Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=[O:7].[F:18][C:19]([Si](C)(C)C)([F:21])[F:20].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1.C(OCC)(=O)C>[F:18][C:19]([F:21])([F:20])[C:6]([C@H:8]1[CH2:9][CH2:10][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]1)([OH:7])[C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)c2nccs2)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CC[C@H](C(O)(c2nccs2)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of methyl trans-4-(thiazole-2-carbonyl)cyclohexanecarboxylate (1.1 g, 4.34 mmol) in THF (20 mL) at 0° C. was added trifluoromethyltrimethylsilane (1.286 mL, 8.68 mmol). Tetrabutylammonium fluoride trihydrate (1M in THF, 17.37 mL, 17.37 mmol) was added slowly maintaining the temperature at 0° C. The reaction was allowed to stir for 1 hr and then water (30 mL) and ethyl acetate (30 mL) was added to quench the reaction. The organic layer was removed, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-20% ethyl acetate in hexane) to afford methyl trans-4-[2,2,2-trifluoro-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexanecarboxylate. MS ESI calcd. for C13H17F3NO3S [M+H]+ 324. found 324. 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J=3.2 Hz, 1H), 7.49 (d, J=3.2 Hz, 1H), 4.77 (s, 1H), 3.65 (s, 3H), 2.40 (m, 1H), 2.30-1.90 (m, 3H), 1.50-1.20 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35]([N:42]1[CH2:46][CH2:45][C@@H:44]([NH2:47])[CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH2:35]([N:42]1[CH2:46][CH2:45][C@@H:44]([NH:47][C:27]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[O:33])[CH2:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H]4CCN(Cc5ccccc5)C4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
Chloroform (10 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) to prepare a solution. Triphosgene (110 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. (3R)-(−)-1-Benzyl-3-aminopyrrolidine (89 mg) was then added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (54 mg, yield 32%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:14])[C:3]=1[C:15]([O:17]CC)=O.[C:20]([O-:23])(=[O:22])[CH3:21].[NH2+:24]1CCCCC1.C(O)C.C1(C)C=CC=CC=1.N12CCCC=C1CCCCN2>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][NH:5][C:4](=[O:14])[C:3]=1[C:15]([NH:24][CH2:21][C:20]([OH:23])=[O:22])=[O:17]
Reactant: CCOC(=O)c1c(O)c(-c2ccccc2)n[nH]c1=O
Reactant: CC(=O)[O-]
Reactant: C1CC[NH2+]CC1
Agent: C1=C2CCCCNN2CCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)CNC(=O)c1c(O)c(-c2ccccc2)n[nH]c1=O
Reaction time: 2 h
Yield: 39 %

Procedure:
Ethyl 5-hydroxy-3-oxo-6-phenyl-2,3-dihydro-4-pyridazinecarboxylate. A 1 M solution of piperidinium acetate in 5% ethanol/toluene (1.10 mL, 1.10 mmol) was added to a solution of the compound from example 4(a) (0.350 g, 1.14 mmol) in toluene (10 mL) and the mixture stirred under reflux for 1 h. Diazabicyclo[5.4.0]undec-7-ene (0.30 mL, 2.00 mmol) was added and the reflux continued for 2 h. After cooling, the mixture was partitioned between 1M aqueous hydrochloric acid and ethyl acetate. The extracts were dried (MgSO4), evaporated under reduced pressure and the residue chromatographed (silica gel, 2-8% methanol/dichloromethane). The partially purified product was triturated with ether to give the title compound (0.115 g, 39%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (t, J=7.20 Hz, 3H) 4.32 (q, J=7.16 Hz, 2H) 7.43-7.49 (m, 3H) 7.64-7.67 (m, 2H) 13.05 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][O:18][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[N:31]([CH3:41])[N:32]=[C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:34]=3)=[O:29])=[C:23]([F:42])[CH:22]=2)[CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>O.C(#N)C>[F:42][C:23]1[CH:22]=[C:21]([C@H:17]2[O:18][CH2:19][CH2:20][NH:15][CH2:16]2)[CH:26]=[CH:25][C:24]=1[NH:27][C:28]([C:30]1[N:31]([CH3:41])[N:32]=[C:33]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:34]=1)=[O:29]
Reactant: Cn1nc(-c2ccccc2)cc1C(=O)Nc1ccc([C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cn1nc(-c2ccccc2)cc1C(=O)Nc1ccc([C@@H]2CNCCO2)cc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 79.4 %

Procedure:
To a stirred solution of trifluoroacetic acid (124 μl) in water (4 ml) was added a solution of (R)-2-{3-fluoro-4-[(2-methyl-5-phenyl-2H-pyrazole-3-carbonyl)-amino]-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (78 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 4 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis); gradient: EtOAc/heptane) to afford 2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid ((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amide (49 mg, 79%) as a white solid. MS (ISP): 381.3 ([M+H]+).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[Na+].[I-].[CH:14]([N:17]1[CH2:24][CH:23]2[CH2:25][CH:19]([CH2:20][NH:21][CH2:22]2)[CH2:18]1)([CH3:16])[CH3:15]>CC#N>[CH:14]([N:17]1[CH2:24][CH:23]2[CH2:25][CH:19]([CH2:20][N:21]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)=[O:4])[CH2:22]2)[CH2:18]1)([CH3:16])[CH3:15]
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CC(C)N1CC2CNCC(C2)C1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)N1CC2CC(CN(CC(=O)c3ccc(F)cc3)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
To a standard setup was added 2-chloro-4'-fluoroacetophenone (7.55 g, 43.8 mmol) and NaI (9.85 g, 65.7 mmol) in H3CCN (30 ml) which was then heated for 30 minutes with stirrring. The solution was allowed to cool to room temperature (30 min) which was followed by dropwise addition of amine 105 (6.7 g, 39.8 mmol) to give a light yellow mixture which was stirred overnight. Filtration (suction) removed excess NaI and the filtrate was diluted with H2O and transferred to a separatory funnel. The resulting homogenous solution (pH~5) was extracted (ether, 3×75 ml) with the latter being discarded, and the pH of the aqueous layer was adjusted to 12 using 10% NaOH. Extraction (ether, 3×75 ml) of the aqueous layer was followed by another extraction (H2CCl2, 3×75 ml) and the ether extracts were discarded. The organic layer (H2CCl2) was dried (Na2SO4, 2 h), filtered, and concentrated (rotary evaporator) to give 2.9 g (86.1%) of amine 55 as a light yellow solid; mp 193°-194° C. IR (KBr) 3060, 3040 (Ar-H), 2940, 2805 (C-H), 1700 (C=O) cm-1 ; 1H NMR (DCCl3) d 1.45 (d, 6 H, CH3 isopropyl), 1.81 [d, 1 H, H(9)ax ], 2.11 [d, 1 H, H(9)eq ], 2.32 lbs, 2 H, H(1,5)], 2.85 (d, 2 H, ring protons), 3.37 (d, 2 H, ring protons), 3.49 (d, 2 H, ring protons), 3.86 (m, 3 H, ring protons, C-H isopropyl), 4.18 (s, 2 H, ArC(O)CH2), 7.15 (t, 2 H, Ar-H), 8.02 (m, 2 H, Ar-H); 13C NMR (DCCl3) ppm 17.01 (CH3 isopropyl), 28.04 [C(1,5)], 30.05 [C(9)], 53.74, 57.2257.34 (ring carbons, C-H isopropyl), 62.22 [ArC(O)CH2 ], 115.58, 115.88, 130.57, 130.70, 131.22, 131.26 (Ar-C), 164.10, 167.49 (J=265.8 Hz, ArC-F), 194.99 (C=O). Ketone 55 was slightly unstable, and thus was reduced to the corresponding alcohol 110.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1.N1CCNCC1.[F:24][C:25]([F:29])=[C:26](F)F.CN(C)C=[O:33]>>[F:24][CH:25]([F:29])[C:26]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1)=[O:33]
Reactant: FC(F)=C(F)F
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Reactant: CN(C)C=O
Agent: C1CNCCN1
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Temperature: 50 °C
Reaction time: 9 h
Yield: 74 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.29 g, 5.0 mmol) and piperazine (0.65 g, 7.5 mmol) in N,N-dimethylformamide (10 ml) charged in a reaction flask was reacted with tetrafluoroethylene, which was made to flow into the flask (ca. 0.7 liter/hr), with vigorous stirring at 50° C. for 9 hours. After cooling to an ambient temperature, the reaction mixture was poured into ice-water, and extracted with diethyl ether. The ether layer was washed with water and then brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, which afforded 2-difluoroacetylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.24 g, 3.7 mmol, yield 74%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([I:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH:18]([CH3:20])[CH3:19])=[CH:6][N:5]=[C:4]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[N:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>O1CCCC1>[I:15][C:13]1[C:12]([O:16][CH3:17])=[CH:11][C:10]([CH:18]([CH3:20])[CH3:19])=[C:9]([CH:14]=1)[O:8][C:7]1[C:2]([NH:1][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[N:3][C:4]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[N:5][CH:6]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(NC(=O)C(C)C)nc2N)cc1I
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(C(C)C)c(Oc2cnc(NC(=O)C(C)C)nc2NC(=O)C(C)C)cc1I
Reaction time: 1 h
Yield: 21.7 %

Procedure:
To N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-isobutyramide (386 mg, 0.82 mmol), dissolved in anhydrous tetrahydrofuran, was added triethylamine (0.13 mL, 0.90 mmol) and isobutyryl chloride (0.09 mL, 0.90 mmol). After stirring one hour, the reaction was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane (50 mL), and the dichloromethane layer was washed with water, dried using anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by preparatory TLC plates (98/2/0.5 dichloromethane/methanol/ammonium hydroxide) yielded 96 mg (22%) of N-[5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-4-isobutyrylamino-pyrimidin-2-yl]-isobutyramide as white solid, MS (M+H)=541.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[S:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccc(-c3cccc([N+](=O)[O-])c3)cc2n1Cc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: O=[N+]([O-])c1cccc(-c2ccc3[nH]c(=S)n(Cc4ccccc4)c3c2)c1

Procedure:
Prepared according to the procedure for Example 24 from 1-benzyl-6-(3-nitrophenyl)-1,3-dihydro-2H-benzimidazole-2-one (0.1 g, 0.29 mmol) and Lawesson's reagent (0.13 g, 0.32 mmol). A yellow solid (0.025 g, 24%): mp 244-245° C.; 1H-NMR (DMSO-d6) δ13.08 (s, 1H), 8.43 (s, 1H), 8.20 (dd, 1H, J=8.2, 1.7 Hz), 8.12 (d, 1H, J=7.8 Hz), 7.72-7.78 (m, 2H), 7.62 (d, 1H, J=8.3 Hz), 7.25-7.43 (m, 6H), 5.62 (s, 2H); MS (ESI) m/z 360 [M−H]−; Anal. Calc. For C20H15ClN2S.0.2H2O: C, 65.81; H, 4.25; N, 11.51. Found: C, 65.56; H, 4.11; N, 11.29.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)nc2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cn1

Procedure:
A solution of 81.7 mg (0.194 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-methyl-5-pyridyl)-2-naphthalenyl)ethynyl]benzoate (Compound 12) and 40.7 mg (0.969 mmol) of LiOH—H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ8.41 (1H, d, J=1.9 Hz), 7.90 (2H, d, J=8.3 Hz), 7.63 (1H, dd, J=2.3, 7.9 Hz), 7.59 (2H, d, J=8.3 Hz), 7.49 (2H, m), 7.33 (1H, d, J=7.8 Hz), 6.95 (1H, s), 6.11 (1H, t, J=4.5 Hz), 2.52 (3H, s), 2.37 (2H, d, J=4.6 Hz), 1.31 (6H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:14])[N:3]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>CS(C)=O.[Cl-].[Na+].O>[CH3:14][C:4]1[CH:5]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[CH:11][CH:10]=2)[N:7]=[C:2]([N:25]2[CH2:26][CH2:27][CH2:28][C@@H:23]([NH:22][C:20](=[O:21])[O:19][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:24]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cc1cc(Nc2ccn[nH]2)nc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(Nc2ccn[nH]2)nc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To the mixture of 2-chloro-6-methyl-N-(1H-pyrazol-5-yl)pyrimidin-4-amine prepared in Referential Example 1 (25.5 mg) and (R)-3-(tert-butoxycarbonylamino)piperidine (50.9 mg) in DMSO (5 ml) was added DIEA (210.0 μL). And the mixture was heated to 110° C. under stirring for overnight. The resulting mixture was cooled to room temperature, poured into brine and extracted with EtOAc. The extract was washed with saturated aqueous solution of NaHCO3, dried over Na2SO4 and concentrated in vacuo. And the residue was purified with silica gel column chromatography (eluent: hexane/EtOAc=99/1˜0/100) to give tert-butyl {(3R)-1-[4-methyl-6-(1H-pyrazol-5-ylamino)pyrimidin-2-yl]piperidin-3-yl}carbamate (26.0 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:16][C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18](I)([F:20])[F:19]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:18]([F:20])([F:19])[C:17]([F:26])([F:16])[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C2CC=CCC2)CC1
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(F)(F)C(F)(F)C(F)(F)F)CC2)CC1

Procedure:
A mixture of 0.1 mol of 4-(trans-4-propylcyclohexyl)-cyclohex-1-ene, 0.1 mol of heptafluoropropyl iodide, 10 mol % of tetrakis-(triphenylphosphine)-palladium and 200 ml of hexane is heated under reflux for 24 hours (compare T. Ishihara, Chemistry Letters (1986) 1895). The isomer mixture of the addition product thus formed is, after the catalyst has been filtered off, first heated with tributyl-tin hydride for 90 hours in toluene and reduced. The all-trans product>.trans-4-(trans-4-propylcyclohexyl)-1-heptafluoropropylcyclohexane, is finally obtained by separating the thiourea inclusion compound from a solution in methanol.
Reaction SMILES: O.[CH2:2]([CH:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:17](O)[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:2]([CH:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC1C(=O)CCC1C(=O)O
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCC1C(=O)CCC1C(=O)OCC

Procedure:
In a 1 L flask, to which is attached a water separator under a reflux condenser, is placed a solution of 20 g of 2-n-hexyl-3-oxo-cyclopentanecarboxylic acid, 9,5 g of absolute ethanol and 1 g of p-toluenesulphonic acid in 500 ml of benzene. The reaction mixture is refluxed until no more water separates. The reaction mixture is then cooled and washed successively with water and sodium carbonate solution and dried over anhydrous sodium sulphate. The solvent is removed by distillation at atmospheric pressure and the residue is distilled through a short Vigreux column. Ethyl 2-n-hexyl-3-oxo-cyclopentanecarboxylate is collected at 102°C/0.25 mm, yield 19,5 g (86%), nD20 1.4535.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19].CO>>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][N:19]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14]
Reactant: CN(C)CCN
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CO
Product: CN(C)CCn1ccc2c([N+](=O)[O-])cccc2c1=O

Procedure:
5-Nitro-isochromen-1-one (1.83 g, 0.00957 mol) and N,N-dimethyl-1,2-ethanediamine (3 g, 0.03 mol) were refluxed in methanol (20 mL, 0.5 mol) for 1 hour. The volatiles were removed via rotovapor. The residue was purified via flash chromatography (40 g of silica gel, 50% EtOAc/CH2Cl2) and gave a light yellow solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[C:12]=1[CH3:19])#[N:10].CN(C)CCN(C)C.[C:28]1([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]I)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1.O>[C:28]1([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:19][C:12]2[C:13]([C:17]#[N:18])=[CH:14][CH:15]=[CH:16][C:11]=2[C:9]#[N:10])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ICCCCCCCCc1ccccc1
Reactant: Cc1c(C#N)cccc1C#N
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(C#N)c1CCCCCCCCCc1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of lithium diisopropylamide 1.5M in tetrahydrofuran (6 ml, 9 mmol) was added dropwise to a stirred solution of 2,6-dicyanotoluene (0.85 g, 6 mmol) and tetramethyl ethylenediamine (1.04 g, 9 mmol) in dry tetrahydrofuran (50 ml), cooled to -70° C. under nitrogen. After one hour, 8-phenyloctyl iodide (2.15 g, 6.8 mmol) was added dropwise at -70° C. to the intense blue suspension, then allowed to warm to 0° C. over one hour. Water (100 ml) was added (cautiously at first) to the brown mixture and then extracted with diethyl ether (50 ml). The extracts were washed with 2M hydrochloric acid, dried, filtered and evaporated to a brown oil (2.67 g). Purified by chromatography on flash silica eluting with dichloromethane gave 2-(9-phenylnonyl)-1,3-benzenedicarbonitrile as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[Br:12]C1(Br)C(=O)NC(=O)NC1=O>C(OCC)C>[Br:12][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])=[O:3]
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Reactant: CC(=O)c1cccc(C#N)c1
Solvent: CCOCC
Product: N#Cc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 162.3 %

Procedure:
To a solution of 1.02 g (7.04 mmol) of 3-acetylbenzonitrile in mL of ethyl ether was added 1.02 g (3.52 mmol, 0.5 equiv) of dibromobarbituric acid. The mixture was allowed to stir at room temperature overnight. The resultant white slurry was filtered and the tiltrate was concentrated. Purification by flash chromotography (silica gel, ethyl acetate/hexane) gave 1.28 g (81%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.26 (t, 1H, J=1.4 Hz), 8.20 (td, 1H, J=1.5, 8.0 Hz), 7.87 (dd, 1H, J=1.3, 7.8 Hz), 7.64 (t, 1H, J=7.9 Hz), 4.40 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][C:16]2[C:17]([F:23])=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[C:6]([CH:14]=1)[C:7](N(CC)CC)=[O:8].C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C>C1COCC1>[Br:1][C:2]1[CH:14]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:15][C:16]1[C:17]([F:23])=[N:18][C:19]([Cl:22])=[CH:20][C:21]=1[C:7]2=[O:8]
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc(Cl)nc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: O=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-2-(6-chloro-2-fluoropyridin-3-yloxy)-N,N-diethylbenzamide (120 mg, 0.299 mmol) in 5 mL of dry THF at −78 C was added dropwise lithium diisopropylamide, 2.0 m heptane/tetrahydrofuran/ethylbenzene (158 μL, 1.195 mmol) (0.6 mL of 2M solution) and the reaction was stirred at −78 C for 3 h. The reaction was quenched at −78 C with sat. NH4Cl and was allowed to warm up to RT. The reaction was extracted with EA, dried over Na2SO4, filtered and evaporated to dryness. CC (hexane to H/DCM=1:1 to DCM) gave 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one as an offwhite solid. MS (M+1): 328.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].Cl.[CH3:9][O:10][C:11](=[O:17])[C@H:12]([CH:14]([CH3:16])[CH3:15])[NH2:13].C(N(CC)CC)C>C1COCC1>[CH3:9][O:10][C:11](=[O:17])[C@H:12]([CH:14]([CH3:16])[CH3:15])[NH:13][C:6]([NH:5][CH2:4][CH2:3][CH2:2][Cl:1])=[O:7]
Reactant: O=C=NCCCCl
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)NCCCCl)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Chloropropylisocyanate (0.31 mL, 3.0 mmol) was added to a slurry of L-valine methyl ester hydrochloride 0.5 g, 3.0 mmol) and triethylamine (0.42 mL, 3.0 mmol) in THF (10 mL). The reaction mixture was stirred for 4 hours at room temperature and was then quenched with the addition of aqueous sodium bicarbonate. The quenched reaction mixture was extracted with ethyl acetate. The organic layer was separated, dried and evaporated to give the desired product.