-6-phenyl-1,2,4-triazine (1.83 g).
Reaction SMILES: [CH2:1]([NH:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.[CH2:20]([N:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])[CH3:21]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:20]([N:22]([CH2:26][CH3:27])[C:23]([N:11]([OH:12])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:24])[CH3:21]
Reactant: CCCCCCCCCCNO
Reactant: CCN(CC)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCN(O)C(=O)N(CC)CC
Reaction time: 2 h

Procedure:
To a stirred solution of N-decylhydroxylamine (2.60 g, 15.0 mmol) and triethylamine (2.3 ml) in tetrahydrofuran (hereinafter THF) (30 ml) at 0° C. was added dropwise N,N-diethylcarbamyl chloride (1.92 ml). After two hours, 4-(dimethylamino)pyridine (1.3 g) was added. After 18 hours, the reaction mixture was quenched with 1N hydrochloric acid (hereinafter HCl), extracted with hexane, and the organic solution was dried over MgSO4, filtered and evaporated. Trituration of the residue with hexane at -30° C. gave the title compound as a while solid (3.1 g, mp 35°-37° C.).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([OH:14])=[O:13])=[CH:3]1.S(=O)(=O)(O)O.[CH3:20]O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([O:14][CH3:20])=[O:13])=[CH:3]1
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 20 g of 1-methyl-3-indole acetic acid in 120 mL of methanol was added 0.5 mL of concentrated sulfuric acid and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated by evaporation and the residue was dissolved in dichloromethane, and then poured into a solution of aqueous saturated sodium bicarbonate. The mixture was then extracted with dichloromethane and excess magnesium sulfate was added to the extract. The product was purified by distillation to give 25 g of yellow oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:21])[C@H:11]([NH2:20])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([NH:29][C@@H:30]([C:42](O)=[O:43])[CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(OC(C)(C)C)=O>>[C:35]([N:20]([C@@H:11]([CH:10]([C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[OH:21])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:42](=[O:43])[C@H:30]([NH2:29])[CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H](CCc1ccccc1)C(O)c1nc2ccccc2s1
Product: CC(C)(C)OC(=O)NCCC[C@@H](N)C(=O)N(C(=O)OC(C)(C)C)[C@H](CCc1ccccc1)C(O)c1nc2ccccc2s1

Procedure:
(1R)-1-[(RS)-(2-Benzothiazolyl)hydroxymethyl]-3-phenylpropylamine (72 mg) was coupled to N,N′-bis-Boc-D-ornithine to afford the title compound (11 mg) as a glassy solid: 1H NMR (400 MHz, CDCl3, 3:2 mixture of diastereomers) δ1.41 (s, 9H), 1.44 (s, 9H), 1.60 (m, 2H ), 1.19 (m, 4H), 2.20 (m, 2H), 2.72-2.91 (m, 2H), 4.11 (m, 1H), 4.31 (m, 0.4H), 4.41 (m, 0.6H), 5.06 (m, 0.6H), 5.19 (d, J=1.1 Hz, 0.4), 7.20 (m, 3H), 7.26 (m, 2H), 7.40 (t, J=8.5 Hz, 1H), 7.49 (t, J=9.3 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H ), and 7.98 (d, J=9.4 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[CH:7]=1)=[O:5])[CH3:2].[I:13]I.O.S(=O)(O)[O-].[Na+]>CC([O-])=O.ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:7]=1[I:13])=[O:5])[CH3:2]
Reactant: II
Reactant: CCOC(=O)c1cc(C)nn1C
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)c1c(I)c(C)nn1C

Procedure:
1,3-Dimethyl-5-pyrazolcarboxylic acid ethyl ester (185 g, 1.1 mol), iodine (140 g, 0.55 mol) and HIO3 (38.7 g, 0.22 mol) are heated, under reflux, in acetic acid glacial (450 ml), water (150 ml) and 1,2-dichloroethane (150 ml) for 1.5 hours. The mixture is discoloured with saturated sodium bisulfite, evaporated under reduced pressure and the product extracted with ether. The organic phase is washed with sodium bisulfite and aqueous sodium bicarbonate solution.
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11](=[CH:14][CH2:15][CH3:16])[CH:12]=[O:13]>CC(C)=O>[CH2:15]([CH:14]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:8][CH:12]([OH:13])[CH:11]1[CH3:10])[CH3:16]
Reactant: N=C(N)c1ccccc1
Reactant: CCC=C(C)C=O
Solvent: CC(C)=O
Product: CCC1N=C(c2ccccc2)NC(O)C1C
Temperature: 25 °C

Procedure:
To an ice cooled mixture of 19.98 g (16.6 mmol) of benzamidine in 80 mL of acetone, was added dropwise over two hours, a solution of 16.35g (16.6 mmol) 2-methyl-2-pentenal and 0.055 g 1,4-hydroquinone, in acetone. The mixture was left to stir cold and warm to room temperature over 20 hours. The product was isolated by vacuum filtration and was washed with a minimal amount of acetone. 15.6 g (44%) of 6-ethyl-5-methyl-4-hydroxy-2-phenyl-3,4,5,6-tetrahydropyrimidine was collected, as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:11]([NH:13][C@@H:14]([CH3:18])[CH2:15][S:16][CH3:17])=[O:12].Cl.CN(C)CCCN1C=CN(C(N2C=CN(CC)C2)=O)C1.[F:40][C:41]([F:62])([F:61])[C:42]1[CH:43]=[C:44]([CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1)[CH2:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[C:48]([CH3:53])[CH:47]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[F:40][C:41]([F:61])([F:62])[C:42]1[CH:43]=[C:44]([CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1)[CH2:45][C:46]1[CH:52]=[CH:51][C:49]([NH:50][C:5](=[O:7])[C:4]2[C:3](=[C:2]([I:1])[CH:10]=[CH:9][CH:8]=2)[C:11]([NH:13][C@@H:14]([CH3:18])[CH2:15][S:16][CH3:17])=[O:12])=[C:48]([CH3:53])[CH:47]=1
Reactant: Cc1cc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1N
Reactant: CSC[C@H](C)NC(=O)c1c(I)cccc1C(=O)O
Agent: CCN1C=CN(C(=O)N2C=CN(CCCN(C)C)C2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CSC[C@H](C)NC(=O)c1c(I)cccc1C(=O)Nc1ccc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
3-Iodo-N-((S)-1-methyl-2-methylthioethyl)-phthalamic acid (0.38 g) and N-(3-dimethylaminopropyl)-N′-ethylcarbonyldimidazole hydrochloride (0.2 g) were stirred in methylene chloride (10 ml) at room temperature for 30 minutes. 4-(3,5-Bis-trifluoromethyl-benzyl)-2-methylaniline (0.3 g) and p-toluenesulfonic acid hydrate (0.02 g) were added thereto and stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography to obtain N1-[4-(3,5-bis-trifluoromethyl-benzyl)-2-methylphenyl]-3-iodo-N2-((S)-1-methyl-2-methylthioethyl) phthalamide (0.15 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:25])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[CH:16][CH:15]=2)[CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:22][CH2:21][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:25])=[CH:15][CH:16]=1)([CH3:24])[CH3:23]
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)cc(-c3ccccc3)n2n1
Temperature: 110 °C
Yield: 49 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide (4G, 44 mg, 1.0 equivalent), phenylboronic acid (1.5 equivalents) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.09 equivalents) in 2:1 dioxane/saturated aqueous NaHCO3 (0.125 M with respect to 4G) was warmed to 110° C. in a microwave reactor. The reaction mixture was cooled to room temperature, diluted with methanol, filtered, and purified via preparative HPLC to afford the title compound (49%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 6H), 2.40 (s, 3H), 3.47 (s, 2H), 4.76 (br. s., 1H), 6.40 (s, 1H), 7.53 (d, J=8.59 Hz, 2H), 7.58-7.68 (m, 3H), 7.94-8.04 (m, 3H), 8.04-8.10 (m, 2H), 11.19 (s, 1H). ESI-MS: m/z 401.1 (M+H)+.