Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:18]2([C:21]([F:24])([F:23])[F:22])[N:20]=[N:19]2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])(C(C)(C)C)(C)C.C(=O)(O)[O-:26].[Na+].[OH-].[K+].[Mn]([O-])(=O)(=O)=O.[K+]>CO.Cl>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][C:12]([C:18]2([C:21]([F:24])([F:23])[F:22])[N:20]=[N:19]2)=[CH:11][C:10]=1[C:9]([OH:8])=[O:26]
Reactant: COc1ccc(C2(C(F)(F)F)N=N2)cc1CO[Si](C)(C)C(C)(C)C
Reactant: O=C([O-])O
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COc1ccc(C2(C(F)(F)F)N=N2)cc1C(=O)O
Reaction time: 4 h
Yield: 72 %

Procedure:
A solution of 3-[3 -(tert-butyldimethylsilanyloxymethyl)-4-methoxyphenyl]-3-trifluoromethyl-3H-diazirine (150 mg, 0.41 mmol) in methanol (5 ml) was stirred for 20 min with conc. HCl (2 drops). The solution was poured onto saturated aqueous sodium bicarbonate (10 ml) and extracted with dichloromethane (3×5 ml). The combined organic extracts were dried over sodium sulfate and evaporated under reduced pressure. The residue was taken up in dioxane (3 ml) and aqueous potassium hydroxide (2.5 ml of a 0.2M solution), potassium permanganate (98 mg, 0.62 mmol) was added and the mixture stirred for 4 h. The mixture was filtered through a pad of Celite and washed with water. The filtrate was extracted with ether (2×10 ml). The aqueous phase was brought to pH 1, extracted with ether (2×10 ml) and these extracts were dried over sodium sulfate and evaporated in vacuo to give the title compound (77 mg, 72%) as an off white solid.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([NH2:10])=[O:9])=[C:5]([CH3:11])[C:4]=1[CH3:12])#[N:2].[H][H].[ClH:15]>CO.[Pd]>[ClH:15].[NH2:2][CH2:1][C:3]1[S:7][C:6]([C:8]([NH2:10])=[O:9])=[C:5]([CH3:11])[C:4]=1[CH3:12]
Reactant: Cc1c(C#N)sc(C(N)=O)c1C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1c(CN)sc(C(N)=O)c1C

Procedure:
19 g (105.42 mmol) of 5-cyano-3,4-dimethylthiophene-2-carboxamide were suspended in 760 ml of methanol and 110 ml of 2N hydrochloric acid solution, 9.5 g of Pd on charcoal (10%) were added, and the mixture was hydrogenated at room temperature. After 4.71 of hydrogen had been taken up (4 h), methanol was distilled out in vacuo, and the aqueous phase was extracted three times with ethyl acetate and subsequently freeze-dried. 16.3 g of the required product resulted as a white solid (70.4% of theory).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:18])[CH:8]=2)[C:3]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([F:18])[CH:8]=3)[C:3]2=[O:19])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: Nn1nc(-c2ccccc2)c2cc(F)ccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2ccccc2)c2cc(F)ccc2c1=O

Procedure:
The product from Example 35E and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.75 (s, 2H) 7.03-7.20 (m, 3H) 7.38 (dd, J=9.46, 2.44 Hz, 1H) 7.52-7.68 (m, 5H) 7.82 (d, J=2.44 Hz, 1H) 8.48 (d, J=3.36 Hz, 1H); MS (ESI) m/z 410 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1>>[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:30])=[CH:27][CH:26]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1ccc(Br)cc1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc(Br)cc2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Bromo-benzoic acid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:4][N:3]=1
Reactant: Oc1ccc(I)nc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(I)nc1
Reaction time: 100 h

Procedure:
To a solution of one gram of 2-iodo-5-hydroxypyridine (prepared as by Edgar, K. J. & Falling, S. N.; (1990) J. Org. Chem., 55: 5287) in dimethylformamide (14 ml) was added cesium carbonate (1.55 g) and bromooctane (1.56 ml). The reaction was allowed to stir for 100 hrs, at which time it was poured into water and extracted with 1:1 hexane:ethyl acetate. The combined organics were washed with brine and dried over sodium sulfate and potassium carbonate. The solvent was removed in vacuo to give a yellow oil. This oil was purified by flash chromatography using 10% ethyl acetate in hexanes as the eluent, giving a clear oil as a product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:18]([O:22][C:23](=[O:39])[NH:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:32]=2[F:38])[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].Cl.C(N=C=NCCCN(C)C)C.ClCCl>CN(C)C1C=CN=CC=1.O>[C:18]([O:22][C:23](=[O:39])[NH:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:7](=[O:9])[C:6]3[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:33][C:32]=2[F:38])[CH2:27][CH2:26]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: COCCOCOc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cc2F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COCCOCOc1ccc(Cl)cc1C(=O)Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
A mixture of 5-chloro-2-(2-methoxyethoxymethoxy)benzoic acid (compound of Reference Example 140; 0.18 g, 0.7 mmol), [1-(4-amino-2-fluorophenyl)piperidin-4-yl]carbamic acid tert-butyl ester (compound of Reference Example 90; 0.28 g, 0.9 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 g, 0.9 mmol), 4-dimethylaminopyridine (0.01 g) and dichloromethane (5 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (0.27 g, 70%) as a colorless solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][C@H:8]3[C:7](=[O:15])[NH:6][C:5]=2[CH:4]=1.[N:16]1([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC.CO>[O:15]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:19]3[CH2:18][CH2:17][N:16]([C:22]4[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=4)[CH2:21][CH2:20]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][C@@H:8]12
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCN43)CC2)cc1
Temperature: 90 °C
Yield: 6.2 %

Procedure:
(S)-3-(hydroxymethyl)-7,8-dihydro-5H-azeto[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one (103 mg, 0.5 mmol), 4-(piperazin-1-yl)benzonitrile (108 mg, 0.575 mmol), (cyanomethyl)trimethylphosphonium iodide (207 mg, 0.850 mmol) and N,N-diisopropylethylamine (0.437 ml, 2.500 mmol) were suspended in Propiononitrile (Volume: 1.502 ml) and heated in a closed vial at 90° C. for 23 h. The reaction mixture was cooled, diluted with MeOH (2 mL) and purified using preparative HPLC (basic phase). The fractions containing product were concentrated in vacuo and crystallized from water-methanol (3 mL, ˜5:1) The precipitate was filtered and dried in vacuum to afford (S)-4-(4-((6-oxo-6,6a,7,8-tetrahydro-5H-azeto[1,2-a]pyrido[3,2-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile (11.7 mg, 0.031 mmol, 6.25% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37-2.47 (m, 4H) 2.68-2.80 (m, 1H) 2.94 (tt, J=10.67, 7.26 Hz, 1H) 3.30 (d, J=4.80 Hz, 4H) 3.36 (s, 2H) 3.87-4.00 (m, 1H) 4.21 (q, J=7.66 Hz, 1H) 4.93 (t, 1H) 6.98 (d, J=1.77 Hz, 1H) 7.00 (d, J=9.09 Hz, 2H) 7.57 (d, J=9.09 Hz, 2H) 7.65 (d, J=1.77 Hz, 1H) 10.34 (s, 1H). [M+H] calc'd for C21H22N6O, 374; found, 374.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[CH:3]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH3:12])[CH:3]=2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cn1cc(I)c2c(N)ncnc21
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc(OCc3ccccc3)cc2)c2c(N)ncnc21

Procedure:
A solution of 5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (5 mg, 0.018 mmol), 4-(benzyloxy)phenylboronic acid (21 mg, 0.091 mmol), K3PO4 (19.3 mg, 0.091 mmol) and Pd(PPh3)4 (12.5 mg, 0.011 mmol) in DMF (3 mL) was heated to 60° C. under an argon atmosphere. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 331.1, found 331.3.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[F:13][C:14]([F:24])([CH2:20][CH2:21][CH2:22][CH3:23])[C:15](OCC)=[O:16].OS(O)(=O)=O>O1CCCC1.CCCCC>[CH3:4][O:3][P:2]([CH2:1][C:15](=[O:16])[C:14]([F:24])([F:13])[CH2:20][CH2:21][CH2:22][CH3:23])(=[O:7])[O:5][CH3:6]
Reactant: CCCCC(F)(F)C(=O)OCC
Reactant: COP(C)(=O)OC
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
A solution of dimethyl methylphosphonoate (6.5 g, 80 mmol, 2.2 equiv) in tetrahydrofuran (100 mL) was cooled to −78° C. and n-butyllithium (2.5 M in hexanes, 14 mL, 36 mmol, 1 equiv) was added dropwise. The solution was stirred at −78° C. for 30 min and ethyl 2,2-difluorohexanoate (6.5 g, 36 mmol, 1 equiv) was added dropwise. The solution was stirred at −78° C. for 1 h and warmed to 0° C. over 1 h. Pentane (100 mL) was added followed by the dropwise addition of 2M H2SO4 to pH=6. The aqueous layer was separated and extracted with pentane (3×15 mL). The organics were combined, dried over sodium sulfate, filtered, and concentrated to dryness under vacuum on a rotary evaporator. The crude oil was purified by column chromatography using methyl tert-butyl ether as eluant to afford 4.1 g of 26 as a yellow oil (44%).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS([O-])=O.[Na+].[NH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:25]#[N:26].C(O)C>O>[O:1]([C:8]1[CH:15]=[CH:14][C:11]([C:12]2[NH:30][C:29]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=3[N:21]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc2[nH]c(-c3ccc(Oc4ccccc4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To 4-phenoxybenzaldehyde (4.0 g, 0.020 mol) was added 20 mL of 40% NaHSO3 (aq). The mixture was stirred for 2 h at 25° C. 3,4-Diaminobenzonitrile (3.36 g, 0.0252 mol) and ethanol (50 mL) were added. The mixture was refluxed for 4 h. The reaction was then poured into water. The precipitate was filtered and recrystallized from ethyl acetate to afford 3.6 g (57%) of 2-(4-phenoxyphenyl)-1H-benzimidazole-5-nitrile.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].ClC1C=C([C:17](=[O:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C=C(Cl)C=1>>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:17](=[O:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Fc1ccccc1Br
Reactant: O=C(Cc1ccccc1)c1cc(Cl)cc(Cl)c1
Product: O=C(Cc1ccccc1)c1ccccc1F
Yield: 33.5 %

Procedure:
Prepared from 1-bromo-2-fluorobenzene following the procedure described in Intermediate 13, where the crude product was purified by column chromatography (PE:EtOAc=100:1) to afford Intermediate 24 (300 mg, yield 33.5%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([Br:12])=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].[ClH:17]>>[ClH:17].[NH2:1][C:2]1[C:11]([Br:12])=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7]
Reactant: CCNCc1cc(C(=O)OC)cc(Br)c1N
Agent: Cl
Product: CCNCc1cc(C(=O)O)cc(Br)c1N
Temperature: -15 °C

Procedure:
2.7 gm of 2-amino-3-bromo-5-carbomethoxy-N-ethyl-benzylamine were boiled for 35 minutes with 65 ml of 6 N hydrochloric acid. Thereafter, upon cooling the reaction solution to -15°C, N-ethyl-2-amino-3-bromo-5-carboxy-benzylamine hydrochloride crystallized out and was recrystallized from ethanol/ether, whereupon it had a melting point of 261°C (decomp.).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.Cl[C:42]1[CH:47]=[C:46]([O:48][C:49]2[CH:50]=[CH:51][C:52]([NH2:59])=[N:53][C:54]=2[C:55]([F:58])([F:57])[F:56])[CH:45]=[CH:44][N:43]=1>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:26][N:27]1[CH:31]=[C:30]([C:44]2[CH:45]=[C:46]([O:48][C:49]3[CH:50]=[CH:51][C:52]([NH2:59])=[N:53][C:54]=3[C:55]([F:56])([F:57])[F:58])[CH:47]=[CH:42][N:43]=2)[CH:29]=[N:28]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)c(C(F)(F)F)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(Oc3ccc(N)nc3C(F)(F)F)ccn2)cn1
Temperature: 85 °C
Yield: 76.7 %

Procedure:
A suspension of triphenylphosphine (0.033 g, 0.125 mmol), K2CO3 (0.118 g, 0.856 mmol), Pd(OAc)2 (0.007 g, 0.031 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole (0.089 g, 0.428 mmol) and 5-((2-chloropyridin-4-yl)oxy)-6-(trifluoromethyl)pyridin-2-amine (0.062 g, 0.214 mmol) in dioxane (6 mL) and water (1.5 mL) was sparged with Ar and heated at 85° C. overnight. The mixture was cooled to RT, treated with brine, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated and purified via silica gel chromatography (MeOH/EtOAc) to afford 5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-(trifluoromethyl)pyridin-2-amine (55 mg, 77%). MS (ESI) m/z: 336.1 (M+H+).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:12](Cl)(=[O:14])[CH3:13]>C(Cl)Cl>[C:1]([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCO
Solvent: ClCCl
Product: CC(=O)OCCNC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of 2-(BOC)aminoethanol (3.2 g, 20.0 mmol) in DCM (60 mL) were added TEA (5.6 mL, 40.0 mL) and acetyl chloride (3.36 mL, 30 mmol) at 0° C. After the reaction solution was stirred for 2 h, the solvent was removed, and the residue dissolved in water. The organic material was extracted with EtOAc, and the extracts were washed with 1N HCl, dried over MgSO4, concentrated in vacuo. The residue was purified by column chomatography (eluent: EtOAc/Hex=1/10) to give the title compound (3.2 g, 80%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])[CH2:4][CH2:3]1.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:10][C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:27])([F:26])[F:17])=[CH:20][CH:21]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(CC(O)c2ccccc2)CC1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCN(CC(Oc2ccc(C(F)(F)F)cc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
2-(4-Methyl-piperazin-1-yl)-1-phenyl-ethanol (38) (2.0 g, 9.09 mmol) was dissolved in 50 mL of THF. 4-trifluoromethyl phenol was added to the solution and then triphenylphosphine. After complete dissolution, the mixture was cooled to 0° C. and after 10 minutes DIAD was added dropwise. Ice-bath was removed and the reaction mixture was stirred at room temperature for 48 hours. The product was purified using flash chromatography, using pure ethyl acetate. The product 14a (2.78 g, 7.64 mmol, 84%) was afforded as a yellow oil. H-NMR (CDCl3): δ 7.39 (2H, d, J=8.62), 7.36 (5H, m), 6.91 (2H, d, J=8.58), 5.38 (1H, dd, J=3.11, 3.10 Hz), 3.03 (1H, dd, J=8.39, 8.38), 2.71 (1H, dd, J=3.14, 3.14), 2.63 (4H, b), 2.44 (4H, b), 2.27 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27](Cl)=[O:28]>CC(C)=O.O>[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27]([NH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:28]
Reactant: O=C(Cl)c1cc2ccccc2s1
Reactant: Nc1ncccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ncccc1C(=O)O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-aminonicotinic acid (91.1 g, 8.0 mmol), triethylamine (2.7 mL, 19.1 mmol) and acetone/H2O (3:1, 100 mL) was added 1-benzothiophene-2-carbonyl chloride (2.04 g, 10.4 mmol) at 0° C. The resulting solution was allowed to warm to rt and stir overnight. The volatile solvent was removed under reduced pressure and the aqueous solution was acidified with HCl (conc.). The resulting precipitate was filtered and then washed with EtOAc and dried under reduced pressure to afford the product. (1.2 g, 52%). NMR (DMSO): 11.7(1H, broad), 8.60(1H, m); 8.36(1H, s); 8.25(1H, d); 8.07(1H, d); 8.02(1H, d); 7.51(2H, m); 7.36(1H, m).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12].[OH-].[Na+].COC1C=CC(O)=CC=1>>[C:10]([NH:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)Cl
Reactant: NCC(=O)NCC(=O)O
Agent: COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: C=C(C)C(=O)NCC(=O)NCC(=O)O

Procedure:
The procedure described above is utilized with 132 g (0.1 mol) of glycylglycine, 105 g of methacryloyl chloride, 80 g of sodium hydroxide and 500 mg of p-methoxyphenol at 0°-5° C. White precipitate is formed from the reaction mixture. The precipitate crystallized from water had a melting point of (192°-196° C.). Yield of product was 150 g (70.8%). NMR (DMSO-d6), 11 gamma (s, 1H, COOH), 7.9 gamma (s, 2H, NH), 5.5 gamma (s, 1H, =CH2C), 5.2 gamma (s, 1H, =CH2), 3.5 gamma (d, 4H, CH2), 2.6 gamma (s, 3H, CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:21](=[O:24])(=[O:23])[NH2:22])[C:12]=1[NH:13][C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1)[C:7]([OH:9])=[O:8])([O-])=O.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:21](=[O:24])(=[O:23])[NH2:22])[C:12]=1[NH:13][C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1cccc(Nc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)c1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Cc1cccc(Nc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)c1

Procedure:
By substituting 3-nitro-5-sulphamyl-4-(m-toluidino)-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 280°-282°C after recrystallization from ethanol.
Reaction SMILES: [O-]I(=O)(=O)=O.[Na+].[CH3:7][O:8][C:9]([C:11]1[O:15][N:14]=[C:13]([O:16][CH2:17][C:18]2[C:19]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[N:20][O:21][C:22]=2[C@@H:23]([OH:32])[C@H](O)C2C=CC=CC=2)[CH:12]=1)=[O:10]>C1COCC1.O>[CH3:7][O:8][C:9]([C:11]1[O:15][N:14]=[C:13]([O:16][CH2:17][C:18]2[C:19]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[N:20][O:21][C:22]=2[CH:23]=[O:32])[CH:12]=1)=[O:10]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2[C@@H](O)[C@H](O)c2ccccc2)no1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C=O)no1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
Sodium (meta)periodate (2.68 g, 8.4 mmol) was added to a solution of 3-[5-((1S,2R)-1,2-dihydroxy-2-phenyl-ethyl)-3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid methyl ester (3.8 g, 8.4 mmol) in THF (21 mL) and de-ionized water (4.3 mL) at 0° C. and the resulting mixture stirred overnight at 0° C. The reaction mixture was extracted with ethyl acetate the combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated to afford the title compound (2.9 g, 100%) which was obtained as a colorless oil and used in the next step directly. MS: m/e=405.1 [M+OAc]−.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:28][S:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1>C(Cl)Cl>[C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([O:10][C:33]2[CH:34]=[CH:35][C:30]([S:29][CH3:28])=[CH:31][CH:32]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccc(O)cc1
Reactant: CCC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC(C(=O)Oc1ccc(SC)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a flask containing 2-phenylbutyric acid (4.93 g, 30 mmol) in 40 mL of CH2Cl2 at 0° C. was added dicyclohexylcarbodiimide (6.19 g, 30 mmol) in 30 mL of CH2Cl2. Solid 4-methylmercaptophenol (4.21 g, 30 mmol) was added and the suspension stirred at room temperature overnight. The precipitated urea was filtered, the filtrate evaporated and the residue chromatographed on silica gel (CH2Cl2)to give 4-(methylmercapto)phenyl 2-phenylbutyrate (6.23 g, 73%) as a light yellow oil which was crystallized from EtOH to give white crystals (mp 28.0°-28.5° C.). 1H NMR (CDCl3) δ0.98 (t, 3H, J=7.3 Hz), 1.89 (m, 1H), 2.22 (m, 1H), 3.68 (t, 1H, J=7.6 Hz), 6.92 (d, 2H, J=8.6 Hz), 7.22 (d, 2H, J= 8.6 Hz), 7.30-7.45 (m, 5H, ArH).