Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][CH:10]=O)=[O:7])(C)(C)C.Cl.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C@@H:31]([NH2:36])CC(O)=O)=[CH:22]1.C([BH3-])#N.[Na+]>CO.C1COCC1.C(OCC)(=O)C>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C@H:31]2[NH:36][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]2=[O:7])=[CH:22]1
Reactant: CC(C)(C)OC(=O)N(CC=O)CCc1ccccc1
Reactant: N[C@@H](CC(=O)O)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1[C@@H](Cc2c[nH]c3ccccc23)NCCN1CCc1ccccc1

Procedure:
Combine N-t-butoxycarbonyl-N-(2-oxo-ethyl)-2-phenyl-ethylamine (5.03 g, 19.0 mmol) and (R)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamine hydrochloride salt ((R)-tryptophan methyl ester hydrochloride salt) (4.9 g, 19.42 mmol) in methanol (50 mL) and stir for 30 minutes. Add sodium cyanoborohydride in solution (15.0 mL, 1M in THF, 15.0 mmol) and stir under an inert atmosphere for 16.5 hours. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo. Chromatograph on silica gel eluting with 50% ethyl acetate/hexane to give the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9].[NH2:14][CH:15]1[CH2:19][CH2:18][C:17](=[O:20])[C:16]1([CH3:22])[CH3:21]>>[CH3:21][C:16]1([CH3:22])[C:17](=[O:20])[CH2:18][CH2:19][CH:15]1[NH:14][C:2]1[C:3]2[N:4]([CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9]
Reactant: NC(=O)c1cnn2cccc2c1Cl
Reactant: CC1(C)C(=O)CCC1N
Product: CC1(C)C(=O)CCC1Nc1c(C(N)=O)cnn2cccc12
Yield: 18.5 %

Procedure:
According to the procedure described in Example 1, 4-chloropyrrolo[1,2-b]-pyridazine-3-carboxamide (100 mg, 0.511 mmol, from Preparation 3) was reacted crude 3-amino-2,2-dimethylcyclopentanone (195 mg, from Step 2). Purification with reverse phase HPLC (Sunfire S10 30×250 mm column), eluting with 30 to 100% solvent B (10% methanol-90% water-0.1% TFA) in solvent A (90% methanol-10% water-0.1% TFA), gave the title compound (27 mg, 18% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 8.15 (1 H, s), 7.50-7.70 (1 H, m), 6.86-7.37 (1 H, m), 6.47-6.90 (1 H, m), 4.49-4.78 (1 H, m), 2.18-2.70 (3 H, m), 1.75-2.26 (1 H, m), 1.03-1.17 (6 H, m); MS (ES+) m/z: 287.2 (M+H); HPLC retention time: 2.487 min (analytical HPLC Method A).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([N:14]1[C@H:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][O:16][C:15]1=[O:26])=[O:13])(=O)OCC)C.[NH2:27][C:28]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][C:31]([CH:32]=O)=[CH:30][C:29]=1[Cl:40].[NH4+].[Cl-]>C1COCC1>[NH2:27][C:28]1[C:35]([C:36]([F:37])([F:38])[F:39])=[CH:34][C:31](/[CH:32]=[CH:11]/[C:12]([N:14]2[C@H:18]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:17][O:16][C:15]2=[O:26])=[O:13])=[CH:30][C:29]=1[Cl:40]
Reactant: CCOP(=O)(CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1)OCC
Reactant: Nc1c(Cl)cc(C=O)cc1C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(/C=C/C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1C(F)(F)F
Temperature: 35 °C
Reaction time: 0.58 h

Procedure:
Under a nitrogen atmosphere 3.93 g (90.0 mmol) of NaH (55% in mineral oil) were added batchwise to a solution of 31.98 g (90.0 mmol) of diethyl[2-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-2-oxo-ethyl]-phosphonate in 400 mL of THF. The reaction mixture was stirred for 30 min at RT and for a further 35 min at 35° C. After the development of gas had ended, 16.0 g (71.5 mmol) of 4-amino-3-chloro-5-trifluoromethyl-benzaldehyde, dissolved in 50 mL THF, were added dropwise and stirred for a further 12 h at RT. The reaction solution was combined with saturated NH4Cl solution, the mixture was extracted exhaustively with EtOAc and the combined extracts were dried and evaporated down i. vac. The residue remaining was purified by chromatography on silica gel. The desired product was obtained in the form of a yellow oil.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2CC(N2CCOCC2)=S)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:22]([OH:25])(=[O:24])[CH3:23]>Cl>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:23][C:22]([OH:25])=[O:24])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: S=C(Cc1ccccc1N1CCOCC1)N1CCOCC1
Agent: Cl
Product: O=C(O)Cc1ccccc1N1CCOCC1

Procedure:
A solution of N-[[2-(4-morpholinyl)-phenyl]thioacetyl]morpholine (2.78 g) in a mixture of acetic acid (25 cc) and 37% hydrochloric acid (25 cc) is refluxed for 8 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in ethyl acetate (20 cc) and normal sodium hydroxide solution (20 cc). The aqueous phase is acidified to pH 5 with acetic acid and then extracted with ethyl acetate (20 cc). This organic phase is washed with water (2×4 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). 2-[2-(4-Morpholinyl)phenyl]acetic acid (0.48 g) melting at 128° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:17]/[C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C(O)C.[OH-].[K+]>O>[CH3:1][C:2]1[C:3](/[C:16](/[Si:29]([CH3:30])([CH3:32])[CH3:31])=[CH:17]/[C:18]2[CH:28]=[CH:27][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1ccc(/C=C(/c2cc3c(cc2C)C(C)(C)CCC3(C)C)[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc2c(cc1/C(=C/c1ccc(C(=O)O)cc1)[Si](C)(C)C)C(C)(C)CCC2(C)C
Temperature: 50 °C

Procedure:
To a solution of ethyl (Z)-4-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trimethylsilyl)vinyl]benzoate (Compound 4, 0.034 g, 0.076 mmol) and 2 mL of ethyl alcohol was added aqueous 1 N KOH (0.5 mL). The resulting solution was heated in an 50° C. bath until the hydrolysis reaction was completed, as judged by thin layer chromatography. The solution was cooled to room temperature, diluted with water and washed once with 1:1 ether:hexane solution, and the layers were separated. The aqueous layer was acidified with 1 N aqueous HCl and the product extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, and dried over MgSO4, and filtered, and the solvents were removed in vacuo to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[CH2:18]([C:20]1[NH:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1)[CH3:19].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[CH2:18]([C:20]1[N:21]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH3:11])=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:3]=2)[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1)[CH3:19]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2ncn(C)c2n1
Temperature: 120 °C
Yield: 60.8 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine (4.0 g, 15.8 mmol), 2-ethylbenzimidazole (2.8 g, 19.0 mmol), tris(dibenzylideneacetone)dipalladium (724 mg, 0.79 mmol), Xphos (1.5 g, 3.16 mmol) and Cs2CO3 (10.3 g, 31.6 mmol) in dioxane (90 mL) was purged with argon then heated at 120° C. for 16 h in a sealed reactor. The reaction mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo and purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording 2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine as an orange solid (3.49 g, 96%). LCMS (method H): RT 3.46 min, [M+H]+ 364.5
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.O>CC#N>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:14][CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:6]=1
Reactant: BrCCCOC1CCCCO1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Ic1cnn(CCCOC2CCCCO2)c1
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a mixture of 4-iodo-1H-pyrazole (2.0 g, 10.3 mmol) and Cs2CO3 (5.04 g, 15.5 mmol) in MeCN (28 mL) was added 2-(3-bromopropoxy)tetrahydro-2H-pyran (1.84 mL, 10.8 mmol) and the mixture stirred overnight. The crude reaction mixture was poured into water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-80% EtOAc in cyclohexane, to give the title compound (2.95 g, 81%). 1H NMR (300 MHz, CDCl3): 150-1.58 (4H, m), 1.65-1.90 (2H, m), 2.12 (2H, qn, J=6.4 Hz), 3.35 (1H, dt, J=10.2, 5.9 Hz), 3.46-3.54 (1H, m), 3.73 (1H, dt, J=10.2, 5.9 Hz), 3.80-3.88 (1H, m), 4.26 (2H, td, J=6.9, 1.5 Hz), 4.54 (1H, dd, J=4.5, 3.1 Hz), 7.46 (1H, s), 7.50 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]([OH:22])=O)[C:5]2[CH:6]=[C:7]([NH:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)[N:8]=[CH:9][C:10]=2[CH:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:54][CH2:55][CH2:56][OH:57]>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:20]([NH:54][CH2:55][CH2:56][OH:57])=[O:22])[C:5]2[CH:6]=[C:7]([NH:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)[N:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: O=C(O)c1cc(F)cc2cnc(N[C@H]3CC[C@H](O)CC3)cc12
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C(NCCO)c1cc(F)cc2cnc(N[C@H]3CC[C@H](O)CC3)cc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
7-fluoro-3-[(trans-4-hydroxycyclohexyl)amino]isoquinoline-5-carboxylic acid (23.0 mg, 0.076 mmol) in 5 ml DMA was treated with HATU (62.1 mg, 0.16 mmol) and triethylamine (49.5 mg, 0.49 mmol). After 1 hour, 2-aminoethanol (15.0 mg, 0.25 mmol) was added and the solution was heated to 50° C. for 2 hours. The reaction was monitored by LC/MS to show no start acid left. The solvent was removed under vacuum and the crude was dissolved in CH2Cl2 and washed with 1 M NaHCO3 aqueous. The organic layers were dried over MgSO4. The crude material after removal of the solvent was purified by prepHPLC to give 5.8 mg (yield 19.3%). 1H NMR (400 MHz, MeOD) ppm 1.21-1.56 (m, 4H), 1.87-2.20 (m, 4H), 3.48-3.67 (m, 4H), 3.77 (m, 2H), 7.02 (s, 1H), 7.46-7.69 (m, 2H), 8.78 (s, 1H). HRMS: m/z 348.17226[M+H]+), calc. 348.17180. MS m/z, (APCI); 348.2 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>CCOCC>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])[N:3]=1
Reactant: Cc1cccc(Br)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(C)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution containing 2-bromo-6-methylpyridine (1.48 g, 8.63 mmol) in ether (15 mL) at −78° C. was treated with n-butyllithium (5.39 mL, 1.6 M in hexanes) dropwise, stirred at −78° C. for 1 hour, treated with tributyltin chloride (4.21 mL, 12.94 mmol), stirred at −78° C. for 4 hours, quenched with saturated ammonium chloride solution, and partitioned between ether and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on neutral alumina eluting with 10% ethyl acetate in dichloromethane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:16]=[C:17]([C:19](OCC)=[O:20])[N:18]=2)[CH:15]=1>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:16]=[C:17]([C:19]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=3)=[O:20])[N:18]=2)[CH:15]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(Nc1cccc(Cl)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 3-chloroaniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([CH2:29][CH2:30][CH2:31][OH:32])[S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:33]1(B(O)O)[CH2:35][CH2:34]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:21]1([C:13]2[C:12]([N:24]([CH2:29][CH2:30][CH2:31][OH:32])[S:25]([CH3:28])(=[O:26])=[O:27])=[CH:11][C:10]3[C:15](=[C:16]([C:17]([NH:19][CH3:20])=[O:18])[N:8]([C:5]4[CH:4]=[CH:3][C:2]([CH:33]5[CH2:35][CH2:34]5)=[CH:7][CH:6]=4)[N:9]=3)[CH:14]=2)[CH2:23][CH2:22]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(C2CC2)cc1
Temperature: 100 °C
Yield: 27.3 %

Procedure:
To a degassed mixture of 2-(4-bromophenyl)-5-cyclopropyl-6-[(3-hydroxypropyl)(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide (10 mg, 0.019 mmol), cyclopropylboronic acid (5 mg, 0.058 mmol), potassium phosphate (17 mg, 0.080 mmol) in toluene (0.5 mL) and water (50 μL) were added tricyclohexylphosphine (1 mg, 0.0038 mmol) and Pd(OAc)2 (0.4 mg, 0.0019 mmol) and the reaction was heated at 100° C. for 2 h. The mixture was concentrated to dryness and purified by preparative LCMS (5-40-100% ACN in 0.1 aqueous formic acid) to afford Compound (53) as a white solid (2.5 mg, 27%). ESI-MS m/z calculated for [M+H]+: 483.2; found: 483.2; 1H NMR (400 MHz, MeOD) δ 7.85 (s, 1H), 7.58-7.43 (m, 2H), 7.39 (s, 1H), 7.28 (d, J=8.5 Hz, 2H), 4.06-3.81 (m, 2H), 3.76-3.57 (m, 2H), 3.17 (s, 3H), 2.94 (s, 3H), 2.54-2.34 (m, 1H), 2.19-1.96 (m, 1H), 1.96-1.68 (m, 2H), 1.21-0.94 (m, 5H), 0.85-0.76 (m, 2H), 0.75-0.59 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17](N)=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[CH:14]1.C(Br)(Br)[Br:25].C(ON=O)(C)(C)C.C1(C)C=CC=CC=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([Br:25])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[CH:14]1
Reactant: BrC(Br)Br
Reactant: Nc1c(SC(F)(F)F)ncn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CC(C)(C)ON=O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: FC(F)(F)Sc1ncn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.44 %

Procedure:
To a solution of 2.0 g (5.05 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-amino-4-trifluoromethylsulfenylimidazole in 10 ml of acetonitrile was added 1 ml of bromoform and 1.20 ml (10.10 mmole) of t-butylnitrite at 0° C. The resulting mixture was stirred at RT under a nitrogen atmosphere for 1.5 h. Ten ml of toluene was added and the mixture was evaporated to dryness under vacuum. The residue was purified by column chromatography on silica gel using 5% ethyl acetate in hexane to give 800 mg (34.44% yield) of the desired product, mp 87.5° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:15][NH:14][C:13](=[O:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[CH2:10][N:9]1[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I>CN(C=O)C>[CH2:1]([CH:8]1[CH2:15][N:14]([CH3:34])[C:13](=[O:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[CH2:10][N:9]1[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])(=[O:23])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COc1ccccc1S(=O)(=O)N1Cc2ccccc2C(=O)NCC1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1S(=O)(=O)N1Cc2ccccc2C(=O)N(C)CC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87.2 %

Procedure:
To a solution of compound 2g (120 mg, 0.28 mmol) in DMF (15 mL) at 10° C., NaH (60% in mineral oil; 13 mg, 0.33 mmol) was added in portions. The mixture was stirred for an additional 45 min and then MeI (116 mg, 0.82 mmol) was added dropwise. The resulting mixture was stirred at 10° C. for 30 min and warmed to rt overnight. The reaction was quenched with water (30 mL) and extracted with EA (40 mL). The organic layer was washed with brine (2×20 mL) and dried over anhydrous Na2SO4. Concentration in vacuo and purification by prep-TLC (PE:EA=1:1) gave compound 2h as a white solid (110 mg, 89% yield). 1H-NMR (400 MHz, CD3OD) δ 7.82 (dd, 1H, J=8.0, 1.6 Hz), 7.51 (t, J=8.8 Hz, 1H), 7.36-7.23 (m, 4H), 7.05-6.99 (m, 5H), 6.72-6.70 (m, 2H), 5.41 (d, J=18.8 Hz, 1H), 4.55 (d, J=19.2 Hz, 1H), 4.10 (m, 1H), 3.82 (s, 3H), 3.28 (dd, J=14.4, 11.6 Hz, 1H), 2.98 (dd, J=15.2, 4.8 Hz, 1H), 2.86 (s, 3H), 2.61 (dd, J=12.8, 9.6 Hz, 1H), 2.47 (dd, J=12.8, 4.8 Hz, 1H). MS (ESI+) m/z: 451 [M+H]+
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[C:21]([C:26](OC)=[O:27])[CH:22]=[N:23]2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCOCC.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[OH:27][CH2:26][C:21]1[CH:22]=[N:23][C:24]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([CH2:15][N:8]([CH3:7])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:25]=2
Reactant: COC(=O)c1cnc2cc(CN(C)c3ccccc3)ccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(Cc1ccc2cc(CO)cnc2c1)c1ccccc1

Procedure:
In a nitrogen atmosphere, lithium aluminum hydride (33 mg, 0.88 mmol.) was suspended in tetrahydrofuran (THF, 1 mL). Under chilling with ice, to this was dropwise added the above methyl 7-(methylphenylamino)methyl-quinoline-3-carboxylate (171 mg, 0.56 mmol.) in dry THF (1.5 mL). The resulting mixture was stirred under chilling with ice for 3 hours. To this were added ether (5 mL) and saturated aqueous sodium sulfate solution (3 mL), so that excessive lithium aluminum hydride was decomposed. The organic portion was recovered by decantation, and the residue was washed with ether. The ether washings were combined with the above recovered organic portion. The solvent was distilled off under reduced pressure to give the desired compound as a brown amorphous product (128 mg, yield: 82%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15]CC2C=CC=CC=2)[C@@H:12]2[CH2:23][C@H:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[C@@H:12]2[CH2:23][C@H:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CNCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CN
Reaction time: 24 h

Procedure:
A solution of (1R,3S,4S)-3-(benzylamino-methyl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (39.8 mmol) in EtOH (120 mL) is treated with Pd/C (10%, 4.0 g) and stirred under a hydrogen atmosphere (7 bar) for 1 d. An additional amount of Pd/C (1.0 g) is added and the mixture is stirred for further 6 h under a hydrogen atmosphere (7 bar). After filtration through celite and removal of the solvents in vacuo the desired amine is obtained which is used without further purification. LC-MS (basic): tR=0.85 min; [M+H]+=227.3.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[NH:20][C:14]2[N:15]=[CH:16][N:17]=[C:18](O)[C:13]=2[CH:12]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:18]1[C:13]2[CH:12]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[NH:20][C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: Oc1ncnc2[nH]c(-c3ccc4ccccc4c3)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2[nH]c(-c3ccc4ccccc4c3)cc12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Under a protective gas, 198.5 mg (0.76 mmol) of 6-(naphth-2-yl)-7H-pyrrolo[2,3-d]-pyrimidin-4-ol in 3 ml of phosphorus oxychloride are heated at boiling for 5 hours. The reaction mixture is poured into ice-water and stirred for 1 hour to complete the reaction. The crystals are filtered off and washed with water. Dissolving the crude product in THF/methanol, filtering through active carbon, concentrating the filtrate by evaporation, stirring the residue in isopropanol and washing with hexane yield the title compound; m.p. 268-269° C. (decomposition); FAB-MS: (M+H)+ =280.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](Cl)=[O:22])[CH:17]=[CH:18][CH:19]=1>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:21](=[O:22])[CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: CCOC(=O)c1ccc(C)[nH]1
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C(=O)Cc2cccc(OC)c2)c(C)[nH]1
Yield: 50 %

Procedure:
4-[2-(3-Methoxy-phenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (126) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (3-methoxyphenyl)-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane/−40° C. Purification: Recrystallization from ether/pentane. Yield: 50%. 1H (CDCl3, 400 MHz): δ 10.80 (NH, broad s), 7.32 (1H, s), 7.18 (1H, dd), 6.85 (1H, d), 6.83 (1H, s), 6.75 (1H, d), 4.33 (2H, q), 4.04 (2H, s), 3.74 (3H, s), 2.55 (3H, s), 1.36 (3H, t) ppm. 13C (CDCl3, 100 MHz): δ 194.3, 161.5, 159.7, 141.1, 136.7, 129.4, 121.9, 121.6, 120.4, 117.2, 115.2, 112.1, 60.8, 55.1, 47.0, 14.4, 13.9 ppm. LC/MS: 100%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C(Cl)(=O)C1C=CC=CC=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[N:3]=[CH:4][N:5]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[C:7]([NH2:9])=[O:8])=[O:24])=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Solvent: O=C(Cl)c1ccccc1
Product: COc1ccc(C(=O)Nc2ncn(Cc3ccccc3)c2C(N)=O)cc1
Yield: 53 %

Procedure:
An amidation reaction and post-treatment were carried out according to the conditions of Example 1, using 1.52 g (7 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in Reference Example 2 and 4-methoxy benzoyl chloride separately prepared according to a conventional method, instead of benzoyl chloride, to obtain a crude amide product. The crude amide product was purified by suspension in hot methanol to obtain 1.31 g of 4-(4-methoxybenzoylamino)-1-benzyl-5-imidazolecarboxamide (yield 53%).