Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][CH:9]1[C:18]2[C:13](=[C:14]([CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][NH:10]1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)=[O:28])=[CH:23][CH:22]=1.P(O)([O-])([O-])=O.[Na+].[Na+]>CCCCCC.C1COCC1>[CH3:6][O:7][CH2:8][C@H:9]1[C:18]2[C:13](=[C:14]([CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][N:10]1[S@@:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=1)=[O:28]
Reactant: COCC1NCCc2c(C)cccc21
Reactant: Cc1ccc(S(=O)O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)cc1
Agent: O=P([O-])([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC[C@H]1c2cccc(C)c2CCN1[S@](=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
A solution of 1.55 M n-butyllithium in hexane (10.94 mL) was added with stirring to a solution of 1-(methoxymethyl)-5-methyl-1,2,3,4-tetrahydroisoquinoline (3.07 g) in THF (60 mL) under an argon atmosphere, over about 8 minutes, at −70° C. or below, followed by further stirring for 30 minutes. To the reaction mixture was added with stirring a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 4-methylbenzenesulfinate (3.375 g) in THF (25 ml) over 5 minutes at −70° C. or below, followed by further stirring for 1 hour. Thereafter, saturated disodium phosphate was added to the mixture at the same temperature and the temperature was increased to room temperature. The mixture was extracted with ether. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:EtOAc) to obtain (1R)-1-(methoxymethy)-5-methyl-2-[(R)-(4-methylphenyl)sulfinyl]-1,2,3,4-tetrahydroisoquinoline (2.144 g) (Rf value=0.14).
Reaction SMILES: [Cl:1][C:2]1[N:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Li+].CC([N-]C(C)C)C.[I:27]I>C1COCC1>[Cl:1][C:2]1[N:17]=[CH:16][C:15]([I:27])=[C:14]([Cl:18])[C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: II
Reactant: O=C(OCc1ccccc1)c1c(Cl)ccnc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1c(Cl)ncc(I)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
Into a solution of benzyl 2,4-dichloronicotinate (4.35 g, 15.4 mmol) in THF (40 mL) at −78° C. was added LDA (1.5 M×11.8 mL, 17.7 mmol) dropwise. The mixture was stirred at −78° C. for 30 min. Iodine (4.7 g, 18.5 mmol) was added portionwise. The temperature was then allowed to rise to room temperature slowly and the reaction was quenched with saturated NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over sodium sulfate, evaporated and purified by silica chromatography (0-7% ethyl acetate in hexanes) to give benzyl 2,4-dichloro-5-iodonicotinate (3.8 g, 60%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([CH3:12])=[N:4][C:3]=1[O:13][CH3:14].C(N(CC)CC)C.C(O)=O>[Pd].CC(C)=O>[CH3:14][O:13][C:3]1[N:4]=[C:5]([CH3:12])[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][CH:2]=1
Reactant: COC(=O)c1nc(Cl)c(OC)nc1C
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)c1ncc(OC)nc1C
Temperature: 0 °C
Yield: 95.1 %

Procedure:
To a mixture of methyl 6-chloro-5-methoxy-3-methylpyrazine-2-carboxylate (6.5 g, 30.0 mmol) and palladium, 10% wt. on activated carbon (3.19 g, 3.00 mmol) in a 500 mL flask under nitrogen, was added acetone (200 mL) carefully. The flask was cooled to 0° C. and triethylamine (30 mL, 216 mmol) was added followed by formic acid (96%) (5.66 mL, 150 mmol) dropwise. The suspension was warmed to room temperature with stirring and then heated at 40° C. for 1 h. The reaction mixture was concentrated, diluted with saturated sodium hydrogenocarbonate solution and extracted with DCM. The organic layer was dried and concentrated. The crude product was purified by ISCO column chromatography using 0-20% EtOAc in DCM to give methyl 5-methoxy-3-methylpyrazine-2-carboxylate (5.2 g, 95% yield). 1H NMR (300 MHz, CDCl3) δ ppm 8.11 (1H, s), 4.02 (3H, s), 3.97 (3H, s), 2.80 (3H, s)
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:17])[CH3:18])=[CH:9][CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 94.2 %

Procedure:
In ethanol (80 ml) was dissolved tert-butyldimethyl-4-nitrobenzyloxysilane (16.5 g), and to the mixture was added dried 5% palladium on carbon (0.83 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 7.5 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1/4) to give 4-aminobenzyloxy-tert-butyldimethylsilane (13.8 g) as colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:11]#[N:12].[H-].[Na+].[CH2:20](I)[CH3:21]>CN(C)C=O>[CH2:20]([O:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:11]#[N:12])[CH3:21]
Reactant: CCI
Reactant: COc1ccc(C#N)cc1OC1COCC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC1COCC1Oc1cc(C#N)ccc1OC
Temperature: 40 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
1.0 g (4.2 mmol) of 3-(4-hydroxytetrahydrofuran-3-yloxy)-4-methoxybenzonitrile (A15) in 5 ml of dimethylformamide are added dropwise under a nitrogen atmosphere to a solution of 140 mg (4.6 mmol) of sodium hydride in 5 ml of dimethylformamide and the mixture is heated at 40° C. for 1 h. 600 μl (7.5 mmol) of ethyl iodide, dissolved in 1 ml of dimethylformamide, are then added dropwise at RT. The mixture is stirred at RT for 2 h, concentrated, treated with 25 ml of water and acidified with 2 N hydrochloric acid. After extraction with 3×25 ml of ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. For further purification, the product is chromatographed on silica gel [toluene/ethyl acetate=4:1]. The product-containing fractions are concentrated and the residue is crystallized from isopropanol. 660 mg of the title compound of m.p. 64-66° C. are obtained.
Reaction SMILES: O[CH:2]1[CH2:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([CH3:17])=[CH:3]1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl>[CH3:17][C:4]1[CH:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]2([CH2:11][CH2:2][CH:3]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: CCOC(=O)C1C(C)=CC(O)CC12CCCC2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C1C(C)=CCCC12CCCC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 70 %

Procedure:
At −20° C., a solution of ethyl 9-hydroxy-7-methylspiro[4.5]dec-7-ene-6-carboxylate (1.5 g, 6.3 mmol, cis/trans 34:66, prepared as described in example 16) in dichloromethane was treated with successively with triethylsilane (3.66 g, 31.5 mmol) and with BF3.OEt2 (1.34 g, 9.4 mmol). The resulting solution was stirred for 45 min., poured into an ice-cold 2M aqueous NaOH solution (50 ml), and extracted twice with MTBE (40 ml). The organic phases were washed with water (40 ml), with a saturated aqueous solution of NaCl (40 ml), dried (MgSO4) and concentrated. FC (100 g SiO2, hexane/MTBE 25:1) of the crude product (1.28 g) gave ethyl 7-methylspiro[4.5]dec-7-ene-6-carboxylate (0.98 g, 70%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][CH3:12])[N:7]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)[C:6]=2[CH:20]=1.[C:21]([Si:23]([CH3:26])([CH3:25])[CH3:24])#[CH:22]>N1CCCCC1.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.[Cu]I>[CH2:11]([O:10][C:8]1[N:7]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[C:6]2[CH:20]=[C:2]([C:22]#[C:21][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=[CH:4][C:5]=2[N:9]=1)[CH3:12]
Reactant: CCOc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CCOc1nc2ccc(C#C[Si](C)(C)C)cc2n1-c1ccnc(N)n1
Temperature: 65 °C

Procedure:
To a solution of 4-(6-bromo-2-ethoxy-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine (270 mg, 0.74 mmol) in piperidine (1.8 mL) was introduced tetrakis(triphenylphosphine)palladium(0) (69 mg, 0.06 mmol), copper(I) iodide (11 mg, 0.06 mmol) and ethynyltrimethylsilane (0.53 mL, 3.71 mmol). The reaction mixture was warmed to 65° C. for 3 hr. After cooling to RT, the reaction mixture was re-treated with further tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.01 mmol), copper(I) iodide (5 mg, 0.03 mmol), ethynyltrimethylsilane (0.20 mL, 1.4 mmol) and warmed to 65° C. for an additional 2 hr. The reaction mixture was concentrated in vacuo and the residue re-dissolved in DCM (10 mL) and re-evaporated to dryness in vacuo (this procedure was repeated twice). Purification of the residue by column chromatography (Biotage, DCM containing a 2-8% gradient of methanol) furnished the title compound as an off-white solid: 1H NMR (250 MHz, DMSO) delta −0.07-0.07 (9 H, m), 1.21 (3H, t, J=7.01 Hz), 4.40 (2H, q, J=7.06 Hz), 6.65-6.81 (1H, m), 6.88 (2H, br. s.), 7.06 (1H, dd, J=8.15, 1.60 Hz), 7.20 (1H, d, J=8.22 Hz), 7.98 (1H, d, J=1.22 Hz), 8.12-8.25 (1H, m); LCMS: m/z=+352.45 (M+H)+.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH:13]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[CH2:14][C:15](OCC)=[O:16].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.C(OCC)(=O)C>O1CCCC1>[CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH:13]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[CH2:14][CH2:15][OH:16]
Reactant: CCOC(=O)CC(c1ccc2ccccc2c1)c1c[nH]c2c(CSC)cccc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSCc1cccc2c(C(CCO)c3ccc4ccccc4c3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 600 mg (1.49 mmol) of the compound from Example 45A in 15 ml of tetrahydrofuran was added dropwise to 5.2 ml (5.2 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 30 ml of tetrahydrofuran at RT under argon. Stirring at RT for 15 min was followed by addition, while cooling in ice, of 1N hydrochloric acid, extraction with ethyl acetate, drying of the organic phase over magnesium sulfate, filtration and concentration. 486 mg (90% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]([C:14]1[CH:15]=[C:16]([C:33]([O:35]C)=[O:34])[N:17]([CH2:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=2)[CH:18]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>C1COCC1.[Pd]>[C:28]([CH2:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:17]2[CH:18]=[C:14]([C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:15]=[C:16]2[C:33]([OH:35])=[O:34])=[CH:21][CH:22]=1)([OH:30])=[O:29]
Reactant: [H][H]
Reactant: CCCCCCCCCCCC(=O)c1cc(C(=O)OC)n(Cc2ccc(/C=C/C(=O)OCC)cc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)c1cc(C(=O)O)n(Cc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C

Procedure:
50 mg (0.1 mmol) of methyl (E)-4-dodecanoyl-1-{4-[2-(ethoxycarbonyl)ethenyl]benzyl}pyrrole-2-carboxylate are dissolved in 5 ml of THF. After addition of a spatula tip of Pd/C, hydrogenation is carried out with vigorous stirring at room temperature under a hydrogen atmosphere produced using a hydrogen-filled balloon fitted onto the reaction flask for 4 h. Addition of kieselguhr is followed by filtration, the solvent is distilled off, the residue is mixed with 12 ml of ethanol and 4 ml of 10% strength aqueous KOH, and the resulting mixture is boiled under reflux for 1 h. Cooling is followed by dilution with water, acidification with dilute HCl and extraction with ether. The organic phase is washed with dilute HCl, dried over Na2SO4 and concentrated. The product is precipitated from petroleum ether.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]([O:13][C:14]3[C:15](=[O:19])[CH2:16][CH2:17][CH:18]=3)=[CH:11][CH:10]=2)O1.[F-].[Cs+].[C:25]([O:28][C@H:29]1[C@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@:33]2([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([CH2:52]Br)[CH:46]=3)[O:44][C@@:30]1([CH2:54][O:55][C:56](=[O:58])[CH3:57])[CH2:31][O:32]2)(=[O:27])[CH3:26]>O1CCOCC1.C(OC(=O)C)C>[C:25]([O:28][C@H:29]1[C@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@:33]2([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([CH2:52][C:9]4[CH:10]=[CH:11][C:12]([O:13][C:14]5[C:15](=[O:19])[CH2:16][CH2:17][CH:18]=5)=[CH:20][CH:21]=4)[CH:46]=3)[O:44][C@@:30]1([CH2:54][O:55][C:56](=[O:58])[CH3:57])[CH2:31][O:32]2)(=[O:27])[CH3:26]
Reactant: CC1(C)OB(c2ccc(OC3=CCCC3=O)cc2)OC1(C)C
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(CBr)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC5=CCCC5=O)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Temperature: 110 °C
Yield: 35.1 %

Procedure:
To a solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)cyclopent-2-enone (295 mg, 0.989 mmol), CsF (296 mg, 1.95 mmol) in dioxane (3.1 mL), (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(3-(bromomethyl)-4-chlorophenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (369.4 mg, 0.65 mmol, Intermediate 2) and Pd(PPh3) (60 mg, 0.05 mmol) were added under N2 atmosphere. The reaction mixture was heated to 110° C. for 1 h. After completion of the reaction as confirmed by TLC, the reaction mixture was diluted with ethylacetate (100 mL), washed with water (20 mL) and brine (20 mL) successively. The organic layer was dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 2:8 Acetone:hexane) to provide title compound (150 mg, 35%) as off-white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[CH3:14])(O)[CH3:7])=[CH:2]1.C[Si]([N:19]=[N+:20]=[N-:21])(C)C.B(F)(F)F.O>C1C=CC=CC=1>[N:19]([C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)([C:9]1[O:13][CH:12]=[N:11][C:10]=1[CH3:14])[CH3:7])=[N+:20]=[N-:21]
Reactant: Cc1ncoc1C(C)(O)c1ccoc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: FB(F)F
Solvent: O
Solvent: c1ccccc1
Product: Cc1ncoc1C(C)(N=[N+]=[N-])c1ccoc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Furyl)-1-(4-methyl-5-oxazolyl)ethanol (1 g) was suspended in benzene (4 ml). Trimethylsilylazide (822 μl) was added followed by borontrifluoride diethyletherate (770 μl). The mixture was stirred overnight at room temperature, then poured into water and extracted to give the title compound.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:13]([O:15][C:16](=[O:29])[C@@H:17]([O:26][CH2:27][CH3:28])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH3:14].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[CH2:13]([O:15][C:16](=[O:29])[C@@H:17]([O:26][CH2:27][CH3:28])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:2]/[CH:3]=[CH:4]/[C:5]#[C:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:23][CH:24]=1)[CH3:14]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: ClC/C=C/C#Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/C#Cc2ccccc2)cc1)OCC

Procedure:
To a solution of (E)-(5-chloro-pent-3-en-1-ynyl)-benzene (177 mg, 1.0 mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (238 mg, 1.0 mmol) in acetone (15 mL) was added potassium carbonate (700 mg, 5.0 mmol) and potassium iodide (17 mg, 0.1 mmol). The mixture was heated to reflux over night with stirring. Water was added and the product extracted with tert-butyl methyl ether (×3) The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo, to give the title compound as a crude product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:18][C:17](=O)[C:9]2[C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][O:12][C:8]=2[CH2:7]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl>C(O)C>[ClH:25].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:18]/[C:17](=[N:24]\[NH:23][C:20]([NH2:22])=[NH:21])/[C:9]2[C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][O:12][C:8]=2[CH2:7]1
Reactant: O=C1CC(c2ccco2)Cc2occ(C(F)(F)F)c21
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: N=C(N)N/N=C1\CC(c2ccco2)Cc2occ(C(F)(F)F)c21
Temperature: 90 °C
Reaction time: 4 h
Yield: 40.6 %

Procedure:
To a mixture of 6-(2-furyl)-3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.22 g) and aminoguanidine hydrochloride (90 mg) were ethanol (16 ml) and 6N hydrochloric acid (0.070 ml), and the mixture was stirred at 90° C. for 4 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(2-furyl)-4-guanidinoimino-3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 54) (0.12 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[N:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[N:28]=1)[C:6](=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])#[N:2]>N.C(O)C.[Rh]>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[N:28]=[C:29]([CH3:34])[CH:30]=[C:31]([CH3:33])[N:32]=1)[C:6](=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCC(=O)N(CCC#N)CCCCCNc1nc(C)cc(C)n1
Agent: [Rh]
Agent: N
Solvent: CCO
Product: CCCCCCCCCCCCCC(=O)N(CCCN)CCCCCNc1nc(C)cc(C)n1
Reaction time: 5 h

Procedure:
The nitrile (XIV) (330 mg) was dissolved in 5 ml of 10% conc. NH3 in ethanol to which was added a spatula tip full of 5% Rh on alumina. After 5 hours stirring under 1 atm H2, there was no reaction indicated by tlc or H2 uptake. Additional catalyst (about 2×) and solvent were added and the hydrogenation continued overnight. The catalyst was filtered off and the solvents removed under vacuum to yield the product XV.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH:27][NH2:28]>>[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[N:27]1[CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])=[N:28]1
Reactant: NNc1nc2ccccc2s1
Reactant: O=C(C=Cc1ccccc1O)c1ccccc1
Product: Oc1ccccc1C1=NN(c2nc3ccccc3s2)C(c2ccccc2)C1

Procedure:
Example 4 is prepared using 2-hydroxychalcone and benzothiazol-2-yl-hydrazine following the procedure described for Example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[N:25]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:28]4[N:24]([CH3:23])[N:25]=[CH:26][CH:27]=4)[CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3ccnn3C)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (116 mg, 0.56 mmol) and K2CO3 (116 mg, 0.84 mmol) in DME-water (2:1) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(1-methyl-1H-pyrazol-5-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) δ (ppm): 7.78 (t, 1H), 7.62 (d, 1H), 7.57 (m, 3H), 7.37 (d, 1H), 7.18 (d, 1H), 7.02 (d, 1H), 6.43 (d, 1H), 4.76 (d, 1H), 4.4 (d, 1H), 3.93 (s, 3H), 3.8 (m, 1H), 3.57 (m, 1H), 3.2 (m, 4H), 3.0 (m, 1H), 2.42 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH2:22][C@H:23]1[C@@H:27]([N:28]2[CH:32]=[CH:31][N:30]=[N:29]2)[CH2:26][NH:25][CH2:24]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:25]2[CH2:26][C@H:27]([N:28]3[CH:32]=[CH:31][N:30]=[N:29]3)[C@H:23]([NH2:22])[CH2:24]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: N[C@@H]1CNC[C@@H]1n1ccnn1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Product: Nc1c(F)c(N2C[C@@H](N)[C@@H](n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 65 %

Procedure:
Prepared by following the same procedure as described for Example 17 by using 5-amino-1-cyclopropyl -6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and cis-3-amino-4-(1,2,3-triazol-1-yl)pyrrolidine. Yield: 65%, m.p. 275°-277° C. 1H NMR (TFA) δ: 1.33-1.50 (m, 4H), 4.32-5.12 (m, 6H), 6.34 (m, 1H), 8.64 (s, 1H), 8.89 (s, 1H), 9.16 (s, 1H).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:9]=1)=[O:3].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[CH:9]=[C:4]([C:2]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:3])[CH:5]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=2)=[CH:11][CH:12]=1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cc(C(=O)Cl)cc(-c2ccc(C)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of ethyl 5-(chlorocarbonyl)-4′-methylbiphenyl-3-carboxylate (5.5 g, 18 mmol) in methylene chloride (100 mL) at 0° C. were slowly added pyrrolidine (2.6 g, 36 mmol) and triethylamine (7.6 mL, 54 mmol). The mixture was stirred at room temperature for 2 h, and then washed with brine, aq. Na2CO3 solution and water. The separated organic phase was dried (Na2SO4), and concentrated. The residue was purified by silica gel column (30-100% EtOAc/hexane) to afford the desired compound.