Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CCN(CC)CC.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:39][CH2:40][CH:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:39][CH2:40][CH:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:7]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)c1cccc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
To a solution of 3-bromobenzoic acid (200 mg, 1.0 mmol) in DCM (8 mL) was added Et3N (303 mg, 3.0 mmol), EDCI (383 mg, 2.0 mmol), HOBt (270 mg, 2.0 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (247 mg, 1.2 mmol). The mixture was stirred at 25° C. for 6 h. The mixture was treated with water and extracted with EA. The organic layer was washed with NaHCO3, brine, dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification (300 mg, Yield 77%). LCMS (m/z): 390.1 (M+1).
Reaction SMILES: ClCCl.[CH3:4][C:5]([NH:15][CH:16]([CH3:20])[C:17](=O)[CH3:18])([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:6].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](Cl)=[O:30].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:6][C:5]([N:15]1[CH:16]([CH3:20])[C:17]([CH3:18])=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])[C:29]1=[O:30])([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:4]
Reactant: CC(=O)C(C)NC(C)(C)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)Cc1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C(c2ccccc2F)C(=O)N(C(C)(C)c2ccc(Cl)c(Cl)c2)C1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To 20 ml of dichloromethane were added 3.0 g of N-[1-methyl-1-(3,4-dichlorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)amine and 3.5 g of pyridine, and 4.0 g of 2-fluorophenylacetyl chloride was then added dropwise thereto at 5° to 10° C. After stirring at room temperature for 1 hour, a saturated aqueous sodium hydrogencarbonate solution was added, followed by extraction with dichloromethane. After dried over anhydrous sodium sulfate, the solution was concentrated by an evaporator, and the resulting oil was dissolved in 20 ml of ethyl acetate. Next, 10 ml of a 28% methanol solution of sodium methylate was added thereto, and after stirring under reflux for 15 minutes, the temperature of the solution was returned to room temperature and water was then added, followed by extraction with ethyl acetate. Afterward, the solution was washed with a 12% hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate, and then dried over anhydrous sodium sulfate. Next, the solution was concentrated by an evaporator, and then subjected to silica gel chromatography to obtain 2.5 g of 1-[1-methyl-1-(3,4-dichlorophenyl)ethyl]-4,5-dimethyl-3-(2-fluorophenyl)-3-pyrroline-2-one.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=O>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: COc1ccccc1C(=O)O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: COc1ccccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 55 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-methoxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate 95:5 to 50:50, 170 mg, 55%) which was obtained as a white foam. MS: m/e=334.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[CH:14](OCC)(OCC)OCC>FC(F)(F)C(O)=O>[CH3:14][NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6]
Reactant: CCOC(OCC)OCC
Reactant: C=CCOC(=O)c1cccc(N)c1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)c1cccc(NC)c1
Yield: 17 %

Procedure:
Allyl 3-aminobenzoate (5 g, 28.2 mM) was dissolved in triethyl orthoformate (50 ml) and trifluoroacetic acid (5 drops) was added. The soluiton was stirred and refluxed up through 3å molecular sieves for 5 hours. Solvent was removed, and the residue dissolved in ethanol (50 ml), followed by the addition of acetic acid (8.08 ml) and sodium cyanoborohydride (6.85 g, 0,108 M) in several portions. The mixture was stirred at ambient temperature for 16 hours, and solvent removed. The residue was dissolved in diethyl ether, washed with water, brine, and dried over MgSO4. Crude product was purified by chromatography on silica, eluting with a gradient from dichloromethane to dichloromethane/ethyl acetate (95:5), to give allyl 3-methylaminobenzoate (0.93 g, 17%). Nmr (CDCl3): δ2.88 (s, 3H); 4.81 (dt, 2H); 5.23-5.45 (m, 2H); 5.94-6.13 (m, 1H); 6.83 (dd, 1H); 7.25 (dd, 1H); 7.33 (t, 1H); 7.43 (dm, 1H).
Reaction SMILES: C[N:2]([C@@:10]1([CH3:15])[CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=O)OC(C)(C)C.C(N(CC)CC)C.[C:23]([C:25]1[C:30]2[N:31]=[C:32]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[O:33][C:29]=2[C:28](F)=[C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:26]=1[CH3:46])#[N:24]>CS(C)=O>[C:23]([C:25]1[C:30]2[N:31]=[C:32]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[O:33][C:29]=2[C:28]([N:12]2[CH2:13][CH2:14][C@:10]([CH3:15])([NH:2][CH3:3])[CH2:11]2)=[C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:26]=1[CH3:46])#[N:24]
Reactant: CN(C(=O)OC(C)(C)C)[C@@]1(C)CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN[C@@]1(C)CCN(c2c(-c3ccccc3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Temperature: 150 °C
Yield: 21.1 %

Procedure:
A dimethyl sulfoxide (1 ml) solution of tert-butyl methyl[(3S)-3-methylpyrrolidin-3-yl]carbamate (I-348) (318 mg, 1.48 mmol) and triethylamine (241 μl, 1.73 mmol) was added to a dimethyl sulfoxide (6 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (400 mg, 1.24 mmol) stirred in an oil bath at 150° C., followed by stirring in an oil bath at 150° C. for 30 minutes. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→1:2, v/v). The obtained yellow foamy substance was dissolved in dichloromethane (3 ml), and with cooling with ice, trifluoroacetic acid (6 ml) was added, followed by stirring at room temperature for 5 hours. The reaction liquid was concentrated under reduced pressure, then an aqueous saturated sodium hydrogencarbonate solution and water were added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v), and the obtained eluate was recrystallized from isopropyl ether to obtain the entitled compound (109 mg, 21%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([N:20]2[CH2:23][CH:22]([O:24][C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][N:26]=3)[CH2:21]2)=[O:19])[N:12]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C(OCC)(=O)C>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([N:20]2[CH2:21][CH:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[CH:27][N:26]=3)[CH2:23]2)=[O:19])[N:12]=1
Reactant: O=C(Nc1cccnn1)N1CC(Oc2ccc(I)cn2)C1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccnn1)N1CC(Oc2ccc(-c3ccccc3F)cn2)C1
Temperature: 100 °C
Yield: 53.2 %

Procedure:
A solution of 4-fluorophenyl boronic acid (0.254 mg, 1.81 mmol) in THF/H2O (10:1; 10 mL) was added to a microwave vial containing 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyridazin-3-ylamide (Example 7, Step 1) (0.480 g, 1.21 mmol) and potassium carbonate (0.50 g, 3.63 mmol). Nitrogen gas was bubbled through the mixture for 5 mins then 1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2 (0.099 g, 10 mole %) was added and the vial sealed and heated at 100° C. in microwave synthesiser for 30 min. The cooled reaction mixture was diluted with ethyl acetate (20 mL) and washed sequentially with saturated aqueous sodium carbonate solution (20 mL) then saturated sodium chloride solution (20 mL). The mixture was dried over magnesium sulphate and filtered. Filtrate solvents were removed in vacuo to afford a brown gum, which was purified by flash chromatography, eluting with a gradient of 50% to 100% ethyl acetate in hexane to a afford a white solid (0.235 g, 53%)
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:22])[C:14]([C:18]([NH:20][OH:21])=[NH:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[Cl:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][CH:49]([CH3:51])[CH3:50])[C:42](Cl)=O>O1CCOCC1>[CH2:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]1[C:17]2[C:12](=[C:13]([CH3:22])[C:14]([C:18]3[N:19]=[C:42]([C:41]4[CH:45]=[CH:46][C:47]([O:48][CH:49]([CH3:50])[CH3:51])=[C:39]([Cl:38])[CH:40]=4)[O:21][N:20]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Reactant: CCCCOC(=O)CC1c2ccc(C(=N)NO)c(C)c2CCN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCOC(=O)CC1c2ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(C)c2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21.3 %

Procedure:
To a solution of 1,1-dimethylethyl 1-[2-(butyloxy)-2-oxoethyl]-6-[(hydroxyamino)(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 19; 264 mg, 0.629 mmol) in dioxane (4 ml) was added triethylamine (0.263 ml, 1.89 mmol) followed by dropwise addition of 3-chloro-4-[(1-methylethyl)oxy]benzoyl chloride (Preparation 33; 176 mg, 0.755 mmol) in dioxane (2 ml). The resulting mixture was stirred at room temperature for 90 min, followed by heating at 100° C. for 24 h. The mixture was cooled to room temperature, most of the solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The layers were separated and the aqueous layer further extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography, eluting with 5-25% ethyl acetate in cyclohexane, gave the title compound as a pale yellow oil (80 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:13][C:12](=[O:20])[C:11]=2[CH:21]=1)[CH3:6])[CH3:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>C(O)C.[Pd].CC(C)=O>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]([C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:13][C:12](=[O:20])[C:11]=2[CH:21]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc2oc(C(C)(C)C)cc(=O)c2c1
Agent: O=[Cr](=O)=O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)C(C)c1ccc2c(c1)C(=O)CC(C(C)(C)C)O2

Procedure:
Ethyl-2-[2-(1,1-dimethylethyl)-4-oxo-4H-1-benzopyran-6-yl]propionate (6.61 g) was taken up in dry ethanol (150 ml) and hydrogenated at 85 p.s.i. with 5% palladium on carbon (0.2 g) and 5% palladium on barium sulphate (0.4 g) for a total of 48 hours. The catalyst was removed by filtration (`Hyflo` supercel) and the ethanol removed in vacuo affording an oil. The oil was taken up in acetone (50 ml) and treated with a slight excess of Jones reagent. The excess oxidant was destroyed with methanol and the reaction mixture was dissolved in water (200 ml) and extracted with ether. The combined ethereal extracts were washed with water, dilute aqueous sodium bicarbonate solution and water, dried (MgSO4) and concentrated in vacuo to give the title compound as an oil - 6 g.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O.C(O)C>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[NH2:19])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Clc1nc(N2CCOCC2)c2ccc(Br)cc2n1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a 50 mL round bottom flask, 4-(7-bromo-2-chloroquinazolin-4-yl)morpholine (1.0 g, 0.0030 mol—Preparation 1), 3-aminophenylboronic acid pinacol ester (0.657 g, 0.0030 mol), sodium carbonate (0.635 g, 0.0060 mol), toluene (20 mL), ethanol (4 mL) and water (3 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.105 g, 0.00015 mol) was added and degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 95° C. for 2 hours. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography (40% ethyl acetate in hexane) to provide the title compound (0.65 g, 62%). 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J=1.6 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.66 (dd, J′=8.4 Hz, J″=1.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.99 (t, J=2.0 Hz, 1H), 6.77 (dd, J′=7.6 Hz, J″=1.2 Hz, 1H), 3.90 (s, 8H), 3.84 (br s, 2H), LC-MS (ESI): Calculated mass. 340.11, Observed mass [M+H]+: 341.1 (RT=0.48 min).
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:24][CH2:23][N:22](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:21][CH2:20][N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.C(O)C.C(OCC)C>CC#N>[NH:10]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOCC
Solvent: CC#N
Product: C1CNCCNCCNCCNCCN1
Temperature: 100 °C
Reaction time: 70 h
Yield: 31 %

Procedure:
A mixture of 1,4,7,10,13-penta(p-toluenesulfonyl)-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 1D (168 g, 0.170 mole) and concentrated H2SO4 (500 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 70 h. To the resulting dark brown solution ethanol (500 ml) was added dropwise with stirring at 0° C. followed by ethyl ether (3 l). The white solid was filtered and washed with ethyl ether. The solid was then dissolved in H2O (500 ml) and the resulting solution washed with ethyl ether. Upon reducing the volume of the solution in vacuo to 200 ml, the pH was adjusted to 10-11 with 10 N NaOH and the solvent was removed in vacuo. Ethanol (500 ml) was then added and removed in vacuo to dryness. The resulting tan oily solid was extracted with hot THF (2×500 ml) and filtered at room temperature. The filtrates were combined and the solvent removed in vacuo to give the crude product as a yellow crystalline solid which was then redissolved in CH3CN and filtered to remove insoluble impurities. Recrystallization from cold (-20° C.) CH3CN gave 11.3 g (31% yield) of the product as colorless needles: mp 108-9° C.; 1H NMR (CDCl3) δ 1.74 (br s, 5 H), 2.73 (s, 20 H); Exact mass (M+Li)+ : calcd, 222.2270; Found, 222.2269 (C10H25N5Li).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([S:14][C:15]#[C:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Li+].CCOCC.O.Cl>C1COCC1>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([S:14][C:15]#[C:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(C#CSc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(SC#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
A solution of methyl 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulphanylethynyl)benzoate (590 mg, 1.6 mmol) and of lithium hydroxide (383 mg, 9.3 mmol) in THF is refluxed for 24 hours. The reaction mixture is poured into an Et2O/water mixture, acidified to pH 1 with concentrated hydrochloric acid solution, and extracted once with ethyl ether. After separation of the phases by settling, the organic phase is washed twice with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The solid obtained is crystallized from heptane and 440 mg (77%) of a white solid are obtained. m.p. (melting point)=193.5° C.
Reaction SMILES: [CH3:1][C:2]1(C)C(C)(C)OB(C=C)O1.I[C:13]1[C:14]([NH2:20])=[N:15][C:16](=[O:19])[NH:17][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CCCC)CCCC)CCC>CO.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].C(Cl)(Cl)Cl>[CH:1]([C:13]1[C:14]([NH2:20])=[N:15][C:16](=[O:19])[NH:17][CH:18]=1)=[CH2:2]
Reactant: Nc1nc(=O)[nH]cc1I
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN(CCCC)CCCC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=Cc1c[nH]c(=O)nc1N
Yield: 67.4 %

Procedure:
7.24 g of 4,4,5,5-tetramethyl-2-vinyl-1,3,2dioxaborolan (46.4 mmol), 10.00 g of 5-iodocytosine (42.2 mmol), 1.11 g of triphenylphosphine (14.2 mmol), 1.05 g of Pd2dba3.CHCl3 (1.1 mmol) and 15.1 ml tributylamine (63.3 mmol) in 200 ml of methanol were heated to reflux for 28 hours. After cooling the suspension to room temperature the crude product was filtered off and washed with methylene chloride. Crystallisation from boiling methanol gave 3.9 g (61%) of 5-vinylcytosine as white crystals, m.p. >290° C., MS (EI-MS): (m/z) 137 [M+H]+. 1H-NMR (250 MHz, D6-DMSO): 5.03 (1H, d, J=11.0), 5.45 (1H, d, J=17.3), 6.52 (1H, dd, J=17.3, 11.0), 6.8-7.2 (3H, br), 7.56 (1H, s).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]([CH:31]1[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37]([CH:34]3[CH2:35][CH2:36][CH:31]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:32][CH2:33]3)=[O:38])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CC(C)(C)C1CCC(C(=O)O)CC1
Agent: Cl
Product: CC(C)(C)C1CCC(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)CC1

Procedure:
The title compound, off-white solid (77 mg, 63%), MS (ISP) m/z=493.4 [(M+H)+], mp 199° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-tert-butyl-cyclohexanecarboxylic acid.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:26]4[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=4)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:36]([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[CH3:36][N:10]1[CH2:11][CH2:12][C:7]([CH2:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[CH:19]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:21]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: [BH3-]C#N
Reactant: N#Cc1ccc(-c2cc(COCC3(c4ccccc4)CCNCC3)cc(C(F)(F)F)c2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3′-(((4-Phenylpiperidin-4-yl)methoxy)methyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (18.3 mg, 0.04 mmol) and formaldehyde (37 wt. % solution in water, 86.4 μL, 3.22 mmol) were combined in acetonitrile (1.0 mL) and cooled to 0° C. The reaction was treated with sodium cyanoborohydride (12.6 mg, 0.2 mmol) and a few drops of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated to afford 12.1 mg (65%). 1H-NMR (CDCl3, 500 MHz) δ 7.74-7.76 (m, 2H), 7.66 (s, 1H), 7.58-7.60 (m, 2H), 7.44 (s, 1H), 7.41 (s, 1H), 7.36-7.38 (m, 2H), 7.30-7.33 (m, 2H), 7.18-7.21 (m, 1H), 4.45 (s, 2H), 3.48 (s, 2H), 2.58-2.60 (m, 2H), 2.17-2.28 (m, 4H), 2.21 (s, 3H), 1.98-2.08 (m, 2H). Mass spec.: 465.11 (MH)+.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[CH:11]#[C:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:17]N(C=O)C>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>[C:11]([C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5])#[C:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C#CCCCC
Reactant: O=C([O-])c1ccccc1I
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CCCCC#Cc1ccccc1C(=O)OC
Yield: 90 %

Procedure:
Coupling of 2-iodobenzoate (3.0 g, 11.5 mmol) with 1-hexyne (2.71 mL, 22.9 mmol) using Pd(PPh3)2Cl2 and CuI in DMF at room temperature gave 2.23 g (90%) of compound 157 as a brown oil. 1H NMR (400 MHz, CDCl3): δ 0.95 (t, J=7.3 Hz, 3H), 1.45-1.55 (m, 2H), 1.55-1.65 (m, 2H), 2.47 (t, J=7.0 Hz, 2H), 3.91 (s, 3H), 7.26-7.33 (m, 1H), 7.37-7.44 (m, 1H), 7.50 (d, J=7.7 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H). LCMS (APCI): m/z 217 (M+H)+.