Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH:10]([CH2:19][CH2:20][CH:21]=C)[C:11]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:12])[O:6][CH2:5][CH2:4][O:3]1.[O:23]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH:10]([C:11]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:12])[CH2:19][CH2:20][CH:21]=[O:23])[O:3][CH2:4][CH2:5][O:6]1
Reactant: C=CCCC(CCCC1(C)OCCO1)C(=O)N1CCOC1=O
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(CCCC(CCC=O)C(=O)N2CCOC2=O)OCCO1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-4 (1.8 g, 5.8 mmol), sudan III (10 mg) and CH2Cl2 (150 mL) at −78° C. under argon was bubbled ozone until the red solution changed to yellow-orange. The solution was purged with argon for 30 minutes. PPh3 (2.26 g, 8.7 mmol) was added followed by the removal of the cooling bath. After 1.5 h, the reaction was concentrated. Flash chromatography (silica, 20%-50% EtOAc/hexanes) gave 2-5 as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=1)[C:5]#N.C([OH:19])C.[OH-:20].[Na+].Cl>O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:9]=1)[C:5]([OH:19])=[O:20]
Reactant: [OH-]
Reactant: CCCCCCOc1cc(F)cc(C#N)c1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(F)cc(OC2CCCCC2)c1
Temperature: 75 °C

Procedure:
A mixture of 3-fluoro-5-hexyloxybenzonitrile (1.0 g, 4.56 mmol), ethanol (12 ml), water (12 ml), and aq. NaOH (50%, 12 ml) is heated at 75° C. for 18 hours. The mixture is then cooled in an ice bath and acidified with concentrated HCl to pH 1. The mixture is extracted with ethyl acetate and the organic layer washed with brine, dried over Na2SO4, and concentrated to afford 3-fluoro-5-cyclohexyloxybenzoic acid as a yellow solid. MS: 239.11(M+1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[NH2:13][C:14]1[C:15](=[O:28])[N:16]([CH2:25][CH2:26][CH3:27])[C:17](=[O:24])[N:18]([CH2:21][CH2:22][CH3:23])[C:19]=1[NH2:20].CCOC(/N=N/C(OCC)=O)=O>C(O)C.C(O)(=O)C>[CH2:25]([N:16]1[C:15](=[O:28])[C:14]2[NH:13][C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)=[N:20][C:19]=2[N:18]([CH2:21][CH2:22][CH3:23])[C:17]1=[O:24])[CH2:26][CH3:27]
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(-c3ccc4c(c3)OCCO4)nc2n(CCC)c1=O
Temperature: 60 °C
Yield: 92.2 %

Procedure:
2.18 g (0.013 mol) of 1,4-benzodioxan-6-aldehyde, 80 ml of ethanol and 2.4 ml of glacial acetic acid are mixed together and 2.8 g (0.012 mol) of 5,6-diamino-1,3-dipropyluracil are added thereto. The clear solution is refluxed for 21/4 hours and then cooled to 60° C. At this temperature, 2.1 ml (0.013 mol) of diethylazodicarboxylate are added dropwise and the viscous suspension produced is mixed with 80 ml of ethanol and refluxed for 2 hours. After a further 20 hours at ambient temperature the mixture is cooled to 5° C., the solid matter is filtered under suction and washed with ethanol and ether. 4.1 g of the title compound are obtained in the form of a grey solid (=92% of theory), melting point 280°-282° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1F>C(#N)C>[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1[N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: C1CSCCN1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(N2CCSCC2)c(F)c1
Yield: 88.6 %

Procedure:
Thiomorpholine (728 mg, 7.06 mmol) was added to a stirring solution of 3,4,5-trifluoronitro benzene (500 mg, 2.82 mmol) in acetonitrile (15 mL) and the reaction mixture was refluxed for 5 h. Evaporation of the solvent in a rotavapor under reduced pressure left a pasty mass which was dissolved in ethyl acetate (50 mL). Ethyl acetate portion was washed with water (30 mL×2) followed by brine (30 mL) and dried over sodium sulfate. Removal of volatiles yielded the title compound as yellow solid (650 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:29])[CH:3]=1.[C:30]1([CH2:36][C:37]([N:39]=[C:40]=[O:41])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.CCCCCC>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:19]1[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:27]=[CH:28][C:2]([NH:1][C:40]([NH:39][C:37](=[O:38])[CH2:36][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:41])=[CH:3][C:4]=3[F:29])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyridine (87.4 mg) in tetrahydrofuran (4.5 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 2.2 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (82 mg, 67%) as white powder.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([CH2:12][CH2:13][CH2:14][NH2:15])=[N:9][N:8]=1.I.CS[C:25]1[C:33]2[CH:34]=[CH:35][CH:36]=[C:31]3[C:32]=2[C:27](=[CH:28][CH:29]=[CH:30]3)[N:26]=1>C(O)C>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([CH2:12][CH2:13][CH2:14][NH:15][C:25]2[C:33]3[CH:34]=[CH:35][CH:36]=[C:31]4[C:32]=3[C:27](=[CH:28][CH:29]=[CH:30]4)[N:26]=2)=[N:9][N:8]=1
Reactant: CSC1=Nc2cccc3cccc1c23
Reactant: NCCCc1nnc(-c2ccccc2-c2ccccc2)s1
Agent: I
Solvent: CCO
Product: c1ccc(-c2ccccc2-c2nnc(CCCNC3=Nc4cccc5cccc3c45)s2)cc1

Procedure:
A solution of 3-(5-(2-biphenylyl)-1,3,4-thiadiazol-2-yl)propanamine in ethanol is treated with 2-methylthiobenz(cd)indole hydriodide by the conditions of Example 52. Neutralization yields the title compound.
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:14]([C:18]([OH:20])=O)=[CH:15][O:16][CH:17]=1)([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].CN(C)C=O.C(Cl)(=O)C([Cl:29])=O.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:14]([C:18]([Cl:29])=[O:20])=[CH:15][O:16][CH:17]=1)([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOP(=O)(OCC=C)OCc1cocc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=CCOP(=O)(OCC=C)OCc1cocc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[[Bis(allyloxy)phosphoryl]oxymethyl]-3-furoic acid (500 mg, 1.65 mmol) obtained from Example 35-(5) was dissolved in dichloromethane (10 ml), and N,N-dimethylformamide (0.03 ml) and oxalyl chloride (0.7 g, 5.5 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, and toluene was added thereto, then the solvent was distilled off under reduced pressure to give crude 4-[[bis(allyloxy)phosphoryl]oxymethyl]-3-furoyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][C:42]=1[N+:50]([O-:52])=[O:51].[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:30][CH2:31]4)[CH2:18]3)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=2)=[CH:43][C:42]=1[N+:50]([O-:52])=[O:51]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Reactant: O=[N+]([O-])c1cc(B(O)O)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(Cl)c([N+](=O)[O-])c2)c1
Temperature: 100 °C
Reaction time: 60 h
Yield: 52 %

Procedure:
To 171.5 mg (0.28 mmol) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 8c) in 7 ml toluene were added 6.5 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium(0), 68.0 mg (0.34 mmol) (4-chloro-3-nitro-phenyl)boronic acid in 1.7 ml ethanol and 50.7 mg (0.87 mmol) potassium fluoride in 1.7 ml water. The mixture was stirred at 100° C. for 60 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 100 mg (47%) tert-butyl 4-{3-[(3R)-3-({1-[5-(4-chloro-3-nitrophenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Cl:24][C:25]([Cl:29])([Cl:28])[CH2:26]O>>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:26][C:25]([Cl:29])([Cl:28])[Cl:24])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OCC(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCC(Cl)(Cl)Cl)o1

Procedure:
The title compound was prepared as described in Example 1 starting from 0.228 g (0.7 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid and 0.196 mL (2.04 mmol) of 2,2,2-trichloroethanol. 1H NMR (400 MHz, DMSO-d6) δ: 7.4 (d, 1H), 5.74 (d, 1H), 5.03 (s, 2H), 4.19 (t, 2H), 1.7 (p, 2H), 1.2-1.5 (m, 22H), 0.85 (t, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1.C(N(CC)CC)C.[S:25](Cl)([CH3:28])(=[O:27])=[O:26]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1)[S:25]([CH3:28])(=[O:27])=[O:26]
Reactant: CNc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(c1ccc([N+](=O)[O-])c(N2CCCCC2)c1)S(C)(=O)=O
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of N-methyl-(4-nitro-3-piperidin-1-yl-phenyl)-amine (128 mg, 0.54 mmol, as prepared in the previous step) and triethylamine (301 μL, 2.16 mmol) in 4 mL of CH2Cl2 was added mesyl chloride (125 μL, 1.62 mmol) via microsyringe and the reaction was allowed to stir overnight. At this time it was diluted with CHCl3 (50 mL), washed with satd aq NaHCO3 (2×50 mL), and dried (Na2SO4). Concentration of the solvent in vacuo and purification of the crude material using preparative TLC (4% MeOH—CHCl3) afforded 154 mg (91%) of the title compound as an oil. Mass spectrum (ESI, m/z): Calcd. for C13H19N3O4S, 314.1 (M+H), found 314.1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:16][C:17]4[CH:22]=[N:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: N#Cc1ccc(N)cn1
Solvent: c1ccncc1
Product: N#Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cn1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 5-aminopicolinonitrile (24 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 307.3, found 308.3 (M+1)+. Retention time 2.87 minutes.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[S:9](=O)(=[O:18])([O:11]C1C=CC=CC=1)[NH2:10].C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH3:7][O:6][C:4]([CH:3]([CH3:8])[CH2:2][O:1][S:9](=[O:18])(=[O:11])[NH2:10])=[O:5]
Reactant: COC(=O)[C@@H](C)CO
Reactant: NS(=O)(=O)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)C(C)COS(N)(=O)=O
Yield: 39.6 %

Procedure:
A mixture of 5.9 g (0.05 mole) of (S)-(+)methyl 3-hydroxy-2-methylpropionate, 9.5 g (0.055 mole) of phenyl sulfamate, 25 ml of toluene and 0.5 g of pyridine was heated at reflux for 2 hr. The reaction solution was concentrated under vacuum, and the residue was chromatographed, using silica gel and eluting with 2% methanol in methylene chloride. The desired fractions were concentrated under vacuum to give 3.9 g (40%) of a pale yellow oil.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([OH:19])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].Br[C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[N:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][C:24]2[CH:29]=[N:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH:13]=1)=[O:10])([CH3:4])[CH3:5])#[N:2]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc([N+](=O)[O-])nc1
Yield: 62.4 %

Procedure:
A solution of 3-(1-cyano-1-methylethyl)-N-(3-hydroxy-4-methylphenyl)benzamide (8.35 g, 28.4 mmol), 5-bromo-2-nitropyridine (5.24 g, 25.8 mmol) and cesium carbonate (16.8 g, 51.6 mmol) in N,N-dimethylformamide (70 mL) was stirred at 60° C. for 4 hr. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL, 2×50 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=90/10→60/40), and fractions containing the desired product were concentrated under reduced pressure to give the title compound (6.70 g, 63%) as a yellow amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.CN1C(=O)N(C)CCC1.[Li+].CC([N-]C(C)C)C.Br[CH2:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[F:55]>C1COCC1>[C:1]([O:5][C:6](=[O:22])[CH:7]([N:8]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[F:55])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(F)c(CBr)c1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(F)c(CC(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)c1
Yield: 80 %

Procedure:
t-Butylglycinate Schiff base 3 (136 mg, 0.46 mmol) in a mixture of dry THF-DMPU 60:40 (2.5 mL) at −78° C. was treated with a 2.0 M LDA solution (0.23 mL, 0.46 mmol) and the mixture was stirred for one h at the same temperature. 2-Fluoro-5-methoxybenzyl bromide (35, 100 mg, 0.46 mmol) in dry THF (2.5 mL) was added dropwise at −78° C. and then the mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous ammonium chloride (10 mL), and the product was extracted with diethyl ether (2×15 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (4×10 mL), dried over sodium sulfate, filtered and evaporated to give 40 as a crude yellow oil (110%). When examined, the pure product 40 was made in 80% yield (175 mg).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:29]=[N:28][N:27]([CH3:30])[C:26]=1[N:31]1[CH2:46][C:35]2([CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36]2)[CH2:34][CH2:33][CH2:32]1)=[O:23])=O)(C)(C)C.ClCCl.Cl>CO.O1CCOCC1>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:29]=[N:28][N:27]([CH3:30])[C:26]=1[N:31]1[CH2:32][CH2:33][CH2:34][C:35]2([CH2:36][NH:37][CH2:38]2)[CH2:46]1)=[O:23]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCCC2(CN(C(=O)OC(C)(C)C)C2)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCCC2(CNC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 147.2 %

Procedure:
tert-butyl 8-[4-[[5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carbonyl]amino]-2-methyl-pyrazol-3-yl]-2,8-diazaspiro[3.5]nonane-2-carboxylate (336 mg, 0.51 mmol) was dissolved in methanol (2 mL) and dichloromethane (2 mL) before the addition of 4 M of hydrogen chloride in 1,4-Dioxane (2 mL). The solution was stirred at room temperature for 16 hr. After evaporation, a crude mixture as an off while solid (345 mg) was obtained. The crude mixture was purified by reverse phase HPLC to give 508 as a white solid (66 mg, 28%). 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.55-7.45 (m, 4H), 7.26 (t, J=8.8 Hz, 2H), 3.66 (s, 3H), 3.54 (s, 1H), 3.22 (s, 4H), 3.12 (s, 2H), 2.94 (t, J=5.3 Hz, 2H), 1.68-1.60 (m, 2H), 1.58-1.50 (m, 2H). MS (ESI) m/z: 460.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.CCCCCC>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(C)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: COC(=O)c1ccc(CBr)nc1
Temperature: 25 °C
Yield: 35.5 %

Procedure:
To a solution of methyl 6-methylnicotinate (6.3 g) in carbon tetrachloride (100 mL) is added successively N-bromosuccinimide (8.9 g) and 2,2′-azobisisobutyronitrile (342 mg), and the mixture is refluxed under heating for 6 hours. After cooling to room temperature, to the reaction mixture is added n-hexane (300 mL) and the insoluble materials are removed by filtration. The filtrate is concentrated in vacuo and the resultant crude product is purified by column chromatography on silica gel (Solvent; n-hexane:ethyl acetate=10:1) and stirred in n-hexane to give methyl 6-(bromomethyl)nicotinate (3.4 g, yield; 35%) as colorless crystals.
Reaction SMILES: O[C:2]1([C:22]([F:25])([F:24])[F:23])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:22]([F:25])([F:24])[F:23])[N:3]=[C:4]2[C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2cccs2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccs2)cc1
Yield: 82 %

Procedure:
A mixture of the 4,5-dihydro-imidazole of step 2 (0.60 g, 1.54 mmol) and p-toluenesulfonic acid monohydrate (0.12 g, 0.63 mmol) in toluene (100 ml) was heated to reflux for 4.5 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture (1.2 g) was chromatographed on silica gel using ethyl acetate/hexane 50/50 to give pure 2-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl) -1H-imidazol-2-yl]thiophene (0.47 g, 82%) as a white solid: mp (DSC) 182° C. Anal. Calc'd. for C15H11N2S2O2F3C, 48.38, H, 2.98, N, 7.52, S, 17.22 Found C, 48.36, H, 3.02, N, 7.42, S, 17.47.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][CH:14]1[C:16]([CH3:18])([CH3:17])[C:15]1([CH3:20])[CH3:19].C(O)(=O)C>[Fe].O>[CH3:11][C:5]1[CH:4]=[C:3]([O:12][CH2:13][CH:14]2[C:15]([CH3:19])([CH3:20])[C:16]2([CH3:18])[CH3:17])[C:2]([CH3:1])=[CH:7][C:6]=1[NH2:8]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1OCC1C(C)(C)C1(C)C
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(OCC2C(C)(C)C2(C)C)c(C)cc1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
A mixture of 0.34 g of 2,5-dimethyl-4-nitro-1-[(2,2,3,3-tetramethylcyclopropyl)methoxy]benzene, 0.34 g of iron powder, 5 mL of acetic acid and 5 mL of water was stirred at 80° C. for 1 hour. The reaction mixture was cooled to around room temperature, and then concentrated under reduced pressure. The resulting residue was converted into basic with an aqueous 1 N sodium hydroxide solution, then ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water, and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.24 g of 2,5-dimethyl-4-[(2,2,3,3-tetramethylcyclopropyl)methoxy]phenylamine.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:28]=[C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:29])[N:19]1[CH2:18][C@@H:17]([NH:16][C:7]([C:5]1[O:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH:4]=1)=[O:9])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:39])([F:38])[F:40]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1oc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1oc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.5 %

Procedure:
To a solution of 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (130 mg, 0.63 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (243 mg, 0.63 mmol) [prepared in Preparation 6] and diisopropylethylamine (0.55 ml, 3.15 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (324 mg, 0.69 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (190 mg, 0.23 mmol, 37% yield) as a clear oil: LCMS (ES) m/e 537 (M+H)+.