Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1)[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([C:24](F)(F)F)[CH:21]=[CH:20][C:19]=1[C:28]#[C:29][C:30](O)=[O:31]>ClCCl.CO>[CH2:15]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][NH:14][C:30](=[O:31])[C:29]#[C:28][C:19]2[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=2[Cl:17])=[CH:11][CH:12]=1)[CH3:16]
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCOc1ccc(CN)cc1
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc(CNC(=O)C#Cc2ccc(C)cc2Cl)cc1

Procedure:
Prepared analogously to Example 2.3.f. from [4-(2-diethylaminoethoxy)phenyl]methylamine and (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 60 mg (22% of theory); melting point: 135° C.-138° C.; C23H24ClF3N2O2 (M=452.90); calc.: molecular ion peak (M+H)+: 453/455; found: molecular ion peak (M+H)+: 453/455; Rf value: 0.4 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH3:9])[CH:3]=1.[CH3:10][S:11]([OH:13])=[O:12].[Na]>[Cu]I.CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:11]([CH3:10])(=[O:13])=[O:12])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1I
Reactant: CS(=O)O
Agent: [Cu]I
Agent: [Na]
Solvent: CS(C)=O
Product: Cc1cc(Br)ccc1S(C)(=O)=O
Temperature: 125 °C
Reaction time: 3 h

Procedure:
A mixture of 4-bromo-1-iodo-2-methylbenzene (240 μL, 1.68 mmol, Aldrich), Copper(I) iodide (353 mg, 1.85 mmol, Alfa Aesar), Methanesulfinic acid, sodium salt (688 mg, 6.74 mmol, Alfa Aesar) and DMSO (7.2 mL) was purged with Argon and then heated under microwave condition at 125° C. for 20 min. The resulting mixture was stirred at 100° C. for 3 h and then cooled to room temperature. The reaction mixture was diluted with H2O and extracted with EtOAc (2×). The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated in vacuo to a white solid. The solid was purified by flash chromatography (SiO2, 0-50% EtOAc in hexanes) to yield 270 mg of desired product as a white solid. MS (ESI) 249 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([O:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1)[CH3:6])C.[OH-].[Na+].Cl>O.C(O)C>[F:15][C:14]([F:16])([F:17])[C:12]1[CH:13]=[C:8]([CH:9]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:11]=1)[O:7][CH:5]([CH3:6])[C:4]([OH:22])=[O:3]
Reactant: CCOC(=O)C(C)Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)O
Temperature: 5 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A stirred charge containing 0.05 mole of ethyl-2-[3,5-bis-(trifluoromethyl)phenoxy]propionate, 150 ml of ethyl alcohol, 8 g (0.1 mole) of 50% aqueous solution of sodium hydroxide and 25 ml of water was heated at reflux for 5 hours and at 25°-30° C. for 18 hours. After cooling to 5° C. 800 ml of water containing 15 g (0.15 mole) of concentrated hydrochloric acid was added slowly. After stirring at 0°-10° C. for one hour, the resulting solid was collected by filtration, washed with cold water and air-dried at 25°-30° C. A product with a melting point of 51°-53° C. was obtained with a yield of 97%.
Reaction SMILES: CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:25]([O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[CH:33][NH:34]2)=[CH:30][CH:29]=1)[CH3:26].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CCOCC.O>[CH3:42][O:41][C:39](=[O:40])[CH2:38][N:34]1[C:35]2[C:31](=[CH:30][CH:29]=[C:28]([O:27][CH2:25][CH3:26])[CH:36]=2)[CH:32]=[CH:33]1
Reactant: CCOc1ccc2cc[nH]c2c1
Reactant: COC(=O)CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOc1ccc2ccn(CC(=O)OC)c2c1
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Potassium tert-butoxide (0.77 g, 6.9 mmol) was stirred with dry ether (50 ml) containing 18-crown-6 (0.164 g, 0.62 mmol). 6-Ethoxyindole (1.0 g, 6.2 mmol) was added portionwise over 15 minutes at room temperature. This was stirred for 1/2 hour then cooled to 0° C. when methyl bromoacetate (0.65 ml, 6.9 mmol) in ether (5 ml) was added dropwise. The reaction mixture was stirred for 16 hours at room temperature then poured into water (150 ml) and extracted with ether (2×100 ml). The extracts were washed with brine (2×75 ml), dried and concentrated to give crude methyl(6-ethoxyindol-1-yl)acetate (1.4 g, 96% yield) as a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C([Li])CCC.CN(C)[CH:22]=[O:23]>O1CCCC1>[O:8]([C:5]1[N:6]=[CH:7][C:2]([CH:22]=[O:23])=[CH:3][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Oc2ccccc2)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Oc2ccccc2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of 5-bromo-2-phenoxy-pyridine described in Manufacturing Example 231-1-1 (18.7 g, 74.6 mmol) in tetrahydrofuran (360 mL) was added n-butyl lithium (31.1 mL, 2.64 M hexane solution, 82.1 mmol) under nitrogen atmosphere at −78° C., which was stirred for 30 minutes at −78° C. To this reaction solution was added N,N-dimethylformamide (7.46 mL, 97 mmol) at −78° C., which was stirred for 1 hour at this temperature. The reaction solution was partitioned into ethyl acetate and water. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=5:1) to obtain the title compound (4.75 g, 32%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:7][CH:6]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])[CH2:5][CH2:4][O:3]1.[CH3:14][CH2:15][Mg+].[Br-].[NH4+].[Cl-].O>C(OCC)C>[CH3:1][C:2]1([CH3:13])[O:7][CH:6]([C:8]([CH3:12])([CH:9]([OH:10])[CH2:14][CH3:15])[CH3:11])[CH2:5][CH2:4][O:3]1
Reactant: CC1(C)OCCC(C(C)(C)C=O)O1
Reactant: CC[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CCC(O)C(C)(C)C1CCOC(C)(C)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 268 mg (1.44 mmol) of aldehyde 45 in 4 ml of diethyl ether is mixed at 0° C. with 528 μl (1.58 mmol, 1.1 equivalents) of a 3 M solution of EtMgBr in ether. It is allowed to stir for 2 hours at 0° C., heated to room temperature and allowed to stir for another hour. For working-up, it is mixed with saturated aqueous NH4Cl solution, and then water is added steadily until the precipitate goes into solution. The aqueous phase is extracted with ether, the combined organic phases are dried on MgSO4 and concentrated by evaporation. The residue is purified by column chromatography with pentane:ether=1:1. 251 mg (1.16 mmol) of alcohol 46, corresponding to a yield of 80%, is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9]([N:12]2[CH2:14][CH:13]2[C:15]([N:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])(=[O:11])=[O:10])[CH:6]=[C:5]([Cl:24])[C:3]=1[NH2:4].[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:4][C:3]1[C:2]([Cl:1])=[CH:8][C:7]([S:9]([NH:12][CH:13]([CH2:14][O:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]([N:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])(=[O:11])=[O:10])=[CH:6][C:5]=1[Cl:24]
Reactant: CC1CCN(C(=O)C2CN2S(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Reactant: Oc1ccccc1
Product: CC1CCN(C(=O)C(COc2ccccc2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1

Procedure:
Examples 100-105 are prepared from 2,6-dichloro-4-({2-[(4-methylpiperidin-1-yl)carbonyl]aziridin-1-yl}sulfonyl)aniline and the appropriate phenol in the same manner that Example 99 is synthesized.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:19](COCC[Si](C)(C)C)[C:18]4[CH:28]=[CH:29][C:30]([C:32]([F:35])([F:34])[F:33])=[CH:31][C:17]=4[N:16]=3)[C:11](=[O:36])[CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1>C(O)(C(F)(F)F)=O.ClCCl>[F:35][C:32]([F:33])([F:34])[C:30]1[CH:29]=[CH:28][C:18]2[NH:19][C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:4]4[C:3]([C:2]([F:1])([F:37])[F:38])=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:10][C:11]3=[O:36])=[N:16][C:17]=2[CH:31]=1
Reactant: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2=O)nc2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN(c2ncccc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)ccc2[nH]1

Procedure:
A solution of 4-(3-trifluoromethyl-pyridin-2-yl)-1-[5-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-piperazin-2-one from step (c) above (114 mg, 0.2 mmol) in 30% TFA in dichloromethane (3 mL) was stirred at room temperature for 5 h. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with EtOAc/hexane (1:3) to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 430 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[O:13]1[CH2:16][CH:15]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH:15]3[CH2:16][O:13][CH2:14]3)[CH2:18][CH2:19]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: C1CN(C2COC2)CCN1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCN(C2COC2)CC1
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzonitrile (7 g, 1.2 eq, 41.2 mmol), 1-(oxetan-3-yl)piperazine (5.0 g, 1.0 eq, 35.2 mmol) was dissolved in annhydrous DMF (100 mL). K2CO3 (12.2 g, 2.5 eq, 87.9 mmol) was added to the above solution and the reaction mixture was stirred at room temperature for over night. The reaction mixture was diluted with of EtOAc (100 mL) and partitioned with H2O (100 mL). Layers were separated and the aqueous layer was washed once with of EtOAc (100 mL). Combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to leave a crude oil. Purification of the crude mixture by column chromatography on silica gel (ISCO System) using 20% MeOH in CH2Cl2/CH2Cl2 (gradient system from 1:9 to 4:6) as eluent gave 5-nitro-2-(4-(oxetan-3-yl)piperazin-1-yl)benzonitrile in 97% yield.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH3:14])=[C:7]([O:15]COC)[C:6]=1[CH3:19].Cl.O>CO>[CH3:19][C:6]1[C:7]([OH:15])=[C:8]([O:11][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:5]=1[OH:4]
Reactant: CCCOc1ccc(OCOC)c(C)c1OCOC
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCOc1ccc(O)c(C)c1O
Yield: 98.8 %

Procedure:
A solution of 5b (580 mg, 2.15 mmol) in MeOH (17.9 mL) was treated dropwise with 3 M HCl (630 μL, 17.2 mmol), then heated to reflux for one hour. Water (20 mL) was added and the solution was extracted with EtOAc (3×20 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), and concentrated to afford 6b as a red amorphous solid (387 mg, 99%). 1H NMR (CDCl3, 500 MHz) δ 6.51 (d, J=8.7 Hz, 1H), 6.21 (d, J=8.6 Hz, 1H), 5.74 (s, 1H), 4.36 (s, 1H), 3.87-3.85 (m, 2H), 2.09 (s, 3H), 1.75-1.71 (m, 2H), 0.96 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 147.5, 143.8, 139.0, 109.8, 108.4, 103.8, 70.2, 21.6, 9.5, 7.3; IR (film) νmax 3520, 3360, 2966, 2880, 2359, 2341, 1636, 1236, 1068, 785, 750 cm−1.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10]([NH2:13])[CH2:11][NH2:12].[C:14]([OH:17])(=[O:16])[CH3:15]>[Pt]>[C:14]([OH:17])(=[O:16])[CH3:15].[C:14]([OH:17])(=[O:16])[CH3:15].[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH2:1][NH:12][CH2:11][CH2:10][NH:13][CH2:5][C:3]1[CH:2]=[CH:8][CH:7]=[CH:15][C:14]=1[OH:17]
Reactant: O=Cc1ccccc1O
Reactant: NCCN
Agent: [Pt]
Solvent: CC(=O)O
Product: Oc1ccccc1CNCCNCc1ccccc1O
Reaction time: 12 h

Procedure:
40.8 g of a bisazomethine prepared from 2 moles of salicylaldehyde and 1 mol of ethylenediamine and having a melting point of 127° C. are hydrogenated, at atmospheric pressure in a hydrogenation flask, in 200 ml of glacial acetic acid in the presence of 1.36 g of 10% platinum/charcoal catalyst at 25° C. After 12 hours, the catalyst is filtered off and used to hydrogenate a further 81.6 g of bisazomethine in 400 ml of glacial acetic acid. After 20 hours, the completely hydrogenated solution is separated from the catalyst and concentrated, together with the above filtrate, in a rotary evaporator. The solid residue is recrystallised from 700 ml of isopropanol, the mother liquor concentrated three times and the products are dried at 90° C. in vacuo, affording a total of 162.2 g of N,N'-bis-(2-hydroxybenzyl)-ethylenediamine diacetate which melts in the range of 120°-130° C.
Reaction SMILES: Cl.C(OCC)(=O)C.C(OC([N:15]1[CH:19]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[C:22]([F:28])[CH:21]=2)[CH2:18][CH2:17][C@H:16]1[C@H:29]([OH:31])[CH3:30])=O)(C)(C)C>C(OCC)(=O)C>[F:26][C:24]1[CH:25]=[C:20]([CH:19]2[NH:15][C@H:16]([C@H:29]([OH:31])[CH3:30])[CH2:17][CH2:18]2)[CH:21]=[C:22]([F:28])[C:23]=1[F:27]
Reactant: C[C@@H](O)[C@@H]1CCC(c2cc(F)c(F)c(F)c2)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@@H]1CCC(c2cc(F)c(F)c(F)c2)N1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
4 N hydrochloric acid/ethyl acetate (26.8 mL) was added to an ethyl acetate (20 mL) solution of (S)-2-((R)-1-hydroxyethyl)-5-(3,4,5-trifluorophenyl)pyrrolidine-1-carboxylic acid t-butyl ester (3.71 g), and stirring was continued for 2 hours at room temperature. The solvent was removed under a vacuum, and 5 N sodium hydroxide solution and dichloromethane were added, and the organic layer was partitioned. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under a vacuum, and the title compound (2.6 g) was obtained. The physical property values are as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH3:17])[C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25].Cl>C1C=CC=CC=1>[C:24]([NH:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH3:17])[C:3]=1[C:4]([OH:6])=[O:5])(=[O:26])[CH3:25]
Reactant: CCOC(=O)c1c(C)cc(N)c(C(=O)O)c1C
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)cc(NC(C)=O)c(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.6 %

Procedure:
To a mixture consisting of 1 g of 2-amino-5-ethoxycarbonyl-4,6-dimethylbenzoic acid, 20 ml of benzene, and 0.7 ml of pyridine in a flask cooled with ice water was added dropwise with stirring a solution of 600 mg of acetyl chloride in 5 ml of benzene. The mixture was further stirred for 5 hours at room temperature, and then heated to reflux for one hour. After cooling, the mixture was shaken with dilute hydrochloric acid and the layers were separated. The acidic aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with water, and dried over sodium sulfate. The solvent was removed by distillation. The resulting residue was recrystallized from ethanol/water to yield 1.02 g of 2-acetylamino-5-ethoxycarbonyl-4,6-dimethylbenzoic acid melting at 170°-171° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[BrH:19]>>[Br:19][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Br
Reactant: COC(=O)c1cc(N)cc(C(=O)O)c1
Agent: O=N[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)cc(C(=O)O)c1
Temperature: 0 °C
Yield: 68 %

Procedure:
3-Amino-5-(methoxycarbonyl)benzoic acid (1.0 g, 5.12 mmol, 1 eq.) was dissolved in 15% HBr (22.5 mL) at RT, then cooled to 0° C. with stirring. A 2.5 M aqueous solution of NaNO2 (2.3 mL, 5.64 mmol, 1.1 eq.) was added slowly via an addition funnel to generate the diazonium salt. In a separate flask, CuBr was partially dissolved in 15% HBr (9 mL) and cooled to 0° C. with stirring, to which the diazonium salt solution was subsequently added. A slight exotherm was observed. The reaction was stirred at RT for 30 minutes then carefully heated at 70° C. for 1 hour. The reaction was worked up by filtering off insoluble material as crude product. The solids were dissolved in water/EtOAc and the layers separated. The aqueous layer was extracted again with EtOAc. The organic layers were combined, dried over sodium sulfate and concentrated to give an off-white solid. The product was purified over silica gel in 1:1 hexanes/EtOAc to 100% EtOAc to 4:1 methylene chloride/MeOH to yield 3-bromo-5-(methoxycarbonyl)benzoic acid (0.90 g, 3.47 mmol, 68% yield) as a white solid. MS found: (M−H)+=257/259.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([C:12]3[N:17]=[CH:16][C:15]([NH:18][CH:19]([C:23]4[CH:37]=[CH:36][C:26]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[O:28])=[CH:25][CH:24]=4)[CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O1CCCC1>[C:1]1([C:7]2[CH:8]=[N:9][N:10]([C:12]3[N:17]=[CH:16][C:15]([NH:18][CH:19]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:36][CH:37]=4)[CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(Nc1ccc(-n2cc(-c3ccccc3)cn2)nc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(Nc1ccc(-n2cc(-c3ccccc3)cn2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.2 %

Procedure:
Methyl 3-(4-(1-(6-(4-phenyl-1H-pyrazol-1-yl)pyridine-3-ylamino)butyl)benzamido)propanoate (82.1 mg, 0.165 mmol) was dissolved in methanol (0.5 mL) and tetrahydrofuran (0.5 mL). 1N Sodium hydroxide (0.33 mL) was added and the reaction was stirred at room temperature for 24 hours. The reaction was then concentrated. The crude residue was taken up in water and acidified with 1N hydrochloric acid to pH=3. A white precipitate formed. The solids were filtered off and dried under vacuum to give (+/−)-3-(4-(1-(6-(4-phenyl-1H-pyrazol-1-yl)pyridine-3-ylamino)butyl)benzamido)propanoic acid (61.6 mg, 77%) as an off-white solid. 1H NMR (400 MHz, CD3OD, δ): 8.57 (d, J=1.0 Hz, 1H), 7.96 (d, J=0.8 Hz, 1H), 7.78-7.69 (m, 3H), 7.61-7.50 (m, 3H), 7.47 (d, J=8.4 Hz, 2H), 7.38-7.31 (m, 2H), 7.24-7.16 (m, 1H), 7.05 (dd, J=8.9, 3.0 Hz, 1H), 4.48-4.41 (m, 1H), 3.63-3.55 (m, 2H), 2.60 (t, J=6.9 Hz, 2H), 1.94-1.69 (m, 2H), 1.58-1.33 (m, 2H), 0.96 (t, J=7.4 Hz, 3H). MS (M+1): 484.4.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[CH2:7]([O:14][NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>ClCCl>[CH2:7]([O:14][NH:15][C:1](=[O:4])[CH:2]=[CH2:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC(=O)Cl
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)NOCc1ccccc1
Temperature: 0 °C

Procedure:
A solution of acryloyl chloride dissolved in dry dichloromethane was cooled at 0° C. with an ice bath. A mixture of O-benzyl hydroxylamine hydrochloride (29) and N,N-diisopropylethylaamine in dry dichloromethane was added. Water was added and the layers were separated. The organic solution was washed with diluted hydrochloric acid, a saturated sodium bicarbonate solution, water, and brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by flash chromatography using a mixture of hexane and ethyl acetate. The purification gave N-benzyloxyacrylamide (30).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:21]([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)NC(C)C
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)c1ccc(Br)cc1)C(C)C
Reaction time: 8 h

Procedure:
A mixture of 4-bromobenzoic acid (200 g, 1 mol) and thionyl chloride (300 mL) was refluxed for 3 hours. The mixture was concentrated in vacuo to remove excessive thionyl chloride, and then azeotroped with toluene (3×). The crude residue was dissolved in CH2Cl2 (2 L) and cooled in ice-water bath. To the resulting solution was added dropwise a mixture of triethylamine (330 mL, 2.38 mol) and diisopropylamine (168 mL, 1.19 mol) over 1 hour. The solution was allowed to stir overnight, and then washed with 1N HCl, followed by brine. The organic layer was dried over MgSO4, filtered, and concentrated to afford 4-bromo-N,N-diisopropylbenzamide. LRMS calc'd for (C13H18BrNO) [M+H]+, 284; found 284.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8][NH2:9])=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>C1C=CC=CC=1.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:7](=[O:10])[CH2:8][NH:9][C:17](=[O:18])[CH2:16][Cl:15])=[CH:11][CH:12]=1
Reactant: O=C(Cl)CCl
Reactant: NCC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: O=C(CCl)NCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
To a well stirred suspension of 20.6 g of 4-chlorophenacylamine hydrochloride in 70 ml of benzene and 70 ml of water which was cooled to below 7° C. were added simultaneously 110 ml of 2N NaOH solution and 12.4 g of chloroacetyl chloride dissolved in 30 ml of benzene. After the addition was complete, the reaction mixture was warmed to room temperature and stirred at room temperature for 3 hours. At the end of this period, the formed precipitate was filtered, and the benzene layer was separated. The aqueous layer was extracted twice with 50 ml of benzene. The combined benzene layer was dried over anhydrous sodium sulfate, and evaporated to dryness. The residue together with the precipitate obtained above was combined and recrystallized from ethanol to give 14.1 g (57 percent) of N-(4-chlorophenacyl) chloroacetamide.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([OH:9])[CH:7]=[CH:6][CH2:5][O:4]1.N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(Cl)Cl>[Si:19]([O:1][CH2:2][C@H:3]1[C@@H:8]([OH:9])[CH:7]=[CH:6][CH2:5][O:4]1)([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@@H]1OCC=C[C@@H]1O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1OCC=C[C@@H]1O
Temperature: 0 °C

Procedure:
To a 0° C., stirred solution of cis-2-hydroxymethyl-3,6-dihydro-2H-pyran-3-ol (0.4 g, 2.84 mmol) in CH2Cl2 (40 ml) under an Argon atmosphere was added imidazole (0.231 g, 3.4 mmol) followed by TBSCl (0.428 g, 3.4 mmol). The resulting mixture was stirred for 1H at 0° C. The reaction mixture was washed with water (10 ml×2) and brine (10 ml). The organic phase was dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude product purified by flash chromatography (25-40% EtOAc in hexane).
Reaction SMILES: C(O)(=O)C.[N+:5]([O-:8])(O)=[O:6].[CH2:9]([S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[C:15]([OH:20])[N:14]=1)[CH2:10][CH3:11]>O>[N+:5]([C:16]1[C:15]([OH:20])=[N:14][C:13]([S:12][CH2:9][CH2:10][CH3:11])=[N:18][C:17]=1[OH:19])([O-:8])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: CCCSc1nc(O)cc(O)n1
Solvent: O
Solvent: CC(=O)O
Product: CCCSc1nc(O)c([N+](=O)[O-])c(O)n1
Reaction time: 1 h

Procedure:
Acetic acid (125 ml) and fuming nitric acid (42.5 ml) were placed in a clean and dry reaction assembly, followed by the addition of 2-propylthio-pyrimidine-4,6-diol (50 g) over a period of 60 minutes at 30-35° C. and with stirring for 1 hour. After completion of the reaction, monitored by TLC, the reaction mass was slowly added to water (250 ml) with maintaining the temperature at below 25° C. The resulting slurry was stirred for 1 hour at 20-25° C. The product was isolated by filtration and washed successively with water (3×100 ml). The wet product was dried under reduced pressure at 40-45° C. to produce 48.28 g of 5-nitro-2-propylthiopyrimidine-4,6-diol as a off-white powder (Purity by HPLC: 99.02 area-%).