Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=O)=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C([N:24](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N>CCCCCC.ClCCl>[C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([NH2:24])=[O:21])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Reactant: CCN(CC)CC
Agent: N
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: NC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Reaction time: 1 h

Procedure:
[2-(1-cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetic acid (100 mg) and triethylamine (53 mg) were added to dichloromethane (2ml). After addition of diphenylphosphoryl azide (145 mg) with stirring under ice cooling, the mixture was stirred at room temperature for 1 hour. Conc. aqueous ammonia (5 ml) was added to the reaction mixture and stirring was further continued for 1 hour. Hexane (5 ml) was added and crystals deposited were filtered off. The crystals were recrystallized from dichloromethane and methanol to obtain the title compound as needles, m.p. 244°-245° C., yield 64 mg (64.6%).
Reaction SMILES: FC1C=CC=C([N+:8]([O-:10])=[O:9])C=1F.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14](NC(=O)OC(C)(C)C)[CH2:13]1>C(#N)C.C(N(CC)C(C)C)(C)C>[N+:8]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(F)c1F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])N1CCCCC1
Yield: 189532 %

Procedure:
A mixture of 1,2-difluoro-3-nitrobenzene (2.38 g, 0.015 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (3.0 g, 0.015 mmol) and N,N-diisopropylethylamine (5.2 ml, 0.030 mmol) was heated in acetonitrile (20 mL) at 80° C. overnight. The solvents were removed in vacuo, and chromatographic purification (ethyl acetate-hexanes) of the residue gave a nitropiperidine as orange oil (3.7 g, 72%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1>[Pd]>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: CC1(C)C=CC(=O)CC1
Agent: [Pd]
Product: CC1(C)CCC(=O)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 64.3 %

Procedure:
A mixture of 4,4-dimethylcyclohex-2-en-1-one (12 mL, 91.2 mmol) and Degussa type 10% Pd on carbon (2 g) was hydrogenated at 40 psi for 18 hours. The mixture was filtered and concentrated (1H NMR showed a mixture of ketone and alcohol in a 5:3 ratio). The mixture was dissolved in acetone (400 mL) and cooled to 0° C. Jones reagent (40 mL) was added over 30 min and the cooling bath was removed. After 2 days the excess acetone was evaporated and the resulting residue was dissolved in water and diethylether. The ether layer was washed with water until colorless, dried, filtered and concentrated to give 4,4-dimethylcyclohexanone (7.4 g, 58.6 mmol, 64%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18]>>[C:14]([C:15]1[CH:16]=[C:17]([NH2:18])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:11])([F:12])[F:1])[N:10]=1)([CH3:21])([CH3:20])[CH3:13]
Reactant: NNc1ccccc1C(F)(F)F
Reactant: CC(C)(C)C(=O)CC#N
Product: CC(C)(C)c1cc(N)n(-c2ccccc2C(F)(F)F)n1
Yield: 64 %

Procedure:
The title compound was prepared from 2-(trifluoromethyl)-phenylhydrazine (1.41 g, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) using the procedure in Example 161A Step 3 to give 3-tert-butyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (1.45 g, 5.12 mmol, 64%). 1H NMR (300 MHz, DMSO-d6) δ 7.86 (d, 1H), 7.75 (t, 1H), 7.65 (t, 1H), 7.49 (d, 1H), 5.27 (s, 1H), 4.97 (s, 1H), 1.18 (s, 9H); LC-MS (ESI) m/z 284 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35]Br>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH2:35][C:34]2[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:33]=2[F:32])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:25][CH:26]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(OC)cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1
Reactant: Fc1ccc(CBr)c(F)c1
Product: C=CCOc1cc(OC)cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 90C and 2,4-difluorobenzyl bromide were processed as described in Example 6B to provide the title compound. MS (APCI+) m/z 547 (M+H)+.
Reaction SMILES: C([N:3]1[CH2:21][CH2:20][C@@:10]23[C:11]4[CH:12]=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][C:16]=4[CH2:17][C@@H:4]1[C@@H:5]2[C@@H:6]([CH3:23])[CH2:7][C:8](=[O:22])[CH2:9]3)#N.[ClH:24]>>[ClH:24].[CH3:19][O:18][C:13]1[CH:14]=[CH:15][C:16]2[CH2:17][C@H:4]3[NH:3][CH2:21][CH2:20][C@@:10]4([C:11]=2[CH:12]=1)[C@H:5]3[C@@H:6]([CH3:23])[CH2:7][C:8](=[O:22])[CH2:9]4
Reactant: COc1ccc2c(c1)[C@]13CCN(C#N)[C@H](C2)[C@@H]1[C@@H](C)CC(=O)C3
Agent: Cl
Product: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@@H]1[C@@H](C)CC(=O)C3

Procedure:
A suspension of 17-cyano-3-methoxy-8β-methylmorphinan-6-one (prepared in Part B) in 2 N HCl (1 g/30 ml) was refluxed for 8 hours. The resulting solution was evaporated to dryness, azeotroped several times with ethanol, and the crystalline residue suspended in ethanol and collected. The product was used without further purification. The yield of crystalline material, mp 204°-208° C., was 90%.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10](N)[CH2:11][NH2:12]>>[NH2:12][CH2:11][CH2:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: NCCN
Product: N#Cc1ccc(CCN)cc1

Procedure:
4-Fluorobenzonitrile is reacted with an excess of ethylenediamine in an aprotic solvent to give 4-(2-aminoethyl)benzonitrile, which is then mono-alkylated with ethyl bromoacetate in a polar solvent such as ethanol or acetonitrile, in the presence of an inorganic base or a tertiary amine. An acylation with chloroacetyl chloride followed by a cyclization and a hydrolysis give the acid (1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:8]([C:12]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:21]3[CH2:26][C@H:25]([CH3:27])[C@H:24]([N:28]4[CH:32]=[CH:31][N:30]=[N:29]4)[C@H:23]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:22]3)=[O:13])=[N:9]2)=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.CC1(C)C(C)(C)OB([C:74]2[CH2:75][CH2:76][O:77][CH2:78][CH:79]=2)O1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl.O>[C:37]([O:36][C:34]([NH:33][C@H:23]1[C@@H:24]([N:28]2[CH:32]=[CH:31][N:30]=[N:29]2)[C@@H:25]([CH3:27])[CH2:26][N:21]([C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[NH:14][C:12]([C:8]2[C:7]([NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[CH:6][C:5]3[C:10](=[CH:11][C:2]([C:74]4[CH2:79][CH2:78][O:77][CH2:76][CH:75]=4)=[CH:3][CH:4]=3)[N:9]=2)=[O:13])[CH2:22]1)=[O:35])([CH3:39])([CH3:38])[CH3:40]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(C4=CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Temperature: 90 °C
Yield: 26.3 %

Procedure:
A pressure tube was charged with benzyl {7-bromo-2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]quinolin-3-yl}carbamate (15 mg, 0.020 mmol), K3PO4 (8.4 mg, 0.04 mmol), 1,4-dioxane (0.3 mL), water (0.04 mL) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (6.3 mg, 0.03 mmol). The reaction mixture was purged with nitrogen for 10 min., then dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (1.6 mg, 0.002 mmol) was added. The pressure tube was sealed and the reaction mixture was heated at 90° C. for 30 min then allowed to cool. The mixture was then filtered and purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a light yellow powder (4 mg, 27%). LCMS calc. for C41H46N9O6 (M+H)+: m/z=760.4. Found: 760.5.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][C:7]([N:10]3[CH2:15][CH2:14][CH:13]([C:16]4([CH3:31])[CH2:20][C:19]5[CH:21]=[C:22]([C:25]6[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=6)[CH:23]=[CH:24][C:18]=5[O:17]4)[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:42])=[O:41]>C(Cl)Cl>[CH:1]1([C:4]2[CH:5]=[N:6][C:7]([N:10]3[CH2:15][CH2:14][CH:13]([C:16]4([CH3:31])[CH2:20][C:19]5[CH:21]=[C:22]([C:25]6[CH2:26][CH2:27][N:28]([S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:42])=[O:41])[CH2:29][CH:30]=6)[CH:23]=[CH:24][C:18]=5[O:17]4)[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC1(C2CCN(c3ncc(C4CC4)cn3)CC2)Cc2cc(C3=CCNCC3)ccc2O1
Reactant: COC(=O)CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCS(=O)(=O)N1CC=C(c2ccc3c(c2)CC(C)(C2CCN(c4ncc(C5CC5)cn4)CC2)O3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.6 %

Procedure:
To a solution of 5-cyclopropyl-2-(4-(2-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydrobenzofuran-2-yl)piperidin-1-yl)pyrimidine (90 mg, 0.216 mmol) and triethylamine (0.061 mL, 0.432 mmol) in CH2Cl2 (2 mL) at 0° C. was added methyl 4-(chlorosulfonyl)butanoate (65 mg, 0.324 mmol). Upon completion of addition, the reaction mixture was warmed to room temperature, where it stirred for 3 h. After this time, the reaction mixture was diluted with CH2Cl2 (4 mL), and the resulting mixture was washed with aqueous NaHCO3 (saturated, 3×3 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified via preparative HPLC (solvent A: 10% MeOH/H2O with 0.1% TFA; solvent B: 90% MeOH/H2O with 0.1% TFA; Column: PHENOMENEX® Axia 5μ C18 30×100 mm, flow rate=40 mL/min) to afford Compound 11H as a white solid (46 mg, 0.079 mmol, 36.7% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.02 (s, 2 H), 7.06 (s, 1 H), 7.01-7.05 (m, 1 H), 6.60 (d, J=8.3 Hz, 1 H), 5.82 (ddd, J=3.2, 1.9, 1.7 Hz, 1 H), 4.65-4.78 (m, 2 H), 3.85-3.92 (m, 2 H), 3.60 (s, 3 H), 3.46 (t, J=5.8 Hz, 2 H), 3.08 (d, J=15.7 Hz, 1 H), 2.98 (dd, J=8.4, 6.7 Hz, 2 H), 2.65-2.78 (m, 3 H), 2.50 (d, J=1.7 Hz, 2 H), 2.44 (t, J=7.0 Hz, 2 H), 2.01-2.13 (m, 2 H), 1.76-1.87 (m, 2 H), 1.67-1.75 (m, 1 H), 1.56-1.65 (m, 1 H), 1.30 (s, 3 H), 1.15-1.28 (m, 2 H), 0.76-0.83 (m, 2 H), 0.45-0.51 (m, 2 H). LC/MS (m/z)=581 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[C:24][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:11])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)C#Cc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
4-iodobenzoic acid methyl ester (500 mg; 1.9 mmol) was suspended in 1,4-dioxane (3 mL) in a 5 mL reaction vial. To the vessel was added dichlorobis(triphenylphosphine)palladium(II) (44 mg; 3 mol %), copper iodide (7.5 mg), N,N-diisopropylethylamine (0.39 mL; 3.5 mmol) and 3,3-dimethylbut-1-yne (0.275 mL; 3.5 mmol). The vessel was sealed and the mixture was heated at 80° C. for 24 hrs. The solvents were evaporated to dryness and 20 mL of tetrahydrofuran and 20 mL of 10N NaOH was added. The mixture was stirred at room temperature for 30 minutes and the solvent was evaporated. The basic layer was acidified with concentrated HCl and extracted three times with EtOAc. The organic layers were washed with brine and dried over Na2SO4, filtered and evaporated to give the desired product as a brown powder (210 mg; 28%). m/z=203 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:31]=[CH:30][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4=CC=CC=C4C3=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.O.NN>C(O)C.C1COCC1>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[CH:30][CH:31]=2)[CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCOc1ccc(CN2CCOCC2)cc1
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: NCCCCCCOc1ccc(CN2CCOCC2)cc1

Procedure:
To a solution of N-(6-[4-(morpholinomethyl)phenoxy]hexyl)phthalimide (1.66 g, 3.94 mmol) in 1:1 ethanol/THF (28 mL) under nitrogen atmosphere was added hydrazine hydrate (1.4 mL, 29 mmol). The reaction was heated to reflux overnight, then cooled and concentrated. THF was added (30 mL) and the mixture sonicated for 30 min, followed by filtration. The filtrate was concentrated, redissolved in 10 mL THF, and dried with Na2SO4. Concentration gave the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:33])[NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[C:25]3[C:31]#[N:32])=[CH:14][CH:13]=1)([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[C:25]3[C:31]#[N:32])=[O:33])=[CH:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1ccc(C(=O)NCCc2ccc3[nH]cc(C#N)c3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(CN)c1ccc(C(=O)NCCc2ccc3[nH]cc(C#N)c3c2)cc1
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of (2-[4-[2-(3-cyano-1H-indol-5-yl)-ethylcarbamoyl]-phenyl]-2-methyl-propyl)-carbamic acid tert-butyl ester (1.16 g, 2.5 mmol) (prepared using the procedure of reference example 1w) in CH2Cl2 (8 ml) was added TFA (1.6 ml) and the reaction stirred 2 hrs. Water (50 μL) was add-ed and the reaction concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 10% 7M NH3 in CH3OH/CH2Cl2) to give 808 mg of product. MS (ion spray) m/z 361 (M+H)+.
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:8]([OH:14])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].[C:15](O)(=O)[CH2:16][C:17]([CH3:19])=O.[C:22](O)(=O)CC(C)=O.C(C(CO)(CO)CC)O.[OH-].[K+]>>[C:1]([O:7][CH2:19][CH2:17][CH2:16][CH2:15][CH2:22][O:13][C:8](=[O:14])[CH2:9][C:10]([CH3:12])=[O:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)[O-]
Reactant: CC(=O)CC(=O)O
Agent: CCC(CO)(CO)CO
Agent: [K+]
Agent: [OH-]
Product: CC(=O)CC(=O)OCCCCCOC(=O)CC(C)=O

Procedure:
Acetoacetate-functional compound B5 1,1,1-Trimethylol propane tri-acetoacetate, Lonzamon MTMP ex Lonza AG. Functionality: 3, acetoacetate equivalent weight: 128.7 (435 mg KOH/g)
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[CH:8][N:9]=1)(=O)C.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[NH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2ncc[nH]2)s1
Agent: Cl
Solvent: CCO
Product: Nc1ncc(Sc2ncc[nH]2)s1
Yield: 23.6 %

Procedure:
A mixture of 2-acetylamino-5-(2-imidazolylthio)thiazole (1.8 g) in a mixture of concentrated hydrochloric acid (10 ml) and ethanol (50 ml) was refluxed for 5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using sodium bicarbonate with cooling. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-5-(2-imidazolylthio)thiazole (0.35 g). The filtrate was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 100 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(2-imidazolylthio)thiazole (0.55 g). Total amount of 2-amino-5-(2-imidazolylthio)thiazole was 0.90 g (yield: 60.4%). mp: 209°-211° C. (dec.) IR (Nujol): 3450, 3300, 1630, 1520, 1315 cm-1
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:27][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH:11]3[CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=4)[NH:19][CH:18]=3)[S:9][C:5]=2[C:4](=O)[CH2:3]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:39]2)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:29])[CH2:27][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH:11]3[CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=4)[NH:19][CH:18]=3)[S:9][C:5]=2[C:4](=[S:39])[CH2:3]1
Reactant: Cc1ccc2[nH]cc(CC3COCCN3c3nc4c(s3)C(=O)CC(C)(C)C4)c2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2[nH]cc(CC3COCCN3c3nc4c(s3)C(=S)CC(C)(C)C4)c2c1
Reaction time: 2 h
Yield: 31.3 %

Procedure:
To a stirred solution of Example 21 (0.06 g, 0.15 mmol) in THF (10 mL) at r.t. was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulphide (0.06 g, 0.15 mmol). The reaction mixture was stirred for 2 h and then poured into aqueous sat. NaHCO3 solution (50 mL) and extracted with DCM (2×50 mL). The combined organic fractions were dried over MgSO4, filtered and the solvent removed in vacuo to give the title compound (0.02 g, 35%) as an orange solid. δH (DMSO-d6) 10.33 (1H, br. s), 7.63 (1H, d, J 8.0 Hz), 7.10 (2H, m), 6.86 (1H, d, J 8.0 Hz), 4.16 (1H, br. s), 3.98 (1H, d, J 8.0 Hz), 3.73 (2H, m), 3.57 (3H, m), 3.31 (1H, m), 3.01 (1H, m), 2.74 (2H, s), 2.57 (2H, d, J 5.6 Hz), 2.40 (3H, s), 1.04 (6H, s). LCMS (ES+) 426.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:5]=[CH:4][N:3]=1.[N:21]1([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:33][C:30]1[CH:29]=[CH:28][C:27]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:32][C:31]=1[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1ccnc(Cl)c1)c1cccc(C(F)(F)F)c1
Reactant: CC1(C)OB(c2cc(N3CCCCC3)ccc2N)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(N2CCCCC2)cc1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N-(2-chloropyridin-4-yl)-3-(trifluoromethyl)benzamide (350 mg, 1.16 mmol, 1.00 equiv), 4-(piperidin-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (430 mg, 1.42 mmol, 1.20 equiv), Pd(PPh3)2Cl2 (81.7 mg, 0.12 mmol, 0.10 equiv), K3PO4.7H2O (790 mg, 2.33 mmol, 2.00 equiv), X-PHOS (91.6 mg, 0.23 mmol, 0.20 equiv) in DME/H2O (10:1) (30/3 mL). The resulting solution was stirred for 2 h at 80° C. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residual solution was diluted with 50 mL of water. The resulting solution was extracted with 2×50 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (100˜100:1˜40:1). This resulted in 350 mg (67%) of N-(2-(2-amino-5-(piperidin-1-yl)phenyl)pyridin-4-yl)-3-(trifluoromethyl)benzamide as a yellow solid
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1.ClCCl>C(#N)C>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][S:2]([CH3:1])(=[O:5])=[O:3])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: COc1ccc(Cc2nc3c(N)nc4ccccc4c3n2CCCCN)cc1
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(Cc2nc3c(N)nc4ccccc4c3n2CCCCNS(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
Methanesulfonic anhydride (0.19 g, 1.1 mmol) was added to a stirring solution of 1-(4-aminobutyl)-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.4 g, 1.07 mmol), dichloromethane (75 ml) and acetonitrile (100 ml). The reaction was maintained at room temperature for 60 hours. The solvent was removed in vacuo and the residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane\methanol). The fractions containing product were combined, washed with saturated aqueous sodium bicarbonate, dried (MgSO4), filtered, and concentrated to provide 0.3 g of N-[4-(4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl]methanesulfonamide as a white solid, m.p. 78.1–79.5° C. 1H NMR (300 MHz, DMSO-d6) δ 7.99 (d, J=7.6 Hz, 1H), 7.62 (dd, J=8.3, 1.2 Hz, 1H), 7.42 (m, 1H), 7.27–7.21 (m, 3H), 6.98 (t, J=5.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 6.58 (broad s, 2H), 4.45 (broad s, 2H), 4.33 (s, 2H), 3.72 (s, 3H), 2.87 (m, 5H), 1.55 (broad s, 2H); MS (CI) m/e 454 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:6](Br)=[C:5]([NH2:8])[S:4][N:3]=1.[C:9]([S-:11])#[N:10].[K+]>CO>[CH3:1][C:2]1[C:6]([S:11][C:9]#[N:10])=[C:5]([NH2:8])[S:4][N:3]=1
Reactant: N#C[S-]
Reactant: Cc1nsc(N)c1Br
Agent: [K+]
Solvent: CO
Product: Cc1nsc(N)c1SC#N

Procedure:
386 g of 3-methyl-4-bromo-5-aminoisothiazole and 200 g of KSCN in methanol are refluxed for 6 hours. The product crystallizes out on cooling. 800 ml of water are added and the product is filtered off under suction and washed with water.
Reaction SMILES: [NH2:1][C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][CH:2]([CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[C:13]([OH:15])=[O:14])=[O:22])=[CH:19][CH:18]=1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: O=C(NC(Cc1c[nH]c2ccccc12)C(=O)O)c1ccc(Cl)cc1
Yield: 74.5 %

Procedure:
By using 10 g of D-tryptophane and 9 g of 4-chlorobenzoyl chloride, and a method similar to that described in reference Example 6, recrystallized from methanol-water, there was obtained 12.5 g of 2-(4-chlorobenzoylamino)-3-(indol-3-yl)propionic acid. Colorless needle-like crystals. Melting point: 100°-102° C. [α]D20 +51.5° (C=1, methanol)