Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].[CH:29]1([CH2:35]Br)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH:29]1([CH2:35][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[C:15]2[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=2[OH:28])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Reactant: BrCC1CCCCC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2OCC2CCCCC2)c1
Yield: 86 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 1.46 ml (10.362 mmol) of cyclohexylmethyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated overnight at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 15 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 50/1) to obtain 215 mg (0.4454 mmol, 86%) of 2-cyclohexylmethoxy-2' -hydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 0.6-2.2 (15H, m, cyclohexyl-H, 2CH2), 2.36 (4H, t, 2CH2), 2.65 (4H, t, 2CH2), 3.66 (6H, s, 2CH3), 3.81 (2H, d, CH2), 6.52 (1H, s, OH), 6.8-7.3 (6H, m, arom-H) MS (FAB): 482 (M+)
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)Cl.CC1(C)N([O])C(C)(C)CCC1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[CH:18]=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2CO)N1OCc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: O=C[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
TEMPO (48 mg, 0.3 mmol) was added in portioned to a solution of (2S,5R)-6-(benzyloxy)-2-(hydroxymethyl)-1,6-diazabicyclo[3.2.1]octan-7-one (7.8 g, 30 mmol) and 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (7.0 g, 30 mmol) in DCM (100 mL) at 0° C. The mixture was stirred at 0° C. for 2 h, and filtered through Celite®. The filtrate was dried over Na2SO4 and concentrated to afford (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbaldehyde (7.0 g, 90%) as a yellow oil. ESI-MS (EI+, m/z): 261.1. 1H-NMR (500M, CDCl3): 9.74 (s, 1H), 7.45-7.36 (m, 5H), 5.07 (d, J=11.5 Hz, 1H), 4.92 (d, J=11.5 Hz, 1H), 3.89 (d, J=8.0 Hz, 1H), 3.27 (m, 1H), 3.21-3.05 (m, 1H), 2.56 (d, J=12.0 Hz, 1H), 2.20-2.15 (m, 1H), 2.05-2.01 (m, 1H), 1.95-1.93 (m, 1H), 1.49-1.46 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][N:37]([CH3:46])[C:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39]>>[CH3:36][N:37]([CH3:46])[C:38]([N:40]1[CH2:41][CH2:42][N:43]([C:20]([N:11]2[C@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C@@:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH3:35])[N:9]=[C:10]2[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH:32]([CH3:33])[CH3:34])=[O:21])[CH2:44][CH2:45]1)=[O:39]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(C(=O)N(C)C)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazine-1-carboxylic acid dimethylamide (Aldrich) to give the title compound. LC-MS: 652.2 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH2:8]([N:10]([CH2:13][CH3:14])[CH:11]=[O:12])[CH3:9]>C(N(CC)CC)C>[CH2:8]([N:10]([CH2:13][CH3:14])[C:11](=[O:12])[C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])=[O:4])[CH3:9]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCN(C=O)CC
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)C(=O)C(Cl)(Cl)Cl

Procedure:
The procedure of Example 1 was followed using 27g (0.15 mole) of trichloracetyl chloride and 45g (0.45 mole) of diethyl-formamide and 15g (0.15 mole) of triethylamine. Obtained following distillation was 14g 0f pure N,N-diethyl 3,3,3-trichloropyruvamide as a clear, colorless liquid: Bp 94°-96° (0.15 mm); ir (λmax, film) 5.7 (s), 6.1 (s), 6.8 (s), 6.9 (s), 9.4 (s), 12.1 (s) microns.
Reaction SMILES: [NH2:1][CH:2]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][N:4]([CH2:10][CH:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].[C:27](=[O:45])([O:38][CH2:39][C:40]1[S:44][CH:43]=[N:42][CH:41]=1)OC1C=CC([N+]([O-])=O)=CC=1>C(OCC)(=O)C>[CH3:7][C:6]([CH3:9])([CH3:8])[CH2:5][N:4]([CH2:3][C@H:2]([NH:1][C:27]([O:38][CH2:39][C:40]1[S:44][CH:43]=[N:42][CH:41]=1)=[O:45])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:10][C@H:11]([NH:19][C:27]([O:38][CH2:39][C:40]1[S:44][CH:43]=[N:42][CH:41]=1)=[O:45])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)CN(CC(N)Cc1ccccc1)CC(N)Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)CN(C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The product from Example 7C (0.34 g) was treated with 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate [prepared from 4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate hydrochloride salt (0.63 g, 1.99 mmol) by extraction with aqueous NaHCO3] in ethyl acetate (10 mL). The mixture was stirred at 60° C. under a N2 atmosphere overnight. The mixture was diluted with ethyl acetate (50 mL), extracted with 10% aqueous K2CO3 (3×20 mL), washed with water (20 mL) and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (ethyl acetate:hexanes, 2:1) to provide the two title compounds combined and a third separated product. The mixture of (S,S) and (R,R) enantiomers were obtained as a colorless amorphous solid. Rf=0.32 (ethyl acetate); 1H NMR (CDCl3) δ 8.73 (s, 2H), 7.75 (s, 2H), 7.30-7.11 (m, 10H), 5.53 (br s, 2H), 5.23 (d, J=12.9 Hz, 2H), 5.16 (d, J=13.2 Hz, 2H), 3.91 (m, 2H), 2.90-2.79 (m, 2H), 2.68 (dd, J=7.5, 13.6 Hz, 2H), 2.42 (t, J=12 Hz, 2H), 2.26 (dd, J=1, 12 Hz, 2H), 1.99 (d, J=13.9 Hz, 1H), 1.87 (d, J=14.2 Hz, 1H), 0.71 (s, 9H); MS (ESI+) m/z 636 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])=[CH:18][CH:17]=2)[N:4]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:15][C@H:10]1[CH2:11][O:12][CH2:13][CH2:14][N:9]1[C:7]1[CH:8]=[C:3]([CH2:2][O:1][S:40]([CH3:39])(=[O:42])=[O:41])[N:4]=[C:5]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:24])=[CH:20][CH:21]=2)[N:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1-[4-[4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-phenyl-urea (388 mg) was dissolved in DCM (15 mL) and triethylamine (0.194 mL) and the solution was cooled to 0° C. Methanesulfonyl chloride (0.108 mL) was added and the reaction stirred for 90 mins at 0° C. The reaction mixture was concentrated in vacuo and partitioned between DCM (20 mL) and water (10 mL). The organic phase was washed with brine (10 mL), dried (MgSO4) and concentrated in vacuo to give the desired compound (273 mg) as a solid.
Reaction SMILES: N1C=CC=C(C[O:8][CH2:9][CH2:10][NH2:11])C=1.[Na].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](CO)[CH:14]=1.ClCC#N>CN(C)C=O>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:8][CH2:9][C:10]#[N:11])[CH:14]=1
Reactant: NCCOCc1cccnc1
Reactant: OCc1cccnc1
Agent: N#CCCl
Agent: [Na]
Solvent: CN(C)C=O
Product: N#CCOc1cccnc1

Procedure:
The starting amine, (3-pyridinyl)methyloxyethylamine, was prepared by the following procedure: reaction of the sodium salt of 3-pyridinylmethanol and chloracetonitrile in dimethylformamide gave 2-(3-pyridinyloxy)acetonitrile, which, upon reduction with borane in tetrahydroduran solution, gave the desired amine.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl:10][S:11](O)(=[O:13])=[O:12].[Cl-].[NH4+]>C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:11]([Cl:10])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 11.6 ml of isopropylbenzene in 100 ml of methylene chloride was added at 5° C. within 30 minutes to 18.3 ml of chlorosulfonic acid. The reaction mixture was stirred at 5° C. for 1 hour, poured on to 500 ml of ice-water and, after stirring for 5 minutes, treated with 100 g of ammonium chloride. After extraction with methylene chloride (1×800 ml, 1×500 ml) the organic phases were combined, dried with magnesium sulphate and the solvent was removed on a rotary evaporator. 12.3 g of 4-isopropyl-benzenesulfonyl chloride separated as a reddish oil, which was used without further purification.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].Cl[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(N(CC)CC)C>[C:1]([O:6][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: CCOC(=O)CCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCC(=O)OCC
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a flask equipped with a stirrer was added 172.8 parts methacrylic acid and 202 parts triethylamine. This mixture was allowed to stir for 5 min. To this was added 245 parts ethyl chloroacetate. The reactants were heated to 60° C. and the exotherm carried the temperature up to 100° C. The temperature was kept between 90°-97° C. by cooling for 1/2 hour after which heat was supplied to hold the temperature at 90° for 1 hour. The mixture was cooled and filtered. This crude product was distilled at 65.5°-66° C. at 0.1 cm to yield 318 g of pure EMA as confirmed by chemical analysis.
Reaction SMILES: Br[CH2:2][C:3]1[CH:29]=[CH:28][C:6]2[N:7]3[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:8]3[C:9]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[O:10][C:5]=2[CH:4]=1.[C:30]([O-:33])(=[O:32])[CH3:31].[K+]>CN(C=O)C.[NH4+].[Cl-]>[C:30]([O:33][CH2:2][C:3]1[CH:29]=[CH:28][C:6]2[N:7]3[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:8]3[C:9]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[O:10][C:5]=2[CH:4]=1)(=[O:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(CBr)ccc1-n1c(C#N)ccc12
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)c1ccc(C#N)n1-2
Temperature: 80 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
tert-Butyl 7′-(bromomethyl)-1′-cyano-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (33.0 mg, 0.0720 mmol) and potassium acetate (35.3 mg, 0.360 mmol) were combined in DMF (0.5 mL) and the mixture was stirred at 80° C. for 18 hours. The mixture was taken up in NH4Cl (10 mL) and was extracted with CH2Cl2 (10 mL). Solvent was removed under reduced pressure and the residue was purified by column chromatography (0-10% EtOAc/CH2Cl2) to obtain tert-butyl 7′-(acetoxymethyl)-1′-cyano-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (19.5 mg, 62%) as a clear oil. ESI-MS m/z calc. 437.2. found 438.5 (M+1)+; Retention time 2.05 minutes (3 min run). tert-Butyl 7′-(acetoxymethyl)-1′-cyano-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate was dissolved in CH2Cl2 (10 mL) before TFA (5.0 mL, 65 mmol) was added. The solvent was removed under reduced pressure to give (1′-cyanospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-yl)methyl acetate (15 mg, 62%). ESI-MS m/z calc. 337.1. found 338.3 (M+1)+; Retention time 1.16 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[N:23]=[N:22][C:21]([C:24]([OH:31])([CH2:29][CH3:30])[C:25]([F:28])([F:27])[F:26])=[N:20]4)=[CH:15][CH:16]=3)[N:11]=[C:10]([C:32]#[N:33])[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:35].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[NH4+].[Cl-]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[N:23]=[N:22][C:21]([C:24]([OH:31])([CH2:29][CH3:30])[C:25]([F:28])([F:27])[F:26])=[N:20]4)=[CH:15][CH:16]=3)[N:11]=[C:10]([C:32]([NH2:33])=[O:35])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCC(O)(c1nnn(Cc2ccc3c(-c4ccc(F)cc4)cc(C#N)nc3c2)n1)C(F)(F)F
Agent: OO
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Product: CCC(O)(c1nnn(Cc2ccc3c(-c4ccc(F)cc4)cc(C(N)=O)nc3c2)n1)C(F)(F)F
Temperature: 50 °C

Procedure:
4-(4-Fluorophenyl)-7-{[5-(1,1,1-trifluoro-2-hydroxybutan-2-yl)-2H-tetrazol-2-yl]methyl}quinoline-2-carbonitrile (3-4, 14 mg, 0.031 mmol, 1.0 equiv) was dissolved in acetone (0.5 mL)/water (0.25 mL) and sodium percarbonate (48 mg, 0.15 mmol, 5.0 equiv) was added. The resulting mixture was heated to 50° C. for two hours. The mixture was cooled and poured over aqueous NH4Cl (1 mL), extracted with ethyl acetate (3×5 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by flash column chromatography (SiO2, 12 g ISCO column, 0-100% EtOAc/hexanes) to give 4-(4-fluorophenyl)-7-{[5-(1,1,1-trifluoro-2-hydroxybutan-2-yl)-2H-tetrazol-2-yl]methyl}quinoline-2-carboxamide (3-6) as a white solid. 1H NMR (3-6) (500 MHz, CDCl3): δ 8.28 (s, 1H); 8.17 (s, 1H); 8.06 (s, 1H); 7.99 (d, J=8.7 Hz, 1H); 7.55-7.44 (m, 3H); 6.05 (s, 2H); 5.84 (s, 1H); 3.92 (s, 1H); 2.33 (dt, J=14.4, 7.4 Hz, 1H); 2.20 (dt, J=14.3, 7.2 Hz, 1H); 0.84 (t, J=7.4 Hz, 3H). LRMS m/z (M+H) 474.9 found, 475.1 required. 1H NMR (3-7) (500 MHz, CD3OD): δ 8.12 (s, 1H); 8.08 (s, 1H); 7.96 (d, J=8.8 Hz, 1H); 7.64-7.55 (m, 3H); 7.34-7.29 (m, 2H); 6.25 (d, J=15.1 Hz, 1H); 6.15 (d, J=15.1 Hz, 1H); 2.57 (dd, J=14.4, 7.3 Hz, 1H); 2.13 (dq, J=14.4, 7.2 Hz, 1H); 0.78 (t, J=7.4 Hz, 3H). LRMS m/z (M+H)+ 474.7 found, 475.1 required.
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH2:15]([O:17][CH:18]([N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1)[CH3:19])[CH3:16].O>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[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>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:23]2[CH:22]=[N:21][N:20]([CH:18]([O:17][CH2:15][CH3:16])[CH3:19])[CH:24]=2)[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=1
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
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: O
Solvent: Cc1ccccc1
Product: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)=O)c2OC)cn1
Temperature: 100 °C
Yield: 46.7 %

Procedure:
A biphasic solution of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.40 g, 1.4 mmol) and 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.46 g, 1.7 mmol) in toluene (4 mL) and 10% sodium carbonate in water (3.0 mL, 2.9 mmol) was degassed under N2. Tetrakis(triphenylphosphine)palladium(0) (83 mg, 0.072 mmol) was added and the mixture was bubbled with N2 for 5 min and heated at 100° C. overnight. The resulting solution was cooled to room temperature and the organic layer was purified on silica gel (eluting with 0-40% of ethyl acetate in hexanes) to give the desired product (0.22 g, 45%). LCMS calculated for C17H22ClN2O3 (M+H)+: m/z=337.1. found: 337.1
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)=[N:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C(N(CC)CC)C.O>C(O)(=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)=[N:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc3ncn(Cc4ccccc4)c3c(=O)[nH]2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1[nH]c(-c2ccc(O)cc2)nc2ncn(Cc3ccccc3)c12
Temperature: 100 °C
Reaction time: 58.5 h
Yield: 39.2 %

Procedure:
1.52 g (4.57 mmol) of 7-benzyl-2-(4-methoxyphenyl) hypoxanthine prepared by the same method as in Example 14 was dissolved in 25 ml of acetic acid. After the addition of 3 ml of hydrobromic acid, the mixture was stirred for 58.5 hours at 100° C. After cooling, 10 ml of triethylamine and 100 ml of distilled water were added to the reaction mixture. The crystals produced were separated by filtration and washed with distilled water and ethanol to obtain 0.57 g of 7-benzyl-2-(4-hydroxyphenyl)hypoxanthine (yield 39%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([C:6]([OH:8])=[O:7])[NH2:5].[C:9]([N:12]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C@@H:13]([C:15]([OH:17])=[O:16])[CH3:14])(=[O:11])[CH3:10]>C(O)C>[C:9]([N:12]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C@@H:13]([C:15]([OH:17])=[O:16])[CH3:14])(=[O:11])[CH3:10].[CH3:1][O:2][CH2:3][C@H:4]([C:6]([OH:8])=[O:7])[NH2:5]
Reactant: COCC(N)C(=O)O
Agent: CC(=O)N(c1cccc2ccccc12)[C@H](C)C(=O)O
Solvent: CCO
Product: COC[C@@H](N)C(=O)O
Temperature: 50 °C
Yield: 128 %

Procedure:
Into a 250 mL round-bottomed flask equipped with a stirrer, reflux condenser and thermometer was added O-methyl-D,L-serine (5 g) in ethanol (150 mL). N-Acetyl-(R)-naphthylalanine (10.80 g) was added in one portion and the mixture heated to 50° C. overnight. The suspension was cooled to room temperature and filtered, and the solid was rinsed with ethanol (5 mL) and dried at 40° C. under vacuum for 3 h. Crude N-acetyl-(R)-naphthylalanine salt of O-methyl-D-serine (6.4 g, 40.5%) was obtained as a white solid with a chiral purity >90%. A portion (5 g) of this solid was suspended in ethanol (30 mL), heated to 50° C. for 4 h, cooled to room temperature and filtered. The resulting solid was rinsed with ethanol (5 mL) and dried at 40° C. under vacuum for 3 h. Pure N-acetyl-(R)-naphthylalanine salt of O-methyl-D-serine (4.6 g, 91.5%) was obtained as a white solid with a chiral purity >95%. Regeneration of the title compound could be effected by adjustment of the pH to 1-2 by treatment with HCl, followed by extraction into an organic solvent and subsequent adjustment of the pH to ˜7 with NaOH.
Reaction SMILES: [CH2:1]([C@@:4]1([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[Li+].[OH-]>>[CH2:1]([C@@:4]1([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(C(=O)OC)cc2)C(=O)O1
Agent: [Li+]
Agent: [OH-]
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(C(=O)O)cc2)C(=O)O1

Procedure:
methyl 4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoate was treated with LiOH to afford 4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoic acid.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[CH2:12]([N:3]([CH2:1][CH3:2])[CH:4]=[C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:14](=[O:16])[CH3:15])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(C=Cc1ccccc1)CC
Product: CCN(C=C(C(C)=O)c1ccccc1)CC

Procedure:
A solution of diethylstyrylamine (1.75 g) in acetic anhydride (5 ml) was heated under reflux for an hour and then distilled under vacuum (0.02 mm) in a bulb-to-bulb apparatus (oven 150° C.). The product was crystallised from ether-petroleum spirit (40°-60° C.) at low temperature, giving crystals of the title product which melted around room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:25]3[C:26]([CH3:34])=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=34)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14](COCC[Si](C)(C)C)[N:13]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:25]3[C:26]([CH3:34])=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:35][CH:36]=1
Reactant: Cc1nn2ccccc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nn2ccccc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
To a solution of 3-[4-(4-chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine (0.182 g, 0.339 mmol) in dichloromethane (3.3 mL) at room temperature was added trifluoroacetic acid (5.1 mL, 66 mmol). The mixture was then stirred at room temperature for 3 hours. The solvent was evaporated and the excess trifluoroacetic acid was removed by azeotroping with toluene. The crude product was purified by column chromatography (SiO2, elution with hexane to 100% ethyl acetate) to yield the title compound (0.0884 g, 64%). LCMS: (FA) ES+, 407. 1H NMR (400 MHz, d6-DMSO) δ: 8.76-8.70 (m, 2H), 8.28-8.22 (m, 1H), 7.53-7.46 (m, 1H), 7.45-7.40 (m, 2H), 7.37-7.31 (m, 2H), 7.07-7.01 (m, 1H), 5.55-5.50 (m, 1H), 4.64 (s, 2H), 2.65 (s, 3H).