Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][C:5]2[NH:6][C:7]([C@@H:9]([NH:28][C:29](=[O:44])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:37])=[C:32]([CH3:43])[CH:31]=3)[CH2:10][CH2:11][C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH2:19][NH:20]C(OC(C)(C)C)=O)=[O:13])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:46]=[CH:45][C:5]2[NH:6][C:7]([C@@H:9]([NH:28][C:29](=[O:44])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:37])=[C:32]([CH3:43])[CH:31]=3)[CH2:10][CH2:11][C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH2:19][NH2:20])=[O:13])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCC(=O)N2CCC[C@@H]2CNC(=O)OC(C)(C)C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: ClCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N[C@@H](CCC(=O)N2CCC[C@@H]2CN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 100 %

Procedure:
Prepared from N-{(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-[(2R)-2-tert-butoxycarbonylaminomethylpyrrolidin-1-ylcarbonyl]propyl}-3-methyl-4-(pyrrolidin 1-ylcarbonyl)benzamide followed by treatment with trifluoroacetic acid analogously to Example 17. Yield: 100%; Rf value: <0.1 (silica gel; ethyl acetate); C29H35ClN6O5 (551.09); mass spectrum: (M+H)+=551/553 (chlorine isotope).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH:20]1[C:25]([C@@H:26]([NH2:29])[CH2:27][OH:28])=[CH:24][CH:23]=[C:22]([F:30])[CH:21]=1.CCN(C(C)C)C(C)C>>[F:30][C:22]1[CH:21]=[CH:20][C:25]([C@@H:26]([NH:29][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH2:27][OH:28])=[CH:24][CH:23]=1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H](CO)c2ccc(F)cc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Then the similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-4-fluoro-phenylglycinol and DIEA to give 2-[(R)-1-(4-fluoro-phenyl)-2-hydroxy-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 394 (MH+).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[CH2:20][CH2:19][N:18]=2)[CH2:16][CH2:15][CH2:14]1.Cl[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>O1CCCC1>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21]([CH2:20][CH2:19][N:18]=[C:17]2[C:13]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:14][CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: Clc1ccccn1
Reactant: COc1ccc2c(c1)C(C1CCC1)=NCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)C(C1(c3ccccn3)CCC1)=NCC2
Temperature: -23 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (7.3 ml, 2.09M in hexanes) was added dropwise at ambient temperature to a solution of diisopropylamine (2.12 ml) in dry tetrahydrofuran (14 ml). After 15 minutes, the solution was cooled to -23° C. and a solution of 1-cyclobutyl-7-methoxy-3,4-dihydroisoquinoline (3 g) in tetrahydrofuran (34 ml) was added. After 30 minutes the mixture was cooled to -78° C., treated with 2-chloropyridine (1.56 ml), stirred for 1 hour then warmed to ambient temperature. The mixture was heated under reflux for 5 minutes, stirred for 16 hours at ambient temperature, then heated under reflux for 30 minutes. The reaction mixture was poured onto water and extracted with ethyl acetate. The extracts were dried and concentrated and the residual orange oil heated at 90° C. at 13.3 mbar to remove excess 2-chloropyridine. The residue was purified by flash chromatography over silica gel using a 5:1 mixture of light petroleum and triethylamine as eluant to give 7-methoxy-1-[1-(2-pyridyl)cyclobutyl]-3,4-dihydroisoquinoline as a solid (0.58 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][CH:29]=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Sn](Cl)Cl.[N+](=[CH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N-]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29](=[O:30])[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: Cl[Sn]Cl
Solvent: ClCCl
Product: CCOC(=O)CC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CC)C1=O
Temperature: 25 °C
Reaction time: 14.25 h

Procedure:
To a suspension of 160 mg (0.36 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetaldehyde (Example 79, Step A) and 20.4 mg (0.11 mmol) of tin(II) chloride in DCM (6 mL) was added 104 μL (1.00 mmol) of ethyl diazoacetate via syringe over 3 min. The resulting yellow slurry was stirred at room temperature for 14.25 h, then was quenched with 1 N HCl and extracted with EtOAc (2×). The combined organic layers were washed with 1 N HCl (1×), then were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 55% MeCN in water to 85% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound as a light yellow oil.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[C:16]1([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Ic1ccccc1
Reactant: C1COCCN1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Solvent: CCCCCC
Product: c1ccc(N2CCOCC2)cc1
Yield: 76 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), morpholine (130 μL, 1.50 mmol), iodobenzene (112 μL, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=20/1, Rf=0.2) afforded N-(phenyl)morpholine (124 mg, 76% isolated yield) as colorless liquid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Desmarets, C.; Schneider, R.; Fort, Y. Tetrahedron Lett. 2000, 41, 2875-2879.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.Br[C:15]1[N:16]=[C:17]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH3:32])[CH2:27][CH2:26]2)[C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.[ClH:33]>>[ClH:33].[CH2:11]([C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([C:15]2[N:16]=[C:17]([N:25]3[CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH2:30]3)[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:7][N:6]=1)=[O:10])[CH2:12][CH3:13]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC(=O)Nc1ccc(Br)cn1
Agent: Cl
Product: CCCC(=O)Nc1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cn1

Procedure:
In the same manners sequentially as in Examples 161-2 and 20, the free compound of the title compound (338 mg, yield; 40%) from 5-bromo-2-propylcarbonylaminopyridine (3.11 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (514 mg). The resulting free compound was converted into a hydrochloride in a conventional manner, to give the hydrochloride of the title compound as yellow crystals.
Reaction SMILES: O.[NH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:42]=[CH:41][C:16]([CH2:17][C:18]2[NH:19][C:20](=[O:40])[C:21]3[C:26]([CH2:27][CH3:28])=[N:25][N:24]([CH:29]([CH3:39])[CH2:30][CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:22]=3[N:23]=2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[NH2:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:42]=[CH:41][C:16]([CH2:17][C:18]3[NH:19][C:20](=[O:40])[C:21]4[C:26]([CH2:27][CH3:28])=[N:25][N:24]([CH:29]([CH3:39])[CH2:30][CH2:31][CH2:32][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:22]=4[N:23]=3)=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCc1nn(C(C)CCCc2ccccc2)c2nc(Cc3ccc(Br)cc3)[nH]c(=O)c12
Reactant: Nc1cccc(B(O)O)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: O
Solvent: C1CCOC1
Product: CCc1nn(C(C)CCCc2ccccc2)c2nc(Cc3ccc(-c4cccc(N)c4)cc3)[nH]c(=O)c12
Temperature: 70 °C
Reaction time: 1 h
Yield: 6.4 %

Procedure:
697 mg (4.5 mmol) of 3-aminophenylboronic acid monohydrate and 150 mg of tetrakistriphenylphosphine-palladium are added under argon to a solution of 1.66 g (3.47 mmol) of 6-(4-bromo-benzyl)-1-(1-methyl-4-phenyl-butyl)-3-ethyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one in 38 ml of THF, and the mixture is stirred for one hour at 70° C. After 4.9 ml of 1N Na2CO3 solution have been added, the mixture is stirred for a further 4 hours at 70° C., the solvent is removed in vacuo, and the residue is taken up in CH2Cl2. The mixture is extracted with 2N HCl, and the aqueous phase is rendered alkaline with 1N NaOH and extracted twice with CH2Cl2. After the extract has been dried over Na2SO4, the solvent is removed in vacuo. Purification by chromatography (toluene/ethyl acetate=4:1) gives 110 mg (6.4%) of a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:26])[C:10]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=2)[N:14]=1)[C:5](O)=[O:6].[CH3:27][N:28](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:29].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>C(#N)C.O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:26])[C:10]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=2)[N:14]=1)[C:5]([N:28]([CH3:29])[CH3:27])=[O:6]
Reactant: Cn1cc(Nc2nccc(NCc3c(F)cc(C(=O)O)cc3F)n2)cn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C)C(=O)c1cc(F)c(CNc2ccnc(Nc3cnn(C)c3)n2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,5-difluoro-4-(((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)methyl)benzoic acid (crude from step i, theoretical 60 mg, 0.17 mmol), HATU (82 mg, 0.22 mmol), DIPEA (43 mg, 0.33 mmol) and dimethylamine (excess) in acetonitrile (10 mL) was stirred at room temperature overnight then further DMF, HATU, DIPEA and dimethylamine were added to push the reaction to completion. After 5 h the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, concentrated in vacuo and purified by prep. TLC (10% v/v MeOH/DCM) to afford 3,5-difluoro-4-(((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)methyl)-N,N-dimethylbenzamide I-7 (30 mg, 0.07 mmol) as a white solid. LC-MS (Method A), RT=7.79 min. (ES+) 388.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[H][H]>N.[Ni]>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:11]
Reactant: [H][H]
Reactant: Cc1cccc(CC#N)c1C
Agent: [Ni]
Agent: N
Product: Cc1cccc(CCN)c1C

Procedure:
A mixture of 2,3-dimethylphenylacetonitrile (J. Org Chem, 51(26), 5157-60; 1986), (190 mg, 1.31 mmol) and Raney® nickel (100 mg) in 2M methanolic ammonia (5 mL) was stirred under 50 psi of hydrogen gas for 4 days. The mixture was then filtered through Arbocel® and concentrated in vacuo to afford the title compound as a solid, 130 mg.
Reaction SMILES: [BrH:1].O.Br.C([O:8][C:9]([CH2:11][CH2:12][C:13]([NH:15][CH2:16][C:17]1[O:21][C:20]([C:22]([O:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:35](=[NH:37])[NH2:36])[CH:31]=3)[CH:26]=2)=[O:23])=[CH:19][CH:18]=1)=[O:14])=[O:10])(C)(C)C>C(O)(=O)C>[BrH:1].[C:9]([CH2:11][CH2:12][C:13]([NH:15][CH2:16][C:17]1[O:21][C:20]([C:22]([O:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:35](=[NH:36])[NH2:37])[CH:31]=3)[CH:26]=2)=[O:23])=[CH:19][CH:18]=1)=[O:14])([OH:10])=[O:8]
Reactant: CC(C)(C)OC(=O)CCC(=O)NCc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)o1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)CCC(=O)O)o3)ccc2c1
Reaction time: 3 h

Procedure:
To 250 g of a 30% hydrobromic acid solution in acetic acid was added with water-cooling 8.0 g of 6-amidino-2-naphthyl 5-(3-t-butoxycarbonylpropionylaminomethyl)furan-2-carboxylate hydrobromide, and the mixture was stirred for 3 hours. The precipitate was filtered off, and the filtrate was poured into 2 l of ether. The mixture was stirred for 3 hours at room temperature and the precipitate was collected by filtration to obtain 5 g of the intended product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][OH:18])=[CH:11][C:10]=2[F:19])=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[N:24]#[C:25][NH2:26].[F:27][C:28]([F:34])([F:33])[S:29]([OH:32])(=[O:31])=[O:30]>C1COCC1>[OH:32][S:29]([C:28]([F:34])([F:33])[F:27])(=[O:31])=[O:30].[C:25](=[NH:24])([O:18][CH2:17][CH2:16][C:12]1[CH:13]=[C:14]([F:15])[C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:20]([F:23])([F:22])[F:21])[CH:4]=2)=[C:10]([F:19])[CH:11]=1)[NH2:26]
Reactant: OCCc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Reactant: N#CN
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 31.3 %

Procedure:
To a solution of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3,5-difluorophenyl)ethanol (3.1 g, 8.79 mmol) and cyanamide (0.443 g, 10.55 mmol) in anhydrous THF (20 mL) was added trifluoromethanesulfonic acid (1.873 mL, 21.10 mmol) at 0° C. The reaction mixture was stirred at 60° C. for 4 h. Purification via reverse phase Biotage then afforded the title compound as a white solid (1.5 g, 31.3% yield). LCMS: rt=3.64 min, [M+H+]=395
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[S:15][C:14]([C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:17])=[CH:13][C:12]=3[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH2:7][CH2:6]2)[O:4]CC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.CC(C)=O>[C:16]([C:14]1[S:15][C:11]([N:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)=[C:12]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[CH:13]=1)(=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)c1cc(-c2ccncc2)c(N2CCC3(CC2)OCCO3)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCN(c2sc(C(=O)c3ccccc3)cc2-c2ccncc2)CC1
Yield: 62.6 %

Procedure:
A solution of [5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-pyridin-4-yl-thiophen-2-yl]-phenyl-methanone (39.5 mg, 0.097 mmole), p-toluenesulfonic acid monohydrate (37 mg, 0.194 mmole, 2 eq.), acetone (2 mL), and water (1 mL) was heated to reflux overnight. The solution was diluted with water and made basic to pH 14 with 4N sodium hydroxide or 1 M sodium carbonate solution. The solution was extracted twice with ethyl acetate. The organic extracts were dried over magnesium sulfate, filtered, and purified by column chromatography to provide the product as yellow solid (22 mg, 63%). 1H NMR (CDCl3) δ 8.61 (m, 2H), 7.81-7.45 (m, 8H), 3.46 (m, 4H), 2.52 (m, 4H). MS (m/z): 363 (MH+), 385 (MNa+).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[CH:16]=[C:15]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14]2)[CH:8]=1.CN(C)[CH:19]=[O:20]>>[CH3:6][C:7]1[CH:8]=[C:9]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=[CH:10]2)[C:16]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: Cc1cc2cccccc-2c1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2cccccc-2c1C=O

Procedure:
POCl3 (3.86 mL, 42.2 mmol) was added slowly to a stirring dimethylformamide (DMF) solution at 0° C. The mixture was cooled for 1 h before a DMF solution of 2-methyl azulene (2.0 g, 14.1 mmol) was added drop-wise. The reaction was mixed for 2 h at 0° C., and then quenched with cold 10% NaOH. The organic layer was extracted into ethyl acetate after which the extracts were washed with water and brine, dried with MgSO4 and purified using flash chromatography (ethyl acetate and hexane). The purified material was dried down into a dark red solid. Yield: 2.389 g, 89%. 1H NMR (400 MHz, CDCl3) δ 10.50 (s, 1H), 9.44 (d, J=9.73 Hz, 1H), 8.29 (d, J=9.72 Hz, 1H), 7.72 (t, J=9.82 Hz, 1H), 7.56 (t, J=9.82 Hz, 1H), 7.46 (t, J=9.67 Hz, 1H), 7.08 (s, 1H), 2.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 185.8, 154.9, 144.4, 142.1, 137.9, 136.4, 129.7, 128.5, 122.5, 120.3, 15.1. HRMS (ES) calcd. MH+(C12H11O) 171.0732 found 171.0804.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20]C=CC=2)[CH:6]=[CH:5][C:4]([C@@:7]2([CH3:15])[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:14])=[CH:3][CH:2]=1.[CH2:22](C1C=CC(C(C(OCC)=O)=O)=CC=1)C(C)C.C1C=CC([C@H](N)CO)=CC=1.C(C1C=CC([C@H](C)C(OC)=O)=CC=1)C(C)C>>[OH:13][C:9]1[C:10](=[O:12])[O:11][C@@:7]([CH3:15])([C:4]2[CH:3]=[CH:2][C:1]([CH2:16][CH:21]([CH3:20])[CH3:22])=[CH:6][CH:5]=2)[C:8]=1[OH:14]
Reactant: CCOC(=O)C(=O)c1ccc(CC(C)C)cc1
Reactant: C[C@]1(c2ccc(-c3ccccc3)cc2)OC(=O)C(O)=C1O
Agent: COC(=O)[C@@H](C)c1ccc(CC(C)C)cc1
Agent: N[C@H](CO)c1ccccc1
Product: CC(C)Cc1ccc([C@]2(C)OC(=O)C(O)=C2O)cc1
Yield: 19 %

Procedure:
(S)-(+)-3,4-Dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone was synthesized in an analogous manner used for the production of (R)-(−)-5-[(1,1′-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone starting with ethyl 4-isobutylbenzoylformate. (S)-(+)-Phenylglycinol was used to resolve the methyl (S)-(+)-2-(4-isobutylphenyl)propionate enantiomer, of which 1.2 g (5 mmol) was converted into 250 mg (19% yield) of (S)-(+)-3,4-dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone as a white crystalline material: mp 175-177° C. dec. (CHCl3/hexanes); [α]25D+132° (c=1.55; MeOH) 1H NMR (acetone-d6) δ 7.44-7.14 (m, 4H), 2.48 (d. 2H, J=7.1 Hz), 1.87-1.82 (m, 1H), 1.83 (s, 3H), 0.88 (d, 6H, J=6.5 Hz). Anal Calcd for C15H18O4: C, 68.68; H, 6.92. Found: C, 68.08; H, 6.90.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:27]=3[CH3:26])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: Cc1cc(Cl)ccc1C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1C(=O)OC1CCN(C)C(=O)N1c1nnc(C(C)(C)C)s1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Methyl-4-chlorobenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro- 1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(2-methyl- 4-chlorobenzoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.[CH3:15][NH:16][CH3:17]>C1COCC1>[CH3:15][N:16]([CH3:17])[CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1
Reactant: CNC
Reactant: Nc1ccc(OCCBr)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(N)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a seal tube was added 4-(2-bromoethoxy)-2-nitroaniline (4.5 g, 17 mmol), THF and 40 mL of 2M dimethylamine in THF. The mixture was heated to 80° C. and was stirred overnight. The suspension was concentrated, and the residue was triturated with ether to give 3.5 g of 4-(2-(dimethylamino)ethoxy)-2-nitroaniline which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.24 (s, 1H), 6.91 (d, 1H), 6.61 (d, 1H), 5.85 (bs, 2H), 4.04 (t, 2H), 2.78 (t, 2H), 2.27 (s, 6H). MS (EI): 226 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:32]=[CH:31][C:15]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:14][C:13]=2[CH3:33])=O)=[CH:4][C:3]=1[CH3:34].Cl.[NH2:36][C:37]([NH2:39])=[O:38]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:12]3[CH:32]=[CH:31][C:15]([O:16][CH2:17][CH:18]4[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]4)=[CH:14][C:13]=3[CH3:33])[NH:39][C:37](=[O:38])[N:36]=2)=[CH:4][C:3]=1[CH3:34]
Reactant: NC(N)=O
Reactant: Cc1cc(/C=C/C(=O)c2ccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)cc2C)ccc1O
Agent: Cl
Product: Cc1cc(-c2cc(-c3ccc(OCC4CCNCC4)cc3C)[nH]c(=O)n2)ccc1O
Temperature: 110 °C
Yield: 6.9 %

Procedure:
To a sealed pressure vessel was added (E)-tert-butyl 4-((4-(3-(4-hydroxy-3-methylphenyl)acryloyl)-3-methylphenoxy)methyl)piperidine-1-carboxylate (100 mg, 0.215 mmol), 4N HCl in dioxanes (2.0 mL), and urea (64 mg, 1.07 mmol). The pressure vessel was sealed and heated to 110° C. overnight. The reaction was then cooled to rt, concentrated via rotary evaporation and purified via preparatory HPLC (5-85% AmAc) to give 4-(4-hydroxy-3-methylphenyl)-6-(2-methyl-4-(piperidin-4-ylmethoxy)phenyl)pyrimidin-2(1H)-one (6.0 mg, 7% yield).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH2:34]>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH:34][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=2)[CH:18]=1
Reactant: NCCc1ccccc1F
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCCc3ccccc3F)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(2-fluorophenyl)ethylamine gave the title compound as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[O:14][C:15](/[CH:18]=[C:19]3/[C:20](=[O:28])[NH:21][C:22]4[C:27]/3=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][CH:17]=2)[CH:8]=1)=[O:5].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CN1C(=O)CCC1>[O:28]=[C:20]1[NH:21][C:22]2[C:27](/[C:19]/1=[CH:18]\[C:15]1[O:14][C:13]([C:9]3[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:12]=[CH:11][CH:10]=3)=[CH:17][CH:16]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: O=C(CCCl)Nc1cccc(-c2ccc(/C=C3/C(=O)Nc4ccccc43)o2)c1
Reactant: C1CCNC1
Solvent: CN1CCCC1=O
Product: O=C(CCN1CCCC1)Nc1cccc(-c2ccc(/C=C3/C(=O)Nc4ccccc43)o2)c1

Procedure:
A solution of (E)-3-chloro-N-(3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)phenyl)propanamide (25 mg, 0.06 mmol) and pyrrolidine (0.025 mL) in NMP (0.75 mL) was heated in microwave (100° C., 5 min). The reaction mixture was purified by RHPLC to yield the desired (E)-N-(3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)phenyl)-3-(pyrrolidin-1-yl)propanamide LCMS (ES): m/z 428 [M+1]+.