Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([OH:10])[CH3:9].Cl[C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([O:10][C:13]1[C:14]2[C:21]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[C:20]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:19][C:15]=2[N:16]=[CH:17][N:18]=1)[CH3:9]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: COC(=O)CCCCC(C)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCCC(C)Oc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Put 1.902 g (11.9 mmol) (+/−)-6-hydroxyheptanoic acid methyl ester under argon in 20 ml THF and cool to 0° C. Add 6 ml (11.9 mmol) of a 2 M solution of the phosphazene base P2-tert.-butyl in THF and stir for a further 10 min at RT. Then cool to 0° C. again. Add 2.00 g (5.94 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and then stir for a further 1 h at RT. Dilute with water, acidify with 10% aqueous citric acid solution and extract twice with ethyl acetate. Combine the ethyl acetate phases and wash once with satd. sodium chloride solution. Dry over magnesium sulphate, concentrate by evaporation and purify the residue by column chromatography on silica gel (solvent: cyclohexane/ethyl acetate 9:1). 1.38 g (78.0% of theor.) of the target compound is obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[NH2:15][CH:16]([CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([NH:15][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:14])[F:13])[CH:4]=1)[CH2:24][CH3:25])[CH:21]([CH3:22])[CH3:23]
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1cccc(C(F)(F)F)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 3-trifluoromethyl-phenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:8]=1[C:9]#[N:10].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>CN(C1C=CN=CC=1)C.ClCCl.CCOC(C)=O>[C:9]([C:8]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:25](=[O:27])[CH3:26])#[N:10]
Reactant: CC(=O)Cl
Reactant: N#Cc1c(OCCCCN)cccc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)NCCCCOc1cccc([N+](=O)[O-])c1C#N
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 2-(4-aminobutoxy)-6-nitrobenzonitrile (Example 234d) (235 mg, 1.0 mmol), triethylamine (3 equiv.), and DMAP (0.1 equiv.) in dry dichloromethane (20 mL) was added dropwise acetyl chloride (1.5 equiv.) at 0° C. under nitrogen. The reaction mixture was then stirred at 0° C.—RT overnight. The reaction was diluted with EtOAc, washed with brine, and dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with 50% EtOAc in hexanes to give the title compound (158 mg, 57%). MS 278 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]([C:15]#[N:16])([CH3:14])[CH3:13].[OH-].[Li+].CO.O>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:12]([C:15]#[N:16])([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccc(Cl)c(C(C)(C)C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C#N)c1cc(C(=O)O)ccc1Cl
Yield: 97.3 %

Procedure:
To a solution of methyl 4-chloro-3-(1-cyano-1-methylethyl)benzoate (8.0 g, 34 mmol) in tetrahydrofuran (30 mL) were added lithium hydroxide.monohydrate (2.13 g, 51 mmol), methanol (100 mL) and water (5 mL), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with water (200 mL). 1N Hydrochloric acid was slowly added to the mixture to adjust the pH to 3. The precipitated white precipitate was collected by filtration, washed with water, and dried to give the title compound (7.4 g, 99%) as a white powder.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[O:6]=[C:7]1[C:11]2([CH2:14][CH2:13][CH2:12]2)[N:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:9](=[S:28])[N:8]1[C:29]1[CH:30]=[C:31]([C:37]([F:40])([F:39])[F:38])[C:32]([C:35]#[N:36])=[N:33][CH:34]=1.C(N(CC)CC)C.CO>C1COCC1>[O:6]=[C:7]1[C:11]2([CH2:14][CH2:13][CH2:12]2)[N:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:9](=[S:28])[N:8]1[C:29]1[CH:30]=[C:31]([C:37]([F:39])([F:38])[F:40])[C:32]([C:35]#[N:36])=[N:33][CH:34]=1
Reactant: CCC(=O)Cl
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(OC4CCNCC4)cc3)C2=S)cc1C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCC(Oc2ccc(N3C(=S)N(c4cnc(C#N)c(C(F)(F)F)c4)C(=O)C34CCC4)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
Propionyl chloride (17 μL, 0.2 mmol) was added to a mixture of 5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (50 mg, 0.1 mmol) and triethylamine (28 μL, 0.2 mmol) in THF (2 mL) and the resulting milky mixture was stirred at room temperature overnight. Methanol was added to quench the reaction and the mixture was absorbed on silica gel and purified by column chromatography on silica gel eluting with 50 to 100% EtOAc/hexanes to afford 21 mg of 5-(8-oxo-5-(4-((1-propionylpiperidin-4-yl)oxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (d, 1H), 8.69 (s, 1H), 7.25 (d, 2H), 7.13 (d, 2H), 4.62 (m, 1H), 3.85 (m, 1H), 3.62 (m, 1H), 3.29 (m, 1H), 3.15 (m, 1H), 2.55-2.52 (m, 2H), 2.42 (m, 2H), 2.39-2.25 (m, 2H), 1.92-1.88 (m, 3H), 1.50-1.45 (m, 3H), 0.93 (t, 3H). LCMS [M+1]+ 558.1.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C1C=CC(CC(NCN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1.[N:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[CH2:57][CH2:58][NH2:59].O>CS(C)=O.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:23]=[C:22]([NH:59][CH2:58][CH2:57][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][N:51]=2)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Reactant: NCCc1ccccn1
Agent: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCc2ccccn2)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 130 °C
Reaction time: 17 h

Procedure:
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (20 mg, 37 μmol) and 2-pyridin-2-yl-ethyl amine (66 μl, 0.56 mmol) were dissolved in a mixture solvent of dimethylsulfoxide (1 mL) and N,N-diisopropylethylamine (0.5 mL), and the solution was stirred at 130° C. for 17 hours. The reaction solution was cooled to room temperature, water and ethyl acetate were added, the organic layer was partitioned, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and the title compound (17.7 mg) was obtained as a trifluoroacetic acid salt.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31](COCC[Si](C)(C)C)[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:17][C:18]#[N:19])[CH2:11][CH2:10]1.C(N(CC)CC)C.O>C(#N)C>[CH:1]1([S:4]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]([N:20]3[CH:24]=[C:23]([C:25]4[C:26]5[CH:33]=[CH:32][NH:31][C:27]=5[N:28]=[CH:29][N:30]=4)[CH:22]=[N:21]3)[CH2:17][C:18]#[N:19])[CH2:11][CH2:10]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CC4CCNCC4)c3)ncnc21
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: N#CCC(CC1CCN(S(=O)(=O)C2CC2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopropanesulfonyl chloride (77.0 mg, 0.548 mmol), 4-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (250 mg, 0.498 mmol), and triethylamine (208 μL, 0.00149 mol) were dissolved in acetonitrile (1.0 mL). The mixture was stirred at RT for 1 h, water was added to make a homogeneous solution and purified with preparative LCMS (pH=10) to provide the desired product. The product was treated with DCM (0.5 mL) and trifluoroacetic acid (0.5 mL, 0.006 mol) for 30 min. The reaction mixture was evaporated under reduced pressure. To the resulting residue was added methanol (5 mL) and ethylenediamine (0.5 mL, 0.007 mol) and the resultant mixture was stirred at RT for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was purified on RP-HPLC (XBridge C-18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH, at flow rate 60 mL/min) to give the desired product (185 mg, 84.5%). LCMS calculated for C21H26N7O2S(M+H)+: m/z=440.2; Found: 440.0. 1H NMR (300 MHz, CD3OD): δ 8.98 (1H, s), 8.88 (1H, s), 8.53 (1H, s), 7.85 (1H, d, J=3.6 Hz), 7.28 (1H, d, J=3.6 Hz), 4.98 (1H, m), 3.68 (2H, m), 3.15 (2H, m), 2.73 (2H, m), 2.37 (1H, m), 2.23 (1H, m), 1.98 (1H, m), 1.87 (1H, m), 1.62 (1H, m), 1.29 (3H, m), 0.97 (4H, m) ppm.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[S:20]>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[CH:14][C:15]([N:18]=[C:19]=[S:20])=[CH:16][CH:17]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: S=C=Nc1ccc(N2CCN(C3CCCC3)CC2)cc1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
A solution of 4-[4-(1-cyclopentyl)-1-piperazinyl]benzenamine (5.7 g, 22.4 mmol) (from Step B above) in N,N-dimethylformamide (75 mL) was added dropwise over 20 min to a cooled (−15° C.) solution of thiocarbonyldiimidazole (4 g, 22.5 mmol) (Aldrich) in N,N-dimethylformamide (40 mL). After the addition was complete, the mixture was stirred at −15° C. for 20 min, then the cooling bath was removed and the solution was stirred for 1 hr. then poured into ice-water (1500 mL), stirred for 30 min. then the precipitate filtered and washed with water and dried under vacuum to give 4-cyclopentyl-1-(4 isothiocyanatophenyl)piperazine (6 g, 93%)
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14](C(OC(C)(C)C)=O)[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].Cl.CO.C(=O)([O-])O.[Na+]>CO>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)cc2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(-c2cc3ccccc3[nH]2)c2c1C(=O)NC2=O
Temperature: 70 °C
Reaction time: 1.3 h
Yield: 87.4 %

Procedure:
3-Amino-6-[1-(tert-butoxycarbonyl)indol-2-yl]phthalimide (21.8 mg, 0.0578 mmol) was dissolved in methanol (2.2 mL), and the solution was added with 10% hydrogen chloride-methanol solution (2.2 mL), followed by stirring at 70° C. for 1.3 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/acetone=6/1, chloroform/methanol=12/1) to obtain Compound 1 (14 mg, yield 87%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([NH:22][NH2:23])[CH:14]=[C:15]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[CH:29]1[CH:34]=[C:33]2[C:35]([CH:38]=O)=[CH:36][NH:37][C:32]2=[CH:31][CH:30]=1>C(O)C>[NH:37]1[C:32]2[C:33](=[CH:34][CH:29]=[CH:30][CH:31]=2)[C:35]([CH:38]=[N:23][NH:22][C:13]2[CH:14]=[C:15]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:10]3[N:9]=[C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)[CH:24]=[C:11]3[N:12]=2)=[CH:36]1
Reactant: Cc1ccc(-c2cc3nc(NN)cc(N4CCOCC4)n3n2)cn1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(-c2cc3nc(NN=Cc4c[nH]c5ccccc45)cc(N4CCOCC4)n3n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
There was suspended, in ethanol (3.0 mL), [2-(6-methyl-pyridin-3-yl)-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidin-5-yl]-hydrazine (70 mg, 0.22 mM), then acetic acid (6.3 μL, 0.11 mM) and indole-3-carboxy-aldehyde (35 mg, 0.24 mM) were added to the suspension and the mixture was stirred at room temperature for 16 hours. The precipitated solid was recovered through filtration and then washed with diethyl ether to thus give the title compound (46 mg, yield: 47%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13]=O.S(=O)(=O)(O)O>Cl>[CH2:13]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]([C:10]([OH:12])=[O:11])[NH:1]1
Reactant: C=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Product: O=C(O)[C@@H]1Cc2ccccc2CN1

Procedure:
5.0 g (30.27 mmol) of L-phenylalanine are dissolved in 50 ml of concentrated hydrochloric acid and 4.0 g of para-formaldehyde and 1 ml of concentrated sulphuric acid are added. This solution is maintained at reflux for two days. After cooling and filtration, the resulting solid is dissolved in a 1/1 (v/v) hot water/ethanol mixture and aqueous NH4OH (30%) is added until a pH 7.0 is reached. The crystals which have precipitated after cooling the solution are recovered by filtration, washed with ethanol and dried. The desired product is thus obtained.
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[CH2:4][C:5]([Cl:20])=[C:6]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C([N-]C(C)C)(C)C.[Li+].[CH:29](=[O:31])[CH3:30]>C1COCC1>[OH:31][CH:29]([C:2]1([CH3:1])[C:8](=[O:9])[N:7]2[CH:3]1[CH2:4][C:5]([Cl:20])=[C:6]2[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[CH3:30]
Reactant: CC1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C1(C)C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC21

Procedure:
Benzyl 6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate is converted to its enolate derivative with lithium diisopropylamide in anhydrous THF at -78° as described in the previous example. To this solution is added 10 equivalents of acetaldehyde. Workup as described in example 12 yields benzyl 6-(1-hydroxyethyl)-6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [C:1]([N:7]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C:8]1=[O:24])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[Li+].CC([N-]C(C)C)C.Br[CH2:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=1[Cl:42]>C1COCC1>[Cl:42][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([F:41])[C:35]=1[CH2:34][C@@H:2]([CH2:3][CH:4]=[CH2:5])[C:1]([N:7]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C:8]1=[O:24])=[O:6]
Reactant: Fc1cccc(Cl)c1CBr
Reactant: C=CCCC(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H](Cc1c(F)cccc1Cl)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Yield: 100.1 %

Procedure:
Dissolve (4S,5R)-3-pent-4-enoyl-4,5-diphenyloxazolidin-2-one (1.0 g, 3.1 mmol) in THF (50 mL) and cool the mixture to −78° C. under N2 with stirring. Add dropwise LDA (2.7 mL, 4.0 mmol, 1.5 M in THF) and stir the mixture for 0.5 hours. Then add 2-(bromomethyl)-1-chloro-3-fluorobenzene (1.39 g, 6.22 mmol). Continue to stir the reaction mixture for one hour until TLC shows that the starting material has been consumed. Add water (50 mL) and extract the aqueous with CH2Cl2 (3×250 mL). Combine the organic layers and dry over Na2SO4. Concentrate and purify by chromatography (Silica gel) to afford (4S,5R)-3-((R)-2-(2-Chloro-6-fluorobenzyl)pent-4-enoyl)-4,5-diphenyloxazolidin-2-one (1.44 g, 75.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].[O:9]1[CH2:14][CH2:13][CH:12](N2C=C(B3OC(C)(C)C(C)(C)O3)C=N2)[CH2:11][CH2:10]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: CC1(C)OB(c2cnn(C3CCOCC3)c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnn(C2CCOCC2)c1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
4-bromo-1H-pyrazole (1 eq, 3.92 mmol, 0.5 g) is dissolved in dry DMF (5 ml) under an inert atmosphere of nitrogen. The reaction mixture is cooled down to −10° C. and sodium hydride (1 eq, 3.92 mmol, 0.157 g) is added portionwise. After 15 mins at 0° C., the reaction was warmed to R.T and stirred for 30 mins at R.T. A solution of methane sulfonic acid tetrahydro-pyran-4-yl ester (Intermediate B18, step1) (1 eq, 3.92 mmol, 0.5 g) in DMF (5 ml) is added and the reaction mixture is stirred at 95° C. overnight. The reaction mixture is quenched at 0° C. with water and extracted with DCM. This organic portion is washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting solid is triturated with MeOH and the solid filtered to afford the title compound; [M+H]+ 231/233.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.ClC(Cl)C.CCOCC.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[CH:25][C:24]=1[O:42][CH3:43].C(N(CC)CC)C>[Cl-].[Zn+2].[Cl-].C(O)(C)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:33][CH2:34]3)=[CH:25][C:24]=2[O:42][CH3:43])[N:7]=1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reaction time: 16 h
Yield: 63.8 %

Procedure:
A solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (981 mg, 4.52 mmol) in 1:1 tert-butanol: dichloroethane (40 mL) was cooled to 0° C. under nitrogen then 1.0 M zinc(II) chloride in ether (4.52 mL, 4.52 mmol) was added dropwise. After one hour a solution of tert-butyl 4-(4-amino-3-methoxyphenyl)piperidine-1-carboxylate (I26) (1.26 g, 4.11 mmol) and triethylamine (0.860 mL, 6.17 mmol) in 1:1 tert-butanol: dichloroethane (50 mL) was added dropwise at −10° C. then the mixture was stirred for 16 hours allowing the temperature to rise to room temperature. The mixture was concentrated, evaporated onto silica and chromatographed (120 g silica cartridge, 0-10% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I27) (1.277 g, 64% yield) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.01 (s, 1H), 6.86 (dd, J=8.3, 1.8 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 4.25 (br s, 2H), 3.91 (s, 3H), 2.87-2.73 (m, 2H), 2.64 (tt, J=12.1, 3.6 Hz, 1H), 1.83 (d, J=12.5 Hz, 2H), 1.69-1.54 (m, overlaps with water), 1.49 (s, 9H). LCMS Method C: rt 7.12 min; m/z 431.0 [M-tBu+2H]+, 387.1 [M-Boc+2H]+; m/z 485.1 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[S-:10][C:11]#[N:12].[K+].BrBr>C(O)(=O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[S:10][C:11]([NH2:12])=[N:9][C:6]2=[CH:5][CH:4]=1
Reactant: N#C[S-]
Reactant: COc1ccc(N)cn1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc2nc(N)sc2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 6-methoxy-pyridin-3-ylamine (5.0 g, 0.0403 mol) in 10 mL of acetic acid is added slowly to a solution of potassium thiocyanate (20 g, 0.205 mol) in 100 mL of acetic acid at 0° C. followed by a solution of bromine (2.5 mL, 0.0488 mol) in 5 mL of acetic acid. The reaction is stirred for 2 h at 0° C. and then allowed to warm to RT. The resulting solid is collected by filtration and washed with acetic acid, then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The insoluble material is removed by filtration and the organic layer is evaporated and dried to afford 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine as a tan solid.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:6]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].C(NC(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:14][Si:15]([C:18]#[C:19][C:2]1[CH:3]=[N:4][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:6]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)n1cc(I)cn1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)n1cc(C#C[Si](C)(C)C)cn1
Temperature: 60 °C
Yield: 92.3 %

Procedure:
tert-Butyl 4-iodo-1H-pyrazole-1-carboxylate (2) (4.67 g 15.9 mmole) and trimethylsilyl acetylene (2.18 g, 22.2 mmole) were dissolved in DMF (22 mL) and placed under argon. Diisopropylamine (2.9 mL, 2.08 g, 20.7 mmole), copper(I) iodide (197 mg, 1.03 mmole), triphenylphosphine (832 mg, 3.18 mmole) and palladium acetate (239 mg, 1.06 mmole) were added and the flask was flushed again with argon. The reaction was heated at 60° C. for 1.25 hours. The reaction was cooled and added to water (220 mL). The product was extracted with ether (3×60 mL). The combined extracts were washed with water (3×50 mL) and with brine, then dried and evaporated. The crude product was flash chromatographed (silica, eluting with 10% ethyl acetate in cyclohexane) to give the title compound (3.88 g, 92%). 1H-NMR (CDCl3, 500 MHz): δ 0.25 (s, 6H), 1.67 (s, 9H), 7.77 (d, J=0.63 Hz, 1H), 8.20 (d, J=0.63 Hz, 1H).