Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:7][C:8]([C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][C:23]([C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=4)=[O:28])=[CH:24]3)=[CH:19][CH:18]=2)[CH:13]=[CH:12][N:11]=1)=S>CCOC(C)=O.[Cl-].[Na+].O>[C:36]([C:32]1[CH:31]=[C:30]([NH:29][C:27]([C:23]2[CH:22]=[CH:21][C:20]3[C:25](=[CH:26][C:17]([O:16][C:14]4[CH:13]=[CH:12][N:11]=[C:10]([C:8](=[NH:7])[N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:15]=4)=[CH:18][CH:19]=3)[CH:24]=2)=[O:28])[CH:35]=[CH:34][CH:33]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: C1COCCN1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc3ccc(Oc4ccnc(C(N)=S)c4)cc3c2)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cccc(NC(=O)c2ccc3ccc(Oc4ccnc(C(=N)N5CCOCC5)c4)cc3c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Morpholine (2.00 mL, 22.9 mmol) and 7-{[2-(aminocarbonothioyl)pyridin-4-yl]-oxy}-N-(3-tert-butylphenyl)-2-naphthamide (0.155 g, 0. 34 mmol) were combined. The reaction mixture was allowed to stir at rt overnight in a sealed vial. And then heated at 60° C. for 6 h. The reaction mixture was diluted with EtOAc and poured into brine. The aqueous and organic solutions were separated and the aqueous solution was further extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, and loaded onto a silica gel column. The product was collected from the column, concentrated, and redissolved in MeOH. To this solution was added 1M HCl in Et2O. The solution was concentrated to give N-(3-tert-butylphenyl)-7-({2-[imino(morpholin-4-yl)methyl]pyridin-4-yl}oxy)-2-naphthamide I-99 (21 mg). 1H NMR (400 MHz, CD3OD; 2*HCl salt) δ: 8.48 (d, 1H), 8.47 (s, 1H), 7.99-8.12 (m, 3H), 7.81 (dd, 2H), 7.58 (dd, 1H), 7.46 (dd, 1H), 7.31 (dd, 1H), 7.22 (ddd, 1H), 7.14 (d, 1H), 7.08 (d, 1H), 3.69 (dd, 4H), 3.31-3.33 (m, 4H), and 1.35 (s, 9H). LCMS: (FA) ES30 509.3, ES− 507.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>O.CN(C)C=O.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:28][P:29](=[O:36])([O:30][CH2:31][CH3:32])[O:33][CH2:34][CH3:35])=[CH:37][CH:38]=2)=[O:18])=[CH:6][CH:7]=1
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: Cn1ncc(/C=C/C(=O)O)c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1)OCC
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a mixture of (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (35.0 g), acetonitrile (245 mL) and dimethylformamide (0.175 mL) was added thionyl chloride (11.4 mL) at 40-45° C. and the mixture was stirred for 1 hr. Then diethyl 4-aminobenzylphosphonate (36.3 g) was added at 5° C. and diisopropylethylamine (61.9 mL) was further added dropwise. The mixture was stirred at room temperature for 1 hr. A 1N aqueous sodium hydroxide solution (140 mL) was added to neutralize the reaction mixture and water (472.5 mL) was further added. The mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration and washed with 30% acetonitrile to give diethyl [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)benzyl]phosphonate (61.5 g, yield 92%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]1[CH:25]=[CH:24][N:23]2[N:26]=[CH:27][C:28]([C:29]([NH:31][CH2:32][C@@H:33]([OH:39])[CH2:34][C:35](OC)=[O:36])=[O:30])=[C:22]2[CH:21]=1.CCOC(C)=O.[NH4+].[Cl-]>C1COCC1.O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]1[CH:25]=[CH:24][N:23]2[N:26]=[CH:27][C:28]([C:29]([NH:31][CH2:32][C@@H:33]([OH:39])[CH2:34][CH2:35][OH:36])=[O:30])=[C:22]2[CH:21]=1
Reactant: COC(=O)C[C@H](O)CNC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NC[C@@H](O)CCO)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reaction time: 1 h
Yield: 10.9 %

Procedure:
LAH (12 mg, 0.33 mmol) was added portionwise to a solution of (S)-methyl 4-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)-3-hydroxybutanoate (100 mg, 0.22 mmol) in THF (2 mL) at 0-5° C. and continued stirring at the same temperature for 1 h. EtOAc was added to the above reaction mixture followed by NH4Cl solution and water. Organic layer separated was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product, which was purified by Preparative TLC (using Silicagel GF254, 1000 u coated 20×20 cm dimension glass plate and 7% MeOH in CHCl3 as eluent) to afford 10.3 mg of the title compound.
Reaction SMILES: Cl.[CH2:2]([N:5]1[C:10](=[O:11])[C:9]2[CH2:12][NH:13][CH2:14][CH2:15][C:8]=2[NH:7][C:6]1=[O:16])[C:3]#[CH:4].C(N(CC)CC)C.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.O>C(Cl)Cl>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:13]2[CH2:14][CH2:15][C:8]3[NH:7][C:6](=[O:16])[N:5]([CH2:2][C:3]#[CH:4])[C:10](=[O:11])[C:9]=3[CH2:12]2)=[O:30])=[CH:27][CH:26]=1
Reactant: C#CCn1c(=O)[nH]c2c(c1=O)CNCC2
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C#CCn1c(=O)[nH]c2c(c1=O)CN(C(=O)c1ccc(Cl)cc1)CC2

Procedure:
3-propargyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione hydrochloride (790 mg) was suspended in methylene chloride, triethylamine (0.95 ml) and 4-chlorobenzoyl chloride (0.42 ml) were added under ice cooling and the resultant mixture was stirred at the same temperature for 30 minutes. To the reaction solution, water was added and the resultant mixture was concentrated. To the residue, diethyl ether was added and insoluble matter was separated by filtration to obtain the titled compound (894 mg) as a white powder. The resultant compound was used in a next reaction without further purifying.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](/[C:15]1[CH2:21][C@H:20]2[N:17]([C:18](=[O:32])[C@@H:19]2[C@H:22]([O:24][Si](C(C)(C)C)(C)C)[CH3:23])[C:16]=1[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])\[CH3:14])=[O:6])[CH:2]=[CH2:3].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](/[C:15]1[CH2:21][C@H:20]2[N:17]([C:18](=[O:32])[C@@H:19]2[C@H:22]([OH:24])[CH3:23])[C:16]=1[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])\[CH3:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(/C(C)=C/[C@@H]2CCCN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: C=CCOC(=O)C1=C(/C(C)=C/[C@@H]2CCCN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 14 h
Yield: 66.6 %

Procedure:
To a solution of allyl (5R,6S)-3-[(E)-2-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (5.36 g) in tetrahydrofuran (60 ml) were added acetic acid (5.6 ml) and a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (49 ml) at 0° C. After standing at ambient temperature for 7 hours and at 5° C. for 14 hours, the reaction mixture was taken up into a mixture of ethyl acetate (200 ml) and water (200 ml). After adjusting pH to around 7 with aqueous sodium hydrogen carbonate, the organic layer was separated, washed in turn with water and brine, and dried over magnesium sulfate. Removal of the solvent gave a residue, which was chromatographed on silica gel (150 ml) eluting with a mixture of n-hexane and ethyl acetate (8:2-3:7 V/V) to give allyl (5R,6S)-3-[(E)-2-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (2.82 g).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C:22]4([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:27][CH2:26][N:25](C(OCC5C=CC=CC=5)=O)[CH2:24][CH2:23]4)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[C].[Pd]>[CH3:42][O:41][C:39](=[O:40])[CH2:38][C:22]1([NH:21][C:19]([C:15]2[N:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:10]3=[N:17][C:16]=2[CH3:18])=[O:20])[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]1
Reactant: COC(=O)CC1(NC(=O)c2c(C)nc3c(OCC4CCCCC4)cccn23)CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1(NC(=O)c2c(C)nc3c(OCC4CCCCC4)cccn23)CCNCC1
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 1.2 g of benzyl 4-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate in 30 ml of methanol was added 300 mg of 10% palladium-carbon, followed by stirring overnight under a hydrogen atmosphere. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure to obtain 900 mg of methyl[4-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)piperidin-4-yl]acetate.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1)[CH:10]=[O:11])(=O)=O.[C:33]1([Sn](CCCC)(CCCC)CCCC)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:28][C:23]1([CH3:27])[CH2:22][CH2:21][C:20]([CH3:29])([CH3:30])[C:19]2[CH:18]=[C:17]([CH2:16][O:15][C:14]3[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:26]=[CH:25][C:24]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(COc3ccc(C=O)cc3OS(=O)(=O)C(F)(F)F)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Product: CC1(C)CCC(C)(C)c2cc(COc3ccc(C=O)cc3-c3ccccc3)ccc21
Yield: 64.6 %

Procedure:
3-Trifluoromethylsulphonyloxy-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]methoxy benzaldehyde (42) (0.745 g., 1.58 mmol) is coupled with phenyltributylstannane (0.870 g., 2.38 mmol) via the method of Example 3 to afford 2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]methoxy-[1,1'-biphenyl]-5-carboxaldehyde (43) (0.404 g., 1.02 mmol, 65%): chromatographed on silica gel using CH2Cl2 /hexane; 1H NMR (300 MHz, CDCl3) δ 9.93 (s, 1H, CHO), 7.87 (d, J =2 Hz, 1H, ArH), 7.84 (dd, J=2, 8 Hz, 1H, ArH), 7.57 (m, 2H, ArH), 7.44-7.32 (m, 3H, ArH), 7.25 (m, 2H, ArH), 7.16 (d, J=8 Hz, 1H, ArH), 7.05 (dd, J=2, 8 Hz, 1H, ArH), 5.14 (s, 2H, ArCH2O), 1.65 (s, 4H, CH2CH2), 1.25 (s, 6H, 2×CH3), 1.20 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ 190.95 (C=0), 160.72, 145.19, 144.65, 137.22, 132.97, 132.59, 131.86, 131.20, 130.00, 129.54, 128.16, 127.48, 126.71, 124.89, 123.96, 112.57, 70.50, 34.99, 34.27, 34.13, 31.83, 31.80; IR (film) 2960, 2926, 1692, 1596, 1504, 1264, 1182 cm-1 ; MS (DCI) m/e 399 (MH+), 201 (C15H21+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:37])[NH:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[NH2:36])=[CH:24][CH:23]=4)[N:16]=3)=[C:12]([CH3:14])[N:13]=[C:7]2[CH:6]=1)=[O:4].[OH-].[Na+]>CO>[NH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:29][C:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:17]2[N:16]=[C:15]([C:11]3[N:8]4[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]4=[N:13][C:12]=3[CH3:14])[CH:20]=[CH:19][N:18]=2)=[CH:27][CH:26]=1)=[O:37]
Reactant: COC(=O)c1ccn2c(-c3ccnc(Nc4ccc(C(=O)Nc5ccccc5N)cc4)n3)c(C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2cc(C(=O)O)ccn2c1-c1ccnc(Nc2ccc(C(=O)Nc3ccccc3N)cc2)n1

Procedure:
Compound 3-{2-[4-(2-amino-phenylcarbamoyl)-phenylamino]-pyrimidin-4-yl}-2-methyl-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (200 mg, 0.4 mmol) was dissolved in MeOH (5 mL) and then treated with 1N NaOH (1 mL). After 2 hours the reaction mixture was evaporated and the solids were re-suspended in water and 1N HCl was slowly added to precipitate the title compound. MS found for C26H21N7O3 as (M+H)+ 480.53. 1H NMR (400 MHz, dmso-d6): δ 9.99 (s, 1H), 9.72 (d, J=5.6 Hz, 1H), 9.47 (s, 1H), 8.59 (d, J=5.5 Hz, 1H), 8.07 (s, 1H), 7.90-7.84 (m, 4H), 7.39 (dd, J=7.2, 6.0 Hz, 1H), 7.18-7.09 (m, 2H), 6.90 (t, J=6.0 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 6.56-6.48 (m, 1H), 2.64 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>COCCOC.C([O-])(O)=O.[Na+].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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:21]1[C:22]([C:23]#[N:24])=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1ccccc1Br
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: [Na+]
Solvent: COCCOC
Product: N#Cc1ccccc1-c1cc([N+](=O)[O-])ccc1F
Temperature: 90 °C
Reaction time: 15 h
Yield: 43.4 %

Procedure:
A mixture of 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (37.62 g, 0.141 mol), 2-bromobenzonitrile (35.30 g, 0.194 mol) and tetrakis(triphenylphosphine)palladium(0) (5.85 g, 5.06 mmol) in ethylene glycol dimethyl ether (350 ml) and saturated aqueous NaHCO3 (150 ml) was degassed by bubbling nitrogen through the mixture for 30 min. The mixture was then stirred at 90° C. under nitrogen for 15 h. After allowing to cool, the mixture was partitioned between dichloromethane (500 ml) and water (400 ml). The organic layer was washed with brine, dried (MgSO4), then passed through a pad of Florisil®, washing the product through with more dichloromethane. The filtrates were evaporated in vacuo, and the residue was triturated with diethyl ether (100 ml) and isohexane (100 ml). The resulting solid was collected by filtration, washed with 50% Et2O/isohexane and dried under vacuum to give 14.82 g (43%) of 2′-fluoro-5′-nitrobiphenyl-2-carbonitrile as a white solid. The combined filtrates were concentrated in vacuo to approximately 100 ml and the resulting solid was collected by filtration, washed with 20% Et2O/isohexane and dried under vacuum to give another 0.94 g (3%) of the product. The filtrates were evaporated in vacuo, and the residue was purified by flash chromatography (silica gel, 10-15% EtOAc/isohexane) to afford another 3.07 g (9%) of the product: 1H NMR (360 MHz, CDCl3) δ 7.40 (1H, t, J 8.5 Hz), 7.53 (1H, d, J 7.8 Hz), 7.59 (1H, td, J 7.7, 1.1 Hz), 7.74 (1H, td, J 7.7, 1.3 Hz), 7.84 (1H, dd, J 7.7, 0.9 Hz), 8.34-8.39 (2H, m).
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][C:11]([C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][C:36]=3[F:42])=[C:12]([C:33]#[N:34])[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[C:8]2[C:7]([CH3:43])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:51](Cl)(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>ClCCl>[C:51]([O:41][C:38]1[CH:39]=[CH:40][C:35]([C:11]2[N:10]=[C:9]3[N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[N:6]=[C:7]([CH3:43])[C:8]3=[C:13]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]4)=[CH:18][CH:19]=3)[C:12]=2[C:33]#[N:34])=[C:36]([F:42])[CH:37]=1)(=[O:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nn(C(C)(C)C)c2nc(-c3ccc(O)cc3F)c(C#N)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(C(C)(C)C)c2nc(-c3ccc(OC(=O)c4ccccc4)cc3F)c(C#N)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.5 %

Procedure:
To a solution of 0.33 g (0.56 mmol) of tert-butyl 4-(4-(1-tert-butyl-5-cyano-6-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)phenyl)piperazine-1-carboxylate and 325 μL (0.24 g, 2.3 mmol) of triethylamine in 17 ml of anhydrous dichloromethane are added dropwise 78 μL (0.09 g, 0.67 mmol) of benzoyl chloride. The mixture is stirred at room temperature for 24 h. The mixture is diluted with dichloromethane and washed with water. The aqueous phase is then extracted with dichloromethane. The organic phases are combined, dried over sodium sulfate, and concentrated to give 0.38 g (quantitative) of tert-butyl 4-(4-(6-(4-(benzoyloxy)-2-fluorophenyl)-1-tert-butyl-5-cyano-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)phenyl)piperazine-1-carboxylate which is used in the following step without purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])=[CH:13][CH:12]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.CO>[CH2:1]([N:8]([CH2:9][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]2[CH2:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:28]2)=[O:19])=[CH:13][CH:12]=1)[CH2:29][CH2:30][CH2:31][N:32]1[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(C(=O)N(CCCN2CCOCC2)Cc2ccccc2)cc1)N1Cc2ccccc2C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(CN(CCCN2CCOCC2)Cc2ccccc2)cc1)N1Cc2ccccc2C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of N-(4-{benzyl[3-(morpholin-4-yl)propyl]carbamoyl}phenyl)-1,3-dihydro-2H-isoindole-2-carboxamide (0.028 g, 0.056 mmol) in THF (1.1 ml) was added 1M borane tetrahydrofuran complex (0.225 ml, 0.225 mmol) dropwise. The mixture was heated at 60° C. for 5 hours. Additional borane complex (0.084 mL) was added and reaction was heated at 60° C. for 1 hour. The reaction was cooled to ambient temperature and 0.3 mL of 1.25 M HCl in methanol was added. The quenched reaction was stirred 30 min and concentrated. The title compound was isolated after flash chromatography. 1H NMR (400 MHz, pyridine-d5, Temp=90° C.) δ ppm 8.05 (s, 1H), 7.88-7.82 (m, 2H), 7.47-7.38 (m, 4H), 7.36-7.29 (m, 2H), 7.26-7.15 (m, 5H), 4.85 (bs, 4H), 3.68-3.59 (m, 8H), 3.48-3.35 (m, 1H), 2.59 (t, J=7.0 Hz, 2H), 2.38-2.29 (m, 6H), 1.79-1.65 (m, 3H); MS (ESI(+)) m/e 485 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[S:19][C:20]([CH3:23])=[CH:21][N:22]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>ClC(Cl)C.O.[Cl-].[Ti](Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]([NH:17][C:18]2[S:19][C:20]([CH3:23])=[CH:21][N:22]=2)[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reactant: Cc1cnc(N)s1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: Cc1cnc(Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Temperature: 25 °C
Yield: 33.6 %

Procedure:
2,6-Di-tert-butyl-1,4-benzoquinone (2.20 g) and 3.43 g of 2-amino-5-methylthiazole were dissolved in 60 ml of anhydrous dichloroethane, 0.55 ml of titanium tetrachloride chloride was added, and the mixture was heated under reflux for 14.5 hours. The mixture was then cooled to room temperature, a solution of 40 g of sodium hydrosulfite in 150 ml of water was added, and the resultant mixture was stirred for 2 hours. The insoluble matter was filtered off, the filtrate was allowed to undergo phase separation, and the aqueous layer was further extracted with dichloromethane. The organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. Purification of the crude product thus obtained by silica gel column chromatography (diethyl ether-hexane =3:7) gave 1.07 g of the desired compound.
Reaction SMILES: Cl[CH2:2][O:3][C:4]([O:6][CH:7]([CH2:24][O:25][C:26](=[O:39])[C@H:27]([CH:36]([CH3:38])[CH3:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][O:9][C:10](=[O:23])[C@H:11]([CH:20]([CH3:22])[CH3:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5].[Na+].[I-:41]>>[I:41][CH2:2][O:3][C:4]([O:6][CH:7]([CH2:24][O:25][C:26](=[O:39])[C@H:27]([CH:36]([CH3:38])[CH3:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][O:9][C:10](=[O:23])[C@H:11]([CH:20]([CH3:22])[CH3:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)OC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)OC(=O)OCI
Temperature: 80 °C
Yield: 92 %

Procedure:
A solution of 2-O-chloromethoxycarbonyl-1,3-di-O-(N-tert-butoxycarbonyl-L-valyl)propane-1,2,3-triol (7.86 g, 13.5 mmol) and NaI (8.09 g, 54.0 mmol) in 135 mL dry acetonitirile was refluxed at 80° C. for 4 h under N2. The reaction mixture was concentrated under vacuum, and then partitioned between 150 mL diethyl ether and 50 mL H2O. The aqueous layer was reextracted with 2×25 mL ether. The combined organic phases were washed successively with 25 mL aqueous Na2S2O3 and 50 mL brine, dried over Na2SO4, and concentrated. Flash column chromatography (silica gel, 2/1 hexane-ethyl acetate gave 8.38 g (92%) title product (alternative name: 2-iodomethoxycarbonyloxy-1,3-bis-(N-tert-butoxycarbonyl-L-valyloxy)propane or 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl iodomethyl carbonate) as a white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][CH:11]([O:22][CH3:23])[CH2:12][N:13]1[CH2:16][CH2:15][CH:14]1C(OCC)=O.[O:24]=O>O1CCCC1.ClCCl.[Zn]>[CH3:9][O:10][CH:11]([O:22][CH3:23])[CH2:12][N:13]1[CH2:16][CH2:15][C:14]1=[O:24]
Reactant: CCOC(=O)C1CCN1CC(OC)OC
Reactant: O=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(CN1CCC1=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 2.2 mmol of lithium diisopropylamide in 15 ml tetrahydrofuran at -78° was added dropwise 0.43 g (2 mmol) of N-(2,2-dimethoxyethyl)-2-carbethoxy azetidine in 3 ml of tetrahydrofuran. After stirring at -78° for 30 minutes, the deep yellow anion was silylated in the usual way and warmed to room temperature. Removal of all volatiles by rotary evaporation with a high vacuum pump gave a purple residue which was redissolved in dichloromethane. Internal photooxidation using 5 g of Photox (trademark for photoconductive lead-free zinc oxides available from The New Jersey Zinc Co.) as the sensitizer required less than 5 minutes for oxygen uptake. The mixture was then filtered free of sensitizer and worked up by aqueous extraction in the usual manner. The pink residue obtained was applied to a 17×2 cm neutral alumina column. Elution with 10:3 ethyl acetate-hexane yielded 0.18 g (56%) of pale yellow liquid, which by NMR analysis was greater than 90% pure. Comparison of its spectral properties (IR, NMR) with those of an authentic known sample confirmed the identity of the product as the expected beta-lactam.