Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[C:11]([CH2:17][CH2:18][CH3:19])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH2:34][C:35]([CH3:56])([CH3:55])[CH2:36][NH:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[CH:43][C:42]=1[F:54])=[O:39].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH2:34][C:35]([CH3:56])([CH3:55])[CH2:36][NH:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH:48]2[CH2:53][CH2:52][N:51]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:20])([F:1])[F:21])=[CH:10][C:11]=3[CH2:17][CH2:18][CH3:19])[CH2:50][CH2:49]2)=[CH:43][C:42]=1[F:54])=[O:39]
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CO
Reactant: CC(C)(N)CNC(=O)Nc1ccc(CC2CCNCC2)cc1F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CN1CCC(Cc2ccc(NC(=O)NCC(C)(C)N)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 5.7 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-(4-(hydroxymethyl)-3-propylphenyl)propan-2-ol (0.474 mmol, 150 mg) was dissolved in dichloromethane (5 mL) and triethylamine (1.423 mmol, 144 mg) added. The mixture was cooled to 0° C. before the addition of methanesulfonyl chloride (0.611 mmol, 70.0 mg). The mixture was stirred at 0° C. for 90 min. The reaction mixture was diluted with dichloromethane (50 mL) and washed with water (2×10 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (4 mL) and 1-(2-amino-2-methylpropyl)-3-(2-fluoro-4-(piperidin-4-ylmethyl)phenyl)urea (0.341 mmol, 110 mg) was added followed by potassium carbonate (1.023 mmol, 141 mg). The mixture was heated to reflux for 16 hours. The mixture was cooled, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC and treated with strong cation exchange column chromatography to afford the title compound (12 mg).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:36][CH2:37]O)[C:6]([C:8]2[C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]3([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:9]=2)=[O:7])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CO>ClCCl.C(OCC)(=O)C>[CH2:15]([O:14][C:13]1[C:12](=[O:22])[N:11]=[C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:25][CH2:26][CH2:27][CH2:28]2)[N:9]2[CH2:37][CH2:36][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:6](=[O:7])[C:8]=12)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)CC1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccc(Cl)cc4)CCCC3)n2CCN1CC1CC1
Yield: 74 %

Procedure:
To a solution of 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid cyclopropylmethyl-(2-hydroxyethyl)-amide (330) (390 mg, 0.73 mmol) in dichloromethane (30 mL) was added triphenyl phosphine (286 mg, 1.09 mmol) and diisopropyl azodicarboxylate (0.22 mL, 1.09 mmol) at room temperature the reaction was stirred for 30 minutes (TLC; 5% methanol in ethyl acetate/UV/SiO2, Rf=0.05). The dichloromethane was removed in vacuo and the crude mass was purified by silica gel (normal, 100-200 mesh) column chromatography using gradient eluent of 1% to 5% methanol in dichloromethane to get pure 9-benzyloxy-6-[1-(4-chlorophenyl)-cyclopentylmethyl]-2-cyclopropylmethyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (331) (280 mg, 74%) as a white sticky solid.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=3)[O:22][C:21]([CH3:31])([CH3:30])[C:20]=2[CH3:32])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([NH:29][S:8]([CH3:7])(=[O:10])=[O:9])=[CH:26][CH:27]=3)[O:22][C:21]([CH3:31])([CH3:30])[C:20]=2[CH3:32])=[CH:15][CH:14]=1
Reactant: CC1=C(c2ccc(F)cc2)c2ccc(N)cc2OC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1=C(c2ccc(F)cc2)c2ccc(NS(C)(=O)=O)cc2OC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under ice-cooling, pyridine (55 μL) and Methanesulfonyl chloride (35 μL) were added dropwise to a solution of [4-(4-fluorophenyl)-2,2,3-trimethyl-2H-chromen-7-yl]amine (a compound of Reference Example 6(5), 64 mg) in chloroform (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel, Solvent: chloroform/methanol=100/0 to 90/10) to give the titled compound (76 mg) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.NC1C=CC(O)=CC=1F>>[NH2:12][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: O=[N+]([O-])c1ccc(O)c2ncccc12
Agent: Nc1ccc(O)cc1F
Product: Nc1ccc(O)c2ncccc12
Yield: 57 %

Procedure:
This compound was prepared from 8-hydroxy-5-nitroquinoline (5.0 g, 26.3 mmol) in the manner described for 4-amino-3-fluorophenol, affording 2.4 g (51.3%) of 5-amino-8-hydroxyquinoline. TLC (5% MeOH/DCM), Rf=0.52.
Reaction SMILES: [CH3:1][O:2][C:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:16])[CH:10]=2)[N:4]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:26]([NH:25][C:20]3[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=3)=[O:27])=[C:11]([CH3:16])[CH:10]=2)[N:4]=1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: COc1nn(-c2ccc(N)c(C)c2)c(=O)o1
Solvent: Cc1ccccc1
Product: COc1nn(-c2ccc(NC(=O)Nc3ccc(Cl)c(Cl)c3)c(C)c2)c(=O)o1

Procedure:
The latter compound was obtained by reacting 5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one with equimolar amounts of 3,4-dichlorophenyl isocyanate in toluene at 50° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[N:6]2[CH3:11].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>ClCCl>[C:22]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[N:6]2[CH3:11])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: Cn1c(C(=O)O)cc2c(O)cccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc2c1cc(C(=O)O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.6 %

Procedure:
To 4-hydroxy-1-methyl-1H-indole-2-carboxylic acid (0.262 mmol, 50 mg) in dichloromethane (1 ml) and triethylamine (2.62 mmol, 365 μl) at 0° C. was added acetyl chloride (0.266 mmol, 19 μl) and the reaction mixture stirred at room temperature for one hour. The reaction was quenched with saturated aqueous sodium hydrogencarbonate and extracted twice with dichloromethane. The organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure to yield 4-acetoxy-1-methyl-1H-indole-2-carboxylic acid (67 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:14])=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH2:22][CH2:23][C:24]1([C:34]#[N:35])[CH2:33][CH2:32][C:27]2([O:31][CH2:30][CH2:29][O:28]2)[CH2:26][CH2:25]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:14])=[CH:8][C:9](=[O:13])[N:10]2[CH2:22][CH2:23][C:24]2([C:34]#[N:35])[CH2:33][CH2:32][C:27]3([O:28][CH2:29][CH2:30][O:31]3)[CH2:26][CH2:25]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C)cc(=O)[nH]c2c1
Reactant: CS(=O)(=O)OCCC1(C#N)CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(C)cc(=O)n(CCC3(C#N)CCC4(CC3)OCCO4)c2c1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To 10 mL of an N,N-dimethylformamide suspension containing 0.63 g of 7-methoxy-4-methylquinolin-2(1H)-one, 0.17 g of 60% sodium hydride at 55° C., and the mixture was stirred at the same temperature for 35 minutes. Thereto was added dropwise 8 mL of an N,N-dimethylformamide solution containing 0.99 g of 2-(8-cyano-1,4-dioxaspiro[4.5]decan-8-yl)ethyl methanesulfonate at 50° C., and the mixture was stirred at 50 to 55° C. for 2 hours and 50 minutes. Thereto was added 53 mg of 60% sodium hydride at the same temperature, and after further stirring for 3 hours, the mixture was added with 0.46 g of potassium carbonate at the same temperature, and further stirred for 3 hours. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash silica gel column chromatography [hexane:gradient elution of ethyl acetate 30:70] to obtain 200 mg g of a white solid, 8-(2-(7-methoxy-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)ethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=S)([CH3:4])([CH3:3])[CH3:2].[N:15]#[C:16][NH2:17].[Pb]>C(O)C>[C:1]([NH:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:17][C:16]#[N:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CN
Reactant: CC(C)(C)NC(=S)Nc1cccnc1
Agent: [Pb]
Solvent: CCO
Product: CC(C)(C)NC(=NC#N)Nc1cccnc1

Procedure:
N-tert-butyl-N'-3-pyridylthiourea (2.1 g) and lead cyanamide (3.7 g) were refluxed in ethanol (20 ml) for 18 hours. The mixture was filtered, and the filtrate was evaporated in vacuo to afford the crude product. Recrystallization from aqueous acetone gave the desired compound. Melting point 205.0°-206.5° C.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[C:4]1/[C:5]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=2[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/1=2.[N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][CH:24]=1>>[CH3:22][O:21][C:19]([C:29]1[CH:30]=[CH:31][C:26]2[N:25]=[CH:24][N:23]([CH2:2]/[CH:3]=[C:4]3/[C:5]4[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=4[O:7][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/3=4)[C:27]=2[CH:28]=1)=[O:20]
Reactant: COC(=O)c1ccc2c(c1)/C(=C/CCl)c1ccccc1CO2
Reactant: c1ccc2[nH]cnc2c1
Product: COC(=O)c1ccc2c(c1)/C(=C/Cn1cnc3ccc(C(=O)OC)cc31)c1ccccc1CO2

Procedure:
In Examples 27 through 32, the products were prepared using Compound h and corresponding benzimidazole derivatives in a manner similar to Example 26.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:32]=[CH:33][C:34]=2[CH3:35])[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH:32]=[CH:33][C:34]=3[CH3:35])[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
Example 32 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.98 (s, 1H), 7.59 (d, 1H, J=1.8 Hz), 7.54–7.51 (m, 1H), 7.32 (m, 3H), 7.21–7.18 (m, 1H), 6.99–6.94 (m, 5H), 4.87 (s, 1H), 3.36 (q, 2H, J=5.8 Hz), 2.92–2.97 (m, 2H), 2.68–2.58 (m, 1H), 2.5 (quintet, 1H, J=7.2 Hz), 2.37 (t, 2H, J=5.7 Hz), 2.25 (s, 3H), 2.01–1.92 (m, 2H), 1.71–1.52 (m, 6H), 1.16 (d, 6H, J=7.2 Hz); ESMS m/e: 548.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43](C=O)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[C@H:51]12[CH2:57][C@H:54]([NH:55][CH2:56]1)[CH2:53][N:52]2[C:58](OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C@H:51]12[CH2:57][C@H:54]([NH:55][CH2:56]1)[CH2:53][N:52]2[CH2:58][C:45]1[CH:46]=[C:41]([C:35]2[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:33]([CH2:32][NH:31][C:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:21]([NH:20][CH2:19][C:10]4[C:11]([NH:12][CH:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)=[C:6]5[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]5=[N:8][C:9]=4[CH2:49][CH3:50])=[O:22])[CH:24]=3)=[O:30])[CH:34]=2)[CH:42]=[CH:43][CH:44]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2OC)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4C[C@@H]5C[C@H]4CN5)c3)ccc2OC)c1
Reaction time: 3 h

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-4-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (54 mg, 0.00008 mol) in DCM, 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (23 mg, 0.00012 mol) and sodium triacetoxyborohydride (34 mg., 0.00016 mol) and AcOH (6 uL) were agitated overnight on a shaker. LC-MS was used to monitor the reaction. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The residue was taken up in DCM (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a peach colored solid [40.9 mg (68%)]. LC-MS m/z 757.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=O)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:37][CH:38]([NH2:45])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>C(OCC)(=O)C>[CH3:37][CH:38]([NH:45][C:16](=[O:18])[CH:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([O:20][CH3:21])[CH:11]=1)[CH3:19])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: COc1cc(C(C)C(=O)O)ccc1OCc1ccccc1
Reactant: CCCCCCC(C)N
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCCCCCC(C)NC(=O)C(C)c1ccc(OCc2ccccc2)c(OC)c1
Reaction time: 0.33 h

Procedure:
A solution of 2-(4-benzyloxy-3-methoxyphenyl)propionic acid (5.0 g, 17.5 mmoles) and 4-methylmorpholine (2.0 mL, 17.5 mmoles) in ethyl acetate (170 mL) at 0° C. was treated with isobutyl chloroformate (2.26 mL, 17.5 mmoles). The resulting white slurry was stirred for 20 minutes. A solution of racemic 2-octylamine (2.7 g, 21 mmoles) in ethyl acetate (10 mL total solution) was added to the suspension which was then stirred for 3 hours. The mixture was extracted with 1M hydrochloric acid (3×50 mL), with a saturated sodium bicarbonate solution (3×50 mL), with brine (1×50 mL) and dried over magnesium sulfate. The ethyl acetate was rotary evaporated affording N-2-octyl-2-(4-benzyloxy-3-methoxyphenyl)proprionamide as a white solid which was crystallized from ether/methylene chloride to give 4.55 g. This racemic mixture of diastereomers was separated by silica gel chromatography.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].[Br:16]Br>C(O)(=O)C>[Br:16][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[N:6][CH:7]=[CH:8][CH:9]=2
Reactant: c1cnc2cccnc2c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1cnc2cccnc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
To a stirred mixture of 1,5-naphthyridine (C-1) (50.0 g, 384 mmol, 1.0 eq) and sodium acetate (62.9 g, 768 mmol, 2.0 eq) in acetic acid (300 mL) at 80° C., a solution of bromine (67.5 g, 422 mmol, 1.1 eq) in acetic acid (80 mL) was added dropwise while keeping the reaction temperature at 80° C. to 90° C. After stirring for 2 h at 80° C., the reaction was complete based on TLC analysis. The resulting mixture was cooled to RT and then filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0-30% ethyl acetate-petroether) to afford the desired product 3-bromo-1,5-naphthyridine (C-2) (36.5 g, 45% yield) as a pale yellow solid. 1H NMR (300 MHz, CDCl3-d6) δ: 8.97 (m, 2H), 8.57 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 7.65 (m, 1H); ESI-MS m/z: 208.96 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:14][O:15][CH3:16])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])(C)(C)C.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[CH3:16][O:15][CH2:14][C@@H:8]([NH2:7])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: COC[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@@H](N)CC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ((S)-1-methoxymethyl-3,3-dimethyl-butyl)-carbamic acid tert-butyl ester (193 mg, 0.787 mmol) in CH2Cl2 (6 mL) was added TFA (0.606 mL, 7.87 mmol). The reaction mixture was stirred at RT for 2 h and concentrated to give the desired material which was used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.83 (bs, 3H), 3.50 (m, 1H), 3.35 (m, 1H), 3.35 8s, 3H), 3.28 (m, 1H), 1.48 (dd, 1H), 1.36 (dd, 1H), 0.92 (s, 9H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:19][CH:18]=1)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:31])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncccc2C#N)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cccnc1-c1ccc(C(=O)Nc2ccccc2N)cc1
Yield: 81.6 %

Procedure:
N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyanopyridin-2-yl)benzamide (210 mg; prepared as described in Method 1 below), 1,4-dioxane (6.8 ml) and a 4M solution of hydrogen chloride in 1,4-dioxane (6.8 ml) were stirred at ambient temperature for 20 hours. The resultant precipitate was collected by filtration and washed with diethyl ether (3×), suspended in water, basified with a 2M aqueous solution of sodium hydroxide and extracted with dichloromethane. The organic extract was dried over sodium sulfate to afford the title compound as a cream solid (130 mg, 82%); NMR Spectrum: (DMSO-d6) 4.94 (br s, 2H), 6.60 (m, 1H), 6.78 (m, 1H), 6.98 (m, 1H), 7.19 (d, 1H), 7.65 (m, 1H), 7.98 (d, 2H), 8.14 (d, 2H), 8.46 (m, 1H), 8.98 (m, 1H), 9.77 (s, 1H); Mass Spectrum: M+H+ 315.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH3:12])[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[C:16]1([NH:22][CH:23]2[CH2:32][CH2:31][C:26]3(OCCO3)[CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>CCOC(C)=O.CC(N(C)C)=O>[CH3:12][C:11]1[NH:10][N:9]=[CH:8][C:7]=1[C:5]1[S:4][C:3]2[C:13](=[O:14])[NH:15][C:26]3([CH2:25][CH2:24][CH:23]([NH:22][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:32][CH2:31]3)[NH:1][C:2]=2[CH:6]=1
Reactant: c1ccc(NC2CCC3(CC2)OCCO3)cc1
Reactant: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCC(Nc3ccccc3)CC1)N2
Temperature: 100 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
A mixture of 3-amino-5-(5-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamide (146 mg, 0.66 mmol), N-phenyl-1,4-dioxaspiro [4.5]decan-8-amine (169 mg, 0.723 mmol), CSA (183 mg, 0.788 mmol), MgSO4 (158 mg, 1.31 mmol) and DMA (1 mL) was stirred at 100° C. for 1 h. EtOAc and saturated aqueous NaHCO3 were added to quench the reaction. The organic materials were extracted with EtOAc/THF. The combined extracts were dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, NH, 95:5 hexane/EtOAc to EtOAc then to 95:5 EtOAc/MeOH), then crystallized from 2-propanol/heptane to give the title compound (41 mg, 16%) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:23])=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[S:24]1[CH:28]=[CH:27][N:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:23])=[C:18]([NH:19][S:29]([C:25]3[S:24][CH:28]=[CH:27][N:26]=3)(=[O:31])=[O:30])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1nccs1
Reactant: CC(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3nccs3)c2F)c(-c2ccnc(Cl)n2)s1
Yield: 30 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-isopropylthiazol-4-yl)-2-fluoroaniline (2.5 g, 7.2 mmol) and thiazole-2-sulfonyl chloride (1.45 g, 7.88 mmol) the title compound of Step A was obtained (1.05 g, 30.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.01 (br. s., 2H), 8.58 (d, J=5.2 Hz, 1H), 8.09 (d, J=3.2 Hz, 1H), 8.01 (d, J=2.8 Hz, 1H), 7.49-7.40 (m, 1H), 7.31-7.25 (m, 1H), 6.88 (d, J=5.6 Hz, 1H), 3.35-3.30 (m, 1H), 1.36 (d, J=6.8 Hz, 6H). MS (ES+): 496 [M+H]+.