Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:34](Br)(Br)([Br:36])[Br:35].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH:9]1[CH:10]=[C:34]([Br:36])[Br:35])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C=C(Br)Br
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a stirred cold (minus 50° C.) solution of N-boc-prolinal (5.98 g, 30 mmol) and PPh3 (62.95 g, 240 mmol) in CH2Cl2 (200 mL) was slowly added a solution of CBr4 (39.80 g, 120 mmol) in CH2Cl2 (50 mL), and the stirring was continued for 1 hr at 0° C. To this mixture was added sat. NaHCO3 and the mixture was extracted with CHCl3. The extract was washed with H2O, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with CHCl3 and n-hexane-AcOEt (4:1, v/v) as eluent to give 7.84 g (74%) 1-(tert-butoxycarbonyl)-2-(2,2-dibromoethenyl)pyrrolidine as colorless plates. mp 61-63; IR (KBr) 1693 cm−1; 1H-NMR (CDCl3) δ1.46 (9 H, s), 1.72-2.19 (4H, m), 3.35-3.45 (2H, m),4.35 (1H, br s), 6.36 (1H, br s); MS (FAB) m/z 352, 354, 356, 358; Anal. Calcd. for C11H17NO2Br2: C, 37.21; H 4.83; N, 3.94. Found: C, 37.14; H, 4.83; N, 4.00.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>>[Cl:26][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:7])[N:9]=1
Reactant: CCCCOC(=O)c1nc(Cl)c2cc(Sc3ccccc3)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(Cl)c2cc(Sc3ccccc3)ccc2c1O

Procedure:
194 mg of 1-chloro-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (0.5 mmol) were reacted with glycine and sodium methylate analogously to Example D-1 g). 168 mg of the title compound were obtained; 1H NMR (DMSO-d6): δ=9.17 (t, 1H), 8.24 (d, 1H), 7.51 to 7.79 (m, 7 H), 4.00 (d, 2 H).
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>N1C=CC=CC=1>[N+:17]([C:12]1[CH:13]=[CH:14][C:15]2[CH2:16][C@H:7]3[CH2:6][S:5][C:4](=[N:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[N:8]3[CH2:9][C:10]=2[CH:11]=1)([O-:19])=[O:18]
Reactant: Nc1cccnc1
Reactant: CSC1=[N+]2Cc3cc([N+](=O)[O-])ccc3C[C@H]2CS1
Agent: [I-]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc2c(c1)CN1C(=Nc3cccnc3)SC[C@@H]1C2
Reaction time: 6 h
Yield: 88.1 %

Procedure:
(S)-3-Methylthio-7-nitro-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (23 g.) is added to a solution of 3-aminopyridine (11 g.) in pyridine (400 cc.). After 6 hours at a temperature of about 20° C., the mixture is concentrated to dryness under reduced pressure (25 mm.Hg). The residue is dissolved in a mixture consisting of methylene chloride (1,500 cc.) and water (500 cc.). The organic phase is decanted, washed with water (3 × 200 cc.), dried over magnesium sulphate, filtered and then concentrated to dryness. The residue obtained is recrystallised from a mixture of acetonitrile and ethanol (1:1 by volume). (S)-7-Nitro-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (16.2 g.) is thus obtained in the form of yellow crystals melting at 234° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=2)[N:5]=[C:4]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCOCC1>[N:31]1([C:2]2[N:7]=[C:6]([N:8]3[CH2:12][CH2:11][CH2:10][CH:9]3[C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH:14]=3)[N:5]=[C:4]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[CH:3]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNC1
Reactant: Cc1cc(Nc2cc(Cl)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N3CCCC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 100 °C
Yield: 53.7 %

Procedure:
A mixture of 6-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}pyrimidine (Example 17) (250 mg, 0.59 mmol), pyrrolidine (0.5 ml, 5.98 mmol) and anhydrous 1,4-dioxane (5.0 ml) was heated at 100° C. in a sealed vessel under microwave irradiation for 1 hour. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water/acetonitrile/TFA (95:5:0.2 decreasing in polarity to 0:100:0.2). Product containing fractions were combined and passed through a 50 g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue triturated with diethylether and collected by filtration to give the title compound (145 mg, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH:10]([OH:12])[CH3:11])=[N:6][CH:7]=1.[H][H]>CCOC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH:10]([OH:12])[CH3:11])=[N:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(O)C#Cc1ccc(Br)cn1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: CC(O)C=Cc1ccc(Br)cn1
Yield: 49.1 %

Procedure:
The 4-(5-bromo-pyridin-2-yl)-but-3-yn-2-ol prepared in Step 1 (2.26 g, 0.010 mol) was dissolved in EtOAc (50 mL). Lindlar's catalyst (1.13 g) was added and the mixture was shaken on a Parr shaker under 55 psi hydrogen for 16 h. The mixture was filtered and concentrated. The residue was chromatographed (SiO2, 9/1 to 4/1 hexane/EtOAc) to afford 4-(5-bromo-pyridin-2-yl)-but-3-en-2-ol as a clear oil (1.12 g, 49%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[N:7][N:8]2[CH3:15])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1n[nH]c2cc(Br)ccc12
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1nn(C)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.4 %

Procedure:
To a mixture of methyl 6-bromo-1H-indazole-3-carboxylate (0.50 g, 1.96 mmol) and potassium carbonate (1.28 g, 9.29 mmol) in acetonitrile (15 mL) is added methyl iodide (1.31 g, 9.29 mmol) at room temperature. The reaction mixture is stirred at room temperature for 15 h. Remove the solvent under vacuum, dilute with water, and extract with ethyl acetate (3×10 mL). The combined organics are dried over sodium sulfate and concentrated under reduced pressure. The crude is purified by flash chromatography eluting with 8:2 hexane/ethyl acetate to give 0.35 g (70%) of the title compound as an off white solid. 1H NMR (400 MHz, CDCl3) δ 4.03 (s, 3H), 4.14 (s, 3H), 7.42 (dd, J=8.4, 1.2 Hz, 1H), 7.66 (s, 1H), 8.08 (d, J=8.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20]CC2C=CC=CC=2)[CH:17]=[C:16]([Cl:28])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[H][H]>[Pd].C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([Cl:28])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCOc1c(Cl)cc(O)cc1Cl

Procedure:
This compound was prepared in a manner analogous to that of Step A of Example 3, using 4.1 grams (0.0096 mole) of N-{3-[2,6-dichloro-4-(phenylmethoxy)phenoxy]propyl}(tert.-butoxy)carboxamide, a catalytic amount of 10% palladium on carbon and a theoretical amount of hydrogen gas in 60 mL of 1:1 ethanol and ethyl acetate in a Parr Hydrogenator. The yield of the subject compound was 3.5 grams.
Reaction SMILES: Cl[CH:2]([CH2:6][C:7]([C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([CH3:16])=[C:11]([Cl:17])[CH:10]=1)=O)[C:3](O)=[O:4].Cl.[NH2:19][NH2:20]>C(O)C.O>[Cl:17][C:11]1[CH:10]=[C:9]([C:7]2[CH:6]=[CH:2][C:3](=[O:4])[NH:19][N:20]=2)[CH:14]=[C:13]([Cl:15])[C:12]=1[CH3:16]
Reactant: NN
Reactant: Cc1c(Cl)cc(C(=O)CC(Cl)C(=O)O)cc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Yield: 66.6 %

Procedure:
1.48 g (0.005 mole) of 2-chloro-4-(3,5-dichloro-4-methylphenyl)-4-oxobutyric acid, prepared as described in step (a) above, were dissolved in a solution of 0.68 g (0.01 mole) of hydrazine hydrochloride in 15 ml of ethanol and 2 ml of water; the solution was then heated under reflux for 3 hours, after which it was cooled. The solvent was then distilled off and 20 ml of water were added to the residue. The mixture was stirred and the resulting crystals were collected by filtration, washed successively with water and with a small amount of diethyl ether and then dried, giving 0.85 g (yield 66.7%) of the desired 6-(3,5-dichloro-4-methylphenyl)-3(2H)pyridazinone, having the same properties as the product obtained in the preceding Examples.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](O)=[O:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[F:54][C:55]1[CH:56]=[C:57]([CH:60]=[CH:61][C:62]=1[O:63][C:64]([F:67])([F:66])[F:65])[CH2:58][NH2:59]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:28](=[O:29])[NH:59][CH2:58][C:57]2[CH:60]=[CH:61][C:62]([O:63][C:64]([F:65])([F:66])[F:67])=[C:55]([F:54])[CH:56]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccc(OC(F)(F)F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)NCc2ccc(OC(F)(F)F)c(F)c2)C1
Yield: 78.4 %

Procedure:
To a solution of the compound (1.35 g) obtained in Example 783, Step 2 in chloroform (15 ml) were added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (625 mg), 1-hydroxybenzotriazole hydrate (499 mg) and 3-fluoro-4-trifluoromethoxybenzylamine (620 mg) with stirring under ice-cooling. After stirring overnight at room temperature, the reaction mixture was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and chloroform, and the aqueous layer was re-extracted twice with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:l) to give the title compound (1.50 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:20][CH2:19][CH2:18][C:17]([C:21]([O:23]CC)=[O:22])=[CH:16][C:15]=3[CH:26]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:20][CH2:19][CH2:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][C:15]=3[CH:26]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reaction time: 64 h
Yield: 85.4 %

Procedure:
To a solution of ethyl 7-(4-tert-butylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (503.8 mg) in ethanol (10 ml)was added 1N sodium hydroxide (2.0 m) at room temperature, and the mixture was stirred for 64 hours and concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (15 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The resulting crystal was collected by filtration to give 7-(4-tert-butylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (396 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1COCC1>[CH3:19][S:20]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:22])=[O:21]
Reactant: OCCOCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCOCc1ccccc1

Procedure:
The 2-benzyloxyethanol (Aldrich, 0.25 g, 1.7 mmol), triethylamine (0.67 mL, 5.0 mmol), and methanesulfonyl chloride (0.19 mL, 2.5 mmol) in 20 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:11]=[C:10]3[C:22]2[N:27]=[C:26]([O:28][C@H:29]3[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][CH2:33][C:30]43[CH2:32][CH2:31]4)[CH:25]=[N:24][CH:23]=2)[CH2:3][CH2:2]1>[Pd].CCO>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[N:12]1[C:13]2[C:9](=[CH:8][C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:15][CH:14]=2)[C:10]([C:22]2[N:27]=[C:26]([O:28][C@H:29]3[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][CH2:33][C:30]43[CH2:32][CH2:31]4)[CH:25]=[N:24][CH:23]=2)=[N:11]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C5=CCOCC5)cc34)n2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C5CCOCC5)cc34)n2)C1
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
Palladium on carbon, 10% (35.1 mg, 0.330 mmol) was added to a solution of (4R)-tert-butyl 4-(6-(5-(3,6-dihydro-2H-pyran-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (194 mg, 0.330 mmol) in EtOH (3.3 mL) at RT in a portable hydrogen reactor; the reaction was stirred under 45 psi of H2 for 1.5 h. The mixture was filtered through a pad of Celite, washed with DCM and MeOH, and concentrated to give (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (180 mg, 0.305 mmol, 92% yield) as an amber oil. MS (ESI, pos. ion) m/z: 590.4 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10](=[O:14])[CH2:11][O:12][CH3:13])=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:19][B:18](B2OC(C)(C)C(C)(C)O2)[O:17]1.C([O-])(=O)C.[K+].B(O)O>O1CCOCC1>[CH3:13][O:12][CH2:11][C:10]([NH:9][CH2:8][C:5]1[N:6]=[CH:7][C:2]([B:18]([OH:19])[OH:17])=[CH:3][CH:4]=1)=[O:14]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: COCC(=O)NCc1ccc(Br)cn1
Agent: CC(=O)[O-]
Agent: OBO
Agent: [K+]
Solvent: C1COCCO1
Product: COCC(=O)NCc1ccc(B(O)O)cn1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A mixture N-((5-bromopyridin-2-yl)methyl)-2-methoxyacetamide (387 mg, 1.494 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (493 mg, 1.942 mmol), PdCl2(dppf)-CH2Cl2Adduct (122 mg, 0.149 mmol) and potassium acetate (366 mg, 3.73 mmol) in dioxane (10 mL) was heated to 70° C. for 3 hr. LCMS indicated that the major product was boronic acid. After cooling to rt, the reaction mixture was filtered through celite and the filtrate was concentrated to afford (6-((2-methoxyacetamido)methyl)-pyridin-3-yl)boronic acid (335 mg, 1.495 mmol, 100% yield) as a brown oil. The material was used as is in the next step. MS (ES+) m/z: 225.0 (M+H); LC retention time: 0.38 min (analytical LCMS Method B).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:3]=1.[CH2:23]([O:27]C=C)[CH2:24]CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]([C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:3]=1)(=[O:27])[CH3:24]
Reactant: COC(=O)c1ccc2c(Br)nn(CC(=O)OC(C)(C)C)c2c1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(C(C)=O)nn(CC(=O)OC(C)(C)C)c2c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A solution of methyl 3-bromo-1-(2-tert-butoxy-2-oxoethyl)-1H-indazole-6-carboxylate (1.00 g, 2.71 mmol), n-butyl vinylether (1.75 mL, 13.5 mmol), palladium acetate (61 mg, 0.27 mmol), triphenylphosphine (142 mg, 0.54 mmol) and triethylamine (0.45 mL, 3.25 mmol) in dry CH3CN (10 mL) was heated at 100° C. under microwave irradiation for 7 h. Then, the mixture was further heated at 120° C. for 5 h under microwave irradiation. The solvent was evaporated, and the residue was then treated with 4N HCl/dioxane with stirring at RT for 16 h. Volatiles were evaporated and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to give after lyophilization of the pure fractions the title compound. MS (LC-MS): 333 [M+H]+, 355 [M+Na]; tR (HPLC conditions k): 3.83 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:39])[CH3:38])[CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[C:10](=[O:25])[C:11]([NH:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:16])=[CH:12][N:13]=2)=[CH:4][CH:3]=1.CO>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:39])[CH3:38])[C:31](=[O:36])[C:32]([F:34])([F:35])[F:33])=[O:28])[C:10](=[O:25])[C:11]([NH:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:16])=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccccn2)c1=O)C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccccn2)c1=O)C(=O)C(F)(F)F

Procedure:
2-[2-(4-Fluorophenyl)-6-oxo-5-(2-pyridylmethoxycarbonylamino)-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide was subjected to a procedure similar to that described in Example 1. Chromatography, with methanol:dichloromethane (gradient, 0:100, 5:95, 7:93) as the eluent, gave 2-[2-(4-fluorophenyl)-6-oxo-5-(2-pyridylmethoxycarbonylamino)-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide as a white solid; NMR (DMSO/H2O): 8.54 (d,2), 8.43 (s,1), 7.82 (m,1), 7.53 (m,3), 7.30 (m,3), 5.22 (s,2), 4.62 (d,1), 4.42 (d,1), 4.00, (d,1), 2.19 (m,1), 0.81 (d,3), 0.70 (d,3).
Reaction SMILES: [C:1]1([CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClC(Cl)(Cl)Cl>[Br:16][CH2:9][C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=Cc1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCC(=Cc1ccccc1)c1ccccc1
Yield: 95.9 %

Procedure:
A mixture of 1,2-diphenyl-1-propene (9.7 g, 50 mmol), N-bromosuccinimide (8.9 g, 50 mmol), dibenzoylperoxide (0.1 g) and tetrachloromethane (50 ml) was heated at reflux for 21 h. The mixture was filtered cold and the solvent evaporated from the filtrate in vacuo to give 13.1 g of 3-bromo-1,2-diphenyl-1-propene as an E/Z isomeric mixture.
Reaction SMILES: [Li]CCCC.[CH2:6]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH3:25][Sn:26](Cl)([CH3:28])[CH3:27]>C1COCC1>[CH3:25][Sn:26]([CH3:28])([CH3:27])[C:22]1[S:21][C:20]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:24][CH:23]=1
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCCCCCCCc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1ccc([Sn](C)(C)C)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
n-BuLi (1.6 M, 42 mL, 67 mmol) was added slowly to a solution of 2-tetradecyl-thiophene (17.0 g, 237 mmol) in THF (150 mL) at −78° C. and stirred for 30 min. Trimethyltin chloride (13.3 g, 67 mmol) in THF (30 mL) was added dropwise to the resultant suspension and then gradually warmed to room temperature. The reaction mixture was stirred for 18 h and quenched with saturated ammonium chloride solution (100 mL). The mixture was extracted with diethyl ether (2×100 mL) and the combined organic extracts were washed with brine (100 mL). The organic phase was dried and concentrated to give brown oil (26.8 g, 99%), which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.02 (d, 1H, J=3.2 Hz), 6.90 (d, 1H, J=3.2 Hz), 2.85 (t, 2H, J=8 Hz), 1.68 (q, 2H, J=7.6 Hz), 1.50-1.20 (m, 22H), 0.88 (t, 3H, J=6.8 Hz), 0.344 (s, 9H).
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[CH3:38][O:39][C:40]1[C:47]([O:48][CH3:49])=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43]>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:43][CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[C:47]([O:48][CH3:49])[C:40]=2[O:39][CH3:38])=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Reactant: COc1cccc(CN)c1OC
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CNCC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)c1OC

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (150 mg, 0.29 mmol, example 105, step B) by following the indications of general procedure H using DIEA (0.14 mL, 0.81 mmol) and 2,3-dimethoxybenzylamine (0.12 mL, 0.81 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (25 mg, 16% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3](=[O:34])[O:4][CH:5]([C:12]1[N:13]([CH3:33])[C:14]([C:23]2[S:24][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH2:32])[C:30]=3[N:31]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[C:6]1C=CC=CC=1.[CH3:36][N:37]1[CH:41]=[CH:40][N:39]=C1C=O>>[CH3:35][N:2]([CH3:1])[C:3](=[O:34])[O:4][CH:5]([C:12]1[N:13]([CH3:33])[C:14]([C:23]2[S:24][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH2:32])[C:30]=3[N:31]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[C:6]1[N:37]([CH3:36])[CH:41]=[CH:40][N:39]=1
Reactant: CN(C)C(=O)OC(c1ccccc1)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Reactant: Cn1ccnc1C=O
Product: CN(C)C(=O)OC(c1nccn1C)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 97 but using 1-methyl-2-imidazolecarboxaldehyde in place of benzaldehyde. Pale yellow oil (33 mg, 46%);