Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@@H:9]([NH:16][C:17]([C:19]1[C:23]2[CH2:24][CH2:25][CH2:26][C:27]3[C:28](=[N:29][C:30]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([C:40](=[O:49])[NH:41][CH:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[CH:36][C:35]=4[O:50][CH3:51])=[N:31][CH:32]=3)[C:22]=2[N:21]([CH3:52])[N:20]=1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.[ClH:54]>CO.C1COCC1.O1CCOCC1>[ClH:54].[ClH:54].[NH2:7][CH2:8][C@@H:9]([NH:16][C:17]([C:19]1[C:23]2[CH2:24][CH2:25][CH2:26][C:27]3[C:28](=[N:29][C:30]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([C:40](=[O:49])[NH:41][CH:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[CH:36][C:35]=4[O:50][CH3:51])=[N:31][CH:32]=3)[C:22]=2[N:21]([CH3:52])[N:20]=1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)-c1c(c(C(=O)N[C@H](CNC(=O)OC(C)(C)C)c3ccccc3)nn1C)CCC2
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)-c1c(c(C(=O)N[C@H](CN)c3ccccc3)nn1C)CCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl[(2S)-2-({[9-({2-methoxy-4-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}amino)-1-methyl-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidin-3-yl]carbonyl}amino)-2-phenylethyl]carbamate (0.010 g, 0.014 mmol) in MeOH (0.2 mL) and THF (0.5 mL), 4M HCl in dioxane (0.2 mL) was added. The mixture was stirred at room temperature for 4 h. The organic solvent was evaporated to dryness to give the title compound in quantitative yield.
Reaction SMILES: Br[C:2](=[CH2:14])[CH2:3][CH2:4][CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Mg].II.[F:18][C:19]1[CH:26]=[C:25]([F:27])[C:24]([C:28]2[CH:29]=[N:30][CH:31]=[N:32][CH:33]=2)=[CH:23][C:20]=1[CH:21]=[O:22]>C1COCC1.O>[Si:7]([O:6][CH2:5][CH2:4][CH2:3][C:2](=[CH2:14])[C:21]([C:20]1[CH:23]=[C:24]([C:28]2[CH:33]=[N:32][CH:31]=[N:30][CH:29]=2)[C:25]([F:27])=[CH:26][C:19]=1[F:18])=[O:22])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: C=C(Br)CCCO[Si](C)(C)C(C)(C)C
Reactant: O=Cc1cc(-c2cncnc2)c(F)cc1F
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: C=C(CCCO[Si](C)(C)C(C)(C)C)C(=O)c1cc(-c2cncnc2)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.99 %

Procedure:
A solution of ((4-bromopent-4-en-1-yl)oxy)(tert-butyl)dimethylsilane (prepared following the procedures of Rostami, Organic Letters, 2007), 9(4), 703-706) (3.30 g, 11.81 mmol) in THF (25 mL) was added to a flask filled with magnesium (0.574 g, 23.62 mmol) and iodine (0.092 g, 0.363 mmol), and the resulting dark brown suspension was stirred at rt for 15 min and then heated under reflux for 45 min. The color changed from brown to deep reddish and the color of iodine faded 10 min under reflux. Eventually, the color of the reaction mixture turned to grey. This regent was cooled to rt and then added to a suspension of 2,4-difluoro-5-(pyrimidin-5-yl)benzaldehyde (Preparation 15, 2 g, 9.08 mmol) in THF (14 mL), and the reaction mixture was stirred at rt for 12 h. Water was added and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was evaporated in vacuo to give the crude product. The crude product was purified by silica gel chromatography eluting with 0-35% EtOAc/Hexane to give 5-((tert-butyldimethylsilyl)oxy)-1-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-2-methylenepentan-1-one (0.95 g, 2.270 mmol, 24.99% yield). 1H NMR (500 MHz, CHLOROFORM-d) δ 9.27 (s, 1H), 8.93 (d, J=1.4 Hz, 2H), 7.59 (dd, J=8.2, 7.3 Hz, 1H), 7.20-7.03 (m, 1H), 6.04 (s, 1H), 5.78 (d, J=1.8 Hz, 1H), 3.70 (t, J=6.3 Hz, 2H), 2.62-2.41 (m, 2H), 1.85-1.70 (m, 2H), 0.93 (m, 9H), 0.09 (m, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][OH:12].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:13][S:14]([O:12][C:11]#[C:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)(=[O:16])=[O:15]
Reactant: OCC#CCOC1CCCCO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC#CCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10.24 ml (15.15 g, 0.1323 mol) of 2-butyne-1,4-diol monotetrahydropyranyl ether was added dropwise to a solution of 15 g (0.088 mol) of methanesulfonyl chloride and 19.79 ml (14.25 g, 0.141 mol) of triethylamine in 250 ml of anhydrous methylene chloride at such a rate to maintain the reaction temperature at 0° C. The reaction mixture was stirred for 30 minutes further at 0° C. Then the reaction mixture was poured into 200 ml of aqueous saturated sodium bicarbonate solution and extracted with methylene chloride. The combined organic extracts were dried over sodium sulfate and the solvent removed in vacuo, to yield crude 4-tetrahydropyranyloxy-butyn-1-ol methanesulfonate. This crude product was dissolved in 50 ml of acetone and treated with a solution of 40.34 g (0.4636 mol) of lithium bromide in 200 ml of acetone, stirring the reaction mixture at room temperature for 1 hour. The solvent was then evaporated and the residue diluted with water (100 ml) and extracted with methylene chloride, the organic extracts were dried over sodium sulfate and evaporated in vacuo. The crude material was purified bysilica gel column chromatography using hexane:ethyl acetate (95:5) as eluant to yield 1-bromobut-2-yn-4-ol-tetrahydropyranyl ether, as an oil.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[C:11](=O)([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>N1C=CC=CC=1>[C:24]1([CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:11]([N:7]2[CH2:8][CH2:9][C:10]3[O:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)=[O:12])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:13]1([OH:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1cc2c(o1)CCNC2
Reactant: O=C(OCCCCc1ccccc1)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=C(OCCCCc1ccccc1)N1CCc2occc2C1
Product: Oc1ccccc1

Procedure:
A solution of 0.220 g (1.378 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride and 0.56 g (2.1 mmol) of phenyl 4-phenylbutyl carbonate in 10 ml of pyridine was stirred at 100° C. overnight. The reaction mixture was poured into aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1 to 9/1) to yield 5-(4-phenylbutoxycarbonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine as a mixture with phenol.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C@H:3]([NH:15][C:16]([C@H:18]([CH2:30][CH:31]=[CH2:32])[C@H:19]([CH2:27][CH2:28][CH3:29])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:4]([NH:6][C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:5].[CH3:35][C:36]1[CH:37]=[C:38](Br)[CH:39]=[CH:40][C:41]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(#N)C>CN(C)C=O>[CH3:34][C:2]([CH3:1])([CH3:33])[C@H:3]([NH:15][C:16]([C@H:18]([CH2:30]/[CH:31]=[CH:32]/[C:38]1[CH:39]=[CH:40][C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:36]([CH3:35])[CH:37]=1)[C@H:19]([CH2:27][CH2:28][CH3:29])[C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])=[O:17])[C:4]([NH:6][C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:5]
Reactant: C=CC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C)[C@H](CCC)C(=O)OC(C)(C)C
Reactant: Cc1cc(Br)ccc1-c1ccccc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCC[C@H](C(=O)OC(C)(C)C)[C@@H](C/C=C/c1ccc(-c2ccccc2)c(C)c1)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Yield: 62.6 %

Procedure:
According to the method of Preparation 3, tert-butyl (2S, 3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-(1-propyl)hex-5-enoate (543 mg, 1.15 mmol) was reacted with 3-methyl-4-phenylbromobenzene (356 mg, 1.44 mmol) under palladium catalysis in a mixture of anhydrous acetonitrile and dimethylformamide (2:5, 7 mL) at 90° C. for 17 h. The mixture was concentrated under reduced pressure, poured into ethyl acetate (100 mL) and washed with water (2×100 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane:ethyl acetate) to give mainly tert-butyl (2S,3R,5E)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]-2-(1-propyl)hex-5-enoate as a colourless gum (460 mg, 63%). 1H nmr suggested that two alkene isomers, the (5Z) and (4E) were also present. The mixture of alkenes was taken onto the next step (see c, below).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1B(O)O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[CH:26]=[C:21]([O:20][CH3:19])[CH:22]=[CH:23][C:24]=3[O:27][CH3:28])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1ccc(OC)c(B(O)O)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCCNC(=O)c1nnc2c(-c3cc(OC)ccc3OC)cccc2c1N
Yield: 87.6 %

Procedure:
Using method B, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (13.0 g, 42.1 mmol), 2,5-dimethoxyphenyl boronic acid (15.4 g, 84.6 mmol) and bis(triphenylphosphine)palladium(II) dichloride (886 mg, 1.3 mmol) were reacted to afford the title compound (13.51 g, 87.7% yield) as an off-white needle. 1H NMR (300 MHz, CDCl3) δ 8.59 (br, 1H), 7.89 (dd, J=7.8 Hz, J′=1.9 Hz, 1H), 7.65-7.77 (m, 2H), 6.85-7.20 (m, 3H), 3.79 (s, 3H), 3.64 (s, 3H), 3.35-3.55 (m, overlapped with H2O), 1.64 (m, J=7.3 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H) MS APCI, m/z=367 (M+H) HPLC 1.72 min.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([CH3:10])[CH:6]=[C:5]([I:11])[C:3]=1[NH2:4].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[F:1][C:2]1[C:8]([F:9])=[C:7]([CH3:10])[CH:6]=[C:5]([I:11])[C:3]=1[N:4]=[C:13]=[O:15]
Reactant: Cc1cc(I)c(N)c(F)c1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cc(I)c(N=C=O)c(F)c1F
Temperature: 100 °C

Procedure:
A mixture of 2,3-difluoro-6-iodo-4-methylaniline D19 (330 mg, 1.2 mmol), triphosgene (150 mg, 0.5 mmol), and dioxan (5 ml) was heated at 100° C. for 15 min then cooled and evaporated to give the crude title compound used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:18])([C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][CH2:4][CH2:5]C#N.[OH2:19].S(=O)(=O)(O)[OH:21]>>[F:1][C:2]([F:18])([C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][CH2:4][C:5]([OH:21])=[O:19]
Reactant: N#CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O
Reactant: O=S(=O)(O)O
Product: O=C(O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C

Procedure:
4,4,5,5,6,6,7,7,7-Nonafluoroheptanecarbonitrile (4.7 g, 17.2 mmol) was stirred in concentrated sulfuric acid (15 ml) for 3 hours at room temperature, cooled to 0° C. and mixed with water (15 ml), followed by heating under reflux for 12 hours. The reaction mixture was extracted with dichloromethane and the resulting organic layer was washed with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give 4,4,5,5,6,6,7,7,7-nonafluoroheptanoic acid (5.1 g, quantitative) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27]([Cl:30])(=[O:29])[CH3:28]>ClCCl>[C:27]([Cl:30])(=[O:29])[CH3:28].[C:27]([O:19][CH2:18][CH2:17][CH2:16][NH:15][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:29])[CH3:28]
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCO
Solvent: ClCCl
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OCCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Reaction time: 0.08 h

Procedure:
To a round-bottomed flask containing 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propan-1-ol (88.15 g) was added dichloromethane (DCM, 600 mL) followed by triethylamine (38 mL, 270.8 mmol) and the solution was stirred for 5 minutes. In a separate flask a solution of acetyl chloride (14.4 mL, 202.5 mmol) in dichloromethane (300 mL) was prepared. The acetyl chloride solution was added to the reaction mixture in a dropwise fashion. The reaction was stirred at ambient temperature for 4 h. Additional acetyl chloride (2.8 mL in DCM (50 mL)) was added and the reaction mixture was stirred at ambient temperature overnight. At this time additional acetyl chloride (1.4 mL in dichloromethane (25 mL)) was added and the reaction was stirred at ambient temperature for 1 h. Additional dichloromethane (200 mL) was then added and the reaction was transferred to a separatory funnel. The organic layer was washed with water (2×800 mL) and brine (1×800 mL). The organic layer was separated, dried (MgSO4), filtered, and the solvent evaporated to afford 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propyl acetate (60.8 g) as a bright yellow solid.
Reaction SMILES: [CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.N1(O)C2C=CC=CC=2N=N1.[C:41]([CH2:43][C:44](O)=[O:45])#[N:42].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][N:4]([C:44](=[O:45])[CH2:43][C:41]#[N:42])[CH2:3]1
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCNC4)c3n2)cc(OC)c1OC
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCN(C(=O)CC#N)C4)c3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A solution of (3-methyl-piperidin-3-yl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (11 mg, 0.27 mmol), benzotriazol-1-ol (4.0 mg, 0.03 mmol), 2-cyanoacetic acid (3 mg, 0.04 mmol), and (3-dimethylamino-propyl)-ethyl-carbodiimide hydrogen chloride (6.0 mg, 0.03 mmol) in anhydrous dichloromethane was treated with triethylamine (0.01 ml, 0.08 mmol) and allowed to stir at room temperature overnight. The reaction mixture was partitioned between dichloromethane/water and the organic layers were collected, dried over MgSO4, filtered, and concentrated. The residue was purified by preparative thin layer chromatography using 0.25:4.75:95 concentrated aqueous NH4OH: MeOH: dichloromethane as eluant to provide 5 mg (42%) of 3-{3-methyl-3-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-piperidin-1-yl}-3-oxo-propionitrile as a light yellow solid. M+H 578.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[N:17]2)=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:55]([NH2:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CN(C)C=O.ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:20]=[C:19]([C:21](=[O:23])[NH:62][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[N:18]=[N:17]2)=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(-n2cc(C(=O)O)nn2)sc1C(=O)NCc1ccccc1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(-n2cc(C(=O)NCc3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8 %

Procedure:
To a solution of 1-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-1H-1,2,3-triazole-4-carboxylic acid (0.25 g, 0.73 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole (0.12 g, 0.87 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.17 g, 0.87 mmol), N,N-diisopropylethylamine (0.38 mL, 2.19 mmol) and benzylamine (0.095 mL, 0.87 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, diluted with dichloromethane (30 mL) and washed with saturated aqueous sodium bicarbonate (15 mL) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a white solid in 8% yield: mp 178-180° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 9.33 (t, J=6.0 Hz, 1H), 9.24 (s, 1H), 9.02 (t, J=6.0 Hz, 1H), 7.36-7.23 (m, 10H), 4.49-4.46 (m, 4H), 2.63 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 160.1, 158.4, 154.2, 152.4, 143.6, 139.1, 138.9, 128.3, 128.2, 127.3, 127.2, 126.9, 126.8, 125.3, 123.5, 42.8, 42.1, 17.1; MS (ES+) m/z 433.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[CH:3]=1.Cl.[CH:11]1([NH:17][C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([NH:17][C:18]([CH:20]2[CH2:21][CH2:22][N:23]([CH2:8][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=Cc1cc(Cl)ccn1
Reactant: O=C(NC1CCCCC1)C1CCNCC1
Agent: Cl
Product: O=C(NC1CCCCC1)C1CCN(Cc2cc(Cl)ccn2)CC1

Procedure:
The title compound is prepared according to the reaction 3.01c described above using 4-chloro-pyridine-2-carboxaldehyde and piperidine-4-carboxylic acid cyclohexylamide hydrochloride as in 3.01c: LC-MS A: tR=0.58 min; [M+H]+=380.19.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16](OCC)=[O:17])=[CH:10][CH:9]=2)[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>C(OCC)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH2:16][OH:17])=[CH:12][CH:13]=2)[CH:2]=1
Reactant: CCOC(=O)/C=C/c1ccc(Cc2cccnc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC/C=C/c1ccc(Cc2cccnc2)cc1
Reaction time: 1 h
Yield: 52 %

Procedure:
In 200 ml of anhydrous diethyl ether was dissolved 24.0 g of ethyl(E)-3-[4-(pyridin-3-ylmethyl)phenyl]acrylate, and thereto was added in small portions 2.4 g of lithium aluminum hydride with ice-cooling over one hour. The resulting mixture was subjected to reaction for one hour with ice-cooling and then for a further one hour at room temperature, after which 91 ml of hydrous tetrahydrofuran (water content: 10% by volume) was added in small portions. Insolubles were removed by filtration and the solvent was removed by distillation under reduced pressure. The resulting oily product was dissolved in 200 ml of chloroform, and 40 ml of water was added to the resulting solution, after which the pH thereof was adjusted to 7 with 2N hydrochloric acid. The organic layer was separated, washed successively with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. 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 10.5 g (yield 52.0%) of colorless, oily (E)-3-[4-(pyridin-3-ylmethyl)phenyl]allyl alcohol. This was crystallized from a mixed solvent of chloroform and diethyl ether to obtain colorless needle crystals having a melting point of 81°-82° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([CH2:24][C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[C:27]([F:43])[CH:26]=2)(C(OCC=C)=O)[C:12]([O:14]CC=C)=[O:13])=[CH:5][CH:4]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(O)=O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([CH2:24][C:25]2[CH:26]=[C:27]([F:43])[C:28]([O:32][Si:33]([CH:34]([CH3:36])[CH3:35])([CH:37]([CH3:39])[CH3:38])[CH:40]([CH3:41])[CH3:42])=[C:29]([F:31])[CH:30]=2)[C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C(CCc1ccc(C#N)cc1)(Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)[Si](Oc1c(F)cc(CC(CCc2ccc(C#N)cc2)C(=O)O)cc1F)(C(C)C)C(C)C
Temperature: 100 °C

Procedure:
4720 mg (7.72 mmol) of diallyl 2-[2-(4-cyanophenyl)ethyl]-2-(3,5-difluoro-4-triisopropylsilanyloxybenzyl)malonate, 34.6 mg (0.15 mmol) of palladium(II) acetate and 141.6 mg (0.54 mmol) of triphenylphosphine are stirred in 180 ml of dioxane under argon. Then a solution of 2576 mg (25.60 mmol) of triethylamine and 887.7 mg (19.29 mmol) of formic acid in 90 ml of dioxane is added dropwise, and the mixture is heated at 100° C. for 2 h. The cooled mixture is concentrated and the crude product is chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1→2:1→1:1). 3682 mg (97.9% of theory) of the title compound are obtained
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C(N(C(C)C)CC)(C)C.Cl[CH2:22][O:23][CH3:24]>C(Cl)Cl>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:22][O:23][CH3:24])[C:6]#[N:7]
Reactant: COCCl
Reactant: COc1cc(C#N)ccc1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(C#N)cc1OC
Reaction time: 3 h
Yield: 79.7 %

Procedure:
A solution of 4-hydroxy-3-methoxy-benzonitrile (11, 1.5 g, 10 mmol) and diisopropylethylamine (2.7 mL, 15 mmol) in CH2Cl2 (50 mL) was treated with chloromethylmethylether (0.92 mL, 12 mmol) and stirred for 3 h. After diluted with CH2Cl2, the mixture was washed with H2O, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel using EtOAc:Hex (1:2) as eluant to give 12 as white solid (1.54 g, 80%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][CH2:10][C:11](=[CH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:12]([OH:14])=[O:13])=[O:8])[CH2:3][CH2:2]1>CO.[H][H].[Pd]>[O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][CH2:10][CH:11]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[C:12]([OH:14])=[O:13])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)C(=Cc1cccc2ccccc12)CCC(=O)N1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)C(CCC(=O)N1CCOCC1)Cc1cccc2ccccc12
Yield: 89.1 %

Procedure:
5.0 g (14.8 mmole) of this 4-morpholinocarbonyl-2-(1-naphthylmethylene)butyric acid were dissolved in 50 ml of methanol and hydrogenated in hydrogen at atmospheric pressure in the presence of 1.0 g of a 10% w/w palladium-on-carbon catalyst. The catalyst was then removed by filtration, after which the solvent was removed by distillation under reduced pressure. The residue was triturated with diethyl ether to precipitate crystals, which were collected by filtration to give 4.5 g of 4-morpholinocarbonyl-2-(1-naphthylmethyl)butyric acid, melting at 130°-135° C.