Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:6]=1)CO.C(O)(=O)C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.CCOCC>[CH:2]([C:5]1[N:10]=[C:9]([C:11]([F:14])([F:12])[F:13])[N:8]=[C:7]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:6]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(O)CO)nc(C(F)(F)F)n2)CC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C=O)nc(C(F)(F)F)n2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-{[6-(1,2-dihydroxyethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate (542 mg, 1.33 mmol) in THF (10. mL) and water (6.0 mL) was added acetic acid (20. μL, 0.35 mmol) and sodium periodate (854 mg, 3.99 mmol) at −5° C. After stirring for 30 minutes, the reaction mixture was diluted with ether and water. The aqueous layer was extracted with ethyl acetate once and the combined organic layers were washed with brine and dried over anhydrous Na2SO4. The organic solvent was removed in vacuo and the residue was purified with silica gel column to give the desired product as colorless oil. LCMS (M+H)+: 376.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][C:10]=1[CH2:11][N:12]([C:20]1[N:25]=[N:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=1)C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][C:10]=1[CH2:11][NH:12][C:20]1[N:25]=[N:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N(Cc2cc(Br)ccc2OCc2ccccc2)C(=O)OC(C)(C)C)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)nn1
Reaction time: 18 h
Yield: 92 %

Procedure:
A mixture of ethyl 6-[N-(2-benzyloxy-5-bromobenzyl)-N-(tert-butoxycarbonyl)amino]-3-pyridazinecarboxylate (2.0 g) and trifluoroacetic acid (25 ml) in CH2Cl2 (25 ml) was allowed to stand for 18 hours. The solvents were evaporated, the residue dissolved in CH2Cl2 and washed with dilute aqueous Na2CO3 solution, dried (MgSO4) and evaporated to give ethyl 6-[2-benzyloxy-5-bromobenzylamino]-3-pyridazinecarboxylate as a solid (1.5 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[CH2:22]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)[CH2:23][CH2:24][CH3:25]>CO.C(Cl)Cl>[CH2:22]([C:26]1[CH:27]=[CH:28][C:29]([NH:30][CH2:1][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]3[S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:31][CH:32]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCc1ccc(N)cc1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1ccc(NCc2ccc3[nH]c(C(N)=O)c(Sc4ccccc4)c3c2)cc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 4-butylaniline (74 mg, 0.50 mmol) as described in General Procedure X to afford Iah (17 mg, 23.4%) as an ivory colored solid, tlc Rf=0.8 (5% MeOH/CH2Cl2−0.2% Et3N), m/z obs=430 (M+1).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][CH2:25][C:26]([NH2:28])=O>C1(C)C=CC=CC=1>[NH2:28][C:26](=[S:10])[CH2:25][CH2:24][C:23]([O:30][CH3:31])=[O:29]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)CCC(N)=O
Solvent: Cc1ccccc1
Product: COC(=O)CCC(N)=S
Yield: 42.3 %

Procedure:
Lawesson's reagent (2.6 g) was added to a toluene (10 ml) solution of methyl succinamate (1.7 g). The reaction mixture was heated under reflux for 4 hours, cooled, and then concentrated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to obtain the entitled compound (400 mg) as an oily substance.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([F:15])=[N:10][CH:11]=[C:12]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: Brc1ccccn1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(Br)cnc1F
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(-c2ccccn2)cnc1F

Procedure:
By carrying out the operation analogously to example 231, starting from 5-bromo-2-fluoro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VIII, and 2-bromopyridine, the desired product is obtained and is used directly in the deacetylation stage.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([OH:17])=O)[C:9]2=[O:18])=[CH:4][CH:3]=1.[C:26]1([C:32]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:36][CH2:35][NH:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:26]1([C:32]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:36][CH2:35][N:34]([C:15](=[O:17])[CH2:14][N:10]3[CH2:11][CH2:12][CH2:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[C:9]3=[O:18])[CH2:33]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: c1ccc(C2(c3ccccc3)CCNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCC(c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid (Example 90D, 0.345 g, 1.0 mmol) in dichloromethane (20 mL) under nitrogen was added 3,3-diphenylpyrrolidine (Example 17A, 0.223 g, 1.0 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.383 g, 2.0 mmol) and N,N-dimethylpyridin-4-amine (0.012 g, 0.10 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 200 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (Analogix®, Burlington, Wis.) eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.32-7.15 (m, 14H), 6.98 (t, J=8.7, 4H), 4.22 (d, J=3.0, 2H), 4.09 (d, J=3.5, 2H), 3.62-3.45 (m, 4H), 2.67-2.49 (m, 4H), 1.84 (d, J=5.6, 2H); MS (DCI) m/z 551.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:29])([CH3:28])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[NH:10][C:11]=2[C:12]([F:15])=[CH:13][CH:14]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[F:15][C:12]1[C:11]2[NH:10][CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[C:8]([CH3:29])([CH3:28])[CH2:7][C:6]=2[C:5]([C:3]([OH:4])=[O:2])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(F)c2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)Cc2c(C(=O)O)ccc(F)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a stirred mixture solution of 8-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (400 mg, 1.0 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 8-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (345 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25FN2O3 (M+H)+: 385.45, observed: 385.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:23])[F:22])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.Cl.[Br:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([C:33](C(OCC)=O)=[N:34][N:35]=2)[CH:32]=1.O.[OH-].[Li+].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C.C1COCC1.O>[Br:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([C:33]([C:14]([N:11]3[CH2:10][CH2:9][CH:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:21]([F:23])([F:24])[F:22])[CH2:13][CH2:12]3)=[O:15])=[N:34][N:35]=2)[CH:32]=1
Reactant: CCOC(=O)c1nnc2ccc(Br)cn12
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)ccc2C(F)(F)F)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cc(Cl)ccc2C(F)(F)F)CC1
Reaction time: 4 h
Yield: 50.6 %

Procedure:
To a solution of tert-butyl 4-(5-chloro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.302 g, 0.830 mmol) in dichloromethane (5 mL) was added HCl solution (2 M in ether, 5 mL). The mixture was stirred for 4 h and evaporated to afford a solid that was dissolved in DMF (8 mL). In a separate flask, to a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.224 g, 0.830 mmol) in THF (5 mL) was added a solution of lithium hydroxide hydrate (0.035 g, 0.830 mmol) in water (2 mL). The mixture was stirred for 20 min, acidified with 2 N HCl to PH 6 and evaporated to dryness. To this residue were added benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (0.550 g, 1.25 mmol), N,N-diisopropylethylamine (0.646 g, 5.00 mmol), and the DMF solution obtained from the first reaction. The mixture was stirred at ambient temperature for 16 h and poured into water. The mixture was extracted with ethyl acetate and the organic layer was washed with brine for three times, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-60% EtOAc in hexanes) to give (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(5-chloro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a solid (0.205 g, 50%): 1H NMR (300 MHz, CDCl3) δ9.38 (m, 1H), 7.79 (dd, J=9.6, 0.9 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.50 (dd, J=9.6, 1.7 Hz, 1H), 7.42 (d, J=1.4 Hz, 1H), 7.31 (dd, J=8.5, 1.3 Hz, 1H), 5.76-5.71 (m, 1H), 5.01-4.95 (m, 1H), 3.38-3.26 (m, 2H), 3.02-2.92 (m, 1H), 2.01-1.82 (m, 4H); MS (ESI+) m/z 489 [M+H]+.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[Cl:10][C:11]1[C:12]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[C:30]#[N:31])=[CH:13][C:14](=[O:22])[N:15]([CH:17]([CH3:21])[C:18]([OH:20])=O)[CH:16]=1.[NH2:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([F:42])[CH:34]=1>ClC(Cl)C>[Cl:10][C:11]1[C:12]([C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[C:30]#[N:31])=[CH:13][C:14](=[O:22])[N:15]([CH:17]([CH3:21])[C:18]([NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([F:42])[CH:34]=2)=[O:20])[CH:16]=1
Reactant: Nc1ccc(C(=O)O)c(F)c1
Reactant: CC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Agent: CC(C)N=C=NC(C)C
Solvent: CC(Cl)Cl
Product: CC(C(=O)Nc1ccc(C(=O)O)c(F)c1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Reaction time: 0.17 h

Procedure:
Under argon and at RT, 37 mg (0.30 mmol, 1.0 eq.) of N,N′-diisopropylcarbodiimide were added to a solution of 100 mg (0.30 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 12.1D) in 2 ml of dichloroethane, the mixture was stirred for 10 min, 46 mg (0.30 mmol) of 4-amino-2-fluorobenzoic acid were added and the mixture was stirred under reflux overnight. Subsequently, the reaction mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (Reprosil C18, water/methanol gradient). Yield: 41 mg (29% of theory)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][C:15]=1[O:23][CH3:24].[CH2:25]1[O:35][C:34]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=2[O:26]1>>[O:35]1[C:34]2[CH:33]=[CH:32][C:29](/[CH:30]=[C:20](/[C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:15]([O:23][CH3:24])[CH:16]=3)\[C:21]#[N:22])=[CH:28][C:27]=2[O:26][CH2:25]1
Reactant: COc1cc(CC#N)ccc1OCCCCCCCCCCCO
Reactant: O=Cc1ccc2c(c1)OCO2
Product: COc1cc(/C(C#N)=C/c2ccc3c(c2)OCO3)ccc1OCCCCCCCCCCCO
Yield: 72 %

Procedure:
(2Z)-3-(1,3-benzodioxol-5-yl)-2-{4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}prop-2-enenitrile is prepared starting from {4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}acetonitrile and commercial 3,4-(methylenedioxy)benzaldehyde according the same procedure following for example 1 in 72% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH3:23]>CN(C=O)C>[CH3:12][O:11][C:10]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1cccc(C(=O)O)c1O
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1c(OC)cccc1C(=O)O
Temperature: 90 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
2-Hydroxy-3-methoxybenzoic acid (15.66 g, 93 mmol), DMF (200 ml), potassium carbonate (51.4 g, 372 mmol) and pentyl bromide (29 ml, 233 mmol) were mixed, and this solution was stirred at 90° C. for 1 hour. DMF was evaporated under reduced pressure, and water (100 ml) was added. The aqueous layer was extracted 3 times with ethyl acetate (150 ml). The organic layers were combined, washed twice with saturated brine (70 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. To the obtained residue were added a 1N aqueous sodium hydroxide solution (70 ml) and ethanol (70 ml), and the mixture was refluxed under heating for 1 hour. A 1N aqueous sodium hydroxide solution (70 ml) and ethanol (70 ml) were further added, and the mixture was refluxed under heating for 2 hours. Ethanol was evaporated under reduced pressure, and conc. hydrochloric acid was added to make this solution acidic. The aqueous layer was extracted 3 times with ethyl acetate (100 ml). The organic layers were combined, washed twice with saturated brine (100 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=2/1-1/1) to give 3-methoxy-2-pentyloxybenzoic acid (20.5 g, 97%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1OS(C(F)(F)F)(=O)=O)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:10][N:9]=1.[CH3:49][O:50][C:51]1[N:56]=[C:55]([O:57][CH3:58])[C:54](B(O)O)=[CH:53][N:52]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O>[F:46][C:43]([F:45])([F:44])[C:41]1[CH:40]=[C:5]([CH:4]=[C:3]([C:2]([F:48])([F:1])[F:47])[CH:42]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:23]=1[C:54]1[C:55]([O:57][CH3:58])=[N:56][C:51]([O:50][CH3:49])=[N:52][CH:53]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][N:13]=1
Reactant: CS(=O)(=O)CCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OS(=O)(=O)C(F)(F)F)nc1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ncc(-c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCS(C)(=O)=O)cn2)c(OC)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 31.3 %

Procedure:
Trifluoromethanesulfonic acid 2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-methanesulfonyl-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl ester (110 mg) is dissolved in 1,4-dioxane (2 ml) and thereto are added 2,4-dimethoxy-pyrimidine-5-boronic acid (70 mg), palladium acetate (13.2 mg), 1,1′-bis(di-tert-butylphosphino)ferrocene (28 mg) and tripotassium phosphate (62 mg) and the mixture is stirred under nitrogen atmosphere at 80° C. for 4 hours. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give (3,5-bis-trifluoromethyl-benzyl)-[2-(2,4-dimethoxy-pyrimidin-5-yl)-5-trifluoromethyl-benzyl]-[5-(2-methanesulfonyl-ethoxy)-pyrimidin-2-yl]-amine (34 mg). MS (m/z): 740 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.[N:29]1([C@@H:34]2[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]2O)[CH2:33][CH2:32][CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:35]4[CH2:36][CH2:37][CH2:38][CH2:39][CH:34]4[N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: O[C@@H]1CCCC[C@H]1N1CCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCCCC3N3CCCC3)cc2)cc1
Yield: 34.9 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.27 g, 3.25 mmol), trans-2-pyrrolidinylcyclohexanol (1.10 g, 6.50 mmol), triphenylphosphine (1.70 g, 6.50 mmol), and DEAD (6.50 mmol) were converted to product by the procedure of Example 11 to give 615 mg of the title compound. Yield: 35%. MS(FD) 541(M+). IR (CHCl3) ν max 3009, 2940, 1645, 1597, 1476, 1254, 1166.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O[C:9](=O)[N:10]([C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]=O)=[C:33]([C:39]([F:42])([F:41])[F:40])[CH:32]=2)=[O:29])=[CH:23][CH:22]=1)C)(C)(C)C>>[CH3:1][N:2]([CH2:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([N:16]3[CH:15]=[N:14][C:13]4[C:17]3=[N:18][CH:19]=[N:20][C:12]=4[NH:10][CH3:9])=[CH:22][CH:23]=2)=[O:29])=[CH:32][C:33]=1[C:39]([F:42])([F:40])[F:41])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(C=O)c(C(F)(F)F)c2)cc1
Reactant: CNC
Product: CNc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(CN(C)C)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be prepared from dimethylamine and (9-{4-[3-(4-formyl-3-(trifluoromethyl)phenyl)-ureido]phenyl}-9H-purin-6-yl)-methyl-carbamic acid tert-butyl ester by using the same techniques as in Example 168.
Reaction SMILES: [CH:1]1([C@@H:7]([NH:11][C:12](=[O:48])[CH2:13][NH:14][C:15](=[O:47])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C@@H:24]3[C@@H:27]([S:28][CH2:29][C:30]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[O:31])[C:26](=[O:39])[N:25]3[C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[CH:20][CH:19]=2)[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C(O)(=O)C>[CH:1]1([C@@H:7]([NH:11][C:12](=[O:48])[CH2:13][NH:14][C:15](=[O:47])[CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C@@H:24]3[C@@H:27]([S:28][CH2:29][CH:30]([C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)[OH:31])[C:26](=[O:39])[N:25]3[C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[CH:22][CH:23]=2)[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@@H](C(=O)O)C1CCCCC1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@@H](C(=O)O)C1CCCCC1
Yield: 79 %

Procedure:
(2R)-cyclohexyl[(N-([4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio)-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl)amino]acetic acid (0.0085 g, 0.013 mmol) was dissolved in methanol (2 ml). NABH4 (0.006 g, 0.159 mmol) was added and when the reaction was complete according to LC-MS a few drops of acetic acid was added. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on a Kromasil C8-column using a stepwise gradient of 35%, 40% then 50% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.007 g (82%) of the title product was obtained. NMR (500 MHz, CD3COOD) 1.05-1.33 (m, 5H), 1.60-1.87 (m, 6H), 2.91-3.07 (m, 2H), 3.94-4.06 (m, 3H), 4.32 (d, 1H), 4.60 (s, 2H), 4.79-4.86 (m, 1H), 4.90 (d, 0.5H), 4.92 (d, 0.5H), 6.96-7.03 (m, 4H), 7.03-7.08 (brd, 2H), 7.25-7.31 (m, 2H), 7.31-7.38 (m, 4H)
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1.[C:16](=[O:18])=[O:17]>O1CCCC1>[Cl:6][C:7]1[C:8]([C:16]([OH:18])=[O:17])=[C:9]([F:15])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: COc1ccc(Cl)cc1F
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (11.7 ml, 18.77 mmol) was added dropwise to a solution of 4-chloro-2-fluoroanisole (2.01 g, 12.52 mmol) in tetrahydrofuran (20 ml) at −78° C. and the reaction was stirred for 30 mins. Crushed solid carbon dioxide was added in one portion and the reaction was then allowed to warm to room temperature. The solvent was evaporated and the residue dissolved in water. Sodium hydroxide (2M to pH˜14) was added and the aqueous layer extracted with ethyl acetate. The aqueous layer was acidified with hydrochloric acid (5M, pH˜1) and the title compound was collected as a colourless solid (2.25 g, 88%). The compound was dried in vacuo.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].C([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[O:22])[CH2:16][CH2:15]1)(=O)C(C)C>>[F:1][C:2]([F:8])([F:7])[CH2:3][C:4]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)=[O:22])[CH2:16][CH2:15]1)=[O:5]
Reactant: O=C(O)CC(F)(F)F
Reactant: CC(C)C(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC1CCN(C(=O)CC(F)(F)F)CC1
Yield: 87 %

Procedure:
3,3,3-Trifluoropropionic acid (67 mg, 0.522 mmol) was reacted with PTU (100 mg, 0.348 mmol) as the same manner as the synthesis of 1-(1-isobutyrylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (120 mg, 0.302 mmol, 87% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.80 (s, 1H), 7.58 (s, 4H), 6.38 (d, J=7.8 Hz, 1H), 4.19 (d, J=13.3 Hz, 1H), 3.79 (d, J=13.8 Hz, 1H), 3.71 (m, 4H), 3.16 (t, J=11.1 Hz, 1H), 2.85 (t, J=11.7 Hz, 1H), 1.84 (m, 2H), 1.30 (m, 2H).