Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>ClCCl>[CH3:1][N:2]([CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18])[C:21](=[O:22])[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Solvent: ClCCl
Product: CN(CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-(2-(Dimethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (1.16 g, 4.40 mmol) was dissolved in dichloromethane (20 mL) in a round bottom flask at room temperature. The solution was cooled to 0° C. and phenyl chloroformate (0.829 mL, 6.61 mmol) was added slowly to avoid an excessive exotherm. The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was then diluted with dichloromethane and quenched with dilute NaOH (˜0.5 M). The aqueous phase was extracted with dichloromethane (3×) and the combined organics were dried over sodium sulfate, filtered and concentrated. The resulting residue was then chromatographed in 50-100% ethyl acetate in hexanes. Yield: 1.29 g, 78%. 1H NMR (CDCl3) δ 8.13 (dd, 1H, J=9.0, 2.7 Hz), 8.05 (t, 1H, J=3.3 Hz), 7.41 (m, 3H); 7.23 (m, 1H); 7.06 (m, 2H), 4.23 (m, 2H), 3.70 and 3.58 (2t, 2H, J=7.2 Hz), 3.19 and 3.09 (2s, 3H), 3.00 (t, 2H, J=7.4 Hz), 2.72 (t, 2H, J=7.4 Hz); ESI-MS (m/z, %): 392 (MNa+, 100), 370 (MH+, 28).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[C:21]3=[N:22][C:23](Cl)=[CH:24][C:25](=[O:26])[N:20]3[CH2:19][C@@:18]2([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:34]12[O:41][CH:38]([CH2:39][CH2:40]1)[CH2:37][NH:36][CH2:35]2.C(N(CC)CC)C>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[C:21]3=[N:22][C:23]([N:36]4[CH2:35][CH:34]5[O:41][CH:38]([CH2:39][CH2:40]5)[CH2:37]4)=[CH:24][C:25](=[O:26])[N:20]3[CH2:19][C@@:18]2([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CC2CNCC1O2
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(Cl)cc2=O)N1CCc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CC4CCC(C3)O4)cc2=O)N1CCc1ccc(OCc2ccccc2)cc1

Procedure:
1.40 g (3.02 mmol) of (S)-1-[2-(4-benzyloxyphenyl)ethyl]-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one, 903 mg (6.04 mmol) of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride and 763 mg (7.54 mmol) of triethylamine were used in the reaction. After purification by chromatography on silica gel (eluent A/B: 2/8 heptane/EtOAc), 1.2 g of (S)-1-[2-(4-benzyloxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[N:8](S(C3C=CC=CC=3)(=O)=O)[C:4]=2[N:5]=[CH:6][N:7]=1.CC([O-])(C)C.[K+].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cc2c(Cl)ncnc2n1S(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc2c(Cl)ncnc2[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the solution of 4-chloro-6-methyl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (10 g, 32.5 mmol, 1.0 eq) in THF (400 mL), t-BuOK (18.23 g, 163.0 mmol, 5 eq) was added and stirred at RT for 12 h. Sat. NaHCO3 (50 mL) was added and extracted with EtOAc. The organic layers were separated, dried and concentrated to afford 4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine as a brown solid (2.7 g, 50% in yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([F:9])[CH:3]=1.[C:10]([CH2:13]C(=O)C)(=[O:12])[CH3:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>CS(C)=O.[Cu]I>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:11][C:10](=[O:12])[CH3:13])=[CH:3][C:4]=1[F:9]
Reactant: CC(=O)CC(C)=O
Reactant: Fc1cc(Br)ccc1Cl
Agent: [Cu]I
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CC(=O)Cc1ccc(Cl)c(F)c1
Temperature: 110 °C
Reaction time: 23 h
Yield: 48.3 %

Procedure:
To a mixture of 4-bromo-1-chloro-2-fluorobenzene (20.90 g, 100.0 mmol) and acetylacetone (30 mL, 300.0 mmol) in DMSO (100 mL) were added tripotassium phosphate (63.70 g, 300.0 mmol) and CuI (3.00 g, 15.80 mmol) under N2 and the mixture was stirred at 110° C. for 23 h. The mixture was cooled to rt and hydrochloric acid (300 mL, 2 M) was added. The resulting mixture was extracted with EtOAc (100 mL×3) and the combined organic phases were washed with brine (100 mL×2), dried over anhydrous Na2SO4 (50 g), and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as yellow liquid (9.02 g, 48.2%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([NH2:10])=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]#[N:10]
Reactant: Cc1nc(C(N)=O)c(Br)s1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(C#N)c(Br)s1

Procedure:
5-Bromo-2-methyl-thiazole-4-carboxylic acid amide (11.3 g, 51.1 mmol) was dissolved in 150 ml dichloromethane and triethylamine (14.2 ml, 102.2 mmol) was added. Trifluoroaceticanhydride (14.3 ml, 102.2 mmol) was added dropwise at 0° C. and the mixture stirred without cooling for 2 hrs. The reaction mixture was quenched with saturated NaHCO3-solution and extracted with ethyl acetate. The organic extract was washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10->20:80 gradient). The desired compound was obtained as a light yellow solid (6.4 g, 62%), MS: m/e=204.0 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[CH:10]=1.CN(C=O)C.[CH2:21]([O:23][C:24](=[O:41])[CH2:25][CH:26]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH3:22]>C(OCC)(=O)C>[I:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH:26]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:41])=[CH:28][CH:29]=1
Reactant: BrCc1cccc(I)c1
Reactant: CCOC(=O)CC(c1ccc(O)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(c1ccc(F)cc1)c1ccc(OCc2cccc(I)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cs2CO3 (4.89 g 15 mmol) and 1-(bromomethyl)-3-iodobenzene (4.45 g, 15 mmol) were added successively to a dry DMF (20 mL) solution of 45.2 (2.88 g, 10 mmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate (200 mL), washed with water (100 mL×2) and brine (100 mL), and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified by flash chromatography to give compound 47.1 as a colorless oil. MS ESI (pos.) m/e: 505.0 (1+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]4[CH2:28][NH:27][CH2:26][CH2:25][N:24]4[CH:29]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:30](N(CC)CC)C.C=O.O.C([BH3-])#N.[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]4[CH2:28][N:27]([CH3:30])[CH2:26][CH2:25][N:24]4[CH:29]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn2c(n1)CNCC2
Reactant: CCN(CC)CC
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn2c(n1)CN(C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxamide (23 mg, 0.056 mmol) was dissolved in methanol (2 ml). Triethylamine (0.078 ml, 0.561 mmol), formaldehyde, 37 w-% solution in water (0.067 ml, 0.561 mmol) and sodium cyanoborohydride (35.3 mg, 0.561 mmol) were added in the solution. The resulting mixture was stirred at RT overnight. The reaction mixture was diluted with DCM, extracted with NaHCO3 solution, combined organic phases were dried with Na2SO4, filtered and evaporated. The product was purified with LC/MS-trigger. Yield 33.6%. 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 2.55 (s, 3H), 2.90 (t, 2H), 3.70 (d, 2H), 4.08 (t, 2H), 4.32 (dd, 1H), 4.40 (dd, 1H), 4.54-4.65 (m, 1H), 6.61 (d, 1H), 7.48 (s, 1H), 7.50 (d, 1H), 7.67 (d, 1H), 7.71 (d, 1H), 7.81 (dd, 1H), 8.02 (d, 1H), 8.06 (s, 1H).
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.[F:66][C:67]1([F:120])[C:79]2[CH:78]=[C:77]([C:80]3[CH:81]=[CH:82][C:83]4[N:87]=[C:86]([C@@H:88]5[C@H:93]6[CH2:94][C@@H:90]([CH2:91][CH2:92]6)[N:89]5[C:95](=[O:108])[C@@H:96]([NH:103][C:104](=[O:107])[O:105][CH3:106])[CH:97]5[CH2:102][CH2:101][O:100][CH2:99][CH2:98]5)[NH:85][C:84]=4[CH:109]=3)[CH:76]=[CH:75][C:74]=2[C:73]2[C:68]1=[CH:69][C:70]([C:110]1[NH:114][C:113]([C@@H:115]3[CH2:119][CH2:118][CH2:117][NH:116]3)=[N:112][CH:111]=1)=[CH:71][CH:72]=2.Cl>>[CH3:106][O:105][C:104](=[O:107])[NH:103][C@@H:96]([CH:97]1[CH2:98][CH2:99][O:100][CH2:101][CH2:102]1)[C:95]([N:89]1[C@H:88]([C:86]2[NH:85][C:84]3[CH:109]=[C:80]([C:77]4[CH:76]=[CH:75][C:74]5[C:73]6[C:68](=[CH:69][C:70]([C:110]7[NH:114][C:113]([C@@H:115]8[CH2:119][CH2:118][CH2:117][N:116]8[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]8[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=8)=[N:112][CH:111]=7)=[CH:71][CH:72]=6)[C:67]([F:66])([F:120])[C:79]=5[CH:78]=4)[CH:81]=[CH:82][C:83]=3[N:87]=2)[C@H:93]2[CH2:94][C@H:90]1[CH2:91][CH2:92]2)=[O:108]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@H](C2)[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6)[nH]5)ccc3-4)cc2[nH]1)C1CCOCC1
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@H](C2)[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)ccc3-4)cc2[nH]1)C1CCOCC1

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-2-((1R,3S,4R)-3-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3× HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 939.91 [M+H]+. (102 mg, 57%).
Reaction SMILES: P([O-])(O)(O)=O.[K+].P([O-])([O-])(O)=O.[K+].[K+].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[F:70][C:71]([F:81])([F:80])[C:72]([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)=[O:73].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[F:70][C:71]([F:80])([F:81])[C@H:72]([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[OH:73]
Reactant: O=C(c1ccccc1)C(F)(F)F
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](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C([O-])[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O[C@@H](c1ccccc1)C(F)(F)F

Procedure:
To 20 ml of 50 mM potassium dihydrogenphosphate-dipotassium hydrogenphosphate buffer (pH 7.0) are added 1 g of the washed bacterial bodies prepared in Example 7, 12 mg of NAD+ and 2.5 g of glucose. After adding 240 mg of 2,2,2-trifluoroacetophenone to this mixture, the pH of this mixture is adjusted to 7.0 with a 15% aqueous sodium carbonate solution. The reaction is executed by stirring thus obtained mixture (reaction mixture) at 30° C. for 4 hours. After completion of the reaction, 25 ml of ethyl acetate is poured into the reaction mixture and stirred, followed by centrifugal separation for separately collecting the organic phase and the aqueous phase. To the collected aqueous phase is added 25 ml of ethyl acetate again, and the similar operation is repeated. After concentrating the combined organic phase obtained in such a manner, the concentrate is dissolved in 30 ml of chloroform and dried using anhydrous Na2SO4. After drying, chloroform is distilled off to obtain (S)-2,2,2-trifluoro-1-phenylethanol.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:21])=[C:7]([CH3:20])[C:8]2[O:13][C:12]([CH3:17])([C:14]([OH:16])=O)[CH2:11][CH2:10][C:9]=2[C:18]=1[CH3:19])(=[O:3])[CH3:2].[C:22]([N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1)(N1C=CN=C1)=O.N1CCNCC1>ClC(Cl)C>[C:1]([O:4][C:5]1[C:6]([CH3:21])=[C:7]([CH3:20])[C:8]2[O:13][C:12]([C:14]([N:29]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:22]3)=[O:16])([CH3:17])[CH2:11][CH2:10][C:9]=2[C:18]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)O)O2
Agent: C1CNCCN1
Solvent: CC(Cl)Cl
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)N1CCNCC1)O2
Reaction time: 1 h

Procedure:
2.7 g (0. 009 mol) of 3,4-dihydro-6-acetoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid are dissolved in 200 cm3 of anhydrous dichloroethane. 1 eq of carbonyldiimidazole (0.009 mol), i.e. 1.5 g, is added. The mixture is left to stir for 1 h and then 7.5 g of piperazine (0.009 mol) dissolved in 200 cm3 of dichlorcethane are added. The oil obtained after evaporation is purified on a silica column by eluting with a CH2Cl2 /ethanol/NH4OH (88/10/2) mixture and crystallized from isopropyl ether.
Reaction SMILES: Cl[C:2]1[C:10]([CH:11]2[CH2:13][CH2:12]2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[N:19][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:11]1([C:10]2[C:2]([C:17]3[CH:18]=[N:19][CH:20]=[C:15]([F:14])[CH:16]=3)=[N:3][N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=23)[CH2:13][CH2:12]1
Reactant: OB(O)c1cncc(F)c1
Reactant: Clc1nn2ccccc2c1C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: Fc1cncc(-c2nn3ccccc3c2C2CC2)c1
Temperature: 100 °C

Procedure:
A solution of 2-chloro-3-cyclopropylpyrazolo-[1,5-a]pyridine (27-4; 0.2 g, 1.042 mmol), (5-fluoropyridin-3-yl)boronic acid (0.147 g, 1.042 mmol), and potassium phosphate tribasic (0.66 g, 3.126 mmol) in tetrahydrofuran (15 mL) was degassed for 10 min. Next 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.085 g, 0.208 mmol) and palladium acetate (0.023 g, 0.104 mmol) were added and heated in a sealed tube at 100° C. for 18 h. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. Purification of the resulting residue by prep HPLC provided 3-cyclopropyl-2-(5-fluoropyridin-3-yl) pyrazolo[1,5-a]pyridine. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1 H), 8.67-8.65 (d, J=8.0 Hz, 1 H), 8.62-8.61 (d, J=2.4 Hz, 1 H), 8.19-8.17 (d, J=8.0 Hz, 1 H), 7.74-7.72 (d, J=8.0 Hz, 1 H), 7.26-7.22 (t, J=8.0 Hz, 1 H), 6.93-6.90 (t, J=8.0 Hz, 1 H), 2.10-2.05 (m, 1 H), 1.02-1.01 (d, J=4.0 Hz, 2 H), 0.43-0.42 (d, J=4.0 Hz, 2 H), MS (M+1): 254.1.
Reaction SMILES: [C:1]([O:6][CH2:7]Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([F:39])=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]([NH:30][C:31]([C:33]3[N:34]=[N:35][N:36]([OH:38])[CH:37]=3)=[O:32])[CH2:24][C@@H:25]([OH:29])[C:26]([OH:28])=[O:27])=[CH:18][CH:17]=2)[CH:15]=1.CC(C)=O.CCN(CC)CC>>[C:1]([O:6][CH2:7][O:38][N:36]1[CH:37]=[C:33]([C:31]([NH:30][C@H:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([C:14]3[CH:15]=[C:10]([Cl:9])[CH:11]=[CH:12][C:13]=3[F:39])=[CH:17][CH:18]=2)[CH2:24][C@@H:25]([OH:29])[C:26]([OH:28])=[O:27])=[O:32])[N:34]=[N:35]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCCl
Reactant: O=C(N[C@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCC(=O)OCOn1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)nn1
Temperature: 65 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
Chloromethyl butyrate (13.7 mg, 100 μmol) was added to a solution of (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-[(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid (30.0 mg, 66.8 μmol) in acetone (0.5 mL, 6.8 mmol). Et3N (18.6 μL, 134 μmol) was added and the resulting mixture was stirred at 65° C. for 2 hours. The mixture was then concentrated in vacuo to yield a yellow liquid. The crude liquid was purified (preparative scale C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (6.0 mg). MS m/z [M+H]+ calc'd for C25H26ClFN4O7, 549.15. found 549.1.
Reaction SMILES: Cl.C[N:3]([CH2:10][CH2:11][Cl:12])[C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[C:13](=O)(O)[O-].[Na+]>O>[ClH:12].[CH3:13][O:9][C:7]([CH:4]1[CH2:5][S:6][CH2:11][CH2:10][NH:3]1)=[O:8]
Reactant: CN(CCCl)[C@@H](CS)C(=O)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)C1CSCCN1
Temperature: 25 °C
Reaction time: 120 h
Yield: 53 %

Procedure:
20 g (0.085 mol) methyl 2-chloroethyl cysteine hydrochloride was dissolved with 200 ml water, and a solution of 7.2 g (0.085 mol) sodium bicarbonate dissolved in 120 ml water was added dropwise to the above-obtained solution under ice bath condition, and then the mixed solution was allowed to react by keeping a constant temperature in the bath ice for 1 hour. The obtained reaction product was extracted with ethyl acetate (100 ml×3), and the resulting ester layers were combined, and dried with anhydrous sodium sulfate for 4 hours. The solvent was removed by evaporation under reduced pressure. The resulting residue was dissolved with 400 ml anhydrous methanol, and reacted with stirring at room temperature for 5 days, followed by removing solvent by evaporation under reduced pressure. The resulting residue was recrystallized with anhydrous methanol/ethyl acetate, obtaining 8.9 g of a white crystal, yield 49.2%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[N+:20]([O-])=O)[CH:5]=1>[OH-].[Na+].[Zn]>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]2=[N:12][N:11]([C:6]3[CH:5]=[C:4]([CH2:3][CH2:2][OH:1])[CH:9]=[CH:8][C:7]=3[OH:10])[N:20]=[C:14]2[CH:15]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1N=Nc1cc(CCO)ccc1O
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Product: OCCc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Yield: 77.1 %

Procedure:
5.91 g (18 mmols) of crude 4-(2-hydroxyethyl)-2-[(4-chloro-2-nitrophenyl)azo]phenol synthesized in Example 4 was dissolved in 18 ml of aqueous solution of 2N sodium hydroxide. Subsequently, 9 ml of previously prepared aqueous solution of 25% sodium hydroxide and 5.4 g (83 mmols) of zinc powder were simultaneously added over a period of about 3 hours. The subsequent treatment was carried out in the same manner as in Example 6, giving 4.02 g of 2-(5-chloro-2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)phenol as pale yellow crystals (yield 68%, purity 88%).
Reaction SMILES: ClC1C=CC(CC2N(C)C(C(C)C(O)=O)=CC=2)=CC=1.[Cl:20][C:21]1[CH:41]=[CH:40][C:24]([C:25]([C:27]2[N:31]([CH3:32])[C:30]([CH:33]([CH3:39])[C:34]([O:36]CC)=[O:35])=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1.[OH-].[Na+].C(O)C>O>[Cl:20][C:21]1[CH:41]=[CH:40][C:24]([C:25]([C:27]2[N:31]([CH3:32])[C:30]([CH:33]([CH3:39])[C:34]([OH:36])=[O:35])=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(C)c1ccc(C(=O)c2ccc(Cl)cc2)n1C
Agent: CC(C(=O)O)c1ccc(Cc2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
5-(p-Chlorobenzyl)-α-methyl-1-methylpyrrole-2-acetic acid: A solution of 4.05 g. (0.0126 mole) of ethyl 5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole- 2-acetate, 15 ml. of 1N sodium hydroxide solution and 2 ml. of ethanol is refluxed for 30 minutes. The solution is cooled, diluted with water and filtered. The filtrate is acidified with dilute hydrochloric acid. The precipitated solid is collected and recrystallized from methanol-water to give a white crystalline solid, 5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid, m.p. 135°-136°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[CH2:22][C:21](=[O:24])[CH2:20][CH2:19]4)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C1C=CC(C2OC(NC3C=CC=C4C=3CC(=O)CC4)=NC=2)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2cccc(Nc3ncc(-c4ccc(Br)cc4)o3)c2C1
Agent: O=C1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: OC1CCc2cccc(Nc3ncc(-c4ccc(Br)cc4)o3)c2C1

Procedure:
The title compound was prepared using the procedure as described in Example 2, substituting the product of Example 8C for the product of Example 1I. 1H NMR (DMSO-d6) δ9.17 (s, 1H), 7.43-7.57 (m, 6H), 7.10 (t, 1H, J=7.3 Hz), 6.81 (d, 1H, J=6.8 Hz), 4.80 (d, 1H, J=3.9 Hz), 3.90 (m, 1H), 2.68-2.96 (m, 4H), 1.82 (m, 1H), 1.60 (m, 1H); MS (ESI+) m/z 385/387 (M+H, 79Br/81Br).