Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].C[S+](C)C.[Li][CH2:7]CCC.[C:11]([Si:15]([O:18][CH2:19][C@@H:20]1[C@H:24]2[O:25][C:26]([CH3:29])([CH3:28])[O:27][C@H:23]2[C@@H:22]2[O:30][C@H:21]12)([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[Si:15]([O:18][CH2:19][C@@H:20]1[C@H:24]2[O:25][C:26]([CH3:29])([CH3:28])[O:27][C@H:23]2[C@H:22]([OH:30])[C:21]1=[CH2:7])([C:11]([CH3:14])([CH3:12])[CH3:13])([CH3:17])[CH3:16]
Reactant: [Li]CCCC
Reactant: CC1(C)O[C@H]2[C@@H]3O[C@@H]3[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2O1
Agent: C[S+](C)C
Agent: [I-]
Solvent: C1CCOC1
Product: C=C1[C@@H](O)[C@@H]2OC(C)(C)O[C@@H]2[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a −10° C. suspension of trimethylsulfonium iodide (30 g, 149.5 mmol) in THF (150 mL) was added n-BuLi 2.5 M hexane solution (46.0 mL, 83.0 mmol). After 30 min, epoxide (10) (5.0 g, 16.6 mmol) in THF (20 mL) was introduced and the reaction slowly allowed to warm to 0° C. over 1 h; the mixture was then stirred at ambient temperature for 2 hr. The reaction was quenched with water and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residues were purified on silica gel column chromatography (10% EtOAc/Hexane) to give allylic alcohol 11 (4 g, 80%) as an oil. [α]22D−20.35° (c 2.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 5.31 (s, 1H), 5.11 (s, 1H), 4.52 (d, J=6 Hz, 1H), 4.32-4.31 (m, 1H), 4.13-4.11 (m, 1H), 3.81-3.79 (m, 2H), 3.62-3.60 (m, 1H), 3.91-3.90 (m, 1H), 2.62 (br, 1H), 1.30 (s, 3H), 1.20 (s, 3H), 0.80 (m, 9H), 0.013-0.006 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 157.9, 115.9, 92.6, 88.8, 84.1, 72.4, 59.0, 32.6, 31.5, 30.4, 24.0, 0.05; HR-MS Calcd. For (C16H30O4Si+H)+ 315.1913. found 315.1892.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=2)[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[F:37][C:38]1([F:43])[CH2:42][CH2:41][NH:40][CH2:39]1.C(N(CC)CC)C>ClCCl>[F:37][C:38]1([F:43])[CH2:42][CH2:41][N:40]([C:19](=[O:20])[CH2:18][C:15]2[CH:14]=[CH:13][C:12]([N:5]3[C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[C:3]([C:2]([F:22])([F:1])[F:23])=[N:4]3)=[CH:17][CH:16]=2)[CH2:39]1
Reactant: FC1(F)CCNC1
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
A solution of {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid (65 mg, 0.2 mmol) in dichloromethane (2 ml) was treated in one portion with solid 1,1′-carbonyldiimidazole (33 mg, 0.2 mmol). This mixture was allowed to stir at room temperature for 15 minutes. 3,3-difluoropyrrolidine hydrochloride (29 mg, 0.2 mmol) was then added followed by triethylamine (21 mg, 0.21 mmol) and the stirring continued for 1 hour at room temperature. The reaction mixture was reduced to minimum volume under reduced pressure then purified by mass directed auto-prep to give the title compound as a yellow oil (53 mg, 64%).
Reaction SMILES: Br[C:2]1[N:3]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[C:9]=2[N+:18]([O-:20])=[O:19])[CH:4]=[C:5]([CH3:7])[N:6]=1.[CH3:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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>[CH3:17][O:16][C:10]1[C:9]([N+:18]([O-:20])=[O:19])=[C:8]([N:3]2[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]2[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:22]=2[CH3:21])[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=1
Reactant: Cc1ccncc1B(O)O
Reactant: COc1cc(OC)c([N+](=O)[O-])c(-n2cc(C)nc2Br)c1
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: [K+]
Product: COc1cc(OC)c([N+](=O)[O-])c(-n2cc(C)nc2-c2cnccc2C)c1
Yield: 69.5 %

Procedure:
Following the general Suzuki coupling procedure, reaction of 2-bromo-1-(3,5-dimethoxy-2-nitrophenyl)-4-methyl-1H-imidazole (1.1 g, 3.2 mmol), 4-methyl-3-pyridylboronic acid (876 mg, 6.4 mmol), K2CO3 (1.32 g, 9.6 mmol) and Pd(PPh3)4 (186 mg, 0.161 mmol) provided 788 mg (69% yield) of the desired product as an off white powder. EIMS 355.1 [M+H]+.
Reaction SMILES: N[C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[I-:12].[K+].N([O-])=O.[Na+]>C(O)(=O)C.O>[I:12][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1
Reactant: [I-]
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]nc1I
Yield: 58.6 %

Procedure:
Ethyl 3-amino-1H-pyrazole-4-carboxylate (860.0 mg, 5.54 mmol) was dissolved in acetic acid (5 mL) and water (5 mL). Potassium iodide (921 mg, 5.54 mmol) was added and the mixture was stirred until all solids had dissolved. A solution of sodium nitrite (386 mg, 5.54 mmol) in water (2 mL) was then added dropwise. The reaction was stirred at room temperature for 2 minutes when stirring became hindered due to precipitate formation. Additional water (5 mL) was added and the reaction was allowed to stir overnight. The acetic acid was removed under reduced pressure. The brown residue was taken up in saturated aqueous sodium bicarbonate and was extracted with ethyl acetate (2×50 mL). The combined organics were washed with saturated aqueous sodium thiosulfate (50 mL), dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (10-80% ethyl acetate/heptanes) gave the title compound (863 mg, 59%) as a white solid. +APCI (M+H) 267.2; 1H NMR (400 MHz, CDCl3, δ): 12.63 (br. s., 1H), 8.13 (s, 1H), 4.34 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][S:7]([CH2:10][CH2:11][OH:12])(=[O:9])=[O:8].CCN(C(C)C)C(C)C.CCOC(C)=O>C(Cl)Cl>[CH3:6][S:7]([CH2:10][CH2:11][O:12][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)CCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.5 %

Procedure:
To a solution of methanesulfonyl chloride (484 mg, 4.23 mmol) in 15 mL of DCM at 0° C. was added 2-methanesulfonyl-ethanol (500 mg, 4.03 mmol) in 10 mL of DCM followed by DIEA (1.05 mL, 6.05 mmol) under Ar. The mixture was warmed to RT and stirred for 20 h under Ar. The mixture was treated with 100 mL of EtOAc and washed with H2O (3×20 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent in vacuo gave 534 mg (66%) of the title compound as a brown oil. 1H-NMR (CDCl3; 400 MHz): δ 4.67 (d, 2H, J=5.5 Hz), 3.46 (d, 2H, J=5.5 Hz), 3.11 (s, 3H), 3.04 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4]([NH2:6])=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([C:12]([F:15])([F:13])[F:14])[C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1c(C(F)(F)F)ccc(Cl)c1Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1c(C(F)(F)F)ccc(Cl)c1Cl
Temperature: 8.5 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
409 g of 2,3-dichloro-6-trifluoromethylbenzamide was dissolved in 2 liters of dioxane, and 263 g of pyridine was further added to the resultant solution. To this solution, 349 g of trifluoroacetic anhydride was added dropwise over 30 minutes while maintaining the temperature from 7 to 10° C. After stirring the solution for 2 hours at 25° C., the reaction mixture was poured into ice water. The precipitated crystals generated were then collected by filtration and were dissolved in ethyl acetate. The solution was then washed with water and saturated saline solution in series and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, and the crude product obtained was washed with n-hexane and filtered to obtain 358 g of the title compound(mp. 53-54° C.).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18](=O)[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14][CH2:13]2)[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1>>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[S:48])[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14][CH2:13]2)[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(NC2CCN(C(=O)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)ncc1[N+](=O)[O-]
Product: Cc1cc(NC2CCN(C(=S)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)ncc1[N+](=O)[O-]

Procedure:
1-[4-(4-Methyl-5-nitro-pyridin-2-ylamino)-piperidin-1-yl]-4-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-butan-1-one (23 mg; 0.043 mmol, prepared in accordance with Example 71) is reacted with Lawesson's reagent (9 mg; 0.043 mmol) according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (9 mg; 0.016 mmol). The structure was confirmed using Protocol 1-B. Calculated mass=551; observed mass=551; HPLC retention time=4.45 min.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]4[C:28]([CH:29]=3)=[N:27][N:26]([CH3:30])[C:25]=4[CH3:31])[N:14]=2)[CH2:2]1.C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)Cl>[Cl:19][C:18]1[C:13]([NH:12][CH:3]2[CH2:4][CH2:5][C:6]3([CH2:7][CH2:8][N:9]([C:39](=[O:41])[CH3:40])[CH2:10][CH2:11]3)[CH2:1][CH2:2]2)=[N:14][C:15]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[C:28]([CH:29]=2)=[N:27][N:26]([CH3:30])[C:25]=3[CH3:31])=[N:16][CH:17]=1
Reactant: Cc1c2ccc(Nc3ncc(Cl)c(NC4CCC5(CCNCC5)CC4)n3)cc2nn1C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC2(CCC(Nc3nc(Nc4ccc5c(C)n(C)nc5c4)ncc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a suspension of N4-(9-azaspiro[5.5]undecan-3-yl)-5-chloro-N2-(2,3-dimethylindazol-6-yl)pyrimidine-2,4-diamine (0.10 g, 0.23 mmol) in anhydrous DCM (10.0 mL) were added N,N-diethylethanamine (0.036 g, 0.35 mmol) and acetyl acetate (0.029 g, 0.29 mmol). The mixture was stirred at room temperature for 30 min then diluted with DCM (40 mL), washed with water (20 mL×2), followed by saturated NaHCO3 (20 mL) and brine (20 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1 to 15/1) to give the title compound as a light green solid (75 mg, 68%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:35][C:36]1[CH:37]=[C:38]([NH2:45])[C:39](=[CH:43][CH:44]=1)[C:40](O)=[O:41]>O.CN(C=O)C>[NH2:45][C:38]1[CH:37]=[C:36]([F:35])[CH:44]=[CH:43][C:39]=1[C:40]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:41]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1cc(F)ccc1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.9 %

Procedure:
A DMF solution (4 ml) of pyrrolidine (1.93 g, 27.1 mmol), a DMF solution (4 ml) of triethylamine (3.79 g, 37.5 mmol), 1-hydroxybenzotriazole (HOBt) (3.11 g, 23.0 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (3.91 g, 20.4 mmol) were added to a DMF solution (4 ml) of 4-fluoroanthranilic acid (2.0 g, 12.8 mmol) in that order. The mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and then concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=30:1). The purified product was concentrated under reduced pressure to thereby obtain 1.65 g of oily orange 1-(2-amino-4-fluorobenzoyl)pyrrolidine (yield: 62%).
Reaction SMILES: [Mg+2].[Cl-:2].[Cl-].[Cl-].[K+].CC1(C)S[C@@H]2[C@H:12](NC([C@H](N)C3C=CC=CC=3)=O)[C:13](=[O:14])N2[C@H]1C(O)=O.O=C[C@H:32]([C@@H:34]([C@@H:36]([CH2:38][OH:39])O)[OH:35])O>>[CH2:13]([O:14][C:38](=[O:39])[CH2:36][C:34](=[O:35])[CH2:32][Cl:2])[CH3:12]
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Product: CCOC(=O)CC(=O)CCl
Reaction time: 7.5 h

Procedure:
A gene encoding the alcohol dehydrogenase YPR1 (described by Nakamura, K., et al., Bioscience, Biotechnology and Biochemistry, (1997) 61, 375-377), is subjected to mutagenesis by error-prone PCR according to the method of May, O., et al., (Nature Biotechnology, (2000) 18, 317-320). The error-prone PCR is performed in a 100 CL reaction mixture containing 0.25 ng of plasmid DNA as a template dissolved in PCR buffer (10 mM TRIS, 1.5 mM MgCl2, 50 mM KCl, pH 8.3), and also containing 0.2 mM of each dNTP, 50 pmol of each primer and 2.5 units of Taq polymerase (Roche Diagnostics, Indianapolis, Ind.). Conditions for carrying out the PCR are as follows: 2 minutes at 94 CC; 30 cycles of 30 sec 94 CC, 30 sec 55 CC; 2 minutes at 72 CC. The PCR product is double digested with Nco I and Bgl II and subcloned into pBAD/HisA vector (Invitrogen, Carlsbad, Calif.) which has been digested with the same restriction enzymes. The resulting YPR1 mutant library is transformed into the E. coli host strain LMG194 (Invitrogen, Carlsbad, Calif.) and plated on LB agar supplied with 100 μg/mL ampicillin. Individual transformants are inoculated into 96-well microtiter plates (hereafter referred to as master plates) containing 0.2 mL LB Broth with 100 μg/mL ampicillin, and growth is allowed to take place for 8 to 16 hours at 37 CC with shaking at 200 rpm. Each well in each master plate is then re-inoculated by a replica plating technique into a new second stage 96-well plate pre-loaded with the same growth media plus 2 g/L of arabinose, and growth is allowed to continue for 5-10 hours at 37 CC with shaking at 200 rpm. The second stage plates are then centrifuged at 14,000 rpm for 20 minutes, and the supernatant is decanted. The cell pellet in each well is washed with 200 CL of water. The washed cell pellet is suspended in 30 CL of B-Per Bacterial Protein Extraction Reagent (Pierce Chemical Co., Rockford, Ill.), hereinafter “B-Per.” After mixing, the suspension of cells in B-Per reagent is allowed to stand for 10 minutes at room temperature, and a reaction solution having the following composition is then added to each well in the plate:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.CS(O[CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:17]3[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 70 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
A mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.73 g, 0.0028 mol), tert-butyl 3-[(methylsulfonyl)oxy]-1-azetanecarboxylate (1.05 g, 0.0042 mol) and cesium carbonate (1.4 g, 0.0042 mol) in N,N-dimethylformamide (25 mL) were stirred at 70° C. under an atmosphere of nitrogen for 16 hours. The mixture was cooled to room temperature. Additional tert-butyl 3-[(methylsulfonyl)oxy]-1-azetanecarboxylate (0.35 g, 0.0014 mol) and cesium carbonate (0.46 g, 0.0014 mol) were added to the mixture. The mixture was stirred at 70° C. under an atmosphere of nitrogen for 16 hours. The solvent was removed under the reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with dichloromethane (3×70 mL). The combined organic extracts were washed with water, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure. The residue was triturated with dichloromethane (2×3 mL) to give tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-azetanecarboxylate (0.57 g, 0.0014 mol).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH2:5][CH:4]=1.[H][H]>CO.CCOC(C)=O.[Pd]>[F:1][C:2]([F:13])([F:14])[CH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: Oc1cccc2c1CC=C2C(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1cccc2c1CCC2C(F)(F)F
Yield: 96.2 %

Procedure:
A mixture of 1-trifluoromethyl-3H-inden-4-ol (70 mg, 0.349) and 10% Pd/C (20 mg) in methanol (2 ml) was hydrogenated under 50 psi hydrogen atmosphere for 3 hours. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated tinder reduced pressure, and dried to give 1-trifluoromethyl-indan-4-ol (68 mg, 97%).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:37])[CH2:33][CH2:34][CH2:35][Cl:36])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1.O>[ClH:36].[C:22]([C:26]1[CH:27]=[CH:28][C:29]([C:32](=[O:37])[CH2:33][CH2:34][CH2:35][N:12]2[CH2:13][CH2:14][C:9](=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10][CH2:11]2)=[CH:30][CH:31]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccc(C(O)(c2ccccc2)C2CCNCC2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=C2CCN(CCCC(=O)c3ccc(C(C)(C)C)cc3)CC2)c2ccccc2)cc1
Product: Cl

Procedure:
A mixture of 25.4 g (0.0905 mole) of α-phenyl-α-(p-tolyl)-4-piperidinemethanol, 26.2 g (0.11 mole) of 4'-tert-butyl-4-chlorobutyrophenone, 22 g of potassium bicarbonate, 0.1 g of potassium iodide, 250 ml of toluene, and 40 ml of water is refluxed for 88 hours. Upon cooling to room temperature the toluene layer is separated, and the aqueous layer is extracted with toluene. The combined toluene extracts are dried over magnesium sulfate, filtered and the filtrate is treated with ethereal HCl. The resulting precipitate is filtered, triturated with ether, and recrystallized from butanone-ether to give 4'-tert-butyl-4-[4-[α-(p-tolyl)benzylidene]piperidino]butyrophenone hydrochloride, M.P. 187°-189°C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[C:12]4[N:13]([CH:20]=[N:21][CH:22]=4)[CH:14]=[CH:15][C:16]=3[C:17]([OH:19])=O)=[C:6]([F:23])[CH:5]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[NH2:55][O:56][CH2:57][C@@H:58]([OH:60])[CH3:59]>CN(C=O)C>[OH:60][C@@H:58]([CH3:59])[CH2:57][O:56][NH:55][C:17]([C:16]1[CH:15]=[CH:14][N:13]2[CH:20]=[N:21][CH:22]=[C:12]2[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:5][C:6]=1[F:23])=[O:19]
Reactant: C[C@H](O)CON
Reactant: O=C(O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CONC(=O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.2 %

Procedure:
A suspension of 8-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (0.11 g, 0.35 mmol), EDCI (0.081 g, 0.42 mmol), HOBt (0.057 g, 0.42 mmol), DIPEA (0.085 mL, 0.88 mmol) and (S)-1-aminooxy-propan-2-ol hydrochloride (0.05 g, 0.39 mmol) in DMF (1.5 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between DCM (5 mL) and saturated aqueous NaHCO3 (5 mL). The organic layer was washed with water (5 mL), followed by brine (5 mL), then dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 60%, ethyl actetate in DCM) to give a yellow sticky solid, which was further purified by preparative HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 5 to 98%, ramp time 20 minutes) to afford the title compound as a yellow solid (38 mg, 27%). LCMS (method A): RT=6.87 min, [M+H]+=385. 1H NMR (DMSO-d6) 10.54 (1H, s), 8.27 (1 H, s), 7.76 (1H, dd, J=7.37, 0.93 Hz), 7.14 (1H, t, J=8.37 Hz), 6.98 (1H, dd, J=11.87, 1.95 Hz), 6.95-6.89 (1H, m), 6.76 (1H, d, J=7.33 Hz), 6.27 (1H, s), 3.89-3.79 (1H, m), 3.72-3.62 (2H, m), 1.99-1.90 (1H, m), 1.04 (3H, d, J=6.34 Hz), 0.99-0.93 (2H, m), 0.76-0.67 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]([C:17]1[N:18]=[C:19]([NH2:22])[S:20][CH:21]=1)=[N:8][O:9][C:10]([C:13](=[O:16])[NH:14][NH2:15])([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:36]([O:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=1[O:49][C:50](=[O:52])[CH3:51])[C:43]([Cl:45])=[O:44])(=[O:38])[CH3:37].CCOCC>C(Cl)Cl.CO>[ClH:45].[C:1]([O:5][C:6](=[O:23])[C:7]([C:17]1[N:18]=[C:19]([NH2:22])[S:20][CH:21]=1)=[N:8][O:9][C:10]([C:13](=[O:16])[NH:14][NH:15][C:43](=[O:44])[C:42]1[CH:46]=[CH:47][C:48]([O:49][C:50](=[O:52])[CH3:51])=[C:40]([O:39][C:36](=[O:38])[CH3:37])[CH:41]=1)([CH3:12])[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1OC(C)=O
Reactant: CC(C)(C)OC(=O)C(=NOC(C)(C)C(=O)NN)c1csc(N)n1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)NNC(=O)C(C)(C)ON=C(C(=O)OC(C)(C)C)c2csc(N)n2)cc1OC(C)=O
Product: Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
In 10 ml of methylene chloride was suspended 0.7 g (1.74 mmole) of 2-(2-amino-1,3-thiazol-4-yl)-2-(1-carbazoyl-1-methylethoxyimino)acetic acid tert-butyl ester, and to the suspension was added 2.16 g (10.6 mmole) of N,O-bis(trimethylsilyl)acetamide to form a solution. To the ice-cooled solution was added 0.488 g (1.9 mmole) of 3,4-diacetoxybenzoic acid chloride and the mixture was stirred for one hour under ice-cooling. The resulting mixture was poured into 150 ml of ether and to the mixture was added a small amount of methanol while stirring. Resulting precipitates were collected by filtration, washed with ether and then dried to obtain 0.96 g of 2-(2-amino-1,3-thiazol-4-yl)-2-{1-[3-(3,4-diacetoxybenzoyl)carbazoyl]-1-methylethoxyimino}acetic acid tert-butyl ester.hydrochloride. (Yield: 97.9%)