Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([CH2:15][C:16]2([CH3:19])[CH2:18][CH2:17]2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[Li+].[OH-]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([CH2:15][C:16]2([CH3:19])[CH2:17][CH2:18]2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CC1(C)CC1)Sc1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(CC(Sc2ccc(Br)cc2)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice cold solution of ethyl 2-[(4-bromophenyl)thio]-3-(1-methylcyclopropyl)propanoate (457 mg, 1.3 mmol) in TBF (8 mL) and MeOH (3 mL) was added a 1.0 N aq. solution of LiOH (2 mL, 2.0 mmol) dropwise. The resulting mixture was stirred at room temperature for 18 h and partitioned between EtOAc and water+1.0 N HCl (5 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give 2-[(4-bromophenyl)thio]-3-(1-methylcyclopropyl)propanoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[S:28][CH:29]=2)[N:3]=1.O.[C:38]1(C)C=CC(S(O)(=O)=O)=C[CH:39]=1.CO>C(=O)C>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[S:28][CH:29]=[C:25]([CH2:24][S:23][C:4]3[C:5]([C:21]#[N:22])=[C:6]([C:11]4[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:15][CH:16]=4)[C:7]4[C:8](=[O:9])[NH:10][CH:38]([CH3:39])[NH:1][C:2]=4[N:3]=3)[N:26]=2)=[CH:35][CH:34]=1
Reactant: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N)c(C(N)=O)c1-c1ccc(OCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC=O
Solvent: O
Solvent: CO
Product: CC1NC(=O)c2c(nc(SCc3csc(-c4ccc(Cl)cc4)n3)c(C#N)c2-c2ccc(OCCO)cc2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 138 mg (0.256 mmol) of the compound from Example 22A were initially charged in 3 ml of acetaldehyde, a spatula tip of 4-toluenesulfonic acid monohydrate was added and the mixture was stirred at RT for 1 h. 2.5 ml of methanol were then added to the reaction solution, and after 2 h the mixture was concentrated and the residue was purified by column chromatography (silica gel, toluene/acetonitrile 2:1→1:1).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li+].[OH-].Cl>CO.O>[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:21]=[CH:22][C:17]([CH2:16][O:15][C:13]([NH:12][CH:4]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3]([OH:29])=[O:2])=[O:14])=[CH:18][CH:19]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)OCc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NC(Cc1ccccc1)C(=O)O)OCc1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
The ester 32 (1.30 g, 3.4 mmol) was dissolved in 25 ml methanol, then treated with 200 mg LiOH in 5 ml water. After 30 minutes at 50° C., the mixture was poured into excess water, made acidic with dilute HCl, and extracted. Recrystallization yielded about 1.12 g of 2-(biphenyl-4-ylmethoxycarbonylamino)-3-phenyl-propionic acid 33, mp. 141.7-142.2° C.
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:49]([OH:50])[CH:41]6[CH:42]([O:43][CH2:44][CH2:45][CH2:46][C:47]#[N:48])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:51]([CH3:53])[CH3:52])=[O:16])C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[C:47]([CH2:46][CH2:45][CH2:44][O:43][CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:16])=[O:14])[C:18]([CH:51]([CH3:52])[CH3:53])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:49]([OH:50])[CH:41]1[O:40]3)[O:36]2)#[N:48]
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(OCCCC#N)C5O2)C4O)C13C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(OCCCC#N)C5O2)C4O)C13C(=O)O
Yield: 27.3 %

Procedure:
20 mg of compound (64) was dissolved in 3 ml of ethyl acetate and stirred together with a catalytic amount of 10% palladium-carbon under a hydrogen atmosphere at room temperature for 1.5 hours. The reaction solution was filtered and concentrated in vacuo. The reaction product was dissolved in 10 ml of methanol and washed with 10 ml of n-hexane four times, and the lower layer was concentrated in vacuo to give 4.2 mg of compound (65) as a colorless solid.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([O:11][C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:25][C:24]([C:26]([O:28][CH3:29])=[O:27])=[C:23]([CH:30]=[O:31])[CH:22]=2)[CH2:17][C@H:16]1[O:32][CH3:33])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+]>C1COCC1>[CH2:4]([O:11][C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:25][C:24]([C:26]([O:28][CH3:29])=[O:27])=[C:23]([CH:30]([OH:31])[CH3:1])[CH:22]=2)[CH2:17][C@H:16]1[O:32][CH3:33])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1sc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)cc1C=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1sc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)cc1C(C)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
A solution of methylmagnesium bromide (0.97 mol/L) in THF (1.59 mL, 1.54 mmol) was added to a solution of methyl cis(±)-5-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-3-formylthiophene-2-carboxylate obtained in Example (246c) (333 mg, 0.77 mmol) in THF (8 mL) at 0° C., and the mixture was stirred at room temperature for five hours. Saturated ammonium chloride solution was added to the reaction solution, and the reaction solution was extracted with ethyl acetate. The combined organic layers were washed with brine and then dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1) to obtain 223 mg of the title compound as a pale yellow solid (65%).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccc(OC(C)CNS(=O)(=O)C(C)C)cc2)cc1
Yield: 14 %

Procedure:
The title compound (34 mg, 14%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (225 mg, 0.669 mmol, prepared in example 1), 4-methoxybenzeneboronic acid (125 mg, 0.822 mmol), dichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.028 mmol), 2 M sodium carbonate (245 mg in 1.15 mL water), and 1,2-dimethoxyethane (4.5 mL) in a manner analogous to the procedure described in Example 8. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 220 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:25])[NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14]2)=CC=1)([O-])=O.[C:26]([NH:33][C@@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].[N-]=C=O>CO.C(Cl)Cl>[C:29]([O:28][C:26](=[O:27])[NH:33][C@@H:34]1[CH2:38][CH2:37][N:36]([C:11](=[O:25])[NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:14]2)[CH2:35]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: O=C(N[C@@H]1CCN(Cc2ccccc2)C1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: [N-]=C=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)N[C@@H]2CCN(Cc3ccccc3)C2)C1
Reaction time: 8 h

Procedure:
A solution of ((R)-1-benzyl-pyrrolidin-3-yl)-carbamic acid 4-nitro-phenyl ester (1 eq.) and (3R)-(+)-3-(Boc-amino)pyrrolidine in MeOH is heated using microwave radiation at 100° C. for 1 hour. The reaction mixture is reduced in vacuo. The resulting oil is dissolved in DCM and isocyanate resin (3 eq.) is added and shaken overnight. The resin was filtered off and the DCM was removed in vacuo to yield the title compound. MS (ES+) m/e 299.21 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].Cl[C:8]([O:10][CH2:11][CH:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9].O>C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>[C:8]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])([O:10][CH2:11][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[C:24]1=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:9]
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Yield: 90.1 %

Procedure:
To a solution of L-alanine (1.78g, 20 mmol) in 10% Na2CO3 (53 ml) was added dropwise (within 50 min) with stirring and ice bath cooling a solution of 9-fluorenylmethyl chloroformate (5.17g, 20 mmol) in dioxane (40 ml). The mixture was stirred for 1 hr at 0° and 15 hr at 5°, poured into H2O (1.5 liters) and extracted with ether (2 x). The aqueous layer was cooled in an ice bath, acidified with concentrated HCl to pH 2-3 (white precipitate) and extracted with EtOAc (3 × 500 ml). The organic phase was washed with H2O, dried (MgSO4), filtered, and evaporated. Ether-petroleum ether was added to the residue which crystallized while being kept at 5°. The crude product (5.94g, 95.5%) was recrystallized from methanol-petroleum ether to yield colorless crystals of Fmoc-L-alanine (5.61g, 90.2%), mp 144.5°-145.5° ; [α]D25 = - 11.7° (c 1, CH3OH); tlc, Rf 0.8 (A), 0.3 (B); uv max (CH2Cl2) 267 nm (ε18,950), 290 (5,280), 301 (6,200).
Reaction SMILES: [C:1]([S:26]([NH:29][CH2:30][CH3:31])(=[O:28])=[O:27])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[C:32]([OH:36])(=[O:35])[CH:33]=[CH2:34]>>[C:1]([S:26]([N:29]([CH2:34][CH2:33][C:32]([OH:36])=[O:35])[CH2:30][CH3:31])(=[O:27])=[O:28])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:24])([F:25])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: C=CC(=O)O
Reactant: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CCN(CCC(=O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Comparative Example C5 was prepared by the Michael addition of C8F17SO2N(C2H5)H to acrylic acid to produce C8F17SO2N(C2H5)CH2CH2CO2H. GLC analysis indicated about 20% unreacted starting material was present. The acid was then converted to the potassium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3ccccc3)nc2-c2ccc(Cl)cc2)cc1
Temperature: 55 °C
Yield: 56.9 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (400 mg, 1.29 mmol) and sodium bicarbonate (216 mg, 2.59 mmol) in isopropanol (25 mL), 2-bromoacetophenone (780 mg, 3.87 mmol) was added. After heating the reaction mixture at 55° C. for 20 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (1.2 g) was chromatographed on silica gel with toluene/ethyl acetate (75/25) to give pure 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-phenyl-1H-imidazole (300 mg, 57%) as a white solid: mp (DSC) 202° C. Anal. Calc'd. for C22H17N2SO2Cl: C, 63.78, H, 4.28, N, 6.76, S, 7.74. Found: C, 63.69, H, 4.11, N, 6.68, S, 7.65. ##STR28##
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:8][CH2:7][O:6][CH2:5]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:18]([CH2:28][C:29]([N:31]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[C:41](Cl)[N:40]=[CH:39][N:38]=4)[CH2:33][CH2:32]3)=[O:30])[N:17]=2)=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:18]([CH2:28][C:29]([N:31]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[C:41]([N:2]([CH3:1])[CH2:3][CH:4]5[CH2:8][CH2:7][O:6][CH2:5]5)[N:40]=[CH:39][N:38]=4)[CH2:33][CH2:32]3)=[O:30])[N:17]=2)=[CH:12][CH:11]=1
Reactant: CNCC1CCOC1
Reactant: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(c2cc(Cl)ncn2)CC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1CCOC1)c1cc(N2CCN(C(=O)Cn3nc(-c4ccc(F)cc4)nc3-c3ccc(F)cc3)CC2)ncn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
58 mg methyl-(tetrahydro-furan-3-ylmethyl)-amine was added to 50 mg 2-(3,5-Bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-1-(4-(6-chloro-pyrimidin-4-yl)-piperazin-1-yl)-ethanone and 35 μl DIPEA in 1 mL DMSO. The reaction was stirred 3 h at 80° C. The mixture was purified by HPLC to give 44 mg of the desired product. Rt: 2.13 min (method M), (M+H)+: 575
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C)C.Cl>CCOCC>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][N:15]2[C:16](=[O:25])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]2=[O:24])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1OC1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.3 %

Procedure:
1.5 g of 69a was taken up with isopropanol (10 mL) and 1 mL of concentrated HCl. The mixture was stirred at room temperature for 3 h, then 1 mL of concentrated HCl was added and the mixture was stirred at 50° C., cooled to room temperature and 10 mL of ether was added. The mixture was cooled to −78° C., filtered; and the solid was washed with ether to yield 0.6 g of solid 70a as an HCl salt.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C:14]2[S:15][C:16]([C:19]3[C:23]([CH3:24])=[C:22]([C:25]([F:28])([F:27])[F:26])[O:21][N:20]=3)=[CH:17][CH:18]=2)=[O:13])[CH2:7]1)=O)C.[NH3:29]>>[CH3:24][C:23]1[C:19]([C:16]2[S:15][C:14]([C:12]([N:8]3[CH2:9][CH2:10][CH2:11][C@H:6]([C:4]([NH2:29])=[O:3])[CH2:7]3)=[O:13])=[CH:18][CH:17]=2)=[N:20][O:21][C:22]=1[C:25]([F:27])([F:28])[F:26]
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1
Reactant: N
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](C(N)=O)C3)s2)noc1C(F)(F)F
Yield: 86 %

Procedure:
A solution of (S)-1-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidine-3-carboxylic acid ethyl ester (Example 65, 88 mg, 0.20 mmol) in 7N methanolic ammonia (5 mL) was heated at 60° C. in a sealed vial for 48 hr. After this time the reaction mixture was evaporated and triturated and filtered with the aid of water. The filtered solids were air dried to afford product as a colorless solid (67 mg, 86%). LC/MS 5.52 min, [M+1]+ 388.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4](F)[C:3]=1[O:10][CH3:11].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:22](#[N:26])[CH:23]([CH3:25])[CH3:24].Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([C:23]([CH3:25])([CH3:24])[C:22]#[N:26])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1c(F)ccc(C)c1F
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1c(C(C)(C)C#N)ccc(C)c1F
Temperature: 25 °C
Reaction time: 240 h
Yield: 54.4 %

Procedure:
14.48 g (91.56 mmol) of 2,6-difluoro-3-methylanisole is dissolved in 800 ml of toluene. After 272.2 ml (137.35 mmol) of a 0.5 molar solution of potassium hexamethyl disilazide in toluene is added, 25.31 g (366.26 mmol) of isobutyronitrile is added in drops. The batch is stirred for 10 days at room temperature and then added to a 1 M HCl solution. After being extracted three times with methyl tert-butyl ether, the combined organic extracts are washed with saturated NaCl solution and dried. After spinning-in and chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 10.32 g (49.5%) of the desired compound is obtained.
Reaction SMILES: [CH2:1]1[O:6][CH:2]1[CH2:3][CH2:4][CH3:5].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]>>[CH2:13]([NH:14][CH2:1][CH:2]([OH:6])[CH2:3][CH2:4][CH3:5])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:1][CH:2]([OH:6])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC1CO1
Reactant: NCCCCCCN
Product: CCCC(O)CNCCCCCCNCC(O)CCC

Procedure:
Condensation of 1-pentene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxypentylamine] (I: R = CH3 (CH2)2, R' = H, X = (CH2)6, Z = H).
Reaction SMILES: [C:1]([C:3](=[C:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)SC)[C:4]([NH2:6])=[O:5])#[N:2].O.[NH2:21][NH2:22]>C(O)C>[NH2:2][C:1]1[NH:22][N:21]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NN
Reactant: CSC(Nc1ccc(C(C)C)cc1)=C(C#N)C(N)=O
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(Nc2n[nH]c(N)c2C(N)=O)cc1
Temperature: 75 °C
Yield: 66 %

Procedure:
2-cyano-3-((4-isopropylphenyl)amino)-3-(methylthio)acrylamide (1.360 g) was suspended in 15 mL of ethanol and hydrazine hydrate (360 μL, 1.5 eq.) was added drop wise to the reaction. Reaction was then heated at 75° C. until the starting material was no longer present and confirmed via HPLC. Once starting material was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-isopropylphenyl)amino)-1H-pyrazole-4-carboxamide as an off white to yellow powder. The product was allowed to dry under vacuum for 1 hr (850 mg, 66% yield).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][N:35]([CH3:40])[CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[CH3:34][N:35]([CH3:40])[CH:36]1[CH2:39][N:38]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:37]1
Reactant: CN(C)C1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CN(C)C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 72.1 %

Procedure:
To 310 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 100 mg of 3-(dimethylamino)azetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 15 minutes. After adding 1 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 87 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][C:11](Cl)=[CH:10][CH:9]1[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Li+].[Li+].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][CH2:11][CH2:10][CH:9]1[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1=CC(Cl)=CC(C2CCCC2)N1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CO
Product: CC1=CCCC(C2CCCC2)N1C(=O)OC(C)(C)C

Procedure:
To a stirred solution of 1-(tert-Butoxycarbonyl)-4-chloro-6-methyl-2-cyclopentyl-1,2-dihydropyridine (2.54 g, 8.53 mmol) in 175 mL of MeOH at 0° C. was added of lithium carbonate (0.63 g, 8.53 mmol) followed by 5% Pd/C. The mixture was placed under a positive pressure of hydrogen gas from a balloon, and the reaction progress was monitored by removing aliquots with a syringe, concentrating the aliquot in vacuo, and examining its 1H NMR spectrum. Upon completion, the mixture was filtered through Celite and evaporated. The residue was dissolved in ether (100 mL) and water (50 mL) was added, and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with 1M NaOH and brine. The organic phase was dried with potassium carbonate, filtered through Celite, and concentrated in vacuo to give the crude product. Purification by column chromatography (silica gel, 5% EtOAc in hexanes) afforded 1.14 g (52%) as a clear oil that was homogeneous by TLC analysis. 1H NMR (300 MHz) δ4.87 (br s, 1 H), 4.45-4.40 (m, 1 H), 2.22, (m, 1H), 2.02 (s, 3 H), 1.99-1.91 (m, 2 H), 1.82-1.20 (m, 21 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.[CH:19](=O)[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25].C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[NH2:1][CH:2]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=[CH2:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Reactant: C=CCCCCC=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCCCC(N)Cc1ccc(OC(C)(C)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.3 %

Procedure:
1.2 g of ethyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropionate [WO 92/10468, example 2, intermediate (c)] was dissolved in THF (20 mL). Hept6-enal (0.43 g) and 4A sieves (0.6 g ) were added. After 10 minutes, 0.25 g of sodium cyanoborohydride was added and the mixture stirred at room temperature for 50 minutes. The reaction mixture was poured into 5% aq. sodium carbonate and extracted with ethyl acetate. The organic extract was washed with brine, dried over MgSO4 and concentrated. Purification by flash chromatography (5-10% MeOH/CH2Cl2) gave 0.15 g of ethyl 2-[4-(2-amino-[6-heptenyl]ethyl) phenoxy]-2-methylpropionate as a light brown viscous oil. This material was dissolved in CH2Cl2 (5 mL) and 4-fluorophenylisocyanate (0.05 mL) was added. The solution was stirred at rt for 3 hours and then concentrated. Purification by flash chromatography gave 0.08 g of ethyl 2-(4-[2-(3-[4-fluorophenyl]-1-[6-heptenyl]ureido) ethyl]phenoxy)-2-methylpropionate as a yellow solid. This material was dissolved in EtOH (3 mL) and 1M aq. NaOH (1.5 mL), and the solution was heated at reflux for 30 min. The solution was concentrated, poured into 1N HCl and extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated to a yellow solid. Recrystallization fron ether/hexane gave 0.05 g of 2-(4-[2-(3-[4-fluorophenyl]-1-[6-heptenyl]ureido)ethyl]phenoxy)-2- methylpropionic acid as a white powder; m.p. 143-5 degC.