Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[O:23][C:18]4=[N:19][CH:20]=[CH:21][CH:22]=[C:17]4[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:25]([CH2:27][O:28]C(=O)C)=[O:26].CCN(C(C)C)C(C)C.C(OC)(C)(C)C>C(Cl)Cl>[O:16]1[C:17]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[O:23][C@@H:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][N:1]3[CH2:6][CH2:5][N:4]([C:25](=[O:26])[CH2:27][OH:28])[CH2:3][CH2:2]3)=[CH:9][CH:10]=2)[CH2:15]1
Reactant: c1cnc2c(c1)OC[C@H](c1ccc(CN3CCNCC3)cc1)O2
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: O=C(CO)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Intermediate S (5.80 g, 17.7 mmol) in DCM (200 mL) at 0° C. is added acetic acid chlorocarbonylmethyl ester (2.16 mL, 19.5 mmol) followed by DIPEA (7.50 mL, 35.4 mmol) and the mixture stirred at rt for 1 h. The reaction was concentrated and the residue dissolved in 4:1 MeOH/water (100 mL) then treated with LiOH monohydrate (2.23 g, 53.1 mmol). After 72 h, the reaction is poured into ice water and the resulting solid isolated by filtration. The solid is suspended in refluxing tert-butylmethyl ether (400 mL) for 20 min and the remaining undissolved material separated out by filtration. The cooled filtrate produces a solid that is then isolated by filtration in several crops. The undissolved material from the first filtration is dissolved in refluxing 1,4-dioxane and cooled to give an additional crop of solid. The crops are combined to give the title product 253. (LC/MS method 16: ES+ m/z 370.3 [M+H]+, Rt=0.35 min)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20]3[N:19]=[C:18]([CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[NH:17][C:16]=3[C:15](=[O:28])[N:14]([CH2:29][CH2:30][CH3:31])[C:13]2=[O:32])=[CH:6][CH:5]=1)([O-])=O.O.NN.[H][H]>[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][N:12]2[C:20]3[N:19]=[C:18]([CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[NH:17][C:16]=3[C:15](=[O:28])[N:14]([CH2:29][CH2:30][CH3:31])[C:13]2=[O:32])=[CH:8][CH:9]=1
Reactant: CCCn1c(=O)c2[nH]c(Cc3cccnc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2[nH]c(Cc3cccnc3)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 2, 3-pyridylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine. By methods well known in the art, 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-1-propyl-8-[(3-pyridyl)methyl]xanthine.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12](OC)=[O:13])[C:3]=1[C:16]([O:18]C)=O.O.[NH2:21][NH2:22]>C(O)C>[OH:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:12](=[O:13])[NH:21][NH:22][C:16](=[O:18])[C:3]=12
Reactant: COC(=O)c1nc2ccccc2c(O)c1C(=O)OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH][nH]c(=O)c2c(O)c3ccccc3nc12
Yield: 112.8 %

Procedure:
To a stirred suspension of dimethyl 4-hydroxyquinoline-2,3dicarboxylate (1.00 g, 3.83 mM, prepared as described by H. Biere and W. Seelen, Liebigs Ann. Chem. 1976, 1972) in ethanol (15 mL) was added hydrazine hydrate (9.64 g, 193 mM) whereupon the solids dissolved. The resulting solution was refluxed for 3 hr during which time a thick precipitate formed. The cooled reaction mixture was filtered and the collected yellow solids were washed with ethanol and then ether. Air drying provided 0.99 g of the hydrazine salt of 2,3-dihydro-10-hydroxypyridazino[4,5-b]quinoline-1,4-dione. This material was boiled in glacial acetic acid (40 mL) and, after cooling to room temperature, the mixture was filtered. The collected solids were washed with several portions of ethyl acetate and then ether. Air drying provided the title pyridazinodione (0.72 g, 82%) as a yellow solid, mp >400° C.; Mass Spectrum (Chemical Ionization): 230 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:7]([S:8][C:9]([F:12])([F:11])[F:10])=[C:6]([NH:13]C(=O)C(F)(F)F)[NH:5][N:4]=1)#[N:2].[OH-].[NH4+].Cl>CO.C(OCC)(=O)C>[C:1]([C:3]1[C:7]([S:8][C:9]([F:12])([F:11])[F:10])=[C:6]([NH2:13])[NH:5][N:4]=1)#[N:2]
Reactant: N#Cc1n[nH]c(NC(=O)C(F)(F)F)c1SC(F)(F)F
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1n[nH]c(N)c1SC(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.6 %

Procedure:
The product of Step E (55 g, 181 mmoles) was dissolved in methanol. 100 ml of ammonium hydroxide were added, the solution was refluxed for 3 hours and then stirred at room temperature for 15 hours. The methanolic solution was brought to pH7 using concentrated aqueous hydrochloric acid and diluted with ethyl acetate. The organic layer was washed several times with water and brine, dried over MgSO4 and concentrated to dryness to give an oily brown residue which was recrystallized from methyl tert-butyl ether to afford 33 g of the title compound, m.p. around 187° C.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>>[CH3:27][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(C=C2c3ccccc3CCc3ccccc32)c1

Procedure:
Combine 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.5 g, 1.75 mmol) and m-tolylboronic acid (0.238 g, 1.75 mmol) using procedures essentially as described in Example 219, below. Pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product: MS (m/e): 296 (M+); HPLC (ISO80-10M)) t=17.78 min (95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:24][CH2:25][C:26]2[N:27]([CH3:31])[N:28]=[CH:29][N:30]=2)=[N:10][N:11]2[C:16]=1[CH:15]=[N:14][N:13]=[C:12]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23].[F:32]C1C=CC=C(F)C=1C(NN)=O>>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:32])[C:17]=1[C:12]1[N:11]2[N:10]=[C:9]([O:24][CH2:25][C:26]3[N:27]([CH3:31])[N:28]=[CH:29][N:30]=3)[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[C:16]2[CH:15]=[N:14][N:13]=1
Reactant: Cn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1ccccc1F
Reactant: NNC(=O)c1c(F)cccc1F
Product: Cn1ncnc1COc1nn2c(-c3c(F)cccc3F)nncc2c1-c1ccccc1F

Procedure:
This compound was prepared using the procedure described in Example 21, steps b) to f), using 3-(2-fluorophenyl)-4-hydroxy-2-furanone (cf Example 2) instead of 3-tert-butyl-4-hydroxy-2-furanone and 2,6-difluorobenzoic hydrazide instead of 2,5-difluorobenzoic hydrazide in step e). Data for the title compound: mp=163° C.; 1H NMR (360 MHz, CDCl3) δ 3.78 (3H, s), 5.52 (2H, s), 7.16 (2H, m), 7.24-7.29 (2H, m), 7.38-7.44 (1H, m), 7.60-7.65 (2H, m), 7.85 (1H, s), 9.31 (1H, s); MS (ES+) m/e 438 [MH]+.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH3:2].C([Li])CCC.[CH3:13][C:14]1([CH3:45])[CH:23]=[C:22](OS(C(F)(F)F)(=O)=O)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:32]#[C:33][C:34]3[CH:44]=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][CH:35]=3)[CH:20]=2)[S:15]1>C1COCC1.[Cl-].[Cl-].[Zn+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([C:3]1([C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:32]#[C:33][C:34]4[CH:44]=[CH:43][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:36][CH:35]=4)[CH:20]=3)[S:15][C:14]([CH3:13])([CH3:45])[CH:23]=2)[CH2:7][CH:6]=[CH:5][S:4]1)[CH3:2]
Reactant: CCc1cccs1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)S3)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C2(CC)CC=CS2)=CC(C)(C)S3)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 2-ethylthiophene (112.0 mg, 1.00 mmol) in 2.0 mL of THF was cooled to -78° C. and n-butyllithium (64.0 mg, 1.00 mmol, 0.63 ml of a 1.6M solution in hexanes) was added and the solution warmed to 0° C. during 1.5 hours. A solution of ZnCl2 (218.0 mg, 1.60 mmol) in 3.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature, stirred for 40 minutes, and transferred via cannula to a solution of ethyl 4-[(2,2-dimethyl-4-trifluoromethanesulfonyloxy-(2H)-thiochromen-6-yl)ethynyl]-benzoate (Compound 224, 200.0 mg, 0.40 mmol) and tetrakis(triphenylphosphine) palladium(0) (24.0 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 2 hours, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. The solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 29.0 mg (16%), was isolated by HPLC (1.25% EtOAc/hexanes) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.01 (2H, d, J=8.4 Hz), 7.65 (1H, s), 7.55 (2H, d, J=8.4 Hz), 7.35 (2H, s), 6.84 (1H, d, J=3.5 Hz), 6.77 (1H, m), 6.02 (1H, s), 4.39 (2H, q, J=7.1 Hz), 2.88 (2H, q, J=7.6 Hz), 1.46 (6H, s), 1.41 (2H, t, J=7.1 Hz), 1.35 (2H, t, J=7.6 Hz),
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH:25]=1>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:24][CH2:25][CH:26]=3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: COC1=CCCc2ccccc21
Product: CC(C)c1nc(CCOC2=CCCc3ccccc32)n(C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 47.7 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the enol ether with 1-methoxy-3,4-dihydronaphthalene (801 mg, 10 mmol) in the same manner as the example 41 to give the compound 51 (226 mg, 47.8%). Mp 99-102° C. PMR (CDCl3 -0.1% d5 -Py): δH1.26 (6 H, d, J 7 Hz, (CH3)2C), 2.73 (2 H, t, J 7.8 Hz, =-CH2), 3.27 (2 H, t, J 6.2 Hz, CH2 -Im), 3.11 (1 H, m, (CH3)2CH), 3.54 (3 H, s, NCH3), 4.22 (2 H, t, J 6.2 Hz, OCH2), 5.04 (1 H, t, J 6.4 Hz, =CH), 6.79 (2 H, d, J 1.6 Hz, arom-H), 7.4-7.0 (5 H, m, arom-H) IR(KBr)cm-1 : 3434, 3060, 1636, 1566, 1252, 1099. Elementary analysis (for C25H26N2Ocl2S) Calcd. : C, 63.42% H, 5.53% N, 5.92% S, 6.77% Cl, 14.98% Found: C, 64.13% H, 5.74% N, 5.74% S, 6.62% Cl, 14.11%
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:14])C(OCC)=O)=[O:5])C.S(=O)(=O)(O)O.O>C(O)(=O)C.O>[N+:21]([C:18]1[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][CH2:6][C:4]([OH:5])=[O:3])=[CH:20][CH:19]=1)([O-:23])=[O:22]
Reactant: CCOC(=O)C(CC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of ethyl 2-ethoxycarbonyl-4-(4-nitrophenyl)-4-oxobutyrate (6.2 g, 19 mmol) and sulphuric acid (1.0 g) in acetic acid:water (4:1, 50 ml) was stirred at reflux for 4 hours, then concentracted in vacuo to small volume. Dilution with water (100 ml) gave a precipitate which was filtered and dried at 50° C. under vacuum. Purification by chromatography on silica gel eluting with methanol:methylene chloride (3:97) and filtration of the resulting solid from diethyl ether containing a small percentage of methanol gave, after drying under high vacuum, 4-(4-nitrophenyl)-4-oxobutyric acid (2.1 g). 1H NMR (DMSO-d6, 300 MHz) δ: 2.62 (t, J=6 Hz, 2H, CH2), 3.33 (t, J=6 Hz, 2H, CH2), 8.22 (d, J=8.5 Hz, 2H, Ar), 8.36 (d, J=8.5 Hz, 2H, Ar), 12.22 (s. 1H, CO2H). Anal. Calculated for C10H9NO5 : C, 53.82; H, 4.06; N, 6.28. Found: C, 53.65; H, 4.02; N, 6.21.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4](/[CH:19]=[CH:20]\[CH3:21])[CH2:3]1.N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[Si:31]([O:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:4](/[CH:19]=[CH:20]\[CH3:21])[CH2:3]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: C/C=C\[C@@H]1C[C@H](O)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C/C=C\[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
Examples 2t and 2u, Step 2: A solution of benzyl (1S,2S,4R)-4-hydroxy-2-((Z)-prop-1-enyl)cyclohexylcarbamate (6.0 g, 20.7 mmol) in methylene chloride (60 mL) was treated with imidazole (2.1 g) and cooled to 0° C. The resultant solution was charged with tert-butylchlorodimethylsilane (3.4 g, 22.8 mmol) and then stirred for 18 h at 30° C. before being quenched with water. The organic phase was separated, and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with brine, dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl (1S,2S,4R)-4-(tert-butyldimethylsilyloxy)-2-((Z)-prop-1-enyl)cyclohexylcarbamate (6.0 g). MS found: (M+H)+=404.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9]C)=[CH:7][N:8]=1)C.NC1C2C(=CC=CC=2)CC1.ClC1C(C)=NC=C(C)N=1>>[CH:12]1([NH:11][C:4]2[C:3]([CH3:1])=[N:8][CH:7]=[C:6]([CH3:9])[N:5]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Agent: Cc1cnc(C)c(Cl)n1
Agent: NC1CCc2ccccc21
Product: Cc1cnc(C)c(NC2CCc3ccccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 1-Aminoindane and 3-chloro-2,5-dimethylpyrazine, and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.88, 2.35, 2.41, 2.77, 2.94, 3.03, 4.55, 5.78, 7.3, 7.64; MS (ESI+) for C15H17N3 m/z 240.30 (M+H)+.
Reaction SMILES: [CH3:1][C@@:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C@H:3]2[CH2:9][C:10]#N.Cl.CC[O:15]CC>[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>[CH3:1][C@@:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C@H:3]2[CH2:9][CH:10]=[O:15]
Reactant: C[C@@]12CCC(C[C@H]1CC#N)C2
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Product: C[C@@]12CCC(C[C@H]1CC=O)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
19.5 g (0.13M) of the nitrile (XI) obtained in 1-9) above was dissolved in 200 ml of absolute ether under a nitrogen gas stream and 160 ml of a 1M solution of diisobutylaluminum hydride in hexane was added dropwise thereto at room temperature. Then the resulting mixture was stirred for one hour, poured into ice/water and acidified with 1N hydrochloric acid. The organic phase was collected and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was distilled under reduced pressure to give 19.0 g (theoretical yield: 96%) of the aimed compound (XII) as a colorless oily material. b.p.: 45° to 47° C./0.5 mmHg.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=2)[N:4]([CH3:12])[N:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]([C:28]([F:31])([F:30])[F:29])[C:24]([NH2:27])=[N:25][CH:26]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.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>[NH2:27][C:24]1[N:25]=[CH:26][C:21]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=3)[N:4]([CH3:12])[N:3]=2)=[CH:22][C:23]=1[C:28]([F:31])([F:29])[F:30]
Reactant: Cn1nc(Br)c2cnc(N)nc21
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(-c2cnc(N)c(C(F)(F)F)c2)c2cnc(N)nc21
Temperature: 25 °C

Procedure:
3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 3) (0.1 g, 0.438 mmol), tetrakis(triphenylphosphine)palladium (0.031 g, 0.027 mmol), 5-(4,4,5,5-tetra methyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (Intermediate 10) (0.135 g, 0.669 mmol), cesium carbonate (0.290 g, 0.892 mmol) and water (1 ml) are suspended in 1,4-dioxane (4 ml) and heated using microwave radiation at 150° C. for 45 minutes. The reaction mixture is cooled to room temperature, filtered through Celite® (filter agent) and washed with EtOAc. The solvents are removed in vacuo and purification of the crude residue by flash chromatography on silica eluting with iso-hexanes:EtOAc (2:1) results in an off white solid. The solid is further purified by recrystallisation from 1:1 MeOH/EtOAc resulting in a white solid which is collected by filtration and dried under vacuum to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([NH:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].C(O)(=O)C.Cl>C(O)C.CCOCC.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: COC(=O)CCNC(C)(C)c1ccc(-c2nc(-c3ccc(OC(C)C)c(Cl)c3)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(C(C)(C)NCCC(=O)O)cc3)n2)cc1Cl
Temperature: 25 °C
Yield: 76.5 %

Procedure:
Methyl 3-(2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)propan-2-ylamino)propanoate (83 mg, 0.181 mmol) was dissolved in ethanol (4 mL) and NaOH (4 mL, 8.00 mmol) was added. The mixture was stirred at room temperature under nitrogen. After about 20 minutes the reaction was neutralized by drop-wise addition of acetic acid. The aqueous mixture was then frozen and lyophilized. DCM was added to the solid, filtered, and washed with DCM. The filtrate was concentrated and ether added to afford a slightly cloudy solution. 1N HCl in ether was added dropwise until white precipitate formed. The material was collected by filtration, washed with ether, and dried in a vacuum oven to give 3-(2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)propan-2-ylamino)propanoic acid as the hydrochloric acid salt (61.5 mg; 70.6%). LCMS (Table 1, Method a) Rt=1.98 min, m/z =444.29 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (d, J=8.57 Hz, 2H), 8.12 (d, J=2.08 Hz, 1H), 8.03 (dd, J=8.64, 2.10 Hz, 1H), 7.85 (d, J=8.59 Hz, 2H), 7.25 (d, J=8.78 Hz, 1H), 4.79 (sept, J=6.11 Hz, 1H), 2.95 (t, J=6.20 Hz, 2H), 2.44 (t, J=6.17 Hz, 2H), 1.84 (s, 6H), 1.40 (d, J=6.04 Hz, 6H).
Reaction SMILES: [C:1]1(=[O:26])[N:5]([C@@H:6]2[C:19](=[O:20])[N:8]3[CH:9]([C:15]([O:17][CH3:18])=[O:16])[C:10]([CH3:14])([CH3:13])[S:11](=[O:12])[C@H:7]23)[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.[Cl:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:13][C:10](=[CH2:14])[CH:9]([N:8]1[C:19](=[O:20])[CH:6]([N:5]2[C:4](=[O:21])[C:3]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]3[C:1]2=[O:26])[CH:7]1[S:11]([Cl:27])=[O:12])[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1N2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2S(=O)C1(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(C)C(C(=O)OC)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1S(=O)Cl
Yield: 95 %

Procedure:
A solution of 18.8 g. (50 mmol) of methyl 6β-phthalimido-2,2-dimethylpenam-3-carboxylate-1-oxide and 6.7 g. (50 mmol) of N-chlorosuccinimide in 1000 ml. of dry carbon tetrachloride was refluxed for 70 minutes. The mixture was cooled and then was washed with water and brine. After drying over MgSO4, the solvent was evaporated, and 19.5 g. (95%) of the title compound as a colorless solid was obtained. The nmr spectrum (CDCl3) indicates that the product is the sulfinyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](Cl)=[N:10][OH:11].[Cl:13][CH:14]([Cl:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[CH:25])[CH:19]=1)=[O:16]>C1COCC1.C(N(CC)CC)C>[Cl:13][CH:14]([Cl:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[O:11][N:10]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[CH:25]=2)[CH:19]=1)=[O:16]
Reactant: C#Cc1cccc(NC(=O)C(Cl)Cl)c1
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,6-Dichloro-N-hydroxybenzenecarboximidoyl chloride (2.72 g, 95.6 mmol) and 2,2-dichloro-N-(3-ethynylphenyl) acetamide (2.5 g, 110 mmol) were dissolved in anhydrous THF (40 mL) and triethylamine (1.8 mL). The mixture was stirred at room temperature for 1 h then heated at reflux for 5 h to generate the 2,6-dichlorophenyl nitrile oxide intermediate, which reacted by a 1,3-dipolar cycloaddition reaction with 2,2-dichloro-N-(3-ethynylphenyl) acetamide. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate. The appropriate fractions were combined and then crystallized from hexanes-ethyl acetate to give 2,2-dichloro-N-[3-[3-(2,6-dichlorophenyl)-5-isoxazolyl]phenyl]acetamide as a white crystalline solid, 1.80 g (m.p. 167° C.). NMR (300 MHz, CDCl3): 8.21 (broad s, 1H, NH), 8.08 (m, 1H), 7.71 (m, 2H), 7.52 (t, 1H), 7.42–7.46 (m, 2H), 7.32–7.38 (m, 1H), 6.69 (s, 1H), 6.07 ppm (s, 1H). MW=416 confirmed by LC-MS, tr=36.9 min (Method W) MH+=415–419.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([C:15]([OH:17])=O)[CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1.[F:18][C:19]([F:34])([F:33])[C@@H:20]([N:22]1[CH:26]=[N:25][N:24]=[C:23]1[C:27]1[S:28][CH:29]=[C:30]([NH2:32])[N:31]=1)[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([C:15]([NH:32][C:30]4[N:31]=[C:27]([C:23]5[N:22]([C@@H:20]([CH3:21])[C:19]([F:34])([F:33])[F:18])[CH:26]=[N:25][N:24]=5)[S:28][CH:29]=4)=[O:17])[CH:10]=3)[CH:8]=2)[CH2:2][CH2:3]1
Reactant: C[C@H](n1cnnc1-c1nc(N)cs1)C(F)(F)F
Reactant: O=C(O)c1cc(-n2cnc(C3CC3)c2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](n1cnnc1-c1nc(NC(=O)c2cc(-n3cnc(C4CC4)c3)ccn2)cs1)C(F)(F)F
Yield: 69.9 %

Procedure:
A solution of 4-(4-cyclopropyl-1H-imidazol-1-yl)picolinic acid (50 mg, 0.218 mmol), (S)-2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazol-4-amine (53 mg, 0.208 mmol), HATU (99 mg, 0.262 mmol), and N-methylmorpholine (30 μL, 0.262 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the residue was suspended in acetonitrile/water and the solids were isolated by filtration, washed with water (2 mL), acetonitrile (2 mL) and diethyl ether (5 mL) and dried under vacuum to afford (S)-4-(4-cyclopropyl-1H-imidazol-1-yl)-N-(2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazol-4-yl)picolinamide as a white powder (69 mg, 71% yield).