Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([O:22][NH:23][C:24]1[C:29]([NH:30][CH:31]=O)=[C:28]([Cl:33])[N:27]=[CH:26][N:25]=1)[CH2:11][O:12][CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OC(OCC)OCC)(=O)C>[Si:1]([O:8][CH2:9][CH:10]([O:22][N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[Cl:33])[CH2:11][O:12][CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCOP(=O)(COCC(CO[Si](C)(C)C(C)(C)C)ONc1ncnc(Cl)c1NC=O)OCC
Agent: CCOC(OCC)OC(C)=O
Product: CCOP(=O)(COCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(Cl)ncnc21)OCC
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of 4-(1-t-butyldimethylsilyloxy-3-diethoxyphosphorylmethoxyprop-2-oxyamino)-6-chloro-5-formamidopyrimidine (0.4 g, 0.76 mmol) in diethoxymethyl acetate (10 ml) was stirred at 120° C. for 4 hours. The solvents were evaporated, the residue dissloved in methanol (10 ml) and 0.88 ammonia (0.3 ml) and stirred for 1 hour. After evaporation, the residue was chromatographed on silica eluting with ethyl acetate and then with chloroform to give 9-(1-t-butyldimethylsilyloxy -3-diethoxyphosphorylmethoxyprop-2-oxy)-6-chloropurine (0.31 g, 80%) as a yellow oil. νmax (film) 3480, 1600, 1540, 1340, 1260, 1030, and 840 cm-1 ; δH [(CDCl3) 0.07(6H, s, (CH3)2Si), 0.87(9H, s, (CH3)3C), 1.35(6H, t, J7.1 Hz, 2×CH2CH3), 3.86(2H, d, J8.2 Hz, CH2P), 4.01 (4H, m, CH2OSi+CH2OCH2P), 4.18(4H, m, 2×CH2CH3), 4.59(1H, m, CHON); 8.43(1H, s, H-2/H-8), 8.76(1H, s, H-2/H-8); Found: MH+ 509.1726; C19H34N4O6ClPSi requires MH+ 509.1752.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[CH3:32][NH:19][CH2:18][C@@H:17]([NH:16][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41]
Reactant: CN(C[C@@H](N)c1cc(F)c(F)cc1F)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1cc(F)c(F)cc1F

Procedure:
Compound 60 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [377 (M+H)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:17]=1.C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:29][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[O:9][C:5]3[C:4]([C:18]([O:20][CH3:21])=[O:19])=[CH:3][C:2]([F:1])=[CH:17][C:6]=3[N:7]=2)=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(F)cc2nc(-c3ccc(C)cc3)oc12
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)cc2nc(-c3ccc(CBr)cc3)oc12
Yield: 65.4 %

Procedure:
To methyl 5-fluoro-2-p-tolylbenzo[d]oxazole-7-carboxylate (420 mg, 1.47 mmol) in CCl4 (5 mL) was added NBS (262 mg, 1.47 mmol) and BPO (69 mg, 0.735 mmol), the resulting mixture was heated to reflux for 24 hr; then the solvent was evaporated and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=100:1-50:1) to obtain methyl 2-(4-(bromomethyl)phenyl)-5-fluorobenzo[d]oxazole-7-carboxylate as a white solid (350 mg, yield 65%). LC-MS (ESI) m/z 264 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:14])[CH2:4][N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[O:25][CH2:26][C:27](OCC)=[O:28])[CH:18]=[CH:17][CH:16]=1>CCO>[OH:14][CH:3]([CH2:4][N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][NH:1][C:27](=[O:28])[CH2:26][O:25][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[N:15]=[CH:16][CH:17]=[CH:18]2
Reactant: CCOC(=O)COc1cccc2cccnc12
Reactant: NCC(O)CN1Cc2ccccc2C1
Solvent: CCO
Product: O=C(COc1cccc2cccnc12)NCC(O)CN1Cc2ccccc2C1
Temperature: 120 °C
Yield: 18 %

Procedure:
1-amino-3-(isoindolin-2-yl)propan-2-ol (50 mg, 0.26 mmol) and ethyl 2-(quinolin-8-yloxy)acetate (60 mg, 0.26 mmol) were dissolved in EtOH (1 mL) and heated under microwave conditions at 120° C. for 0.5 h. The reaction mixture was concentrated and purified by preparative HPLC purification. (17.2 mg, yield 18%) MS (ESI+) e/z: 378.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 8.95-8.87 (m, 1H), 8.45-8.36 (m, 1H), 7.67-7.56 (m, 3H), 7.35-7.25 (m, 1H), 7.24-7.12 (m, 4H), 4.83-4.76 (m, 2H), 4.09-4.03 (m, 1H), 4.02-3.95 (m, 4H), 3.60-3.54 (m, 1H), 3.46-3.40 (m, 1H), 2.92-2.86 (m, 1H), 2.84-2.78 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C(O[CH2:27][N:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:34]([N:28]1[CH2:29][CH:10]2[CH:9]([C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12][C:11]2=[O:14])[CH2:27]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C1C=CC(c2cccc(Cl)c2)(c2cccc(Cl)c2)CC1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCC(c2cccc(Cl)c2)(c2cccc(Cl)c2)C2CN(Cc3ccccc3)CC12
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (15 drops) is added to a solution of 4,4-bis(3-chlorophenyl)cyclohexenone (26.8 g) and N-butoxymethyl-N-(trimethylsilylmethyl)benzylamine (33 cc) in dry dichloromethane (200 cc). The reaction mixture is brought to reflux, then stirred for 16 hours after the temperature has been allowed to return to 25° C. and for a further 15 minutes after the addition of potassium carbonate (16 g). After filtration and concentration to dryness under reduced pressure (2.7 kPa), the residue is chromatographed on a column of silica gel (particle size 0.04-00063 mm, diameter 7 cm, height 40 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (75:25) and collecting 500-cc fractions. Fractions 12 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-benzyl-7,7-bis(3-chlorophenyl)perhydro-4-isoindolone (16.2 g) in the form of a yellow oil.
Reaction SMILES: [NH2:1][CH:2]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[N:15][C:16]=3[NH2:18])[N:11]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[N:10]=2)=[CH:5][CH:4]=1.[C:38]1([CH2:44][CH:45]=O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:31][N:28]1[CH2:27][CH2:26][N:25]([CH:22]2[CH2:23][CH2:24][CH:19]([N:11]3[C:12]4=[N:13][CH:14]=[N:15][C:16]([NH2:18])=[C:17]4[C:9]([C:6]4[CH:5]=[CH:4][C:3]([CH:2]([NH:1][CH2:45][CH2:44][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)=[CH:8][CH:7]=4)=[N:10]3)[CH2:20][CH2:21]2)[CH2:30][CH2:29]1
Reactant: O=CCc1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(N)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN(C2CCC(n3nc(-c4ccc(C(NCCc5ccccc5)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Reaction time: 18 h
Yield: 46.6 %

Procedure:
To a solution of cis-3-{4-[amino(phenyl)methyl]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.10 mmol), phenylacetaldehyde (13 mg) and glacial acetic acid (0.013 mL) in 1,2-dichloroethane (1 mL) under nitrogen was added sodium triacetoxyborohydride (2 equivs., 43 mg). The solution was stirred for 18 h then concentrated in vacuo, partitioned between dichloromethane (10 mL) and saturated aqueous NaHCO3 (10 mL) and the organic layer separated. The aqueous layer was further extracted with dichloromethane (4×10 mL) and the combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness. Purification was effected using mass actuated preparative RP-HPLC (Micromass/Gilson, Hypersil BDS C18, 5 μm, 100×21.2 mm column; 0-100% acetonitrile and 0.05M ammonium acetate, buffered to pH 4.5, over 12.5 min at 25 mL/min) to afford 1-[4-(4-methylpiperazino)cyclohexyl]-3-{4-[(phenethylamino)(phenyl)methyl]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (28 mg); RP-HPLC (10 to 90% CH3CN in 0.1 N aqueous ammonium acetate, buffered to pH 4.5, over 12 min at 2 mL/min using a Waters Symmetry C18, 250×4.6 mm column) Rt=12.269 min, 95.2%; m/z (MH+) 601.3.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([C:19]#[N:20])=[CH:9]2)=[CH:5][CH:4]=1)=[O:2].[OH-:21].[Na+]>O1CCCC1.[Ag]=O>[C:19]([C:10]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:12][N:8]([C:6]2[O:7][C:3]([C:1]([OH:21])=[O:2])=[CH:4][CH:5]=2)[CH:9]=1)#[N:20]
Reactant: N#Cc1cn(-c2ccc(C=O)o2)cc1-c1ccccc1
Reactant: [OH-]
Agent: O=[Ag]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cn(-c2ccc(C(=O)O)o2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(5-formylfuran-2-yl)-4-phenyl-1H-pyrrole-3-carbonitrile (0.14 g) in tetrahydrofuran (4 mL) were added silver oxide (0.15 g) and sodium hydroxide aqueous solution (2 mol/L, 0.4 mL), and this mixture was stirred at room temperature for 6 hours. The insoluble material was removed by filtration, and this filtrate was concentrated. To this residue were added water (15 mL) and hydrochloric acid (2 mol/L, 2 mL), this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This residue was purified by column chromatography on silica gel (eluent: methanol/dichloromethane=1/10-1/5) to give the title compound (0.040 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[C:6]([O:9][CH3:10])=[N:7][CH:8]=1.[Cl:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][N:20]=1.C([O-])(O)=O.[Na+]>C(#N)C.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].C(Cl)Cl>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([CH2:2][C:3]2[CH:8]=[N:7][C:6]([O:9][CH3:10])=[C:5]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:4]=2)=[CH:21][N:20]=1
Reactant: COc1ncc(CBr)cc1-c1cccc(Cl)c1
Reactant: OB(O)c1cnc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CC#N
Solvent: ClCCl
Product: COc1ncc(Cc2cnc(Cl)nc2)cc1-c1cccc(Cl)c1
Temperature: 120 °C
Yield: 54.9 %

Procedure:
To a solution of 5-(bromomethyl)-3-(3-chlorophenyl)-2-methoxypyridine (Intermediate 2, 100 mg, 0.321 mmol), (2-chloropyrimidin-5-yl)boronic acid (76 mg, 0.481 mmol) in ACN (3.2 mL) was added NaHCO3 (417 mg, 1.282 mmol) and PdCl2(dppf)-DCM (23 mg, 0.032 mmol). The reaction was heated under microwave conditions, at 120° C. for 12 minutes. Water was removed from the reaction with a pipette, and the crude reaction mix was filtered thru CELITE®, and washed with EtOAc. The combined organics were dried (Na2SO4), filtered and concentrated onto silica. Purification (FCC, SiO2, 30-70% EtOAc/hexanes) afforded the title compound (61 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 2H), 8.11 (d, J=2.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.58 (t, J=1.8 Hz, 1H), 7.53-7.36 (m, 3H), 3.83 (s 2H), 3.73 (s, 3H). [M+H]=346.11.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:8]1[CH:26]=[CH:25][C:11]([O:12][CH2:13][CH:14]([OH:24])[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:10][CH:9]=1)#[N:7].O.C(Cl)Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:1][S:2]([O:24][CH:14]([CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:26][CH:25]=1)[CH2:15][NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:23])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NCC(O)COc1ccc(C#N)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(COc1ccc(C#N)cc1)OS(C)(=O)=O
Yield: 103.9 %

Procedure:
Methanesulfonyl chloride (22.3 g 0.195 mol) was added over the course of 1.5 hours to a cooled (0° C.) solution of tert-butyl 3-(4-cyano-phenoxy)-2-hydroxypropylcarbamate (from step (iii) above; 51.2 g, 0.177 mol) and 4-(dimethylamino)pyridine (1.3 g, 10.6 mmol) in pyridine (250 mL), kept under an inert atmosphere. The reaction mixture was stirred for 2 h at rt before water and DCM were added. The organic layer was separated, washed with water, dried (MgSO4) and concentrated in vacuo to yield 68.1 g (100%) of the sub-title compound.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:15][CH2:14][CH2:13]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[F:32])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:64][N:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14][CH2:15]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:64][N:65]5[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]5)=[O:28])=[CH:25][C:24]=4[F:32])=[N:21][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(N)CC1
Reactant: CN1C(=O)C2(CCC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC3(CCC3)C(=O)N4C)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-fluorobenzoic acid (Intermediate 10) (100 mg, 0.23 mmol, 1 eq), DIPEA (80 μl, 0.46 mmol, 2 eq) and TBTU (80 mg, 0.25 mmol, 1.1 eq) were added to 1 mL DMF and the resulting solution stirred at rt for 10 min before the addition of 1-amino-4-methylpiperazine (33 μL, 0.27 mmol, 1.2 eq). The RM was then stirred at rt for 1 hour before splitting into two equal batches and purifying by preparative RP-HPLC-MS (Preparative 3) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-fluoro-N-(4-methylpiperazin-1-yl)benzamide (0.05 g, 41%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2.[H-].[Na+].[CH:21]1([CH2:27]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[Cl-].[NH4+]>CN(C)C=O>[CH:21]1([CH2:27][N:7]2[C:8]3[C:13](=[CH:12][C:11]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrCC1CCCCC1
Reactant: CS(=O)(=O)c1ccc2[nH]c(-c3ccco3)cc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(c1)cc(-c1ccco1)n2CC1CCCCC1
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
To a solution of 2-(2-furanyl)-5-methanesulfonylindole (150 mg) in N,N-dimethylformamide (6 ml), 60% sodium hydride (34.4 mg) was added at 0° C. under nitrogen atmosphere and the mixture was stirred for 15 minutes. Subsequently, cyclohexylmethyl bromide (205 mg) was added to the mixture, followed by stirring for 3 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with toluene, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (methanol:chloroform 1:100) to obtain 164 mg of the desired product as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=O)[O:22]C(C)(C)C)[N:15]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=2)[N:6]=1.[C:28]1([CH2:34][C:35](Cl)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH3:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:3][C:4]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:22])[CH2:5][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:15]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(-c2nc(N)sc2-c2ccnc(NC(=O)OC(C)(C)C)n2)c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(-c2nc(NC(=O)Cc3ccccc3)sc2-c2ccnc(NC(=O)Cc3ccccc3)n2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 26.6 %

Procedure:
To a solution of tert-butyl 4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyrimidinylcarbamate (0.50 g, 1.3 mmol) in N,N-dimethylacetamide (5 mL) was added phenylacetylchloride (0.52 mL, 3.9 mmol) and the mixture was stirred at 80° C. for 14 hrs. Into the reaction mixture was poured aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate=7:3), and the obtained oil was recrystallized from ethyl ether to give the title compound (0.09 g, yield 13%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1.[CH2:35]([O:37][C:38](=[O:45])[C@H:39]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH2:40])[CH3:36]>>[NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:40][C@H:39]([C:38]([O:37][CH2:35][CH3:36])=[O:45])[CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:34])[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)OCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)c(F)c1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Product: CCOC(=O)[C@H](CC(C)C)NCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)c(F)c1

Procedure:
From Intermediate 4E and L-leucine ethyl ester LCMS purity 98%, m/z 560 [M+H]+, 1H NMR (400 MHz, CD3OD), δ: 1.10-1.20 (6H, m), 1.45-1.55 (3H, t), 1.65-1.85 (2H, m), 1.90-2.00 (1H, m), 2.15-2.30 (2H, m), 2.85-3.05 (2H, m), 3.55 (1H, m), 4.35-4.50 (4H, m), 6.00 (1H, d), 7.10 (1H, d), 7.45-7.55 (1H, m), 7.80-7.85 (1H, m), 7.95 (1H, d).
Reaction SMILES: Cl.Br[C:3]1[CH:12]=[N:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][NH:8]2.[CH3:13][N:14]1[C:23]2[C:18](=[CH:19][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=[O:33].CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:13][N:14]1[C:23]2[C:18](=[CH:19][C:20]([C:3]3[CH:12]=[N:11][CH:10]=[C:9]4[C:4]=3[CH2:5][CH2:6][CH2:7][NH:8]4)=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1=[O:33]
Reactant: Brc1cncc2c1CCCN2
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCCN4)ccc21
Temperature: 120 °C
Yield: 72.3 %

Procedure:
A microwave vial was charged with 5-bromo-1,2,3,4-tetrahydro-1,7-naphthyridine hydrochloride (0.1 g, 0.401 mmol), 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1, 0.127 g, 0.441 mmol) and DMF (2.5 mL). The reaction mixture was purged with Argon. Then, bis(triphenylphosphine)palladium(II)chloride (0.028 g, 0.040 mmol), followed by a 1N aqueous Na2CO3 solution (1.6 mL, 1.6 mmol) were added and the reaction mixture was heated in the microwave at 120° C. for 30 min. The reaction mixture was diluted with EtOAc, filtered through Dicalite and washed with EtOAc (2×20 mL). The resulting filtrate was washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.085 g, 72%) as a white solid. MS: 294.2 (M+H+).
Reaction SMILES: [CH:1]1([CH:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=[NH:32])[NH:30]O)=[CH:25][CH:24]=2)[C:8]([N:10]([CH2:18][C:19]([OH:21])=[O:20])[CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.[Pd]>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([N:10]([CH2:18][C:19]([OH:21])=[O:20])[CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:9])=[CH:28][CH:27]=1)(=[NH:30])[NH2:32]
Reactant: N=C(NO)c1ccc(CC(C(=O)N(CC(=O)O)CC2CCCCC2)C2CCCCC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)c1ccc(CC(C(=O)N(CC(=O)O)CC2CCCCC2)C2CCCCC2)cc1

Procedure:
({2-(R,S)-Cyclohexyl-3-[4-(N-hydroxycarbamimidoyl)-phenyl]-propionyl}-cyclohexylmethyl-amino)-acetic acid (1.5 g, 3.38 mmol) was dissolved in acetic acid (40 ml). After addition of palladium on charcoal (10%, 100 mg), hydroxgen was bubbled in the reaction mixture at 50°C. for 8 hours. The catalyst was filtered off and washed with acetic acid. The filtrate was evaporated, the residue dissolved in water, lyophilized and purified by chromatography on Sephadex LH20 employing n-butanol (17): glacial acetic acid (1): water (2) was eluent. Pure fractions were combined. The solvent was evaporated, the residue was taken up in water, and the aqueous solution was lyophilized. Yield: 190 mg (13%), MS m/z 428.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11](=[O:14])[CH2:12][CH3:13])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br-:15].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:15][CH:12]([CH3:13])[C:11]([C:8]1[S:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[CH:9]=1)=[O:14]
Reactant: [Br-]
Reactant: CCC(=O)c1cc2c(Cl)cccc2s1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(Br)C(=O)c1cc2c(Cl)cccc2s1
Reaction time: 18.5 h
Yield: 236.8 %

Procedure:
A mixture of 1-(4-chlorobenzo[b]thiophen-2-yl)propan-1-one (1.65 g), phenyltrimethylammonium tribromide (2.76 g) and tetrahydrofuran (20 ml) was stirred under nitrogen for 18.5 hours, then it was filtered and diluted with water (200 ml). The product was extracted into dichloromethane (3×40 ml), the combined extracts were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to leave 2-bromo-1-(4-chlorobenzo[b]thiophen-2-yl)propan-1-one (3.06 g) as a pale yellow solid, m.p. 104-106° C.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[Cl:22][C:23]1[C:24]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[N:25][CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:28]3[CH:27]=[CH:26][N:25]=[C:24]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[C:23]=3[Cl:22])=[CH:14][C:6]1=2
Reactant: CC1(C)OB(c2ccnc(N3CCOCC3)c2Cl)OC1(C)C
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(N5CCOCC5)c4Cl)cc32)c1Cl
Yield: 49 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with 4-[3-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]morpholine as in General Procedure 4A to give the title compound as a tan foam (49% yield). M.p. (foam), LCMS: m/z=493.59 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.28 (t, J=5.3 Hz, 2H), 3.38 (t, J=4.8 Hz, 4H), 3.52-3.58 (m, 2H), 3.89 (t, J=4.3 Hz, 4H), 4.47 (d, J=1.3 Hz, 2H), 5.16 (bs, 1H), 6.89 (d, J=5.0 Hz, 1H), 6.97-7.06 (m, 2H), 7.08-7.15 (m, 1H), 7.56 (d, J=1.8 Hz, 1H), 8.17 (d, J=5.0 Hz, 1H).