Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[C:18]([NH:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:15])=[CH:11][C:10]=1[C:18]([NH:20][C:21]1[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: C1CCNCC1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(=O)N2CCCCC2)ccc1OCc1ccccc1
Yield: 56.4 %

Procedure:
Using 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid (compound of Example 84(2)) and piperidine as the raw materials, the same operation as the Example 84(3) gave the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([CH2:22][CH2:23][OH:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@@:13]([CH2:22][CH2:23][OH:24])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:12][C:11]3=[O:25])[CH3:9])=[CH:4][CH:3]=2)=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@@](CCO)(c2ccccc2)CC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@@](CCO)(c2ccccc2)CC1=O
Yield: 11.6 %

Procedure:
A mixture of (S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-hydroxyethyl)-4-phenyl piperidin-2-one (25 mg, 0.062 mmol), 4-fluorophenylboronic acid (15 mg, 0.093 mmol), Pd(Ph3P)2Cl2 (5 mg), and aqueous Cs2CO3 (0.1 mL, 2M) in 1,4-dioxane (2 mL) was stirred and heated at reflux for 2 hours. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to give (S)-1-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-4-(2-hydroxyethyl)-4-phenylpiperidin-2-one (3.0 mg, 12%). LC-MS Method 2, tR=2.167 min, m/z=440.1. 1H NMR (CDCl3): δ 1.18 (d, 3H), 1.86 (m, 2H), 2.06 (m, 2H), 2.54 (m, 2H), 2.64 (m, 1H), 3.10 (dd, 1H), 3.31 (m, 1H), 3.46 (m, 1H), 6.04 (q, 1H), 7.02 (m, 2H), 7.20 (m, 4H), 7.32 (m, 2H), 7.46 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:25])=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[CH:7]=1.C([O:28][CH:29]=[CH:30][CH3:31])C.C(N(CC)CC)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][C:3]1[C:2]([C:29](=[O:28])[CH2:30][CH3:31])=[CH:7][N:6]2[N:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=[C:5]2[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1
Reactant: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(Br)cn2n1
Reactant: CC=COCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)c1cn2nc(NC(C)=O)nc2c(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 130 °C
Reaction time: 120 h
Yield: 11 %

Procedure:
A mixture of N-[6-bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 18, 0.5 g, 1.21 mmol) was combined with ethyl-1-propenyl ether (125 mg, 1.45 mmol), triethylamine (202 μL, 1.45 mmol), palladium (II) acetate (3 mg, 0.012 mmol), tri-O-tolylphosphine (15 mg, 0.048 mmol) in DMF (7 mL) was degassed and then heated at 130° C. for 5 hrs. Further amounts of palladium (II) acetate (3 mg) and ethyl-1-propenyl ether (125 mg) were added and heating was continued for 5 days. 1 M HCl (5 mL) was added and the mixture was stirred vigorously for 40 mins. The mixture was partitioned between EtOAc (100 mL) and water (100 mL) and the organic layer was washed with saturated brine, then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by chromatography, eluting with a gradient of 0-10% MeOH in DCM followed by trituration with DCM and ether. The resultant precipitate was collected by filtration and dried to afford the title compound as a white solid (11%)
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[CH2:17]([N:19]1[C:28]2[C:23](=[CH:24][N:25]=[C:26]([NH:29][CH3:30])[CH:27]=2)[CH:22]=[C:21]([C:31]2[C:32]([F:45])=[CH:33][C:34]([F:44])=[C:35]([NH:37][C:38](=O)[O:39]C(C)=C)[CH:36]=2)[C:20]1=[O:46])[CH3:18]>O1CCOCC1.CN1CCCC1>[CH2:17]([N:19]1[C:28]2[C:23](=[CH:24][N:25]=[C:26]([NH:29][CH3:30])[CH:27]=2)[CH:22]=[C:21]([C:31]2[C:32]([F:45])=[CH:33][C:34]([F:44])=[C:35]([NH:37][C:38]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[C:3]([CH2:9][N:10]4[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]4)[CH:4]=3)=[O:39])[CH:36]=2)[C:20]1=[O:46])[CH3:18]
Reactant: CN1CCN(Cc2cc(N)ccc2F)CC1
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)cc3n(CC)c2=O)c(F)cc1F
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccc(F)c(CN4CCN(C)CC4)c3)c(F)cc2F)cc2cnc(NC)cc21
Temperature: 80 °C
Yield: 30.7 %

Procedure:
A mixture of Example D2 (0.060 g, 0.269 mmol) and prop-1-en-2-yl (5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)carbamate (0.086 g, 0.208 mmol) in dioxane (2 mL) was treated with 1-methylpyrrolidine (2 drops) and heated at 80° C. overnight. The mixture was concentrated to dryness, treated with EtOAc and the resulting solid collected via filtration and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over MgSO4 and concentrated to dryness to afford 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (37 mg, 31% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1H), 8.94 (s, 1H), 8.86 (t, J=8.5 Hz, 1H), 8.59 (s, 1H), 7.93 (dd, J=6.5, 2.8 Hz, 1H), 7.76 (m, 2H), 7.62 (s, 1H), 7.13 (t, J=9.5 Hz, 2H), 6.25 (s, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.55 (s, 2H), 3.08 (d, J=4.9 Hz, 3H), 2.50 (br s, 4H), 2.30 (br s, 4H), 2.10 (s, 3H), 1.18 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 580.2 [M+H]+.
Reaction SMILES: CN([CH2:20][CH2:21][OH:22])C/C(/C)=C/C1C=CC(CC2C=NC=CC=2)=CC=1.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1>C(OCC)(=O)C>[C:26]([O:28][CH2:24][CH3:23])(=[O:27])[CH2:25][C:21]([CH3:20])=[O:22]
Reactant: C=C1CC(=O)O1
Reactant: C/C(=C\c1ccc(Cc2cccnc2)cc1)CN(C)CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)=O
Yield: 65.8 %

Procedure:
In 5 ml of ethyl acetate was dissolved 1.26 g of 2-[N-methyl-N-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]2-methylallyl]amino]ethanol, and to the resulting solution was dropwise added a mixture of 0.36 ml of diketene and 1 ml of ethyl acetate under reflux over one hour, after which the resulting mixture was subjected to reaction at the same temperature for 30 minutes. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (1:1 by volume)] to obtain 1.06 g (yield 65.8%) of colorless, oily 2-[N-methyl-N-[(E)-3-[4-pyridin-3-ylmethyl)phenyl]-2-methylallyl]amino]ethyl acetoacetate.
Reaction SMILES: [C:1]([C:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:11]([N:13]=[C:14]=[S:15])[CH3:12]>O1CCCC1>[CH2:11]([NH:13][C:14]([N:8]1[CH2:7][CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]1)=[S:15])[CH3:12]
Reactant: CCN=C=S
Reactant: CC(C)(C)C1=CCNCC1
Solvent: C1CCOC1
Product: CCNC(=S)N1CC=C(C(C)(C)C)CC1

Procedure:
In 20 ml. of anhydrous tetrahydrofuran there is dissolved 5.0 grams of 4-t-butyl-1,2,3,6-tetrahydropyridine. Stirring is initiated and there is added 3.14 grams of ethylisothiocyanate in 10 ml. of anhydrous tetrahydrofuran allowing the reaction to run at room temperature. After stirring the reaction mixture for 18 hours, the tetrahydrofuran is evaporated in vacuo to give N-ethyl-4-t-butyl-1,2,3,6-tetrahydro-1-pyridinethiocarboxamide.
Reaction SMILES: C[C:2]1C=CC=[C:4](C)[C:3]=1[C:9]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[CH:19][CH:18]=2)[CH:10]=1.[N:34]1C=C(B(O)O)C=[N:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:32][C:30]([F:33])([F:31])[C:26]1[CH:25]=[C:24]([O:23][C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:9]([C:3]4[CH:4]=[N:34][CH:35]=[N:36][CH:2]=4)[CH:10]=3)=[CH:22][CH:21]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Cc1cccc(C)c1-c1cc(Nc2ccc(Oc3ccnc(C(F)(F)F)c3)cc2)nc(N)n1
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(Nc2ccc(Oc3ccnc(C(F)(F)F)c3)cc2)cc(-c2cncnc2)n1
Yield: 22.9 %

Procedure:
A suspension of 6-chloro-N4-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine (150 mg, 0.39 mmol, see example 335), pyrimidin-5-ylboronic acid (97.37 mg, 0.79 mmol), tetrakis(triphenylphosphin)palladium(0) (45.41 mg, 0.04 mmol), sodium carbonate (208.23 mg, 1.96 mmol) in 2.5 mil of anhydrous DMF was degassed for 10 min. The mixture was reacted under microwave condition at 180° C. for 20 min. The reaction mixture was filtered and concentrated. The residue was extracted with EtOAc (6 ml) and washed with 1 M NaOH solution (1 mL×2) and water (1 mL×3). The organic layer was dried to furnish 129 mg of the crude product. The crude product was purified by prep-TLC (Hex:EtOAc=2:8) to give 38 mg (23%) of the title compound as a yellow solid. 1H NMR (CD3OD): δ 9.28 (s, 2H), 9.20 (s, 1H), 8.54 (d, 1H), 7.88 (d, 2H), 7.32 (d, 1H), 7.15 (m, 3H), 6.56 (s, 1H) ppm; MS ES 426 (M+H)+, calc. 426, RT=2.35 min; TLC (Hexane:EtOAc=1:9) Rf=0.25.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([C:2]2[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Product: Nc1ccc(-c2ccccc2)nc1
Yield: 71 %

Procedure:
Obtained (71% yield) following the procedure described in Intermediate 39, starting with 6-bromopyridin-3-amine and phenylboronic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][C:12]1[C:13]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[C:12]([CH3:11])=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=3)[CH2:20][CH2:21]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Yield: 99.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 67 and using 6-bromonicotinic acid (808 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (765 mg) described in Preparation Example 47, the title compound (1.5 g) was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][C:6](=[NH:8])[NH2:7].C[O-].[Na+].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([C:32](=O)[CH2:33][CH2:34][CH2:35][CH3:36])[C:28](OC)=[O:29])=[CH:22][CH:21]=1)#[N:13]>CO>[CH2:33]([C:32]1[N:8]=[C:6]([CH2:5][CH2:4][O:3][CH3:2])[NH:7][C:28](=[O:29])[C:27]=1[CH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:15]2[C:14]([C:12]#[N:13])=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:25][CH:24]=1)[CH2:34][CH2:35][CH3:36]
Reactant: COCCC(=N)N
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(CCOC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 43.5 %

Procedure:
A solution of 3-methoxypropanimidamide hydrochloride (4.0 g), 28% sodium methoxide (8.7 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (5.0 g) in methanol (50 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and water and 1 M hydrochloric acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (2.5 g, 44%) as a pale-yellow solid.
Reaction SMILES: [C:1]([C:4]1[NH:20][C:7]2=[CH:8][C:9]3[C:10]([CH3:19])([CH3:18])[C:11](=[O:17])[N:12]([CH2:15][CH3:16])[C:13]=3[CH:14]=[C:6]2[N:5]=1)(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:33]1[CH:38]=[CH:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[C:1]([C:4]1[N:20]([CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][O:33]2)[C:7]2=[CH:8][C:9]3[C:10]([CH3:19])([CH3:18])[C:11](=[O:17])[N:12]([CH2:15][CH3:16])[C:13]=3[CH:14]=[C:6]2[N:5]=1)(=[O:3])[CH3:2]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(C(C)=O)nc3cc21
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CCN1C(=O)C(C)(C)c2cc3c(cc21)nc(C(C)=O)n3C1CCCCO1
Yield: 44.4 %

Procedure:
2-Acetyl-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (11.7 g, 43.1 mmol) and p-toluenesulfonic acid monohydrate (0.82 g, 4.3 mmol) were dissolved in dichloromethane (200 mL). To this solution 3,4-dihydro-2H-pyrane (4.81 g, 56 mmol) was added and the mixture stirred at reflux for 24 h. The mixture was filtered, the filtrate washed with water (2×100 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica (dichloromethane/methanol 93:3) yielding 6.8 g (44%) of a light yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH:9]([CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]2=[O:14])[CH2:7]1)=[O:5])[CH3:2].C[Si](C)(C)[O:32][CH2:33][CH2:34]O[Si](C)(C)C.C[Si](Cl)(C)C>C(O)CO>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH:9]([CH:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:10]32[O:32][CH2:33][CH2:34][O:14]3)[CH2:7]1)=[O:5])[CH3:29]
Reactant: CCN(CC)C(=O)C1CN2CCC1C(=O)C2C(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: OCCO
Product: CCN(CC)C(=O)C1CN2CCC1C1(OCCO1)C2C(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 88.5 %

Procedure:
A mixture of (3R*, 4R*)-N,N-diethyl-6-diphenylmethyl-5-oxo-1-azabicyclo[2.2.2]octane-3-carboxamide (10 g, 26 mmol), 1,2-bis(trimethylsiloxy)ethane (6 g, 29 mmol), trimethylsilyl chloride (20 ml) and ethylene glycol (50 ml) was heated at 100° C. for 3 hours. After by-products were removed by distillation 93° C./atmosphere pressure), the mixture was poured into cold aqueous sodium bicarbonate (NaHCO3) (250 ml) and extracted with methylene chloride (CH2Cl2) (100 ml) three times. The combined extracts were dried over sodium sulfate (Na2SO4) and concentrated. The clude was purified by recrystallization from ethyl acetate (EtOAc)/hexane to give 21 (1:2 mixture at 6-position; 23 mmol, 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:11])[C:12]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:18][C:19]=2[CH2:20][CH3:21])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C(Cc1cc(F)cc(F)c1)c1ccccc1O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccccc2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
Intermediate 70 (2.0 g, 8.08 mmoles) was taken in a RB flask and to this triethylamine (20 ml) and propionic anhydride (3.26 g, 25.2 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as off-colourless liquid (1.65 g, 72% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.05(dd, J=7.9,1.2 Hz, 1H), 7.84(dt, J=8.5,1.4 Hz, 1H), 7.68(d, J=8.4 Hz, 1H), 7.51(t, J=7.8 Hz, 1H), 7.30(tt, J=7.2,2.2 Hz, 1H), 7.07(d, J=6.1 Hz, 2H), 2.58(q, J=7.5 Hz, 1H), 1.21(t, J=7.6 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.[K].O>CS(C)=O>[CH2:2]([N:12]1[C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]2[C:8]1=[O:18])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCCCCBr
Agent: [K]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCN1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 100.3 %

Procedure:
This example illustrates a synthesis of N-(5,6-Oxidohexyl)phthalimide (inventive compound no. 1103). 1-bromo-5-hexene (6.52 g, 40 mmol) was added to a potassium phthalimide (7.4 g, 40 mmol) suspension in 50 mL of dimethyl sulfoxide and stirred overnight. After 12 hours of stirring at room temperature, the reaction was poured into a separatory funnel containing 300 mL of water and extracted with dichloromethane (5×200 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel (eluant: 10% acetone/hexane) to yield 9.2 g (100% yield) of N-(5-Hexenyl)phthalimide (inventive compound no. 1101).
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6]1[CH:7]([OH:16])[CH:8]([OH:15])[CH:9]([C:12]([CH3:14])=[CH2:13])[CH2:10][CH:11]=1>C(Cl)Cl>[CH3:5][C:6]1[C@@H:7]([OH:16])[C@H:8]([OH:15])[C@H:9]([C:12]([CH3:14])=[CH2:13])[CH2:10][CH:11]=1
Reactant: C=C(C)C1CC=C(C)C(O)C1O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C=C(C)[C@@H]1CC=C(C)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 945 mg epoxide (−)-cis-verbenole (1R,2R,4S,5R,6S)-2 ([α]D25=−85.6 (c0.82, CHCl3)) in 12 ml methylene chloride was added, stiffing continuously, into a suspension of 2 g K10 (Fluka) clay (calcinated for 3 hours under 110° C.) in 15 ml of methylene chloride. The reaction mixture was stirred for 1 hour under room temperature. The catalyst was filtered, rinsed by ethyl acetate, the solvent was evaporated. The residue was separated by column chromatography using SiO2 (60-200μ; Merck), a solution of diethyl ether in hexane 5 to 100% was used as an eluent. 270 mg (29%) of (1R,2R,6s)-1a (ee 94%, ([α]D27=−84.0 (c 3.47, CHCl3)) was obtained as a result. Enantiomeric purity of the compound 1a was evaluated by the data of gas-liquid chromatography with mass spectroscopy in chiral column.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1)#[N:2].CN1CCOCC1.ClC(OCC(C)C)=O.[C:27]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH2:41])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:30]([O:29][C:27](=[O:28])[NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:7]([C:6]1[CH:5]=[N:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=1)=[O:9])([CH3:33])([CH3:31])[CH3:32]
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C#N)nc1
Temperature: 5 °C
Yield: 78.3 %

Procedure:
To a solution of 444 mg (3.0 mmol) 6-cyano-nicotinic acid and 354 mg (3.5 mmol) N-methylmorpholine in 7 ml DMF at −20° C. was added 450 mg (3.3 mmol) isobutyl chloroformate. The reaction mixture was warmed to 5° C., and 625 mg (3.0 mmol) mono-boc-ortho-phenylenediamine was added. The reaction mixture was warmed to rt overnight and then poured into 50 ml 5% aqueous citric acid. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with bicarbonate and brine and dried over Na2SO4. The solvent was evaporated and the residue was subjected to silica gel chromatography (petrol ether/ethyl acetate 2:1) to yield 795 mg (2.35 mmol) {2-[(6-Cyano-pyridine-3-carbonyl)-amino]-phenyl}-carbamic acid t-butyl ester; mp.183–184° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[CH:15][C:16]([CH:17]=[C:18]3[S:22][C:21](=O)[NH:20][C:19]3=[O:24])=[C:10]2[N:9]=1.[S:25]1CC(=O)NC1=S>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[CH:15][C:16]([CH:17]=[C:18]3[S:22][C:21](=[S:25])[NH:20][C:19]3=[O:24])=[C:10]2[N:9]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=C1NC(=O)C(=Cc2cnn3ccc(-c4ccccc4F)nc23)S1
Product: O=C1NC(=S)SC1=Cc1cnn2ccc(-c3ccccc3F)nc12

Procedure:
5-((5-(2-Fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-2-thioxothiazolidin-4-one was prepared using the same procedure as for the synthesis of 5-((5-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione using Rhodanine instead of thiazolidine-2,4-dione.
Reaction SMILES: C(O[C:9](=O)[NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:35])[CH:20]([C:22](=[O:34])[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[CH3:21])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])C1C=CC=CC=1.[CH3:37][C:38]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:39]=1C=O.C([BH3-])#N.[Na+]>CO.[Pd]>[CH3:37][C:38]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:39]=1[CH2:9][NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:35])[CH:20]([CH3:21])[C:22]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=1)=[O:34])[C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16]
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)C(C)C(=O)Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(C=O)c(C)c1
Agent: [Pd]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)NC(=O)C(C)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of {(2S,3S)-3-hydroxy-2-[2-(3-trifluoromethyl-phenylcarbamoyl)-propionylamino]-hex-4-ynyl}-carbamic acid benzyl ester (40 mg, 0.08 mmol) in MeOH (2 mL) was charged with 5% Pd/C, Degussa style (8 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (2 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde (0.009 mL, 0.06 mmol) and sodium cyanoborohydride (5 mg, 0.08 mmol), stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=494.4.
Reaction SMILES: [NH3:1].[NH2:2][CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([O:12]CC)=O)[N:5]=1>C(O)C>[NH2:2][CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([NH2:1])=[O:12])[N:5]=1
Reactant: N
Reactant: CCOC(=O)c1nc(CN)n(C)n1
Solvent: CCO
Product: Cn1nc(C(N)=O)nc1CN
Reaction time: 8 h

Procedure:
Ammonia gas was passed for 20 minutes at −10° C. into a solution of 6.8 g (not more than 23.2 mmol) of ethyl 5-aminomethyl-1-methyl-1H-[1,2,4]-triazole-3-carboxylate in 200 ml of ethanol. Stirring was continued for one hour at 0° C. and overnight at room temperature. Since the reaction was incomplete, the procedure of passing in gas was repeated twice more (as described above) and the mixture was stirred overnight at 0° C. The mixture was concentrated on a rotary evaporator and the residue was purified by column chromatography (dichloromethane +5-10% methanol, Rf=0.3 in dichloromethane/methanol 9:1). This gave 4.71 g as colorless oil. 1H NMR (270 MHz, DMSO-d6): δ=1.4 (s, 9H), 3.85 (s, 3H), 4.3 (d, J=5 Hz, 3H), 7.4 (bs, 1H), 7.6 (bs, 1H), 7.65 (bs, J=5 Hz, 1H).