Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:54]=[CH:53][C:23]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][C:35]4[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][C:36]=4[F:42])=[C:28]3[C:27]([NH:43][CH:44]3[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][F:52])[CH2:46][CH2:45]3)=[N:26]2)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][C:35]4[CH:40]=[CH:39][C:38]([NH:41][C:15]([C:12]5[C:13](=[O:14])[N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[N:9]=[CH:10][CH:11]=5)=[O:17])=[CH:37][C:36]=4[F:42])=[C:28]3[C:27]([NH:43][CH:44]3[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][F:52])[CH2:48][CH2:49]3)=[N:26]2)=[CH:53][CH:54]=1
Reactant: COc1ccc(Cn2nc(NC3CCN(CCF)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Product: COc1ccc(Cn2nc(NC3CCN(CCF)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Yield: 80 %

Procedure:
Prepared from 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (177 mg, 0.755 mmol, prepared according to the procedure for Example 19, Step C) and 1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-(2-fluoroethyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (128 mg, 0.252 mmol) according to the procedure for Example 138, Step D. The product was obtained as a waxy solid (145 mg, 80%). LRMS (APCI+): 100% purity, 220 nm, m/z 725 (M+1) detected.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH:9]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O)(C)(C)C.[NH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1>>[CH2:28]([C@H:9]1[NH:8][CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:35][CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)[N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:10]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC1Cc1ccccc1
Reactant: NCCc1ccc(O)cc1
Product: Oc1ccc(CCNc2nccc(-c3cccc(CN4CCN[C@H](Cc5ccccc5)C4)c3)n2)cc1

Procedure:
Intermediate 110 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 481. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.59 (s, 1H), 8.33 (d, 2H), 7.90 (d, 1H), 7.67 (t, 1H), 7.61 (d, 1H), 7.28 (m, 5H), 7.11 d, 2H), 6.68 (s, 2H), 4.64 (d, 2H), 4.16 (m, 1H), 3.91 (m, 2H), 3.56 (m, 6H), 3.30 (m, 2H), 2.92 (t, 2H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][C@@H:30](O)[CH2:31][C@H:32]([OH:34])[CH3:33].COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[C:1]([O:9][C@@H:30]([CH3:29])[CH2:31][C@H:32]([OH:34])[CH3:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: O=C(O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)C[C@H](C)OC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
After benzoic acid (300 mg, 2.46 mmol), triphenylphosphine (775 mg, 2.95 mmol), (2R,4R)-2,4-pentanediol (308 mg, 2.95 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (691.1 mg, 2.95 mmol) dissolved in THF (6 mL) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for one hour. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 mL,×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 40% ethyl acetate-hexane solution) to give (4S,2R)-4-benzoyloxypentane-2-ol as a colorless oily substance (379 mg, yield: 74%/benzoic acid).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:20]=[CH:21][C:14]=23)[CH:8]=1)([CH2:5][CH3:6])[C:3]#[N:4].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH:19]1[C:15]2=[N:16][CH:17]=[CH:18][C:13]([C:9]3[CH:8]=[C:7]([C:2]([CH3:1])([CH2:5][CH3:6])[C:3]#[N:4])[CH:12]=[CH:11][CH:10]=3)=[C:14]2[CH:21]=[N:20]1
Reactant: CCC(C)(C#N)c1cccc(-c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)(C#N)c1cccc(-c2ccnc3[nH]ncc23)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
2-Methyl-2-(3-(1-trityl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)butanenitrile (240 mg, 0.46 mmol) was dissolved in dichloromethane (10 ml) and cooled down in an ice-bath. Triethylsilane (2.5 ml) was added followed by trifluoroacetic acid (2.5 ml). The resulting mixture was stirred at 0° C. for 2 hours and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium carbonate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (92 mg, 70% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:16](Br)=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][CH:21]=[CH:22][Sn](CCCC)(CCCC)CCCC)[CH3:19]>CN(C=O)C>[CH2:1]([N:8]1[C:16]([CH:19]=[CH:18][O:20][CH2:21][CH3:22])=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1nc2cncnc2n1Cc1ccccc1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCOC=Cc1nc2cncnc2n1Cc1ccccc1
Temperature: 65 °C

Procedure:
A mixture of 9-benzyl-8-bromopurine 13 (1.0 g, 3.4 mmol) bis(triphenylphosphine)palladium(II)chloride (0.242 g, 0.30 mmol) and ethoxyvinyl(tributyl)tin (1.49 g, 4.14 mmol) in dry DMF (50 mL) was heated under N2 at 65° C. for 48 h. DMF was distilled off under reduced pressure and the resulting residue was redissolved in EtOAc (50 mL) and filtered through a pad of celite. The EtOAc was distilled off and the residue obtained was purified by flash chromatography. Yield 0.579 g, (59.7%). 1H NMR (CDCl3): δ 1.33 (t, 3H, CH3, J=7.5 Hz), 3.99 (q, 2H, CH2, J=13.7 Hz), 4.66 (d, 1H, CH, J=3 Hz), 5.34 (d, 1H, CH, J=3 Hz), 5.48 (s, 2H, benzylic CH2), 7.30-7.38 (m, 5H, Ar—H), 9.09 (s, 1H, purine C8—H), 9.2 (s, 1H, purine C2—H). 13C NMR (CDCl3): δ 14.2, 47.3, 64.2, 91.8, 126.8, 126.8, 127.7, 128.6, 128.6, 133.1, 136.4, 148.2, 151.2, 151.9, 152.8, 153.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:21]3[CH:26]=[CH:25][C:24](F)=[CH:23][C:22]=3F)[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:29].[ClH:30]>C(Cl)Cl.O1CCOCC1>[Cl:30][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[C:18]2[C:13]=1[CH2:12][CH2:11][C:10](=[O:29])[N:9]2[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8].[ClH:1]
Reactant: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 1 (0.95 g, 1.68 mmol), 1a (0.76 g, 2.19 mmol), Pd(PPh3)4 (0.19 g, 0.17 mmol) and LiCl (0.28 g, 6.72 mmol) in 30 mL of dioxane were purged with nitrogen for 3 times and the solution was heated at 108° C. for 20 h. Solvent was removed by vacuum and the residue was dissolved in EtOAc. The organic layer was washed with aqueous NaHCO3, dried with Na2SO4 and was purified by flash chromatography EtOAc/hexane=1:3 to give compound 2. Step B: Compound 2 (1.00 g, 1.68 mmol) in 10 mL of CH2Cl2 was added solution of HCl in dioxane (6.7 mL as 4M solution) and the resulting solution was stirred at rt for 24 h. Volatiles were removed by vacuum to give compound 6 as HCl salt. Mass spectrum (ESI), 499 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[C:18](=[O:30])[N:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:20]([CH3:23])[C:21]=3[CH3:22])=[O:16])=[CH:10][CH:9]=2)[C:5](/[N:31]=C/N(C)C)=[N:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>CS(C)=O.CC#N.C([O-])([O-])=O.[K+].[K+]>[NH2:31][C:5]1[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]3[C:18](=[O:30])[N:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:20]([CH3:23])[C:21]=3[CH3:22])=[O:16])=[CH:12][CH:13]=2)=[N:7][C:2]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:3][N:4]=1
Reactant: C1CCNCC1
Reactant: Cc1c(C(=O)Nc2ccc(-c3nc(Br)cnc3/N=C/N(C)C)cc2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CS(C)=O
Product: Cc1c(C(=O)Nc2ccc(-c3nc(N4CCCCC4)cnc3N)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 120 °C
Yield: 586.9 %

Procedure:
The compound prepared in Example 36 (80 mg) and piperidine (0.300 mg) were mixed in DMSO (0.400 mL) and heated to 120° C. for 18 hours. The reaction mixture was then diluted with MeCN (10 mL) and aqueous 1M K2CO3 (7 mL) and heated to 155° C. for 17 minutes in the microwave. The organic products were extracted with EtOAc/CH2Cl2 (9:1) and washed with brine. The material was purified by HPLC (H2O/MeCN with 0.1% TFA). The solvent was removed and the residue was dissolved in CH2Cl2 and the residual TFA was removed by PL-HCO3 MP SPE ion exchange column to give the title compound (10 mg) having the following physical data.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](Cl)=[O:7])=[CH:2]1.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>C(Cl)Cl>[CH2:9]([N:11]([CH2:12][CH3:13])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:7])[CH3:10]
Reactant: CCNCC
Reactant: O=C(Cl)c1ccsc1
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
Thiophene-3-carbonyl chloride was dissolved in methylene chloride (100 mL) and added to a mixture of diethylamine (43.8 g, 0.6 mol) and methylene chloride (100 mL) placed in an ice bath. Following the addition, the ice bath was removed and the resulting reaction mixture stirred at room temperature over a period of 4 h. The reaction mixture was washed several times with water and the organic layer dried over anhydrous magnesium sulfate and concentrated. Vacuum distillation of the crude residue afforded the title compound as a light yellow oil (yield: 91%): GC-Ms: 183; 1H NMR (300 MHz, CDCl3, ppm) δ: 7.36(d, 1H), 7.22-7.19(m, 1H), 7.08-7.06(m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[CH3:25][N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([NH2:36])[CH:34]=2)[CH2:29][CH2:28][CH2:27]1>CS(C)=O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:36][C:33]3[CH:34]=[C:35]4[C:30]([CH2:29][CH2:28][CH2:27][N:26]4[CH3:25])=[CH:31][CH:32]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12
Reactant: CN1CCCc2ccc(N)cc21
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Solvent: CS(C)=O
Solvent: CO
Product: CN1CCCc2ccc(Nc3ncc4c(=O)n(-c5ccccc5Cl)c5nccn5c4n3)cc21

Procedure:
A mixture of Example 1E (60.0 mg, 0.167 mmol) and 1-methyl-1,2,3,4-tetrahydroquinolin-7-amine (48.7 mg, 0.300 mmol) was heated in a capped vial at 90° C. for 1 hour. After cooling, the residue was treated with dimethylsulfoxide/methanol (2 mL). The precipitate was filtered, washed with methanol and water, and oven-dried to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77-1.99 (m, 2H), 2.69 (t, J=6.26 Hz, 2H), 2.90 (s, 3H), 3.11-3.28 (m, 2H), 6.92 (d, J=7.93 Hz, 1H), 7.02 (d, J=7.32 Hz, 1H), 7.07 (s, 1H), 7.18 (s, 1H), 7.50-7.65 (m, 3H), 7.69-7.74 (m, 2H), 9.09 (s, 1H), 10.53 (s, 1H). MS (ESI+) m/z 458.2 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].CS(Cl)(=O)=O.C(N(CC)CC)C.[CH3:26][NH:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]>C(Cl)Cl>[CH2:28]([N:27]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:26])[CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CNCCC(C)C
Reactant: COC(=O)c1cc(C)cc(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(C)cc(CN(C)CCC(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To methyl 3-(hydroxymethyl)-5-methylbenzoate prepared by the method in EXAMPLE SP-198, Step 2 in anhydrous methylene chloride at −30° C. is added methanesulfonyl chloride (601 μL, 7.8 mmol), then triethylamine (1.5 mL, 11.1 mmol), and the reaction is stirred at 0° C. 15 min. The resulting precipitate is filtered, and the filtrate is added to N-methylisoamylamine (2.1 mL, 16.7 mmol). The reaction stirred at room temperature 16 h. The solution is concentrated under reduced pressure, redissolved in ethyl acetate and washed with saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 20% ethyl acetate/hexanes) provides the title compound. ESI MS m/z 264.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Br:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Br:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]#N>ICC.CO>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Br:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Br:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][CH3:22]
Reactant: N#CSc1c(C#N)nn(-c2c(Br)cc(C(F)(F)F)cc2Br)c1N
Solvent: CCI
Solvent: CO
Product: CSc1c(C#N)nn(-c2c(Br)cc(C(F)(F)F)cc2Br)c1N

Procedure:
5-amino-1-[2,6-dibromo4-(trifluoromethyl)phenyl]-4-thiocyanato-1H-pyrazole-3-carbonitrile, which was used directly in step 2 with iodoethane and methanol as solvent to give the 5-amino-1-[2,6-dibromo-4-(trifluoromethyl)phenyl]-4-methylthio-1H-pyrazole-3-carbonitrile, m.p.211-214° C.
Reaction SMILES: O=[C:2]([C:6]1([C:9]([F:12])([F:11])[F:10])[CH2:8][CH2:7]1)[CH2:3][C:4]#[N:5].[OH-].[Na+].Cl.[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO.O>[C:16]1([N:22]2[C:4]([NH2:5])=[CH:3][C:2]([C:6]3([C:9]([F:10])([F:11])[F:12])[CH2:8][CH2:7]3)=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CCC(=O)C1(C(F)(F)F)CC1
Reactant: NNc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(C2(C(F)(F)F)CC2)nn1-c1ccccc1
Temperature: 90 °C
Yield: 43.1 %

Procedure:
To 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile (230 mg, 1.3 mmol) in EtOH (5 mL, 200 proof) was added H2O (3.7 mL), 1N NaOH(aq) (1.3 mL), and phenylhydrazine hydrochloride (188 mg, 1.3 mmol) and the mixture heated at 90° C. overnight. After cooling to room temperature, the mixture was diluted with H2O, extracted with EtOAc, the org layer concentrated in vacuo, and purified by column chromatography (5-25% EtOAc/hexanes) to give 1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (150 mg, 0.56 mmol, 43%). LC-MS (ESI) m/z 268 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH:18]([C:19](OCC)=[O:20])[CH2:17][CH2:16][CH:15]1[C:24](OCC)=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH:18]([CH2:19][OH:20])[CH2:17][CH2:16][CH:15]1[CH2:24][OH:25])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C1CCC(C(=O)OCC)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CCC(CO)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a suspension of lithium aluminum hydride (10.25 g) in tetrahydrofuran (550 ml) was added dropwise a solution of 1-benzyl-2,5-bis(ethoxycarbonyl)pyrrolidine (55 g) in tetrahydrofuran (100 ml). The reaction mixture was stirred for 30 minutes at 0° C., allowed to warm to room temperature and then stirred at the same temperature for 1 hour. And then water was added carefully until excess lithium aluminum hydride was decomposed. After the precipitate was filtered off, the filtrate was evaporated under reduced pressure to give crude 1-benzyl-2,5-bis(hydroxymethyl)pyrrolidine (38.52 g).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.[Si:46]([O:63][CH:64]1[CH2:67][NH:66][CH2:65]1)([C:59]([CH3:62])([CH3:61])[CH3:60])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O>[Si:46]([O:63][CH:64]1[CH2:65][N:66]([C:1]([C:4]2[N:5]=[C:6]([N:9]3[CH2:10][CH:11]([S:13][C:14]4[C@H:15]([CH3:45])[C@@H:16]5[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:38])[CH3:39])[CH3:35])[C:32](=[O:44])[N:17]5[C:18]=4[C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])[CH2:12]3)[S:7][CH:8]=2)=[O:3])[CH2:67]1)([C:59]([CH3:62])([CH3:60])[CH3:61])([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)O)cs4)C3)[C@H](C)[C@H]12
Agent: CCP(=O)(C#N)CC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N5CC(O[Si](c6ccccc6)(c6ccccc6)C(C)(C)C)C5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 32.2 %

Procedure:
Subsequently, to a solution of p-nitrobenzyl (1R,5S,6S)-2-[1-(4-carboxy-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.71 g, 2.53 mmol) and 3-t-butyldiphenylsilyloxyazetidine (947 mg, 3.04 mmol) (obtained as described above) in dimethylformamide (86 ml) were added diethylphosphoryl cyanide (461 μl, 3.04 mmol) and triethylamine (426 μl, 3.04 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred at room temperature for 5.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed successively with 0.5M aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (4:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(3-t-butyldiphenylsilyloxyazetidine-1-carbonyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (789 mg, yield 32%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][CH:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:21]=[O:22])C>C(Cl)Cl>[CH:21]([C:9]1[NH:10][CH:11]=[CH:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)=[O:22]
Reactant: CN(C)C=O
Reactant: Ic1ccc(-c2cc[nH]c2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1[nH]ccc1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4 (5.15 g, 19.1 mmol) in DMF (6.1 mL) and CH2Cl2 (140 mL) under argon was cooled to 0° C. and then POCl3 (2.11 mL, 22.6 mmol) was added dropwise. After 1 h, the flask was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 2.5 M NaOH (100 mL). The mixture was poured into water (500 mL), extracted with CH2Cl2, and the combined organic layers were washed with water, brine, dried (Na2SO4), and the solvent was removed in vacuo. 1H NMR spectroscopy showed two regioisomers in a ˜6:1 ratio. The minor isomer exhibited signals at δ 7.21 and 7.39 ppm, compared with signals at δ 6.42 and 7.14 for the major isomer. The most downfield signal (7.39 ppm) is assigned to the proton adjacent to a formyl group, which occurs in the 2-formyl-4-aryl substituted pyrrole. Recrystallization from ethyl acetate afforded an orange solid corresponding to the major aldehyde (2.25 g). The mother liquor was concentrated and purified by flash column chromatography [silica, hexanes/ethyl acetate (3:1)]. The first fraction corresponded to the major aldehyde (1.25 g). The total yield of the title compound was 3.50 g (62%): mp 153-154 ° C.; 1H NMR δ 6.42 (m, 1H), 7.14 (m, 1H), 7.22 (m, 2H), 7.76 (m 2H), 9.59 (s, 1H), 10.72 (br, 1H); 13C NMR δ 93.5, 104.3, 111.4, 125.8, 128.6, 130.8, 133.1, 137.8, 179.4; FAB-MS obsd 296.9663, calcd 296.9651; Anal. Calcd for C10H8INO: C, 44.5; H, 2.7; N, 4.7. Found: C, 44.4; H, 2.7; N, 4.6.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)(=O)=O.[CH3:20][C:21]1([CH3:33])[C:25]([CH3:27])([CH3:26])[O:24][B:23]([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)[O:22]1.C(=O)([O-])[O-].[Ce+3].C(=O)([O-])[O-].C(=O)([O-])[O-].[Ce+3]>C(#N)C>[CH3:20][C:21]1([CH3:33])[C:25]([CH3:26])([CH3:27])[O:24][B:23]([C:28]2[CH:32]=[N:31][N:30]([CH2:6][C@H:7]3[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8]3)[CH:29]=2)[O:22]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Ce+3]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a mixture of (S)-tert-butyl 2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate (430 mg, 1.46 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (283 mg, 1.46 mmol) in 50 mL of acetonitrile was added cerium carbonate (1.43 g, 4.37 mmol), and the mixture was stirred at 60° C. for 3 h. TLC and LCMS showed the reaction was completed. After the solvents were removed under reduced pressure, the residue was diluted with 50 mL of ethyl acetate, and washed with water (50 mL×3) and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate=5:1) to get the title product (300 mg, 52%) as colorless oil. MS (ES+) C19H32BN3O5 requires: 393. found: 394 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[C:37]1([CH2:36][NH:43][C:19](=[O:21])[CH2:18][N:17]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[C:9]2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:4][CH:5]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.21 g, 0.010 mole), 1,1'-carbonyldiimidazole (1.62 g, 0.010 mole), and anhydrous tetrahydrofuran (75 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 3 hours. The nitrogen flow was stopped and a solution of benzylamine (1.39 g, 0.013 mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was concentrated in vacuo and the residue triturated in potassium bicarbonate solution (50 ml) and filtered. The filter cake was washed with water and recrystallized from isopropyl alcohol-isopropyl ether, giving 2.8 g (68%). Recrystallization from isopropyl alcoholisopropyl ether gave 2.3 g of white flakes, mp 224°-225° C.