Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].Cl.[CH3:27][O:28][CH2:29][CH:30]1[CH2:35][NH:34][CH2:33][CH:32]([CH2:36][O:37][CH3:38])[N:31]1[CH3:39].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:38][O:37][CH2:36][CH:32]1[N:31]([CH3:39])[CH:30]([CH2:29][O:28][CH3:27])[CH2:35][N:34]([CH2:2][C:3]([NH:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([NH:14][C@H:15]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH2:17][CH2:16]4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:33]1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: COCC1CNCC(COC)N1C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CN(CC(=O)Nc2ccc3c(c2)COC(N[C@@H]2CCc4ccccc42)=N3)CC(COC)N1C
Yield: 10.5 %

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3 step A) (100 mg, 0.281 mmol), the above described (2SR,6SR)-2,6-bis-methoxymethyl-1-methyl-piperazine hydrochloride (69.5 mg, 0.309 mmol) and diisopropylethyl amine (144 ul, 0.843 mmol) in acetonitrile (2 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a light yellow solid (15 mg, 11%), MS (ISP) m/e=508.4 [(M+H)+].
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([NH:14][C:15]2[S:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][N:19]=2)=[O:13])[N:10]=1)=[O:4].[CH3:23][NH:24][CH3:25].CO.[I-].[K+].Cl>O>[CH3:23][N:24]([CH3:25])[CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([NH:14][C:15]2[S:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][N:19]=2)=[O:13])[N:10]=1)=[O:4]
Reactant: CNC
Reactant: CC(C)c1cnc(NC(=O)Cc2csc(NC(=O)CCl)n2)s1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)c1cnc(NC(=O)Cc2csc(NC(=O)CN(C)C)n2)s1
Yield: 20 %

Procedure:
A mixture of 2-chloro-N-(4-{2-[(5-isopropyl-1,3-thiazol-2-yl)amino]-2-oxoethyl}-1,3-thiazol-2-yl)acetamide (0.5 g, 1.4 mmol), 2M dimethylamine in methanol (3.5 ml, 7 mmol) and potassium iodide (0.116 g, 0.7 mmol) was refluxed for about 6 hours. After cooling, the solution was diluted with water, acidified with 1N HCl and extracted with diethyl ether to eliminate the unreacted products. The aqueous solution was then basified with 1N NaOH and extracted with diethyl ether. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel, using CH2Cl2:MeOH 97:3 and then 95:5 as eluent. The title compound was obtained in 20% yield (0.1 g) as a light yellow solid.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9](=[O:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:24](Cl)(=[O:29])[CH2:25][CH2:26][CH:27]=[CH2:28]>C1COCC1>[C:24]([N:8]1[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:10][C:9]1=[O:18])(=[O:29])[CH2:25][CH2:26][CH:27]=[CH2:28]
Reactant: C=CCCC(=O)Cl
Reactant: O=C1N[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Yield: 66.5 %

Procedure:
Charge a 250 mL, single-neck, round-bottomed flask with (4S,5R)-4,5-diphenyloxazolidin-2-one (5.0 g, 21.0 mmol) and THF (300 mL). Stir the mixture at −78° C. and add dropwise BuLi (13.7 mL, 21.9 mmol). Stir the reaction mixture for 0.5 hours and then add pent-4-enoyl chloride (3.71 g, 31.3 mmol). Stir the reaction mixture one hour until TLC shows that the starting material has been consumed. Add water (100 mL) and extract the aqueous with CH2Cl2 (3×250 mL). Combine the organic layers and dry over Na2SO4. Concentrate and purify by chromatography (Silica gel) to afford (4S,5R)-3-Pent-4-enoyl-4,5-diphenyloxazolidin-2-one (4.49 g, 67%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: CN1CCNCC1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCN(C)CC3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide was prepared from 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3yl)isonicotinamide and N-methylpiperazine using method A. NMR; δH [2H6]—DMSO 10.31,(1H, s), 8.62,(1H, t), 8.24,(1H, d), 7.93,(2H, d), 7.71,(1H, dd), 7.64,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 7.23,(1H, s), 7.06,(1H, d), 3.55,(4H, m), 3.16,(2H, t), 2.40,(4H, t), 2.21,(6H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 2.74 min, MH+484.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl[C:44]1[CH:49]=[C:48]([C:50]2[CH:55]=[CH:54][N:53]=[C:52]([Cl:56])[CH:51]=2)[CH:47]=[CH:46][N:45]=1.[NH2:57][CH:58]([CH3:62])[CH2:59][O:60][CH3:61].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:56][C:52]1[CH:51]=[C:50]([C:48]2[CH:47]=[CH:46][N:45]=[C:44]([NH:57][CH:58]([CH3:62])[CH2:59][O:60][CH3:61])[CH:49]=2)[CH:55]=[CH:54][N:53]=1
Reactant: COCC(C)N
Reactant: Clc1cc(-c2ccnc(Cl)c2)ccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COCC(C)Nc1cc(-c2ccnc(Cl)c2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Xantphos (32 mg), and Pd2(dba)3 (25 mg) were suspended in toluene (8 ml) and stirred under argon for 10 mins, then 2,2′-dichloro-[4,4′]-bipyridinyl (250 mg), 2-amino-1-methoxypropane (0.117 ml) and sodium tert-butoxide (150 mg) were added. The mixture stirred at 60° C. for 6 hours then cooled to room temp, poured onto water and extracted with ethyl acetate, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by passing the crude mixture down Kieselgel using a gradient of hexane and ethyl acetate as the eluent.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:19][C:20]=3[O:22][CH:23]([CH3:25])[CH3:24])[N:15]=[CH:14][N:13]=2)=[C:4]2[O:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1.Cl.[CH3:36][N:37]([CH3:42])[CH2:38][C:39](Cl)=[O:40].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][N:32]([C:39](=[O:40])[CH2:38][N:37]([CH3:42])[CH3:36])[CH2:31][CH2:30]4)=[CH:19][C:20]=3[O:22][CH:23]([CH3:25])[CH3:24])[N:15]=[CH:14][N:13]=2)=[C:4]2[O:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)Oc1cc(OCCN2CCNCC2)cc2ncnc(Nc3c(Cl)cnc4c3OCO4)c12
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1cc(OCCN2CCN(C(=O)CN(C)C)CC2)cc2ncnc(Nc3c(Cl)cnc4c3OCO4)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
4-(5-Chloro-2,3-methylenedioxypyrid-4-ylamino)-5-isopropoxy-7-(2-piperazin-1-ylethoxy)quinazoline (0.2 g) was added to a stirred mixture of 2-dimethylaminoacetyl chloride hydrochloride (0.097 g), triethylamine (0.15 ml) and methylene chloride (5 ml) that had been cooled to 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. A second portion of each of 2-dimethylaminoacetyl chloride hydrochloride (0.097 g) and triethylamine (0.057 ml) were added and the reaction was stirred at ambient temperature for 16 hours overnight. Methylene chloride (50 ml) was added and the reaction mixture was extracted twice with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar solvent mixtures, starting with a 9:1 mixture of methylene chloride and methanol and ending with a 90:8:2 mixture of methylene chloride, methanol and a saturated methanolic ammonia solution. There was thus obtained the title compound as a foam (0.155 g); NMR Spectrum: (CDCl3) 1.55 (d, 6H), 2.3 (s, 6H), 2.6 (m, 4H), 2.9 (t, 2H), 3.1 (s, 2H), 3.65 (m, 4H), 4.25 (t, 2H), 4.85 (s, 1H), 6.15 (s, 2H), 6.55 (s, 1H), 6.85 (s, 1H), 7.75 (s, 1H), 8.6 (s, 1H), 9.6 (s, 1H); Mass Spectrum: M+H+ 572 and 574; Elemental Analysis: Found C, 55.1; H, 6.1; N, 16.8; C27H34ClN7O5 0.75H2O requires C, 55.4; H, 6.1; N, 16.7%.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:13].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=[CH:6][C:5]=2[CH3:13]
Reactant: Cc1cc(=O)c2cccc(C)c2o1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(=O)c2c([N+](=O)[O-])ccc(C)c2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 g (11.48 mmol) of 2,8-dimethyl-4H-chromen-4-one are dissolved in 15 ml of concentrated sulfuric acid and, at 0° C., 0.7 g (11.48 mmol) of fuming nitric acid is added, during which the temperature should not exceed 5° C. The mixture is then stirred at room temperature for 1 h. The reaction mixture is poured into ice-water, whereupon a colorless solid precipitates. This is filtered off and washed several times with water and ice-cold methanol. 2.3 g (90.8% of theory) of the title compound are obtained.
Reaction SMILES: [Na].[C:2]1([N:8]=[N+:9]=[N-:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]>C(O)C.O>[NH2:12][C:11]1[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[N:10][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: CCOC(=O)CC#N
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1nnn(-c2ccccc2)c1N
Temperature: 45 °C
Reaction time: 0.08 h

Procedure:
A solution of sodium (2.04 g; 0.089 mole) in ethanol (50 ml) was added to a mixture of phenyl azide (11.9 g; 0.1 mole) and ethyl cyanoacetate (11.3 g; 0.1 mole) and the product gently warmed to 45° C. with stirring for 5 mins. After stirring at ambient temperature for a further 15 minutes the flask was immersed in water at room temperature for 3 hrs. A white solid separated which was filtered off after dilution of the mixture with water and washed with water. Recrystallisation from ethanol gave 18.4 g. (79%) of material of mp 124.5-125.5° C. (lit mp 126°; B. R. Brown, D. L. Hammick and S. G. Heritage J. Chem. Soc. 3820 [1953]).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:5]([OH:7])=O)[CH3:2].C(Cl)CCl.C(N(C(C)C)CC)(C)C.[CH:42]1[CH:47]=[CH:46][C:45]([CH:48]([NH2:51])[CH2:49][OH:50])=[CH:44][CH:43]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(OCC)(=O)C>[CH2:1]([O:3][C@H:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:22][CH:23]=2)=[CH:13][CH:14]=1)[C:5]([NH:51][C@H:48]([C:45]1[CH:46]=[CH:47][CH:42]=[CH:43][CH:44]=1)[CH2:49][OH:50])=[O:7])[CH3:2]
Reactant: NC(CO)c1ccccc1
Reactant: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCO[C@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)N[C@@H](CO)c1ccccc1
Yield: 32.7 %

Procedure:
A solution of 2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl} ethoxy)phenyl]propanoic acid (10.5 g; 25.7 mmole) in dry dichloromethane (150 ml) was cooled on an ice-bath and EDC (5.42 g; 28.3 mmole), diisopropylethylamine (4.8 ml; 28.3 mmole) and HOBtxH2O (3.82 g; 28.3 mmole) were added. After 20 minutes the ice-bath was removed and (R)-phenylglycinol (3.88 g; 28.3 mmole) was added. After stirring at room temperature over night dichloromethane (100 ml), citric acid (60 ml, 10%) and ethyl acetate were added and the phases were separated. The organic phase was washed with citric acid (60 ml), sodium bicarbonate (2×60 ml) and brine (60 ml), dried (sodium sulfate), filtered and the solvent evaporated in vacuo. The crude product was crystallized twice in ethyl acetate/heptan to give 4.43 g of (R)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic amide. The mother liquids were combined, the solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel using ethyl acetate:heptan (gradient 25 to 100% ethyl acetate) to give 5.14 g (yield 38%) of (S)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)-phenyl]propanoic amide and 0.51 g (totally 4.94 g, yield 36%) of (R)-2-ethoxy-N-(2-hydroxy-(R)-1-phenylethyl)-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoic amide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:19]([O-])=O)[C:5]([C:8]2([C:14](OCC)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1>[Fe].CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[NH:19][C:14](=[O:15])[C:8]3([CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)C1(c2ncc(Br)cc2[N+](=O)[O-])CCOCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cc(Br)cnc2C12CCOCC2
Temperature: 100 °C

Procedure:
Prepared according to procedure J using ethyl 4-(5-bromo-3-nitropyridin-2-yl)tetrahydro-2H-pyran-4-carboxylate (250 mg, 0.724 mmol), AcOH (4 mL) and Fe powder (202 mg, 3.62 mmol) and heating the mixture at 100° C. for 2 h. After purification 6′-bromo-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-2′(1′H)-one was obtained.
Reaction SMILES: COB1[CH:8]2[CH2:9][CH2:10][CH2:11][CH:4]1[CH2:5][CH2:6][CH2:7]2.B(F)(F)F.[CH3:16]COCC.B(Cl)(Cl)Cl>O1CCCC1.CCCCC.C(OCC)C.COC(C)(C)C.CCCCCC>[CH3:16][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:4]
Reactant: COB1C2CCCC1CCC2
Reactant: CCOCC
Agent: ClB(Cl)Cl
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: COC(C)(C)C
Product: CCCCCCCCC

Procedure:
For example, the appropriate lithium trisubstituted-silylacetylene (2) is contacted with an equimolar amount of B-methoxy-9-borabicyclo[3.3.1]nonane (3) in a suitable anhydrous inert organic solvent such as tetrahydrofuran, hexane, t-butyl methyl ether, diethyl ether, pentane and the like with tetrahydrofuran being preferred. The reactants are typically stirred together under an inert atmosphere for a period of time ranging from 5 minutes to 48 hours at a temperature range of from -78° C. to room temperature. A temperature range of -78° C. to -40° C. and a reaction time of 1.5 hours to 5 hours are preferred. The intermediate "ate" complex thus formed is contacted with a molar excess of a suitable lewis acid such as boron trifluoride etherate, boron trichloride and the like with boron trifluoride etherate being preferred. The reactants are typically stirred together under an inert atmosphere for a period of time ranging from 5 minutes to 24 hours and at a temperature range of from -78° C. to room temperature. A temperature range of -78° C. to -40° C. and a reaction time of 15 minutes to 1 hour are preferred. The B-(2-(trisubstitutedsilyl)ethynyl)-9-boracyclo[3.3.1]nonane of formula (I) is isolated as a tetrahydrofuran complex by evaporation of the volatiles. It may be purified by crystallization from a suitable inert organic solvent such as pentane, hexane and the like. Starting materials for use in Scheme A are readily available to one of ordinary skill in the art.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([O:19][C:20]([N:22]1[CH2:30][CH2:29][CH2:28][CH:24]([C:25]([OH:27])=[O:26])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O>[C:15]([O:19][C:20]([N:22]1[CH2:30][CH2:29][CH2:28][CH:24]([C:25]([O:27][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:26])[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
Benzyl bromide (4.34 g, 25.4 mmol) and potassium carbonate (4.80 g, 34.7 mmol) were added to 1-(tert-butoxycarbonyl)nipecotic acid (5.30 g, 23.1 mmol) in N,N-dimethylformamide (20 mL). The mixture was stirred at room temperature for 6 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The organic layer washed sequentially with water and brine and was dried over sodium sulfate. The solvent was then evaporated to give 7.11 g (96%) of the desired compound as a pale yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[O:47]=[C:48]([NH:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[CH:57]=1)[CH2:49][CH2:50][C:51](O)=[O:52]>C1COCC1>[O:52]=[C:51]([N:7]1[CH2:8][CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]1[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:50][CH2:49][C:48]([NH:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:63])([F:64])[F:65])[CH:57]=1)=[O:47]
Reactant: O=C(O)CCC(=O)NCc1cccc(C(F)(F)F)c1
Reactant: c1csc(C2NCCc3ccccc32)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCC(=O)N1CCc2ccccc2C1c1cccs1)NCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
236 mg (1.1 mmol) of 1-(thiophen-2-yl)-1,2,3,4-tetrahydroisoquinoline, 380 mg (1.0 mmol) of HATU and 263 μl (1.9 mmol) of NEt3 were added in succession to a solution of 275 mg (1.0 mmol) of 4-oxo-4-(3-(trifluoromethyl)benzylamino)butyric acid (intermediate VVV01) in THF (8 ml) and the mixture was then stirred for 24 h at RT. Then it was diluted with EE (30 ml) and washed twice with a 4M aqueous NH4Cl solution and with a 1M aqueous NaHCO3 solution. The organic phase was dried over MgSO4, filtered and concentrated to small volume under vacuum. Column chromatography (EE) of the residue produced 410 mg (0.87 mmol, 87%) of 4-oxo-4-(1-thien-2-yl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(3-(trifluoromethyl)benzyl)butyric acid amide. MS: m/z 473.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:15])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[Cl:16][C:17]1[N:22]=[CH:21][C:20](I)=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>C1COCC1.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>[Cl:16][C:17]1[N:22]=[CH:21][C:20]([C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH:5]([CH3:6])[C:4]([NH:3][CH2:1][CH3:2])=[O:15])=[CH:12][CH:11]=2)=[CH:19][N:18]=1
Reactant: C#Cc1ccc(C(C)C(=O)NCC)cc1
Reactant: Clc1ncc(I)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)C(C)c1ccc(C#Cc2cnc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1.10 g (5.46 mmol) N-ethyl-2-(4-ethynyl-phenyl)-propionamide (XVII.1) in 10 mL THF are added 1.31 g (5.46 mmol) 2-chloro-5-iodo-pyrimidine under argon, followed by 0.42 g (0.60 mmol) Pd(PPh3)2Cl2 as catalyst, 57 mg (0.30 mmol) copper(I)iodide and 2.1 mL (12 mmol) DIPEA as base. The mixture is stirred at rt for 4 h. After that time, the mixture is filtered and the solvent is evaporated from the filtrate. The residue is purified by column chromatography (silicia gel; DCM:MeOH gradient 1:0/1:1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[C:23](=[O:24])[CH2:22][CH2:21][CH:20]1[C:25]#N.C(O)(=[O:29])C>C1C=CC=CC=1.C(OCC)C>[OH:24][CH:23]1[CH2:22][CH2:21][CH:20]([CH:25]=[O:29])[CH:19]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][OH:11]
Reactant: N#CC1CCC(=O)C1CCCCCCCO
Reactant: CC(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=CC1CCC(O)C1CCCCCCCO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
A solution of diisobutylaluminium hydride (25.6 g., 0.18 mole) in benzene (250 ml.) was added, with rapid stirring, to a solution of 2-(7-hydroxyheptyl)-3-oxocyclopentanecarbonitrile (10 g., 0.045 mole) in dry diethyl ether (250 ml.) at 10°-15°C. Stirring at ambient temperature was contined for 15 minutes and the mixture was added to 2N aqueous acetic acid (300 ml.) at a temperature lower than 15°C. The organic phase was separated and the aqueous layer was extracted with diethyl ether. The combined organic phases were washed with aqueous sodium bicarbonate, dried over magnesium sulphate and the solvents were removed in vacuo. The residue was distilled under reduced pressure to give 3-hydroxy-2-(7-hydroxyheptyl)cyclopentanecarbaldehyde (4.5 g., 43%), b.p. 185°-193°C./0.1 mm.Hg, nD22.5 1.4995.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH2:4][CH:5]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:12])[CH2:7][C:6]2=[CH2:13].[H][H]>C(OCC)(=O)C>[CH3:1][C:2]1[CH2:3][CH2:4][CH:5]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:12])[CH2:7][CH:6]2[CH3:13]
Reactant: C=C1CC(=O)CCC2=C(C)CCC12
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: CC1=C2CCC(=O)CC(C)C2CC1

Procedure:
528 mg of 1-methyl 4-methylen-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene were hydrogenated in 20 ml of ethyl acetate with the aid of 200 mg of palladium-on-calcium carbonate (5%). After hydrogen uptake was completed the mixture was filtered off from the catalyst, the filtrate concentrated under reduced pressure and distilled. There was obtained pure 1,4-dimethyl-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene, b.p.0.06 60°; IR(film): νmax = 1700, 1450, 1378, 1250, 1190 cm-1. The compound has a woody, earthy, camphorous odour.
Reaction SMILES: [OH:1][C@H:2]1[CH2:15][C@@H:14]([OH:16])[C@H:13]([CH2:17][CH2:18]/[CH:19]=[CH:20]/[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:25]1[CH2:35]CN2C(=NCCC2)C[CH2:26]1.C(I)(C)C>C(#N)C>[CH:25]([O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7]/[CH:6]=[CH:5]\[CH2:4][C@@H:3]1[C@@H:13]([CH2:17][CH2:18]/[CH:19]=[CH:20]/[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:14]([OH:16])[CH2:15][C@@H:2]1[OH:1])([CH3:35])[CH3:26]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCC/C=C/CC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Solvent: CC#N
Solvent: CC(C)I
Product: CCCC/C=C/CC[C@@H]1[C@@H](C/C=C\CCCC(=O)OC(C)C)[C@@H](O)C[C@H]1O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The compound 28 obtained obove (237 mg, 0.70 mmole) was dissolved in acetonitrile (3 ml), and 1,8-diazabicyclo[5.4.0]-7-undecene (0.178 ml, 1.2 mmole) and isopropyl iodide (0.12 ml, 1.2 mmole) were added thereto and the mixture was stirred at room temperature for 15 hours. Then, the reaction mixture was treated following the procedure similar to that of Example 5, to yield 266 mg of the title compound 29 as a colorless oil (quantitative).