Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>C1(C)C=CC=CC=1>[C:26]1([NH:25][C:10](=[O:11])[C:9]2[CH:13]=[C:5]([O:4][C:3]3[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=3[Cl:1])[CH:6]=[CH:7][C:8]=2[N+:14]([O-:16])=[O:15])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: Nc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 62.6 %

Procedure:
To a stirred solution of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoyl chloride (5.68 g, 0.015 mole) in toluene (35 ml) was added aniline (2.8 g, 0.30 mole). The temperature immediately rose to 45° C. The reaction was then heated to reflux for twelve hours. The cooled reaction was poured into dilute hydrochloric acid solution. The residual solids were filtered, washed with warm water and dried to give 4.1 g of a gray solid m.p. 190°-4° C. Recrystallization from methanol gave 3.8 g, m.p. 191°-4° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)=[CH:12][N:11]3[C:25]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.[C:30]1([C:36]([NH2:39])([CH3:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:21])[NH:39][C:36]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)([CH3:38])[CH3:37])[CH:17]=4)=[CH:12][N:11]3[C:25]=2[C:26]([NH:27][CH3:28])=[O:29])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(-c3cccc(C(=O)O)c3)cn12
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
3-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)imidazo[1,2-a]pyridin-6-yl)benzoic acid (40 mg, 0.10 mmol) and 2-phenylpropan-2-amine (21 mg, 0.15 mmol) were dissolved into DMF (0.7 mL) and TEA (0.1 mL). HATU (59 mg, 0.15 mmol) was added to this solution (solution became yellow). The reaction was stirred at rt for 2 hrs (complete by LCMS). The reaction was diluted with MeOH (0.7 mL), filtered and purified by prep HPLC (acetonitrile/water, with 10 mM ammonium acetate buffer) to yield 2-(4-fluorophenyl)-N-methyl-6-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)imidazo-[1,2-a]pyridine-3-carboxamide (24.1 mg, 0.045 mmol, 44% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 9.25 (br s, 1H), 8.14 (br s, 1H), 7.92-7.86 (m 3H), 7.81-7.79 (m, 3H), 7.63 (t, J=7.8 Hz, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.35 (d, J=7.3 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.9 Hz, 1H), 7.27 (d, J=8.6 Hz, 1H), 7.22 (t, J=7.2 Hz, 1H), 2.90 (s, 3H), 1.81 (s, 6H). LC-MS retention time 1.74 min; m/z 507 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 mM, and an analysis time of 5 min where solvent A was 10% acetonitrile/90% H2O/0.1% TFA and solvent B was 10% H2O/90% acetonitrile/0.1% TFA. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]1)=[O:7].O[N:28]=[C:29]([NH2:33])[CH:30]([CH3:32])[CH3:31]>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[CH2:11][CH:10]([C:24]2[O:25][N:33]=[C:29]([CH:30]([CH3:32])[CH3:31])[N:28]=2)[CH2:9]1)=[O:7]
Reactant: CC(C)C(N)=NO
Reactant: COCCNC(=O)N1CC(C(=O)O)CC(c2ccc(C(F)(F)F)cc2)C1
Product: COCCNC(=O)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C(C)C)no2)C1
Yield: 51.4 %

Procedure:
100 mg (0.267 mmol) of the compound from Example 105A and 51 mg (0.497 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Diastereomer separation of 83 mg of the cis/trans isomer mixture according to Method 14C gave 60.5 mg of the title compound and 6.7 mg of the trans isomer.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:30])[C@H:24]([C@H:26]([CH2:28][CH3:29])[CH3:27])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:30])=[O:22])[C@H:26]([CH2:28][CH3:29])[CH3:27])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1)C(=O)O

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-isoleucine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:17]=1[C:18](Cl)=[O:19]>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[C:17]2[C:16]([F:15])=[CH:24][CH:23]=[CH:22][C:21]=2[F:25])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)c1c(F)cccc1F
Temperature: 0 °C
Yield: 66.3 %

Procedure:
To a stirred and 0° C. cooled solution of 4-bromoaniline (1.0 g, 5.8 mmol, 1.0 eq) and pyridine (0.61 mL, 7 mmol, 1.2 eq) in DCM (20 mL) was added drop wise a solution of 2,6-difluorobenzoyl chloride (0.8 mL, 6.4 mmol, 1.1 eq) in DCM (5 mL). After stirring the resulting mixture at the same temperature for 1 h, the solvent was removed under vacuum. The residue was taken into ethyl acetate (20 mL) and water (20 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to afford 1.20 g of the desired product as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 7.78 (brs, 1H, D2O exchangeable), 7.53-7.37 (m, 5H), 7.02-6.95 (m, 2H); ESI-MS (m/z) 312, 314 [(MH)+ Br79,81].
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10]OC1CCCCO1.[O:22]1C=C[CH2:25][CH2:24][CH2:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][CH:9]1[CH2:10][CH2:25][CH2:24][CH2:23][O:22]1
Reactant: C1=COCCC1
Reactant: Brc1ccccc1COCCOCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Brc1ccccc1COCCOC1CCCCO1
Reaction time: 4 h

Procedure:
The reaction and work up was conducted as described in the preparation of compound 420. Starting materials were compound 417 (8.0 g, 34.9 mmol) in 20 mL dry THF, 3,4-dihydro-2H-pyran (3.2 mL, 34.9 mmol) and p-toluenesulfonic acid (0.14 g, 0.76 mmol) and the reaction time was 4 h. The crude product was purified by flash chromatography using EtOAc/petroleum ether 1:2 as the eluent to afford the title compound as a colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[CH:31]=[CH:30][N:29]=[C:28]([O:27][CH3:26])[CH:33]=5)[CH:3]=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1cc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)n2)ccn1
Temperature: 80 °C
Yield: 35.3 %

Procedure:
N-(6-Chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in a reaction tube. 2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (55 mg, 0.36 mmol), 0.3 mL of an aqueous 2 M sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol) were added and the reaction mixture was heated at 80° C. overnight. The reaction mixture was diluted with dichloromethane (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexane to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-4-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (31 mg, 35%). ESI-MS m/z calc. 439.1. found 440.3 (M+1)+. Retention time 2.12 minutes.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[C:26]([C:30]1[O:34][C:33]([CH3:35])=[C:32]([C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:31]=1)([CH3:29])([CH3:28])[CH3:27].NC1C=CNN=1>O1CCCC1>[C:26]([C:30]1[O:34][C:33]([CH3:35])=[C:32]([C:36]2[CH:37]=[C:38]([NH:41][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:13])[NH:39][N:40]=2)[CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1oc(C(C)(C)C)cc1-c1cc(N)[nH]n1
Reactant: O=C1Nc2cc(F)ccc2/C1=C/O
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: Cc1oc(C(C)(C)C)cc1-c1cc(NC=C2C(=O)Nc3cc(F)ccc32)[nH]n1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 5-(5-tert-butyl-2-methyl-furan-3-yl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one (0.033 gms.) is reacted with 0.089 gms. 5-(5-tert-butyl-2-methyl-furan-3-yl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (0.88 mL) to afford the named compound in the amount of 0.0362 gms.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.N1C=CC=CC=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26][C:27](=O)[CH2:28][CH2:29][CH2:30][OH:31])=[CH:21][CH:20]=1>CO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[C:27]([CH2:28][CH2:29][CH2:30][OH:31])[CH:26]=2)=[CH:23][CH:24]=1
Reactant: O=C(CCCO)CC(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(-n2nc(CCCO)cc2-c2ccc(Cl)cc2)cc1
Reaction time: 1.5 h
Yield: 72 %

Procedure:
4-Methoxyphenylhydrazine hydrochloride [35.0 grams (g), 0.20 moles] was added to CH3OH [50 milliters (ml)] containing pyridine (20 ml). An additional amount of CH3OH (25 ml) was added to the thick resulting slurry. 1-(4-Chlorophenyl)-6-hydroxyhexan-1,3-dione (48.2 g, 0.20 moles), was added neat, followed by more CH3OH (25 ml). The slurry was stirred at room-temperature for 1.5 hours, after which time the mixture was concentrated and taken up in CHCl3 (300 ml). The CHCl3 solution was washed with 1N HCl (300 ml), dried (Na2SO4), fitered, and concentrated. The oil was decolorized (Norit) in hot diethyl ether (Et2O) (300 ml). The Et2O solution was cooled, and crystallization from Et2O (300 ml) afforded 2 (49.4 g). From the filtrate was obtained additional 2 (9.28 g), total yield 91%, mp 87.5°-88°. NMR (CDCl3) 1.7-2.3 (m, 2H, CH2CH2CH2), 2.55 (brs, 1H, OH), 2.80 (t, 2H, J=7 Hz, CH2), 3.75 (t, 2H, J=6 Hz, CH2O), 3.77 (s, 3H, OCH3), 6.28 (s, 1H, C4 --H), 6.93 (ABq, 4H, J=12, 9, 4--OMe--C6H4), 6.9-7.3 (m, 4H, 4--Cl--C6H4); IR (KBr) 3320, 2920, 1495; MS, m/e 342 (M+), 312, 298 (100%);
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:21]=[CH:22][C:23]([OH:53])=[C:24](/[CH:26]=[CH:27]/[CH:28]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([O:51][CH3:52])=[O:50])=[CH:45][CH:44]=2)[CH2:29][CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH:25]=1>C(#N)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:53][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)=[C:24](/[CH:26]=[CH:27]/[CH:28]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([O:51][CH3:52])=[O:50])=[CH:45][CH:44]=2)[CH2:29][CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH:25]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2cc(F)ccc2O)CCc2ccc(C(=O)OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2cc(F)ccc2OCc2ccc(C(F)(F)F)cc2)CCc2ccc(C(=O)OC)cc2)cc1
Temperature: 60 °C

Procedure:
280 mg (1.2 mmol) of 1-(bromomethyl)-4-(trifluoromethyl)benzene and 162 mg (1.2 mmol) of anhydrous potassium carbonate are added to a solution of 279 mg (0.59 mmol) of methyl 4-[(4E)-5-(5-fluoro-2-hydroxyphenyl)-3-{2-[4-(methoxycarbonyl)phenyl]ethyl} pent-4-en-1-yl]benzoate in 6.5 ml of dry acetonitrile, and the mixture is then heated at 60° C. for 12 hours. The mixture is then filtered, and the filtrate is evaporated to dryness. The residue is purified by preparative HPLC. This gives 274 mg (0.43 mmol, 74% of theory) of a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:29][C:30]([NH:32][C@@H:33]([CH3:37])[C:34](O)=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]=[C:37]2[C@@H:33]([NH:32][C:30]([O:29][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:31])[CH3:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccccc2N)C1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.4 %

Procedure:
A mixture of (R)-3-(2-aminophenylamino)piperidine-1-carboxylic acid tertbutyl ester (2.25 g, 7.72 mmol), (S)-2-benzyloxycarbonylaminopropionic acid (1.9 g, 8.49 mmol), HOAt (1.16 g, 8.49 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.63 g, 8.49 mmol) and 4-methylmorpholine (1.87 mL, 16.98 mmol) in anhydrous DCM (50 mL) was stirred at RT for 1.5 h. The reaction mixture was diluted with DCM (200 mL) and washed with a 10% citric acid solution, followed by a saturated solution of NaHCO3 and then brine. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (20 mL) and heated at 70° C. for 20 h and then at 80° C. for 2 h. After cooling to RT, volatiles were then removed in vacuo and the residue was dissolved in EtOAc (200 mL) and washed with a saturated solution of NaHCO3 (100 mL×2). The organic layer was then washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) affording (R)-3-[2-((S)-1-Benzyloxycarbonylaminoethyl)benzoimidazol-1-yl]piperidine-1-carboxylic acid tertbutyl ester as a white foam (2.75 g, 74%). LCMS: RT 3.16 min [M+H]+ 479.1.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Cl:34][C:35]1[N:40]=[N:39][C:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][C@H:42]2[CH3:47])=[C:37]2[CH:48]=[N:49][CH:50]=[CH:51][C:36]=12>CN(C=O)C>[Cl:34][C:35]1[N:40]=[N:39][C:38]([N:41]2[CH2:46][CH2:45][N:44]([C:8]([CH:5]3[CH2:4][CH2:3][C:2]([F:1])([F:11])[CH2:7][CH2:6]3)=[O:10])[CH2:43][C@H:42]2[CH3:47])=[C:37]2[CH:48]=[N:49][CH:50]=[CH:51][C:36]=12
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: C[C@@H]1CNCCN1c1nnc(Cl)c2ccncc12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)C2CCC(F)(F)CC2)CCN1c1nnc(Cl)c2ccncc12
Temperature: 55 °C
Reaction time: 17 h

Procedure:
4,4-difluorocyclohexanecarboxylic acid (277 mg, 169 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (411 mg, 1.61 mmol) were stirred in DMF (3 ml) and triethylamine (0.4 ml) for 2 minutes. The solution was added to (R)-1-chloro-4-(2-methylpiperazin-1-yl)pyrido[3,4-d]pyridazine 59 (387 mg, 1.47 mmol) and washed in with an additional 1 ml DMF. The reaction was heated at 55° C. for 1.5 hours and then stirred at RT for 17 hours. The reaction was added to saturated NaHCO3 (80 ml) and extracted three times with dichloromethane (50 ml). The combined organics were dried (MgSO4) and evaporated to give a yellow solid. The residue was chromatographed over silica with a gradient of hexane and 0-100% ethyl acetate to give (R)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-3-methylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone 60 as a yellow solid, 236 mg. LC/MS m/z=410 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][C@H:5]1[O:8][C:7](=[O:9])[CH2:6]1.[OH-:19].[Na+]>C1COCC1.O>[OH:8][C@H:5]([CH2:4][CH:3]([O:2][CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][C:7]([OH:19])=[O:9]
Reactant: [OH-]
Reactant: CCCCCCCCCC(C[C@@H]1CC(=O)O1)OC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCC(C[C@@H](O)CC(=O)O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(ref. Gu, et al. Nature 459, 731-735 (2009)). To a solution of 6 (92.0 mg, 0.359 mmol, 1.0 equiv) in THF (1.5 mL) was added a solution of NaOH (15.7 mg, 0.394 mmol, 1.1 equiv) in water (1.5 mL). The reaction mixture was stirred at rt for 1 h. During this time, its appearance changed from turbid to clear (t=about 0.5 h). The solution was quenched by addition of 1 M HCl (1 mL) and extracted with ether (2×5 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), dried (Na2SO4) and concentrated in vacuo to afford a pale yellow oil. Purification of the crude product by chromatography on SiO2 (1:1 EtOAc/hexanes containing 0.5% AcOH) provided (3R)-1 (94.4 mg, 96%) as a colorless oil: ATR/IR 2920, 2851, 1709, 1413, 1187, 1079, 736 cm−1; 1H NMR (CDCl3) 4.35-4.20 (m, 1H), 3.55-3.45 (m, 1H), 3.38, 3.37 (2s, 3H), 2.56-2.50 (m, 2H), 1.80-1.35 (m, 3H), 1.35-1.25 (m, 14H), 0.90 (t, 3H, J=6.9 Hz); 13C NMR (CDCl3) 176.4, 175.7, 68.1, 65.4, 56.7, 56.0, 41.6, 41.5, 39.7, 39.1, 32.9, 32.8, 31.9, 29.8, 29.6, 29.5, 29.3, 25.2, 24.5, 22.7, 14.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Cl:18][C:19]1[CH:33]=[CH:32][C:22]2[NH:23][C:24]([C@@H:26]([NH2:31])[CH2:27][CH2:28][O:29][CH3:30])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:33]=[CH:32][C:22]2[NH:23][C:24]([C@@H:26]([NH:31][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[CH2:27][CH2:28][O:29][CH3:30])=[N:25][C:21]=2[CH:20]=1
Reactant: COCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c(C)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propylamine, TBTU and DIPEA in THF with subsequent purification by chromatography on silica gel.
Reaction SMILES: C(OC(=O)C([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:25])[NH2:24])[CH:18]=2)=[O:15])=[N:10][CH:9]=1)C)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=[C:45]([CH2:47][C:48]([OH:50])=[O:49])N=2)CCCC1.C1(CNC2C=C(C=CC=2)C(N)=O)CCCC1.C(OC(=O)C(SC1SC(N)=NC=1)C)C>>[C:23]([C:19]1[CH:18]=[C:17]([N:16]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:45][CH2:47][C:48]([OH:50])=[O:49])=[CH:9][N:10]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:25])[NH2:24]
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(N)=O)c2)s1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: CCOC(=O)C(C)Sc1cnc(N)s1
Agent: NC(=O)c1cccc(NCC2CCCC2)c1
Product: NC(=O)c1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-carbamoyl-phenyl)ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-benzamide and (2-amino-thiazol-5-ylsulfanyl) propionic acid ethyl ester