Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[CH3:5]CCCCC.Br[C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([S:21]([F:26])([F:25])([F:24])([F:23])[F:22])[CH:20]=1)[C:15]([OH:17])=[O:16].O>C1COCC1.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>[CH3:5][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([S:21]([F:26])([F:25])([F:24])([F:23])[F:22])[CH:20]=1)[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Reactant: CCCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Temperature: 150 °C

Procedure:
1.15 ml (2.29 mmol) of a 2 M solution of trimethylaluminium in a hexane fraction were added to a solution of 250 mg (0.764 mmol) of the compound of Example 15A and 27 mg (0.023 mmol) of tetrakis(triphenylphosphine)palladium(0) in 2.5 ml of anhydrous THF, and the mixture was then, under an argon atmosphere, heated in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 150° C. for 120 min. After cooling to RT, about 10 ml of water were added, and the reaction mixture was extracted three times with in each case about 10 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness on a rotary evaporator. The product was isolated by preparative HPLC (Method 9). Concentration of the product fractions and drying of the residue under high vacuum gave 98 mg (47% of theory, 95% pure) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15]CC3C=CC=CC=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].C(O)(=O)C.[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2cc(OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)Cn1ccc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
(5-Benzyloxy-indol-1-yl)-acetic acid ethyl ester (3.49 g, 11.31 mmol) is dissolved in EtOH (50 mL) and glacial acetic acid is added (2.0 mL). Palladium on carbon (20% by wt., 0.700 g) is then added to the homogenous solution, and a hydrogen filled balloon is connected to the round bottom flask. A vacuum is created within the flask until the ethanol began to bubble, and the hydrogen allowed to enter the flask; this procedure is repeated three times, then the reaction is left to stir at room temperature overnight. Upon completion, the reaction is diluted with DCM (200 mL), and water (100 mL) is added. The mixture is filtered through a celite plug and the two phases are separated. The organic layer is washed with brine (2×75 mL), then dried over anhydrous magnesium sulfate, and concentrated to yield the title compound (2.42 g) in 98% yield. The residual acetic acid is removed by flash column chromatography. 1H NMR (DMSO-d6, 400 MHz): δ 1.18 (t, J=7.34 Hz, 3H), 4.12 (q, J=6.85 Hz, 2H), 4.99 (s, 2H), 5.73 (s, 1H), 6.23 (d, J=2.94 Hz, 1H), 6.60 (dd, J1=1.96 Hz, J2=8.80 Hz, 1H), 6.84 (d, J=2.45 Hz, 1H), 7.12 (d, J=8.80 Hz, 1H), 7.19 (d, J=2.94 Hz, 2H); MS (ES, m/z):C12H13NO3: 220.21(M++1), 218.7(M+−1).
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[C:6]([CH3:16])=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:17][CH2:18][CH2:19]Br>C(O)C>[Br:17][CH2:18][CH2:19][O:4][C:5]1[C:6]([CH3:16])=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1cccc(O)c1C
Reactant: BrCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cccc(OCCBr)c1C

Procedure:
13.6 g (0.2 mol) of sodium methoxide are dissolved in 200 ml of ethanol. 36 g (0.2 mol) of ethyl 3-hydroxy-2-methylbenzoate are then added and the mixture is refluxed for 2 hours. 61.4 g (0.32 mol) of 1,2-dibromoethane are then added dropwise and the mixture is heated to reflux for 20 hours. The cooled reaction mixture is concentrated on a rotary evaporator. The residue is taken up with ethyl acetate and washed 3 times with dilute sodium hydroxide solution. The organic phase is dried and the solvent is distilled off. The useful product is purified by column chromatography. Yield: 14.6 g of oil
Reaction SMILES: [CH2:1]([N:5]1[N:6]([CH3:28])[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1F)[CH2:2][CH2:3][CH3:4].[SH:29][CH2:30][C:31]([NH2:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[NH2:33][C:31](=[O:32])[CH2:30][S:29][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]=1[C:11](/[N:10]=[C:9]1/[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]([CH3:28])[C:7]([C:24]([CH3:25])([CH3:27])[CH3:26])=[CH:8]/1)=[O:23]
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)cc(C(C)(C)C)n1C
Reactant: NC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2SCC(N)=O)cc(C(C)(C)C)n1C
Yield: 49.9 %

Procedure:
A mixture of Example 81C (400 mg, 1 mmol), 2-mercaptoacetamide (183 mg, 2 mmol) and potassium carbonate (277 mg, 2 mmol) in DMA (10 mL) was heated at 50° C. for 14 hours. The mixture was then poured into water and extracted with ethyl acetate. The acetate layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by chromatography (SiO2, EtOAc-MeOH: 9:1) afforded 235 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.81-1.02 (m, 3H), 1.27-1.44 (m, 11H), 1.56-1.78 (m, 2H), 3.55 (s, 2H), 3.88 (s, 3H), 4.27-4.50 (m, 2H), 6.83 (s, 1H), 7.12 (s, 1H), 7.41-7.73 (m, 3H), 8.32 (d, J=2.0 Hz, 1H). MS (ESI+) m/z 471 (M+H)+. Anal. calculated for C22H29F3N4O2S.0.25H2O: C, 55.62 H, 6.26 N, 11.79. Found: C, 55.46 H, 6.32 N, 11.50.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:10][C:11]1[CH:12]=[C:13]([OH:20])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[O:20][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OCC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]

Procedure:
In a similar manner to Example 2, starting material step (b), t-butyl bromoacetate (2.9 ml), 3-methyl-4-nitrophenol (2.5 g), anhydrous potassium carbonate (2.7 g) and acetone (100 ml) were reacted to give t-butyl 3-methyl-4-nitrophenoxyacetate (4.19 g) as an off-white solid: NMR Spectrum (DMSO-d6) 1.44 (9H, s), 2.56 (3H, s), 4.71 (2H, s), 6.94 (1H, dd), 7.03 (1H, d), 8.06 (1H, d); Mass Spectrum m/Z 268 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)(N)CO
Solvent: C1CCOC1
Product: CC(C)(CO)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 88.7 %

Procedure:
As shown in Scheme ??, mix 5-bromo-2-fluoronitrobenzene (11.2 g, 50.5 mmol) and 2-amino-2-methyl-1-propanol (10.5 mL, 110 mmol) in THF (120 mL). Heat at reflux for 48 h and then cool to room temperature. Remove most of the THF under reduced pressure and then partition the residue between water and EtOAc. Wash the organic layer a second time with water and the dry (MgSO4) and concentrate to give an orange solid. Triturate the solid with hexane (200 mL) and dry to yield 12.95 g (89%) title compound. MS (es) 288 (M−1). HPLC (ISO80-10M) t=2.67 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][O:7][C:6]=1[CH3:10])=[O:4].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:18])[O:7][C:6]=1[CH3:10])=[O:4]
Reactant: COC(=O)c1ccoc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)oc1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 78.5 %

Procedure:
DK001 (The following reaction is carried out under exclusion of light.) Dissolve 2-Methyl-furan-3-carboxylic acid methyl ester (52) (3.60 mL, 28.5 mmol) in chloroform (20 mL) and glacial acetic acid (20 mL) and add NBS (6.90 g, 38.8 mmol) portionwise in between a period of 95 min. Stir the reaction suspension for additional 19 h at rt. Add water to the reaction mixture and extract the aqu. layer with dichloromethane (2 times), wash the combined organic layer with 2M aqu. NaOH, water (3 times) and brine and dry it with Na2SO4 to obtain 5-Bromo-2-methyl-furan-3-carboxylic acid methyl ester (53) (4.90 g, 78%) as a red brown oil. No further purification. 1H NMR (400 MHz, CDCl3): 2.54 (s, 3H); 3.80 (s, 3H); 6.53 (s, 1H).
Reaction SMILES: Cl.NCCC[CH:6]=[C:7]([CH3:11])[C:8]([NH2:10])=[O:9].[C:12](OC(=O)CCC)(=O)[CH2:13][CH2:14]C.C(N(CC)CC)C.C([NH-])(=O)CCC>CO>[CH3:12][CH2:13][CH2:14][NH:10][C:8](=[O:9])[C:7]([CH3:11])=[CH2:6]
Reactant: CCCC(=O)OC(=O)CCC
Reactant: CC(=CCCCN)C(N)=O
Agent: CCCC([NH-])=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C=C(C)C(=O)NCCC
Yield: 92 %

Procedure:
0.8 g of 3-aminopropyl methacrylamide hydrochloride was dissolved in a methanol solvent and 1.5 g of butyric anhydride and 0.9 g of triethylamine (TEA) were added thereto. The resultant mixture was stirred under ice-cooling for 4 hours. After the completion of the reaction, the solvent was distilled off with an evaporator and the precipitate was filtered off. The filtrate was recovered and introduced into a silica column. Thus, the eluate fraction containing the target product was taken up and subjected to recrystallization to thereby purify the target butyrylamide, N-3-propyl methacrylamide (yield: 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22]CC)=O)[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[N:26]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:33][N:26]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:22])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: NN1CCCCCC1
Product: O=C(NN1CCCCCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and hexahydro-1-H-azepin-1-amine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 12.90 (1H, br), 11.80 (1H, br), 10.13 (1H, br), 8.15 (1H, br s), 7.23 (3H, m), 7.11 (2H, t, J=8.8 Hz), 3.97 (2H, s), 2.94 (4H, m), 1.59 (8H, m); ES+ MS: 411 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.NN.C1CN([P+](O[N:45]2[N:53]=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)(=[O:24])=[O:25])=[C:6]([CH2:8][C:9]([NH:45][NH2:53])=[O:11])[CH:7]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NNC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (23.6 mg, 0.066 mmol) and hydrazine (6.3 uL, 0.13 mmol) in 1 mL of DMF were added PyBOP (69 mg, 0.13 mmol) and triethylamine (31 uL, 0.22 mmol). The reaction mixture was stirred at room temperature for 1 hour. The crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a white solid (5.0 mg, yield 16%). MS calcd for (C15H17BN4O5S): 376.1. MS found (ESI negative): (M−H)−=375.1. 1H NMR (DMSO-d6) δ (ppm): 10.4 (bs, 1H), 9.74 (s, 1H), 9.11 (bs, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 6.34 (m, 2H), 5.89 (bs, 2H), 4.81 (s, 2H), 3.76 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][NH:8][C:9]3=[O:14])[C:4]=2[CH2:3]1.[C:16]([O:19][CH2:20][C:21]1[C:26]([Br:27])=[CH:25][CH:24]=[CH:23][C:22]=1Br)(=[O:18])[CH3:17]>[Cu]I.COCCOC>[C:16]([O:19][CH2:20][C:21]1[C:22]([N:8]2[CH2:7][CH2:6][N:5]3[C:10](=[CH:11][C:12]4[CH2:13][C:2]([CH3:15])([CH3:1])[CH2:3][C:4]=43)[C:9]2=[O:14])=[CH:23][CH:24]=[CH:25][C:26]=1[Br:27])(=[O:18])[CH3:17]
Reactant: CC(=O)OCc1c(Br)cccc1Br
Reactant: CC1(C)Cc2cc3n(c2C1)CCNC3=O
Agent: [Cu]I
Solvent: COCCOC
Product: CC(=O)OCc1c(Br)cccc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 150 °C
Yield: 31.5 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 167e (301 mg, 1.47 mmol), 2,6-dibromobenzyl acetate 104g (1.1 g, 3.0 mmol), CuI (140 mg, 0.7 mmol) Cs2CO3 (961 mg, 3.0 mmol), N′,N′,N′,N′-tetramethylethylenediamine (0.22 mL, 1.5 mmol) and 1,2-dimethoxyethane (4.1 mL). The mixture was heated in microwave to 150° C. for 3 h. After this time, the mixture was filtered and the resulting solid was washed with 9:1 CH2Cl2/MeOH (50 mL). The combined organics were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of hexanes-ethyl acetate to afford a 32% yield (200 mg) of 167f.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[CH2:27][NH2:28])[NH:20][CH:19]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:28][CH2:27][C:25]4[CH:24]=[CH:23][CH:22]=[C:21]5[C:26]=4[C:18]([CH3:17])=[CH:19][NH:20]5)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: Cc1c[nH]c2cccc(CN)c12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2cccc(CNc3nccc(Nc4cc(C5CC5)[nH]n4)n3)c12
Temperature: 120 °C

Procedure:
A tube was charged with 53 (200 mg, 0.85 mmol), 234 (181 mg, 1.13 mmol), DIPEA (0.2 mL) and IPA (2 mL), degassed, sealed and heated at 120° C. overnight. The solvent was concentrated to dryness in vacuo. The residue was purified by preparative HPLC to afford 80 mg (26%) of I-92 as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C:5]([CH2:14][N:15](C)[C@@H:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)=[C:6]([CH:12]=[O:13])[O:7]2.[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[NH:25][C:17](=[O:19])[C@@H:16]([N:15]1[CH2:14][C:5]2[CH2:4][C:3]3[C:2]([Cl:1])=[CH:11][CH:10]=[CH:9][C:8]=3[O:7][C:6]=2[C:12]1=[O:13])[CH2:20][CH:21]([CH3:22])[CH3:23]
Reactant: CC(C)C[C@@H](C(=O)O)N(C)CC1=C(C=O)Oc2cccc(Cl)c2C1
Reactant: Nc1nccs1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1nccs1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Yield: 44.7 %

Procedure:
A solution of (S)-2-[(5-chloro-2-formyl-4H-chromen-3-ylmethyl)-methyl-amino]-4-methyl-pentanoic acid (300 mg, 2.1 mmol) (Example 3, Step 1c), commercially available 2-aminothiazole (109 mg, 1.07 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (190 mg, 0.98 mmol), and N-hydroxybenzotriazole (HOBt) (132 mg, 0.982 mmol) in methylene chloride (15 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid thiazol-2-yl-amide (200 mg, 53%), as a light yellow solid. 1H NMR (DMSO-d6) δ: 12.58 (br. s., 1H), 7.50 (d, J=3.4 Hz, 1H), 7.19-7.36 (m, 3H), 7.09 (dd, J=7.1, 2.2 Hz, 1H), 5.05 (dd, J=10.8, 4.9 Hz, 1H), 4.40 (d, J=19.1 Hz, 1H), 4.09 (d, J=18.6 Hz, 1H), 3.76 (br. s., 2H), 1.78-1.92 (m, 1H), 1.63-1.76 (m, 1H), 1.46 (br. s., 1H), 0.93 (t, J=7.1 Hz, 6H).
Reaction SMILES: S(Cl)(Cl)=O.C([NH:8][C:9]1[C:17]([Cl:18])=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([O:19][CH3:20])[CH:10]=1)(=O)C.[NH2:21][CH:22]1[CH2:26][N:25]([CH2:27][CH3:28])[N:24]([CH2:29][CH3:30])[CH2:23]1>>[NH2:8][C:9]1[C:17]([Cl:18])=[CH:16][C:12]([C:13]([NH:21][CH:22]2[CH2:26][N:25]([CH2:27][CH3:28])[N:24]([CH2:29][CH3:30])[CH2:23]2)=[O:15])=[C:11]([O:19][CH3:20])[CH:10]=1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Reactant: CCN1CC(N)CN1CC
Solvent: O=S(Cl)Cl
Product: CCN1CC(NC(=O)c2cc(Cl)c(N)cc2OC)CN1CC

Procedure:
The title compound was prepared as described in Example 6 of U.S. Pat. No. 4,207,327 from 4-acetamido-5-chloro-2-methoxy-benzoic acid thionyl chloride and 4-amino-1,2-diethylpyrazolidine, m.p. 117°-119° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1>N1C=CC=CC=1.C(Cl)Cl.C(Cl)Cl>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1cccnc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccnc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phenyl chloroformate (0.733 mL, 5.84 mmol) is suspended in pyridine/DCM (3 mL, 2:1). The solution is stirred at 0° C., and 3-aminopyridine (500 mg, 5.31 mmol) dissolved in DCM (1 mL) is added dropwise. The reaction mixture is at 0° C. for 1 hour. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate. This organic portion is washed with 0.1 M HCl and then concentrated in vacuo to afford the titled compound. (MH+215)
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl.C(N(CC)CC)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[C:15]([F:14])([F:25])[F:26])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-Boc-piperazine (1.96 g, 10.5 mmol) in dichloromethane (50 mL) was added 2-trifluoromethylbenzoyl chloride (2.08 g, 10.0 mmol) dissolved in dichloromethane in the presence of triethylamine (3 mL) at 0° C. The resulting mixture was stirred at room temperature for 18 hours and then quenched with water (25 mL). The organic phase was washed with water, brine, then dried over MgSO4 and concentrated in vacuo to afford 4-(2-trifluoromethylbenzoyl)piperazine-1-carboxylic acid tert-butyl ester as a pale yellow solid.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12]([Br:16])=[C:11]([O:17][CH2:18][C:19]#[N:20])[CH:10]=[CH:9]3)=[CH:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]1=2.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:16][C:12]1[C:13]2[C:8](=[CH:7][C:6]([C:5]3[S:1][C:2]4[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=4[C:4]=3[C:32](=[O:33])[CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]=1[O:17][CH2:18][C:19]#[N:20]
Reactant: N#CCOc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Br
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#CCOc1ccc2cc(-c3sc4ccccc4c3C(=O)Cc3ccccc3)ccc2c1Br
Temperature: 25 °C
Yield: 8.4 %

Procedure:
To a 0° C. mixture of (6-benzo[b]thiophen-2-yl-1-bromo-naphthalen-2-yloxy)-acetonitrile (4.87 g, 12.4 mmol) in chloroform (250 mL) was added phenylacetyl chloride (2.0 mL, 15 mmol) and tin (IV) chloride (2.2 mL, 19 mmol). It was refluxed for five hours. During reflux, additional phenylacetyl chloride (2.0 mL, 15 mmol) and tin (IV) chloride (2.2 mL, 19 mmol) were added. The reaction mixture was then allowed to cool to ambient temperature and poured into ice water. It was diluted with additional chloroform and washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtrered and solvent evaporated. After stirring the residue in ether and filtering, the filtrate was concentrated and purified by flash chromatography using 25–45% methylene chloride in hexane and 100% methylene chloride as eluent and then further purified by HPLC using 86% acetonitrile (0.1% formic acid) as the mobile phase. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at 60° C. for one hour yielded the title compound as a hard amber gum (0.531 g, 8.36%); mass spectrum (+EI, [M+H]+) m/z 512/514. 1H NMR (500 MHz, DMSO-d6): δ8.30 (d, 1H, J=8.70 Hz), 7.74 (d, 1H, J=9.17 Hz), 7.85 (dd, 1H, J=8.70 Hz and 1.83 Hz), 8.21–8.25 (m,2H), 8.07–8.10 (m, 1H), 7.90–7.94 (m, 1H), 7.44–7.50 (m, 2H), 7.13–7.19 (m, 3H), 6.91–6.94 (m, 2H), 5.47 (s, 2H), 3.8 ppm (s, 2H). Elemental Analysis for C28H18BrO2S: Calcd: C, 65.63; H, 3.54; N, 2.73; Found: C, 65.48; H, 3.43; N, 2.35.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][C:18]([CH3:27])([CH3:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.O.[NH2:29][NH2:30]>C(O)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][C:18]([CH3:27])([CH3:26])[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:30][N:29]=1
Reactant: CC(C)(Cc1ccccc1)Nc1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(Cc1ccccc1)Nc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 120 °C

Procedure:
A mixture of 4-{2-amino-6-[(1,1-dimethyl-2-phenylethyl)amino]-4-pyrimidinyl}-2-fluorobenzonitrile (210 mg, 0.58 mmol) and hydrazine hydrate (99%, 2 mL) in ethanol (3 mL) was stirred and heated at 120° C. for 1 h in a Biotage Initiator microwave synthesizer. The mixture was cooled to room temperature and concentrated in vacuo. Water (100 mL) was added, and the resulting mixture was filtered. The solids were dried under vacuum to afford the title compound (90 mg) as a yellow solid. LC-MS (ES) m/z=374 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.34 (s, 6H), 3.26 (s, 2H), 5.37 (s, 2H), 6.05 (s, 2H), 6.34 (s, 1H), 6.40 (s, 1H), 7.10-7.25 (m, 5H), 7.39 (d, 1H), 7.70 (d, 1H), 7.84 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:15](=[O:16])[C:14](=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:13][S:12](=[O:27])(=[O:26])[CH2:11]2)=[CH:5][CH:4]=1.[NH2:28][C:29]1[S:30][CH2:31][CH2:32][N:33]=1>CCC(C)=O>[S:30]1[CH2:31][CH2:32][N:33]=[C:29]1[NH:28][C:15]1([OH:16])[C:10](=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:11][S:12](=[O:26])(=[O:27])[CH2:13][C:14]1=[CH:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(C=C2CS(=O)(=O)CC(=Cc3ccc(OC)cc3)C2=O)cc1
Reactant: NC1=NCCS1
Solvent: CCC(C)=O
Product: COc1ccc(C=C2CS(=O)(=O)CC(=Cc3ccc(OC)cc3)C2(O)NC2=NCCS2)cc1
Yield: 102.8 %

Procedure:
A stirred solution of tetrahydro-3,5-bis(4-methoxyphenylmethylene)-4H-thiopyran-4-one-1,1-dioxide (5.7 g, 0.014 mole) in 100 ml of MEK is treated with 2-amino-2-thiazoline (2.1 g, 0.020 mole). After heating at reflux for 1 hour the yellow mixture becomes colorless. After cooling for several hours, the product is filtered and washed with MEK and ether to give 7.0 g (97%) of colorless product, m.p. 194°-196°.