Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[C:8]([CH3:22])[CH:7]=1)[NH2:5].F[C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][CH:2]([CH3:23])[CH2:3][CH:4]([NH:5][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][N:26]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)=[C:8]([CH3:22])[CH:7]=1
Reactant: Cc1cc(C(N)CC(C)C)ccc1-c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)c(C)c2)nc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
A mixture of 3-methyl-1-(2-methyl-4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine (250 mg, 0.778 mmol), methyl 6-fluoronicotinate (264 mg, 1.17 mmol), and potassium carbonate (323 mg, 2.33 mmol) in N,N-dimethylformamide (4 mL) was stirred for 12 hrs at 120° C. The reaction was concentrated and purification by column chromatography gave methyl 6-(3-methyl-1-(2-methyl-4′-(trifluoromethyl) biphenyl-4-yl)butylamino)nicotinate (300 mg). 1H NMR (400 MHz, CD3OD, δ): 8.65 (s, 1H), 7.87 (d, 1H), 7.58 (d, 2H), 7.33 (d, 2H), 7.13 (d, 2H), 7.09 (s, 1H), 6.20 (d, 1H), 4.65 (m, 1H), 3.78 (s, 3H), 2.17 (s, 3H), 1.72 (m, 2H), 1.67 (m, 1H), 0.94 (d, 3H), 0.91 (d, 3H).
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23](O)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23]([NH:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)=[O:24])=[O:18])=[CH:29][CH:30]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: NCCCn1ccnc1
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)O)ccn1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)NCCCn2ccnc2)ccn1
Yield: 88.2 %

Procedure:
To solution of 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-isonicotinic acid (40 mg, 0.098 mmol), 1-(3-aminopropyl)imidazole (24.65 mg, 0.196 mmol) and DMAP (24.06 mg, 0.196 mmol) in DMF was added PyBOP (102.4 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-(3-imidazole-1-yl-propyl)-isonicotinamide as a colorless solid (44.4 mg, 87.85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10]O)[CH2:7][C:6]=2[CH:12]=1.N1C=CC=CC=1.S(Cl)([Cl:21])=O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][Cl:21])[CH2:7][C:6]=2[CH:12]=1
Reactant: OCC1Cc2cc(Cl)ccc2O1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: ClCC1Cc2cc(Cl)ccc2O1
Temperature: 80 °C
Reaction time: 7 h
Yield: 46.2 %

Procedure:
To a solution of (5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol (3 g, 16 mmol) in benzene (50 ml) was added pyridine (1.55 g, 19.6 mmol, 1.2 eq) and thionyl chloride (2.72 g, 23.0 mmol) dropwise with stirring at 0° C. for 7 hours at 80° C. in an oil bath. The reaction mixture was adjusted to ˜pH 8 with aqueous sodium bicarbonate and then extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 3% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 5-chloro-2-(chloromethyl)-2,3-dihydro-1-benzofuran as an off-white solid (1.5 g, 46%); 1H NMR (300 MHz, CDCl3): δ 7.06-7.14 (m, 2H), 6.70 (d, J=8.4 Hz, 1H), 4.99-5.10 (m, 1H), 3.64-3.76 (m, 2H), 3.32-3.40 (dd, J=9.3 Hz, 16.2 Hz, 1H), 3.09-3.17 (dd, J=6.6 Hz, 16.2 Hz. 1H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[CH2:9]([O:16][C:17](Cl)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:9]([O:16][C:17](=[O:18])[NH:1][C@H:2]([CH2:7][OH:8])[C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](N)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
To a solution of L-isoleucinol (2.20 g, 18.8 mmol) in methylene chloride (66 ml) were added chloroformic acid benzyl ester (3.22 ml, 22.5 mmol) and triethylamine (3.15 ml, 22.5 mmol) in an ice bath, and the mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:1) as the eluant to afford [(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]carbamic acid benzyl ester (4.17 g, yield 88%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[C:57]3[C:52](=[N:53][CH:54]=[C:55]([F:58])[CH:56]=3)[NH:51][CH:50]=2)=[CH:45][C:44]=1[NH:59][C@H:60]1[CH2:65][CH2:64][CH2:63][C@@H:62]([NH2:66])[CH2:61]1>C1COCC1>[C:1]([C:3]1([C:6]([NH:66][C@@H:62]2[CH2:63][CH2:64][CH2:65][C@H:60]([NH:59][C:44]3[CH:45]=[C:46]([C:49]4[C:57]5[C:52](=[N:53][CH:54]=[C:55]([F:58])[CH:56]=5)[NH:51][CH:50]=4)[CH:47]=[CH:48][C:43]=3[F:42])[CH2:61]2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(C(=O)O)CC1
Reactant: N[C@@H]1CCC[C@H](Nc2cc(-c3c[nH]c4ncc(F)cc34)ccc2F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(C(=O)N[C@@H]2CCC[C@H](Nc3cc(-c4c[nH]c5ncc(F)cc45)ccc3F)C2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-cyano-1-cyclopropane-carboxylic acid (0.058 g, 0.527 mmol) in THF at room temperature was added HATU (0.200 g, 0.527 mmol) followed by N,N-diisopropylethylamine (0.334 mL, 1.91 mmol). The solution was stirred for 10 minutes. (1S,3R)—N1-(2-fluoro-5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)cyclohexane-1,3-diamine, 44e, (0.200 g, 0.584 mmol) was then added and solution stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and purified via silica gel chromatography (30-60% Ethyl Acetate/hexanes) to give 80 mg of 871 as off-white solid.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[OH-].[Na+].O.C(O)(=O)C.[CH3:19][C:20]([CH3:22])=[O:21]>>[CH3:19][C:20](/[CH:22]=[CH:7]/[C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1)=[O:21]
Reactant: CC(C)=O
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)/C=C/c1ccc2c(c1)OCO2

Procedure:
A solution of 100 g piperonal in 900 ml acetone was stirred at room temperature with 15 ml of 10% aqueous sodium hydroxide and 30 ml of water. After 3 hours 5 ml of acetic acid was added and the reaction mixture was evaporated. The residue was recrystallized from methanol and dried in vacuo to yield 60 g of piperonalacetone, m.p. 104°-105° C. (EtoAc).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12](OC1C=CC=CC=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[Li+].[OH-:23]>CO.O>[O:23]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:3])=[O:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cc2c(Oc3ccccc3)cccc2[nH]1
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2ccccc2n1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
132 (160 mg, 0.569 mmol) is dissolved in 5 ml of methanol and treated with a solution of LiOH (27.2 mg, 1.138 mmol) in 3 ml of water. The mixture is stirred at room temperature overnight. Since the reaction is not complete (TLC), additional LiOH (30 mg, 1.25 mmol) is added and the stirring is continued for additional 18 h. After evaporation, the crude product is acidified at 0° C. with 2M HCl and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:20]=[CH:21][N:22]=2)[CH:5]=[C:6]([C:17](O)=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16].[OH:23][C:24]1([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:27][NH:26][CH2:25]1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:4]([CH:20]=[CH:21][N:22]=2)[CH:5]=[C:6]([C:17]([N:26]2[CH2:27][C:24]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([OH:23])[CH2:25]2)=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C1(O)CNC1
Reactant: O=C(O)c1cn2ccnc2c(Cl)c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1C1(O)CN(C(=O)c2cn3ccnc3c(Cl)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.3 %

Procedure:
A solution of 8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridine-6-carboxylic acid (78 mg, 0.18 mmol) (prepared using procedures similar to those described in US 2006030610 and US 2005054701), 1,1-dimethylethyl 2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate (46.7 mg, 0.18 mmol), 4-(dimethylamino)pyridine (66 mg, 0.55 mmol), and finally 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42 mg, 0.21 mmol) in dimethylformamide (2 mL) was stirred at room temperature for 15 hours. The reaction mixture was partition between 5% aqueous lithium chloride and ethyl acetate and the aqueous portion was extracted twice using ethyl acetate. The combined organic portion was washed with 1 N HCl, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by column chromatography. Eluting with ethyl acetate, the isolated product was concentrated in vacuo to afford 101 mg, 0.15 mmol (83%) of 1,1-dimethylethyl 2-[1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate as a white solid. The solid was immediately dissolved in methanol (5 mL) and 4 N HCl in dioxane was added. The solution was briefly heated to reflux and then was concentrated in vacuo. The resultant residue was purified by preparative reverse phase HPLC. Isolated product was concentrated in vacuo to afford 36 mg, 0.06 mmol (40%) of 1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-piperidin-2-ylazetidin-3-ol acetate as a white solid. 1H NMR (400 MHz, DMSO): 8.78 (s, 1H), 8.19 (s, 0.5H), 8.15 (s, 0.5H), 8.00 (s, 1H), 7.62 (s, 1H), 7.55 (d, 1H), 7.31 (d, 1H), 6.54-6.49 (m, 1H), 4.24-4.12 (m, 1H), 3.97-3.86 (m, 2H), 3.63-3.56 (m, 1H), 2.98-2.90 (m, 1H), 2.50-2.40 (m, 1H), 1.72-1.61 (m, 1H), 1.56-1.43 (m, 2H), 1.32-1.14 (m, 2H), 1.07-0.94 (m, 1H); MS (EI) for C22H22ClFI5O2: 570 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH3:6][C:7]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18](Cl)=[O:19])[C:10]=2[O:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O.CC(C)=O>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:18]([C:17]1[C:10]2[O:9][C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:7]([CH3:6])[C:12](=[O:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1)=[O:19]
Reactant: CNCCO
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)Cl)cccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)N(C)CCO)cccc2c1=O
Reaction time: 2.5 h

Procedure:
A solution of 1.6 ml of 2-methylaminoethanol in 10 ml of water was added dropwise over a period of 5 minutes to a suspension of 6 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride (prepared as described in Da Re, P. et al., J. Med. Pharm. Chem. 2: 263 (1960)) and 1.52 g of potassium carbonate in 60 ml of acetone. After stirring for 2.5 hours at 20°-25° C., the solvent was removed in vacuo and the residue was taken up in 150 ml of acetone. The mixture was refluxed for 15 minutes, and was then filtered. The solvent was evaporated from the filtrate and the residue was dissolved in 20 ml of dimethylformamide, treated with 14 ml of a 1.4% sodium carbonate solution, stirred for 30 minutes at 20°-25° C. and diluted by addition of 150 ml of water. The mixture was extracted with chloroform and the organic layer was washed with 0.5N hydrochloric acid and then with water. The solution was dried on anhydrous sodium sulphate, filtered and evaporated to dryness in vacuo. The resulting oil was taken up in 200 ml of diethyl ether and stirred for 2 hours at 20°-25° C. The solid was collected by filtration and crystallized from ethyl acetate to give 2.97 g of the title compound, melting point 128°-130° C.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[K].[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.CN(C=O)C>O>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:26]3[C:25](=[O:27])[C:24]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]4[C:22]3=[O:32])=[N:12][C:11]=2[CH:13]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 120 °C
Reaction time: 6 h
Yield: 61.6 %

Procedure:
A mixture of 1.41 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 1.85 g of phthalimide potassium and 8 ml of DMF was stirred while heating at 120° C. After six hours, 0.92 g of phthalimide potassium was added and stirred while heating at 140° C. for further one hour. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, which followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, sequentially, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.26 g of N-{4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-yl}phthalimide.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[CH2:26]([O:25][C:23](=[O:24])[C:22]([CH3:29])([CH3:28])[O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:27]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 41.5 %

Procedure:
To a solution of methyl 4-hydroxy-3-nitrobenzoate (18.0 g) in N,N-dimethylformamide (70 ml) were added potassium carbonate (25.1 g) and ethyl 2-bromoisobutyrate (20.0 g), and the mixture was heated at 80° C. with stirring. Ten hours later, the reaction solution was cooled to 25° C., and water was added to the reaction solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the title compound (11.8 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+]>C1(C)C=CC=CC=1>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([O:14][CH3:13])[CH:11]=1
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(Cl)c2ccccc2n1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
To a solution of (2.5 g, 12.6 mmol) 2,4-dichloro-quinoline in anhydrous toluene (20 ml) was added a suspension of solid sodium methoxide (2.5 g, 46.3 mmol) in anhydrous toluene (20 ml). The mixture was stirred under reflux for 16 hours and then allowed to cool to room temperature. The solid that had formed was filtered off and washed with 50 ml toluene. The filtrate was evaporated to dryness under reduced pressure to yield a red solid (2.1 g, 10.8 mmol, 86%). MS (ES) m/z=193.1 [M+H]+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.Cl.O.[C:13]([OH:17])(=[O:16])[CH:14]=O>O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]/[N:10]=[CH:14]/[C:13]([OH:17])=[O:16])=[CH:5][CH:4]=1
Reactant: O=CC(=O)O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: O
Product: O=C(O)/C=N/Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of (4-bromophenyl)hydrazine HCl (2.01 g, 8.81 mmol) in water (20 mL) was added conc. HCl (1 mL) followed by glyoxylic acid monohydrate (811 mg, 8.81 mmol). The mixture was stirred vigorously at rt for 30 min and the light yellow suspension was filtered, washed with water (3×15 mL), and dried under suction followed by high vacuum to afford compound 84a as a light yellow solid, used without further purification in the following step. Mass spectrum (LCMS, ESI pos.): Calcd. for C8H7BrN2O2, 243.0/245.0 (M+H). found 243.2/245.1.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:4][CH:5]([C:11]([F:14])([F:13])[F:12])[CH2:6][CH2:7][CH2:8][CH2:9]I.C(O)C.[S-:25][C:26]#[N:27].[K+]>C(O)(=O)C>[F:1][C:2]([F:21])([F:20])[C:3]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:4][CH:5]([C:11]([F:14])([F:13])[F:12])[CH2:6][CH2:7][CH2:8][CH2:9][S:25][C:26]#[N:27]
Reactant: FC(F)(F)C(CCCCI)CC(F)(C(F)(F)F)C(F)(F)F
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: N#CSCCCCC(CC(F)(C(F)(F)F)C(F)(F)F)C(F)(F)F
Yield: 99.5 %

Procedure:
According to scheme (16) above, in a flask that can be equipped with an agitator, thermocouple and a reflux condenser, 30 grams (67 mmol) of 1,1,1,2-tetrafluoro-2,4-bis(trifluoromethyl)-8-iodooctane (see, e.g. Published International Patent Applications), 35 ml of absolute ethanol, 9.8 grams of potassium thiocyanate (KSCN) and 1.4 ml of glacial acetic acid (HOAc) can be placed to form a mixture. The mixture can be heated to reflux (about 84.7 C) and maintained for overnight while stirring. The mixture can be observed as a light yellow slurry and can be concentrated in vacuo to afford a viscous yellow slurry. The slurry cab be extracted with 300 mL of diethyl ether, (decanted twice) and filtered to afford a wet cake and a filtrate. The wet cake can be washed with three 100 mL portions of diethyl ether wherein the collected washings can be combined with the filtrate and concentrated in vacuo to afford 25.28 grams (99.5% yield) of the 1,1,1,2-tetrafluoro-2,4-bis(trifluoromethyl)-8-thiocyanatooctane product that can be observed as a light yellow oil. The product structure can be confirmed by NMR and/or chromatographic analysis.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Cu])#N.C[N:13]([CH:15]=[O:16])C>Cl>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([NH2:13])=[O:16])=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: N#C[Cu]
Agent: Cl
Product: NC(=O)c1ccc(F)cn1
Temperature: 100 °C
Reaction time: 15.5 h
Yield: 31.2 %

Procedure:
Take up 2-bromo-5-fluoropyridine (0.750 g, 4.26 mmol) and CuCN (0.954 g, 10.7 mmol) in DMF (10.7 mL). Heat to reflux for 5 hours. Cool the reaction mixture to 100° C. Add a solution of FeCl3.6H2O (0.654 g) in 10% HCl solution (30 mL) and stir for 15.5 hours. Cool the reaction mixture to 80° C. and filter. Add 1.0 N NaOH until the reaction mixture becomes basic and extract with dichloromethane (3×200 mL). Wash the organic layer with brine (1×75 mL), dry over Na2SO4, filter and concentrate to give the title compound (0.186 g, 31.2%): TOF MS EI+ 140.0 (M)+, base peak EI+ 97.0 (M-CONH)+, HRMS calcd for C6H5N2OF 140.0386 found 140.0378, time 3.40 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=7.5 min, 100% purity.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH2:16])=[CH:10][CH:9]=1.[CH2:17]([O:19][C:20](=[O:22])C)[CH3:18]>C(Cl)(Cl)Cl.CCCCCC>[CH2:17]([O:19][C:20](=[O:22])[NH:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)[CH3:18]
Reactant: NCCc1ccc(Cl)cc1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
Chloro ethyl formate (1.92 mL) and 2N Na2CO3 solution (20 mL) were added to a stirred solution of 2-(4-chloro-phenyl)-ethylamine (I-1b: 2.6 g, 0.01667 mmol) in chloroform (20 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (20% ethylacetate in hexane). The reaction mixture was partitioned between water and chloroform. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography on silica gel (10% ethylacetate in hexane) afforded 2 g of the product (52.6% yield).
Reaction SMILES: C(Br)C.[Mg].[CH3:5][CH:6]([OH:9])[C:7]#[CH:8].[CH3:10][CH:11]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH3:20])[CH2:12][CH2:13][OH:14]>O1CCCC1>[CH3:10][CH:11]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH3:20])[CH2:12][CH:13]([OH:14])[C:8]#[C:7][CH:6]([OH:9])[CH3:5]
Reactant: CCC/C=C\CC(C)CCO
Reactant: C#CC(C)O
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCC/C=C\CC(C)CC(O)C#CC(C)O
Reaction time: 1.5 h
Yield: 81.6 %

Procedure:
A solution of 10.4 g (95.6 mmol) of ethyl bromide in 40 mL of dry tetrahydrofuran was added dropwise over a period of 30 min to a vigorously stirred suspension of 2.32 g (95.6 mmol) of magnesium turnings in 15 mL of dry tetrahydrofuran, with the reaction being initiated by occasional heating with a heat gun. After stirring the reaction mixture for 90 min under reflux, it was allowed to cool down to room temp., and a solution of 2.95 g (42.1 mmol) of but-3-yn-2-ol in 40 mL of dry tetrahydrofuran was added dropwise with stirring. The reaction mixture was then again refluxed for 3 h, the heating bath removed and a solution of 6.50 g (42.2 mmol) of (5Z)-3-methylnon-5-en-1-ol (vide supra) in 40 mL of dry tetrahydrofuran added at room temp. with stirring over a period of 30 min. The reaction mixture was refluxed with stirring overnight, allowed to cool to room temp., and quenched by pouring into 100 mL of an aqueous satd. NH4Cl solution. The organic layer was separated, and the aqueous one extracted three times with 500 mL of ether each. The combined organic extracts were dried with sodium sulphate, and concentrated to dryness in a rotary evaporator. The resulting residue (8.85 g) was purified by flash chromatography (200 g of silica gel, pentane/ether, 1:1, Rf=0.21) to furnish 7.71 g (82%) of (9Z)-7-methyltridec-9-en-3-yne-2,5-diol as a colourless oil.