Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)=[O:5].FC(F)(F)C(O)=O>[Pt].C(O)C>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH2:12][CH2:11][CH2:10]2)=[O:5]
Reactant: CC(C)(C)CC(=O)Nc1ccc2ncccc2c1
Agent: [Pt]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)CCCN2
Reaction time: 48 h
Yield: 86.1 %

Procedure:
A mixture of 3,3-dimethyl-N-quinolin-6-ylbutanamide (2.4 g), 5% platinum on carbon (0.15 g), trifluoroacetic acid (2.0 mL) and ethanol (50 mL) was hydrogenated at 45 PSI on a Parr shaker for 48 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was dissolved in ethyl acetate and washed carefully with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4) and concentrated. The resulting oil was dissolved in ether and 4 N HCl was added. The solid was collected by filtration to yield 3,3-dimethyl-N-1,2,3,4-tetrahydroquinolin-6-ylbutanamide (2.1 g) as its HCl salt. MS (ES) m/z 247.2.
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>ClCCl.N1C=CC=CC=1>[CH2:22]([O:21][C:19]([NH:1][C:2]1([C:5]2[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1)=[O:20])[CH:23]=[CH2:24]
Reactant: CC(C)(C)OC(=O)c1ccc(C2(N)CC2)cc1
Reactant: C=CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)NC1(c2ccc(C(=O)OC(C)(C)C)cc2)CC1
Temperature: 0 °C

Procedure:
3 g of tert-butyl 4-(1-aminocyclopropyl)benzoate was placed in 30 mL of dichloromethane and 1.8 mL of pyridine. The solution was cooled to 0° C. and 1.2 mL of allyl chloroformate (dissolved in 5 mL of dichloromethane) was added dropwise at 0° C.-5° C. The mixture was left to react for 30 minutes at 0° C. and 2 hours at RT. The solution was combined with silica gel and evaporated down to the residue. This was chromatographed with dichloromethane on silica gel 70. Yield: 1.46 g of oil.
Reaction SMILES: Br[CH:2]1[C:11](=O)[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH2:35])=[S:34])=[CH:28][C:27]=2[O:36][CH3:37])[CH:25]=1>C(O)C.CCOC(C)=O>[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]3[S:34][C:2]4[CH2:3][C:4]5([O:8][CH2:7][CH2:6][O:5]5)[CH2:9][CH:10]([C:13]5[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=5)[C:11]=4[N:35]=3)=[CH:28][C:27]=2[O:36][CH3:37])[CH:25]=1
Reactant: O=C1C(Br)CC2(CC1c1ccc(F)cc1)OCCO2
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CC2(CC3c3ccc(F)cc3)OCCO2)ccc1-n1cnc(Cl)c1
Yield: 57 %

Procedure:
A mixture of 7-bromo-9-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-on (50 mg, 0.177 mmol, preparation AAC) and 1-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)thiourea (91 mg, 0.276 mmol, from step 4 of preparation A) was heated in ethanol (0.25 mL) at 80° C. for 45 min. The crude reaction was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo. The crude product was purified using preparatory TLC (50% acetone/hexanes) to give 54 mg (57% yield) of the titled compound as a white solid. LC-MS (M+H)+ 513.2. 1H NMR (400 MHz, chloroform-d) δ ppm 7.49 (dd, J=11.21, 1.89 Hz, 2 H) 7.15-7.24 (m, 2 H) 7.08 (d, J=8.31 Hz, 1 H) 6.93-7.04 (m, 3 H) 6.58 (dd, J=8.56, 2.27 Hz, 1 H) 4.16-4.33 (m, 1H) 3.89-4.15 (m, 4H) 3.49 (s, 3 H) 3.13 (dd, J=16.37, 3.02 Hz, 1 H) 2.82-2.98 (m, 1H) 1.98-2.32 (m, 2 H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([OH:9])=[O:8].[CH3:11][CH2:12]O.OS(O)(=O)=O>C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([O:9][CH2:11][CH3:12])=[O:8]
Reactant: O=C(O)C(=O)c1ccco1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)c1ccco1
Temperature: 65 °C
Yield: 86.2 %

Procedure:
2-(Furan-2-yl)-2-oxoacetic acid (15.0 g, 107 mmol) was dissolved in chloroform (420 mL) and treated with EtOH (165 mmol) and H2SO4 (1 mL). The reaction was heated to 65° C. overnight, at which point LC-MS indicated disappearance of starting material and product formation. The crude reaction was cooled and washed with sat. aq. NaHCO3 (3×100 mL) and brine (100 mL). The organics were concentrated to provide ethyl 2-(furan-2-yl)-2-oxoacetate (15.5 g, 64%) as a brown oil, which was used without further purification.
Reaction SMILES: [OH-].[K+].[S:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[CH2:5][CH2:4]1.[CH3:14][C:15]1[N:19]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[N:17][C:16]=1[CH:39]=O>CO>[CH3:14][C:15]1[N:19]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:18]=[N:17][C:16]=1/[CH:39]=[C:5]1/[CH2:4][S:3][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]/1=[O:13]
Reactant: O=C1CCSc2ccccc21
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(/C=C2/CSc3ccccc3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3.5 h
Yield: 74.4 %

Procedure:
A solution of potassium hydroxide (0.5 g) in methanol (5 ml) was added to a solution of thiochroman-4-one (0.93 g) and 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (2 g) in methanol (25 ml), and the resulting solution was stirred at 50° for 3.5 h. The resultant precipitate was filtered off, washed with methanol (20 ml) and dried to give the title compound (2.1 g), m.p. 225°-226°.
Reaction SMILES: [Cl-].[Na+].[C:3]([C:7]1[N:8]=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:15]=3[CH:16]=2)[S:10][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].P([O-])([O-])(O)=[O:24].[Na+].[Na+].S.[Na]>C(O)(C)(C)C.O1CCCC1.O>[C:3]([C:7]1[N:8]=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]([OH:24])=[O:22])=[CH:17][C:15]=3[CH:16]=2)[S:10][CH:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C=O)ccc3o2)n1
Reactant: O=P([O-])([O-])O
Agent: S
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(-c2cc3cc(C(=O)O)ccc3o2)n1
Reaction time: 4 h
Yield: 87.8 %

Procedure:
Sodium chloride (0.47 g) was added to a mixture of 4-tert-butyl-2-(5-formylbenzofuran-2-yl)thiazole (0.41 g), sodium hydrogenphosphate 12 water (0.23 g) and 2-methyl-2-butane (0.69 ml) in a mixed solvent of water (3 ml), tetrahydrofuran (7.5 ml) and tert-butanol (12.6 ml). After 4 hours, aqueous sodium hydrogensulfide solution was added to the mixture. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 1N-sodium hydroxide and the solution was treated with carbon powder and acidified with diluted hydrochloric acid. The resulting precipitates were collected and washed with water to give 2-(4-tert-butylthiazol-2-yl)benzofuran-5-carboxylic acid (0.38 g).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[Na+]>O>[CH2:9]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([NH:8][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9])=[CH:2][CH:1]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: Nc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCNc1ccc(NCCCCCCCCCCCCCCCCCC)cc1
Yield: 40.7 %

Procedure:
A mixture of 15.6 g of p-phenylenediamine, 15.5 g of stearyl bromide, and 1.96 g of powdered sodium hydroxide was heated to 140° to 150° C. for about 3.5 hours with stirring under nitrogen gas stream. After the reaction was over, 50 ml of water was poured to the reaction mixture and black-purple solids thus formed were recovered by filtration. When the solids were washed with water, ethanol, and methylene chloride and filtered to provide about 5.8 g of a pink powder of N,N'-distearyl-p-phenylenediamine. The structure was confirmed by 1HNMR, IR spectra, and elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23]([O:25]C)=O.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:29]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1F
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1F
Yield: 40 %

Procedure:
A solution of the 9-[(2-fluorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (237.5 mg, 0.68 mM) in 10 mL THF and 40 mL concentrated aqueous ammonium hydroxide was sonicated for 20 h at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 89.7 mg (40%) of the 9-[(2-fluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.5-6.9 (m, 7H), 6.65 (m, 2H), and 5.75 (s, 2H). IR (KBr, cm1) 3395, 3192 (br), 1621, 1599, 1580, 1564, 1491, 1455, 1334, 1261, and 774. MS (ES) m/e 333, 335.
Reaction SMILES: C(O[C:4]([CH:6]([C:17](=O)[CH:18]([CH3:20])[CH3:19])[CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)=[O:5])C.[C:22]([CH2:24][CH2:25][NH:26][NH2:27])#[N:23]>C(O)(=O)C>[C:22]([CH2:24][CH2:25][N:26]1[C:4]([OH:5])=[C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:15][CH:16]=2)[C:17]([CH:18]([CH3:19])[CH3:20])=[N:27]1)#[N:23]
Reactant: N#CCCNN
Reactant: CCOC(=O)C(Cc1ccc(C(=O)O)cc1)C(=O)C(C)C
Solvent: CC(=O)O
Product: CC(C)c1nn(CCC#N)c(O)c1Cc1ccc(C(=O)O)cc1
Temperature: 100 °C

Procedure:
15 g of compound 45 are dissolved in 100 ml of glacial acetic acid. 7.4 ml of 2-cyanoethylhydrazine are added, and the solution is heated at 100° C. for 2 h. The mixture is added to ice-water and extracted several times with ethyl acetate. The organic phase is extracted with 20% strength ammonium chloride solution and saturated sodium chloride solution and dried over sodium sulfate. 2.40 g of the desired compound 46 crystallize out with the ethyl acetate phase. The mother liquor is concentrated and chromatographed on silica gel (dichloromethane:methanol:glacial acetic acid=100:10:1). A further 1.10 g of compound 46, plus 7.0 g of reisolated precursor 45, are obtained. C17H19N3O3 (313.4); MS (ESI+): 314.2 (M+H)+, tR=0.97 min (Gradient 2).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9]Br.[Cl:11][C:12]1[N:13]=[C:14]([Cl:25])[C:15]2[CH:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[NH:18][C:16]=2[N:17]=1>CN(C=O)C>[Cl:25][C:14]1[C:15]2[CH:20]=[C:19]3[N:18]([CH2:8][CH2:9][O:24][C:21]3([CH3:22])[CH3:23])[C:16]=2[N:17]=[C:12]([Cl:11])[N:13]=1
Reactant: BrCCBr
Reactant: CC(C)(O)c1cc2c(Cl)nc(Cl)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OCCn2c1cc1c(Cl)nc(Cl)nc12
Temperature: 100 °C

Procedure:
Cesium carbonate (1.2 g, 3.7 mmol) and 1,2-dibromoethane (316 μL, 3.7 mmol) were added to a solution of 2-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-propan-2-ol (304 mg, 1.23 mmol) in DMF (4 mL) and the reaction mixture was heated at 100° C. for 45 min, then partitioned between water and ethyl acetate. The organic extract was separated and washed with brine, then dried (Na2SO4) and concentrated in vacuo affording 1,3-dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b-triaza-fluorene. A mixture of 1,3-dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b-triaza-fluorene (1.23 mmol), morpholine (236 μL, 2.69 mmol) and triethylamine (342 μL, 2.46 mmol) in IMS (3 mL) was heated at reflux for 3 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0 to 40% ethyl acetate in cyclohexane) affording 3-Chloro-8,8-dimethyl-1-morpholin-4-yl-5,6-dihydro-8H-7-oxa-2,4,4b-triaza-fluorene (159 mg, 40%). LCMS (method A): RT=3.13 min, [M+H]+=323.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[N:3]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[CH:19]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: OB(O)c1cccc(Cl)c1
Product: O=Cc1c(Cl)n(-c2cccc(Cl)c2)c2ccccc12
Yield: 70 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 3-chlorophenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(3-chlorophenyl)-1H-indole-3-carboxaldehyde (70% yield) as a cream solid. ESI/MS 290 (M+H); RT=3.55 min; NMR 10.13 (1H, s); 8.21 (1H, d); 7.84 (1H, d); 7.74 (3H, m); 7.38 (2H, m); 7.16 (1H, d, J=9 Hz).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[C@@H:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=2[S:30]([CH3:33])(=[O:32])=[O:31])[NH:3]1.[CH:34]([N-]C(C)C)(C)C.[Li+].CI>CN(C)C=O.C(#N)C>[CH3:34][N:3]1[C@H:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=2[S:30]([CH3:33])(=[O:31])=[O:32])[C:5]2[C:20](=[O:21])[CH2:19][CH2:18][C:6]=2[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[C:2]1=[O:1]
Reactant: CC(C)[N-]C(C)C
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Agent: [Li+]
Solvent: CI
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)[C@H]1c1ccc(C#N)cc1S(C)(=O)=O

Procedure:
A solution of (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 10A, 50 mg, 0.11 mmol) in N,N-dimethylformamide (1.0 mL) is treated with lithium diisopropylamide (1.8 M in tetrahydrofuran/heptane/ethylbenzene, 63 μL, 0.12 mmol) and methyl iodide (9 μL, 0.14 mmol). After 20 min the mixture is diluted with acetonitrile and purified by reversed phase HPLC (Agilent ZORBAX™ SB-C18, gradient of acetonitrile in water, 0.1% formic acid). Yield: 15 mg; ESI mass spectrum [M+H]+=490; Retention time HPLC: 1.00 min (Z017_S04).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:23])[CH:3]=1.[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:24]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[C:31]([CH3:36])=[CH:30][C:29]=1[S:37][C:3]1[C:4](=[O:23])[O:5][C:6]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][C:2]=1[OH:1])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: O=C1C=C(O)CC(CCc2cccc(O)c2)(c2ccccc2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3cccc(O)c3)(c3ccccc3)OC2=O)c(C(C)(C)C)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 using 4-hydroxy-6-[2-(3-hydroxy-phenyl)-ethyl]-6-phenyl-5,6-dihydro-pyran-2-one (0.155 g, 0.5 mmol) from Example UU, toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF; 0.2 g, 0.55 mmol), K2CO3 (0.27 g, 1.95 mmol), and DMF (3 mL). The solution was stirred overnight at room temperature, concentrated and the residue partitioned between 1N HC1 and EtOAc. The organic phase was dried (MgSO4), and concentrated. Purification by silica gel chromatography, eluting with MeOH:CHCl3 :hexane (5:90:10 to 10:90:10) gave the title compound, m.p. 132°-135° C. 1H NMR (DMSO-d6) δ 1.45 (s, 9 H), 1.76 (s, 3 H), 2.08-2.24 (m, 3 H), 2.48 (m, 1 H), 3.41 (dd, 2 H), 4.32 (s, 2 H), 4.91 (br s , 1 H), 6.17 (s, 1 H), 6.46-6.55 (m, 3 H), 7.02 (t, 1 H), 7.22 (s, 1 H), 7.35-7.46 (m, 5 H), 9.23 (s, 1 H) 12.15 (bs, 1 H).
Reaction SMILES: [F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13](B1OC(C)(C)C(C)(C)O1)[CH:12]=2)=[O:6].Br[C:28]1[C:29]([CH2:36][OH:37])=[N:30][CH:31]=[C:32]([F:35])[C:33]=1[CH3:34].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:28]1[C:29]([CH2:36][OH:37])=[N:30][CH:31]=[C:32]([F:35])[C:33]=1[CH3:34])[CH:12]=2)=[O:6]
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)[C@@H]4C[C@@H]4F)ncc3c2)OC1(C)C
Reactant: Cc1c(F)cnc(CO)c1Br
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1c(F)cnc(CO)c1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Temperature: 130 °C
Yield: 10.9 %

Procedure:
A mixture of (1S,2S)-2-fluoro-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)cyclopropanecarboxamide (230 mg, 0.648 mmol), (3-bromo-5-fluoro-4-methyl-2-pyridyl)methanol (143 mg, 0.648 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (46 mg, 0.065 mmol) and saturated aqueous sodium carbonate solution (0.3 mL) in acetonitrile (3 mL) was heated under microwave irradiation (Biotage) at 130° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (15 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water w/0.1% NH4OH, 14 min). Desired fractions were combined and evaporated in vacuo to afford the title compound as an off-white solid (26 mg, 11%). 1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 9.16 (s, 1H), 8.54 (s, 2H), 7.99 (m, 2H), 7.59 (d, J=8.4 Hz, 1H), 5.08-4.81 (m, 2H), 4.24 (s, 2H), 2.34-2.22 (m, 1H), 2.00 (s, 3H), 1.70 (m, 1H), 1.20 (m, 1H). LCMS (Method E): RT=6.66 min, M+H+=370.0.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][CH:24]([C:26](O)=[O:27])[CH3:25])[CH:19]=[CH:20][C:21]=1[Cl:22]>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:26](=[O:27])[C@H:24]([CH3:25])[NH:23][C:18]1[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using L-phenylalanine methyl ester hydrochloride (Sigma) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a solid (mp=122-124.5° C.). The reaction was monitored by tlc (Rf=0.47 in 1:1 EtOAc:Hexanes) and the product was purified by flash chromatography using 1:1 EtOAc:Hexanes as the eluent.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7](=[O:24])[C@@H:8]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.[Li+].[OH-].C(O)(=O)C>C1COCC1.CO>[C:10]1([CH2:9][C@H:8]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7](=[O:24])[CH2:6][CH2:5][C:4]([OH:25])=[O:3])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CCC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a stirred solution of the intermediate ethyl-(5S)-6-phenyl-5-[(tert-butyloxy-carbonyl)-amino]4-oxo-hexanoate (0.250 g, 0.716 mmol) in THF-MeOH (8:2 ratio)(10 mL) was added 0.5N LiOH (10 mL) and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was then neutralized with glacial acetic acid and then extracted with EtOAc (3×25 mL). The organic extract was dried over anhydrous MgSO4 and evaporation of the solvent afforded a crude yellow residue. Column chromatography on silica gel elution with 50% EtOAc-hexane afforded (5S)-6-phenyl-5-[(tert-butyloxycarbonyl)-amino]-4-oxo-hexanoic acid 9 as a cream yellow solid (0.225 g, 98%); mp 108-110° C.; Rf 0.41 (50% EtOAc-hexane); IR (KBr) ν 1730 (CO), 3200 (broad, COOH) cm−1; 1H NMR (300 MHz, CDCl3) δH 1.39 (9H, s, (CH3)3), 2.62-2.73 (4H, m, —COCH2CH2CO), 2.94 (1H, dd, J=6.9 and 13.8 Hz, —CHαPh), 3.10 (1H, dd, J=6.0 and 13.8 Hz, —CHβPh), 4.54 (1H, m, —CH—), 5.08 (1H, d, J=8.1 Hz, —NH—) and 7.13-7.35 (5H, m, Ar—H); 13C NMR (75 MHz, CDCl3) δC 27.5, 28.3, 35.0, 37.5, 60.1, 80.1, 127.0 (2C), 128.7 (2C), 129.2 (2C), 129.3, 136.2, 155.4, 177.4 and 207.4; HRMS m/z calcd for C17H23NO5 (M+) 321.15831, found 321.15762. Anal. Calcd. for C17H23NO5: C, 63.54; H, 7.21; N, 4.36. Found: C, 63.55; H, 7.34; N, 4.30.
Reaction SMILES: CO[C:3](=[C:5]([C:8]#[N:9])[C:6]#[N:7])[CH3:4].[NH:10]([C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:15]=[C:14]([C:30]([F:33])([F:32])[F:31])[N:13]=1)[NH2:11]>CO>[NH2:9][C:8]1[N:10]([C:12]2[C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:15]=[C:14]([C:30]([F:33])([F:32])[F:31])[N:13]=2)[N:11]=[C:3]([CH3:4])[C:5]=1[C:6]#[N:7]
Reactant: COC(C)=C(C#N)C#N
Reactant: NNc1nc(C(F)(F)F)nc(-c2ccccc2)c1-c1ccccc1
Solvent: CO
Product: Cc1nn(-c2nc(C(F)(F)F)nc(-c3ccccc3)c2-c2ccccc2)c(N)c1C#N

Procedure:
1-Methoxyethylidene malononitrile (0.17 g, 1.36 mmol) (prepared from malononitrile and triethyl orthoacetate by heating with acetic anhydride) was heated with 4-hydrazino-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.15 g, 0.45 mmol) in methanol (6 ml), overnight at 60-65° C. The solid that separated out from the reaction mixture was filtered and washed with methanol (5 ml), to yield the title compound. 1H-NMR (DMSO-d6) δ: 1.97 (s, 3H), 6.97 (br, 2H, D2O exchangeable), 7.07 (d, 2H), 7.26-7.38 (m, 7H), 7.40-7.41 (m, 1H); MS m/z: 421.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>ClCCCl>[Cl:15][CH2:16][CH2:17][C:18]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])=[O:19]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccccc1F
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(CCCl)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of 2-fluoroaniline (6.67 g, 60 mmol) and pyridine (5.21 g, 66 mmol) in 1,2-dichloroethane (50 mL) was added 3-chloropropionyl chloride (8.38 g, 66 mmol) dropwise at 15° C. After stirring at room temperature for 2 hours, the mixture was washed with water and then hydrochloric acid (2 N, aqueous). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford title compound (10.9 g, yield: 90%) as an oil. MS: 202.1 (M+H+)+.