Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3]([O:5][CH2:6][C:7](=[O:14])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH-].[Na+]>C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1>[CH3:1][C:2]([CH3:16])([CH3:15])[C:3]([O:5][CH2:6][C@H:7]([OH:14])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(C)(C)C(=O)OCC(=O)c1cccnc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: CC(C)(C)C(=O)OC[C@H](O)c1cccnc1
Reaction time: 2 h
Yield: 104.1 %

Procedure:
2-Oxo-2-pyridin-3-ylethyl 2,2-dimethylpropanoate (2 g), 2.8 g of glucose, 2.3 mg of NADP and 0.02 ml of Triton X×100 were added to 20 ml of the same culture fluid as used in Example 11, and the reaction was carried at 30° C. with stirring for 2 hours while adjusting the pH to 6.5 with a 5 N aqueous sodium hydroxide solution. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the 30 extract was concentrated under reduced pressure to give 2.1 g of (R)-2-hydroxy-2-pyridin-3-ylethyl 2,2-dimethylpropanoate as a light-yellow oil. The optical purity was determined by the same method as used in EXAMPLE 10 and was 100% ee.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9](O)[N:4]2[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[NH2:1][C:2]1[N:12]=[C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([Cl:15])[N:4]2[N:3]=1
Reactant: Cc1cc(O)n2nc(N)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)n2nc(N)nc2n1

Procedure:
2-Amino-7-hydroxy-5-methyl-s-triazolo[1,5-a]pyrimidine (20 g) was suspended in 120 ml of phosphorus oxychloride under ice cooling, and the suspension was refluxed for two hours. Excess phosphorus oxychloride was removed by distillation under normal pressure. The 40 ml of reddish brown oil left was shaken with 300 ml of dichloromethane and 200 ml of water and the organic layer was collected. The aqueous layer was again extracted with 200 ml of fresh dichloromethane, and the combined organic extract was treated with saturated sodium bicarbonate solution until the pH of washings rose to 7 to 8, then washed with 100 ml of saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the dried solution was concentrated under reduced pressure to about 30 ml, and the concentrate was crystallized using 80 ml of n-hexane, affording 17 g of the objective compound as faint yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[CH:22]1([CH2:25]Br)[CH2:24][CH2:23]1>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[O:8][CH2:25][CH:22]1[CH2:24][CH2:23]1
Reactant: CCOC(=O)Cc1cc(Cl)c(O)c(Br)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)Cc1cc(Cl)c(OCC2CC2)c(Br)c1
Temperature: 60 °C
Yield: 72 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (4 g, 0.011 mol) and K2CO3 (2.8 g, 0.02 mol) in 100 ml of DMSO was slowly added cyclopropyl methylbromide (1.46 ml, 0.017 mol) at room temperature. Upon completion of the addition, the reaction mixture was heated at 60° C. for 4 h. Upon completion of the reaction, the mixture was poured onto water and extracted with EtOAc (×2). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated in vacuo to give ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate in 72% yield. (93.4 g). 1HNMR (CDCl3): 7.38 (bs, 1H); 7.28 (s, 1H); 4.16 (q, 2H); 3.87 (d, 2H); 3.58 (s, 2H); 1.38 (m, 1H); 1.28 (t, 3H); 0.63 (m, 2H); 0.38 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:14]=2)[N:9]([CH3:24])[C:8]=1[C:25]([O:27]CC)=[O:26])=[O:5])[CH3:2].C(O)C.[OH-].[K+]>O1CCCC1>[CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:14]=2)[N:9]([CH3:24])[C:8]=1[C:25]([OH:27])=[O:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1c(C(=O)OCC)n(C)c2cc(OCc3ccccc3)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)Nc1c(C(=O)O)n(C)c2cc(OCc3ccccc3)ccc12

Procedure:
A suspension of 28.1 g (0.0708 mol) of ethyl 3-[(ethoxycarbonyl)amino]-1-methyl-6-(phenylmethoxy)-1H-indole-2-carboxylate in 170 ml of 96° ethanol is brought to reflux. 64 ml of a 10% ethanolic potassium hydroxide solution and 50 ml of tetrahydrofuran are added to this mixture. The suspension is left at reflux for 150 min, is then concentrated under reduced pressure, diluted with a mixture of water and ice and acidified with 6N hydrochloric acid. The product is then extracted with a mixture of dichloromethane and tetrahydrofuran, the organic phase is washed with water and dried over sodium sulphate and the solvent is evaporated under reduced pressure. The residue is triturated in diisopropyl ether and 24.8 g of product are recovered.
Reaction SMILES: Cl.O1CCOCC1.C(OC(=O)[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][N:23]=2)=[CH:17][CH:16]=1)(C)(C)C>C(Cl)Cl>[Cl:28][C:26]1[N:25]=[CH:24][N:23]=[C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=2)[CH:27]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1ccc(Cc2cc(Cl)ncn2)cc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 136.3 %

Procedure:
A 4 N solution of HCl in dioxane (11.7 mL, 46.9 mmol, 30 equiv) is added to a solution of [4-(6-chloro-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (Example 117) (0.50 g, 1.56 mmol) in CH2Cl2 (6.7 mL), under an argon atmosphere. The resulting white suspension is stirred at rt for 6.5 h. Additional 4 N HCl solution (1.1 mL, 4.6 mmol, 3.0 equiv) is added. The reaction mixture is allowed to stir for 0.5 h and concentrated in vacuo to afford 0.467 g of crude 4-(6-chloro-pyrimidin-4-ylmethyl)-phenylamine as a white solid. An 8 M solution of methylamine in EtOH (5.1 mL, 40.0 mmol, 30 equiv) Is added to a solution of crude 4-(6-chloro-pyrimidin-4-ylmethyl)phenylamine (0.300 g, 1.37 mmol) in EtOH (2.7 mL), under an argon atmosphere. The mixture Is heated to 50° C. (oil bath temperature) for 5 h, allowed to cool to rt and concentrated in vacuo. The residue is purified by silica gel (48 g) column chromatography (CH2Cl2/MeOH, 85/15) to afford the title compound as a light yellow oil: ES-MS: 215.0 [M+H]+; single peak at tR=3.03 min (System 2); Rf=0.49 (CH2Cl2/MeOH, 85/15).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][OH:28]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:25][CH2:26][CH2:27][OH:28])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: OCCCBr
Reactant: Oc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OCCCOc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.4 %

Procedure:
1.45 g (corresponding to 5.0 mmol) of 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 50 mL of N,N-dimethylformamide, and 2.07 g (corresponding to 15.0 mol) of potassium carbonate was added thereto. The mixture was supplemented with 680 μL (corresponding to 7.5 mmol) of 3-bromo-1-propanol, and then the solution was stirred at room temperature for 17 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was recrystallized from methanol to obtain 1.28 g (corresponding to 3.67 mmol) of 6-bromo-2-[4′-(3″-hydroxypropoxy)phenyl]imidazo[1,2-a]pyridine (FIG. 1-2, Step 3).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Br:17][C:18]1[CH:23]=[C:22](F)[CH:21]=[C:20]([Cl:25])[CH:19]=1>CS(C)=O.CCOC(C)=O>[Br:17][C:18]1[CH:23]=[C:22]([O:8][C:7]2[C:6]([F:9])=[C:5]([CH3:10])[CH:4]=[CH:3][C:2]=2[Cl:1])[CH:21]=[C:20]([Cl:25])[CH:19]=1
Reactant: Cc1ccc(Cl)c(O)c1F
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a solution of 6-chloro-2-fluoro-3-methylphenol (7.67 g, 47.7 mmol) in DMSO (100 ml) was added potassium t-butoxide (1.0 M solution in THF) (50.1 ml, 50.1 mmol) and the mixture was stirred at room temperature for 30 minutes. Next, 1-bromo-3-chloro-5-fluorobenzene (10.0 g, 47.7 mmol) was added and the mixture was heated at 135° C. for 3 days. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with water. The solvent was removed to give 2-[(3-bromo-5-chlorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (9.54 g, 27.3 mmol, 57% yield) which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.44 (s, 1H), 7.33-7.40 (m, 1H), 7.27 (t, 1H), 7.07 (s, 1H), 6.95-7.02 (m, 1H), 2.23 (d, 3H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18](I)[C:9]=2[C:8]1=[O:20].[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O>>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH3:30])[C:9]=2[C:8]1=[O:20]
Reactant: Cc1ccccc1B(O)O
Reactant: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1ccccc1-c1ccnc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 99.4 %

Procedure:
In a similar manner to Reference Example 4, 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (300 mg) was reacted with 2-methylphenylboronic acid (116 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (278 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[OH:10].Cl.[CH2:12]([O:14]CC)C>CO>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[N:9][O:14][CH3:12])[CH:5]=[CH:4][C:3]=1[OH:10]
Reactant: N#Cc1ccc(O)c(Cl)c1
Reactant: CCOCC
Agent: Cl
Solvent: CO
Product: CON=Cc1ccc(O)c(Cl)c1
Reaction time: 8 h

Procedure:
While being cooled in ice, a solution of 4.5 g of 2-chloro-4-cyanophenol in 50 ml of methanol was saturated with dried gaseous hydrogen chloride (HCl). The solution was left standing overnight at room temperature and mixed with 100 ml of ethyl ether to precipitate crystals which were collected by filtration to obtain 4.0 g of 2-chloro-4-methoxyiminomethylphenol hydrochloride.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[F:13][C:9]1[CH:8]=[C:7]([CH:2]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C(Br)c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(Nc1ccccc1)c1cccc(F)c1
Temperature: 100 °C
Yield: 73 %

Procedure:
Methyl 2-bromo-2-(3-fluorophenyl)acetate (I15) (300 mg, 1.21 mmol), DIPEA (0.32 ml, 1.82 mmol), and aniline (0.17 ml, 1.82 mmol) were dissolved in acetonitrile (4 ml) and heated under microwave irradiation at 100° C. for 1 hour. Acetonitrile was evaporated, and the residue was purified by flash chromatography (Petroleum ether/EtOAc=95/5) to obtain intermediate I16 (229 mg, 73% yield).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[S:18][CH:19]=[C:20]([C:22](=[O:25])[CH2:23]Br)[N:21]=1.C([SiH](CC)CC)C>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][N:4]2[CH2:3][CH2:2][O:25][CH:22]([C:20]3[N:21]=[C:17]([C:16]([F:27])([F:26])[F:15])[S:18][CH:19]=3)[CH2:23]2)=[CH:8][CH:9]=1
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Reactant: COc1ccc(CCNCCO)cc1
Agent: CC[SiH](CC)CC
Product: COc1ccc(CCN2CCOC(c3csc(C(F)(F)F)n3)C2)cc1

Procedure:
Prepared analogously to Example 32 by reaction of N-(2-hydroxyethyl)-2-(4-methoxyphenyl)ethanamine with 2-trifluoromethyl-4-bromoacetyl-thiazole followed by reduction with triethylsilane.
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9](=[N:22][NH2:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:10]1([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:22][NH:23][C:2]2[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: Cc1ncccc1Br
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ncccc1NN=C(c1ccccc1)c1ccccc1
Temperature: 120 °C
Yield: 75 %

Procedure:
3-Bromo-2-methyl-pyridine (1.0 g, 5.80 mmol) in 15 mL dry toluene was treated with benzophenone hydrazone (1.25 g, 6.39 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (170 mg, 0.29 mmol), sodium tert-butoxide (835 mg, 8.70 mmol), and Pd(II)(OAc)2 (67 mg, 0.30 mmol). Heated to 120° C. in the microwave for five minutes. Extracted using EtOAc/H2O (3×100 mL EtOAc, 1×100 mL H2O, lx 100 mL brine). Dried using Na2SO4 and then purified by flash chromatography (silica, 10-50% EtOAc/Hexane) to afford 3-(2-(diphenylmethylene)hydrazinyl)-2-methylpyridine (1.25 g, 4.35 mmol, 75%). 1H NMR (300 MHz, DMSO-d6) δ 7.95 (d, 1H), 7.85 (d, 1H), 7.70-7.53 (m, 6H), 7.45-7.34 (m, 5H), 7.20 (d, 1H), 2.07 (s, 3H); LC-MS (ESI) m/z 288 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Br:19][CH:20](Br)[CH3:21].[NH4+].[Cl-]>O1CCCC1.CCCCC>[Br:19][CH2:20][CH2:21][C:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(Br)Br
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: BrCCc1cccc2c1Cc1ccccc1-2
Reaction time: 1 h

Procedure:
In this reaction, 8.3 g (0.05 m) of fluorene was dissolved in 150 ml of tetrahydrofuran. Then 31.8 ml (0.05 m) of butyl lithium (1.6 molar in hexane) was added dropwise to this solution. After one hour, this solution was added gradually to a stirred solution of 9 ml (0.1 m) of dibromoethane in 300 ml of pentane within 2 hours. Then the reaction mixture was treated with 50 ml of an aqueous NH4Cl solution, and then washed with 50 ml of water. The organic phase was dried over Na2SO4. Then the solvent was removed in vacuo. The yellow residue was dissolved in pentane. The pentane solution was filtered over silica. The solution was concentrated to about 20% of the original volume and then the product was crystallized at −30° C. A yield of 10.88 g of 1-bromo-2-(fluorenyl)ethane was obtained. The product was characterized through 1H NMR, 13C NMR, and Mass spectroscopy.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)[CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH3:11])[CH:7]=1.[CH3:21][O:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[N:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1.N1(C([O-])=O)CCNCC1>>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:2]2[N:3]=[C:4]([O:12][C@@H:13]([C@@H:15]3[CH2:16][C:17](=[O:20])[NH:18][CH2:19]3)[CH3:14])[C:5]3[N:6]([N:8]=[CH:9][C:10]=3[CH3:11])[CH:7]=2)[CH:26]=[CH:25][C:24]=1[N:38]1[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cnn2cc(Cl)nc(O[C@H](C)[C@H]3CNC(=O)C3)c12
Agent: O=C([O-])N1CCNCC1
Product: COc1cc(-c2cn3ncc(C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Following the procedure of Example 5.55, beginning with (R)-4-((R)-1-(6-chloro-3-methylpyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 5.54 (25.3 mg, 0.086 mmol) and tert-butyl 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate 7.08 (44 mg, 0.105 mmol), tert-butyl 4-(2-methoxy-4-(3-methyl-4-4R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazin-6-yl)phenyl)piperazine-1-carboxylate 5.59 (35 mg) was synthesized.
Reaction SMILES: [Li].[C:2]1([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:13][CH:14]=[O:15])[CH2:9][CH2:10][C:11]#[N:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[NH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:13][CH2:14][OH:15]
Reactant: N#CCCC(CC=O)(c1ccccc1)c1ccccc1
Agent: [Li]
Solvent: C1CCOC1
Product: NCCCC(CCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of lithium aluminumhydride (0.57 g. 15 mmol) in anhydrous THF (20 mL) was added carefully dropwise a solution of 4,4-diphenyl-5-formylpentanonitrile (1.96 g. 7.4 mmol) in anhydrous THF (20 mL). The mixture was stirred at rt for 1.5 hr. The reaction mixture was quenched by careful addition of SN NaOH (2.5 mL) and followed by water (1.5 mL). The mixture was stirred at room temperature for 10 min and then filtered and the solid was washed twice with diethylether. The organic filtrates were combined, dried (Na2SO4) and concentrated to give the desired product as solid foam (1.60 g, 80%): MS showed (M+H)+ (270; 1H-NMR (CDCl3, δ): 1.17-1.34 (m, 2H), 2.12-2.22 (m, 2H), 2.31-2.43 (m, 2H), 2.62-2.74 (m, 2H), 3.30-3.40 (m, 2H), 7.11-7.34 (m, 1OH).
Reaction SMILES: C([O:3][P:4]([CH:9]([NH:17][S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>ClCCl>[C:11]1([CH2:10][CH:9]([P:4](=[O:3])([OH:5])[OH:8])[NH:17][S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOP(=O)(OCC)C(Cc1ccccc1)NS(=O)(=O)c1cccs1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)C(Cc1ccccc1)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a solution of diethyl phosphonate (xii) (745 mg; 1.8 mmol) in dichloromethane (8 mL) at 0° C. was slowly added bromotrimethylsilane (2 mL; 15.2 mmol). The reaction was gradually warmed to room temperature and the following day the solution was evaporated. The residue was redissolved in dichloromethane (10 mL), evaporated and the process repeated once more. Methanol (10 mL) was added to the residue and the solution stirred at room temperature for 30 minutes, then the solution was filtered and concentrated. The oily residue was triturated with 1:1 ether-hexanes and the orange solid collected by filtration. Finally, the orange solid was boiled in dichloromethane (5 mL), cooled and filtered to yield pure phosphonic acid (xiii) (512 mg, 80%) as a colorless solid: 1H NMR (400 MHz, CD3OD) δH 2.71 (dt, J=14, 10 Hz, 1H, CHPh), 3.13 (ddd, J=4, 8, 14 Hz, 1H, CHPh), 3.89 (ddd, J=4, 10, 14 Hz, NCHP), 6.86 (dd, J=3.5, 5 Hz, 1H, Ar—H), 7.07-7.15 (m, 6H, Ar—H), 7.53 (dd, J=1.5, 5 Hz, 1H, Ar—H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([OH:15])([C:11]([F:14])([F:13])[F:12])[CH2:4]/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8]>[Pd].C(OCC)(=O)C>[F:1][C:2]([F:16])([F:17])[C:3]([OH:15])([C:11]([F:13])([F:14])[F:12])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)/C=C/CC(O)(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCCC(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
To a 330 mL thick-walled glass hydrogenation vessel was added 37.7 g E-methyl 6,6,6-trifluoro-5-hydroxy-5-(trifluoromethyl)hex-2-enoate (I) (141 mmol), 0.5 g palladium-on-carbon (5 wt % Pd), and 150 mL ethyl acetate. The reaction vessel was attached to a Parr hydrogenation apparatus and the reaction solution degassed via three successive pump-backfill cycles with nitrogen. The reaction vessel was pressurized to 40 psi with hydrogen and shaken at room temperature for 20 hours, after which the pressure had fallen to 34 psi. The excess hydrogen was removed via three successive pump-backfill cycles with nitrogen and the palladium catalyst removed via filtration through 1.0 micron glass fiber and 0.2 micron PTFE filters. The solvent was removed in vacuo and the crude reaction mixture distilled under vacuum (6 Torr, 64-74° C.) to afford 34.4 g (91%) of methyl 6,6,6-trifluoro-5-hydroxy-5-(trifluoromethyl)hexanoate (II) as a colorless liquid.
Reaction SMILES: [CH2:1]1[O:6][C:4](=[O:5])[C@H:3]([OH:7])[C@H:2]1[OH:8].[NH3:9]>CO>[O:5]=[C:4]([NH2:9])[C@@H:3]([C@H:2]([CH2:1][OH:6])[OH:8])[OH:7]
Reactant: O=C1OC[C@H](O)[C@H]1O
Reactant: N
Solvent: CO
Product: NC(=O)[C@H](O)[C@@H](O)CO
Temperature: 0 °C

Procedure:
A solution of 5.50 g (46.57 mmoles) L-threonolactone in 100 mL MeOH, previously saturated with anhydrous NH3 at 0° C., was kept at room temperature for 48 h in a pressure bottle. The solvent was evaporated in vacuo, the residual oil re-evaporated from absolute EtOH, and the resulting solid crystallized from boiling EtOH. The crystals were collected after cooling at 0° C., washed with EtOH-Et2O (1:1 parts by volume), then with Et2O, and dried at 40° C./0.005 mm Hg to give 6.023 g (95.7%) of analytically pure product L-threonamide, m.p. 105°-107° C.
Reaction SMILES: [CH2:1]([SiH:7]([Cl:9])[Cl:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC([P]([Pt]([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>[CH2:1]([Si:7]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([Cl:9])[Cl:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=Cc1ccccc1
Reactant: CCCCCC[SiH](Cl)Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pt]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCCC[Si](Cl)(Cl)CCc1ccccc1
Temperature: 60 °C
Yield: 91.1 %

Procedure:
3.80 g (20.5 millimol) of n-hexyldichlorosilane, 2.00 g (19.2 millimol) of styrene, and 0.023 g (1.92×10-5 mol) of tetrakis(triphenylphosphine)platinum (O) were introduced into a flask and reacted with stirring by heating in an oil bath at 60° C. for 8 hours and then subjected to distillation under a reduced pressure to produce 5.6 g (17.5 millimol) of n-hexylphenethyldichlorosilane.