Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]([N:19]3[CH2:24][CH2:23][C:22]4([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[CH2:26][O:25]4)[CH2:21][CH2:20]3)=[O:18])=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:33]C(O)=O.[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]([N:19]3[CH2:24][CH2:23][C:22]4([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[CH2:26][O:25]4)[CH2:21][CH2:20]3)=[O:18])=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:16][CH2:15][N:14]([CH3:33])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(c1cn(CC2CCNC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC(Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1′-{[6-chloro-1-(pyrrolidin-3-ylmethyl)-1H-indol-3-yl]carbonyl}-3H-spiro[2-benzofuran-1,4′-piperidine] in MeOH was treated with aq. H2CO (1.5 eq), AcOH (1.1 eq) and stirred for 15 min at room temperature, then treated with NaCNBH3 (1.1 eq) and stirred at room temperature for 1 h. Concentration and purification by preparative HPLC gave the desired product. ES-MS m/e (%): 464.2(M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][C:24]#[N:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.S(C)C.CO>C1COCC1>[NH2:25][CH2:24][CH2:23][O:22][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2cccc(Cl)c2)C1
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Temperature: 25 °C

Procedure:
(R)-tert-Butyl 3-((R)-(3-chlorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate (23 g, 0.04 mol) was dissolved in anhydrous THF (300 mL), and the solution was heated to reflux under nitrogen. A solution of BH3.Me2S (12 mL, 0.12 mol) in THF was added dropwise, and stirring was continued at reflux overnight. The resulting solution was cooled to rt and MeOH was added dropwise to quench the reaction. After evaporation of the solution, the crude (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate was obtained which was used for the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH3:17])=[CH:4][CH:3]=1.[ClH:19].Cl.[NH2:21][CH2:22][CH2:23][O:24][NH2:25].N1C=CC=CC=1>C(O)C>[ClH:19].[ClH:19].[NH2:21][CH2:22][CH2:23][O:24][N:25]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH3:17]
Reactant: NCCON
Reactant: Cc1nccn1CCCC(=O)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1nccn1CCCC(=NOCCN)c1ccc(F)cc1
Reaction time: 3 h
Yield: 116 %

Procedure:
A mixture of 1-(4-fluorophenyl)-4-(2-methyl-1-(1H)-imidazolyl)-1-butanone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.18 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for three hrs. The reaction mixture was evaporated, toluene was added and evaporated. The residue was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized from absolute ethanol/ether to give 3.2 g (70%) of product, mp 219°-221° C. (dec).
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[CH3:36][NH:37][CH3:38].C1COCC1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([N:37]([CH3:38])[CH3:36])[C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])=[CH:16][N:17]=4)=[O:23])[CH2:26][CH2:25]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: CNC
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Temperature: 25 °C
Yield: 82 %

Procedure:
(6-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate (0.12 mmol) was dissolved in NMP (2 ml) following by addition of 2M solution of dimethylamine in THF (600 μl, 0.12 mmol) and DIEA (21 μl, 0.12 mmol). The reaction mixture was maintained at ambient temperature for 16 h. The resulting mixture was subjected to HPLC purification to provide the trifluoroacetic salt of target material (55 mg, 82%) as a colorless solid. 1H-NMR (DMSO): δ 8.43 (s, 1H), δ 8.40 (d, J=2 Hz, 1H), δ 8.06 (d, J=8.7 Hz, 1H), δ 7.96 (dd, J=2 Hz, J=8.7 Hz, 1H), δ 7.56 (bd, J=6.5 Hz, 1H), δ 7.39 (bt, J=6.5 Hz, 1H), δ 7.05-7.11 (m, 3H), δ 6.96 (s, 2H), δ 6.05 (s, 2H), δ 5.68 (bm, 1H), δ 3.85 (s, 3H), δ 2.75 (s, 6H), δ 1.42-1.45 (m, 2H), δ 1.13-1.16 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([F:63])([F:62])[C:12]([F:61])([F:60])[O:13][C:14]([F:59])([F:58])[C:15]([F:57])([F:56])[O:16][C:17]([F:55])([F:54])[C:18]([F:53])([F:52])[O:19][C:20]([F:51])([F:50])[C:21]([F:49])([F:48])[C:22]([F:47])([F:46])[C:23]([F:45])([F:44])[C:24]([F:43])([F:42])[O:25][C:26]([F:41])([F:40])[C:27]([F:39])([F:38])[C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([N+:35]([O-])=O)[CH:29]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([O-])=O.Cl>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:11]([F:62])([F:63])[C:12]([F:60])([F:61])[O:13][C:14]([F:58])([F:59])[C:15]([F:56])([F:57])[O:16][C:17]([F:54])([F:55])[C:18]([F:52])([F:53])[O:19][C:20]([F:50])([F:51])[C:21]([F:48])([F:49])[C:22]([F:46])([F:47])[C:23]([F:44])([F:45])[C:24]([F:42])([F:43])[O:25][C:26]([F:41])([F:40])[C:27]([F:39])([F:38])[C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([NH2:35])[CH:29]=2)[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=[N+]([O-])c1cc(C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)c2ccc(O)c([N+](=O)[O-])c2)ccc1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1cc(C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)c2ccc(O)c(N)c2)ccc1O

Procedure:
1,17-Bis(3-nitro-4-hydroxyphenyl)perfluoro-3,6,9,15-tetraoxaheptadecane (3.00 g, 0.0030 mole) was dissolved in 180 ml of methanol and the solution deoxygenated by passing nitrogen through the boiling solution for 15 minutes. Concentrated hydrochloric acid (20 ml, 0.23 mole) and 10% Pd/C (0.30 g) were cautiously added to the cooled solution and catalytic reduction to the desired product took place over night at 50 psi of hydrogen. The catalyst was filtered off and the clear white solution evaporated to dryness under reduced pressure to yield the slightly off-white dihydrochloride salt. It was stirred vigorously in a water-ether mixture which was treated carefully with solid sodium bicarbonate. The ether layer was washed several times with water, dried over magnesium sulfate and evaporated to dryness. The residue was recrystallized twice from approximately 1400 ml of heptane (charcoal) to yield 1.41 g (50% yield) of slightly off-white product (VIII), m.p. 92°-95° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:12][CH2:13][CH2:14][OH:15]>CN(C)C=O.O>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: OCCCCl
Reactant: Oc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCOc1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a pre-dried round bottom flask, equipped with a magnetic stirrer, add sodium hydride (60% dispersion in mineral oil, 4.80 g, 0.120 mol) under a nitrogen atmosphere. Wash the sodium hydride with hexanes (3×100 mL) to remove the mineral oil then dimethylformamide (165 mL) is added. The resulting suspension is cooled to 0° C. and a solution of 3-fluorophenol (11.20 g, 0.100 mol) in dimethylformamide (35 mL) is added dropwise resulting in gas evolution and a color change from green to blue-green. After stirring the reaction mixture at rt for approximately 30 min the reaction is recooled to 0° C. and a solution of 3-chloro-1-propanol (9.46 g, 0.100 mol) in dimethylformamide (35 mL) is added dropwise. The resulting reaction mixture is heated to 60° C. for 2.5 h. The solution is cooled, the dimethylformamide is removed under reduced pressure and the resulting reaction mixture is diluted with water (250 mL) and extracted with diethyl ether (3×150 mL). The combined organic extracts are washed with water (200 mL), 2 M aqueous sodium hydroxide (200 mL), water (200 mL) and brine (200 mL). The organic layer is dried over magnesium sulfate, filtered and concentrated to afford the slightly impure title compound (13.32 g, 78%) as an amber oil which is used directly in the next reaction without purification: Rf 0.40 (19:1 CH2Cl2/MeOH); 1H NMR (300 MHz; CDCl3), δ 1.68 (t, J=5.1 Hz, 1H), 2.04 (quintuplet, J=6.0 Hz, 2H), 3.83-3.89 (m, 2H), 4.10 (t, J=6.0 Hz, 2H), 6.59-6.70 (m, 3H), 7.17-7.25 (m, 1H); 19FNMR (282 MHz, CDCl3), δ-112.13; APCI MS m/z 153 [C9H11FO2+H—H2O]+.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[C:3](=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=2)[C:7](O)=[O:8])[O:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:17].C(Cl)(Cl)(Cl)Cl>C1CCCCC1>[CH2:1]1[O:12][C:11]2[C:3](=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=2)[C:7]([Cl:17])=[O:8])[O:2]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Solvent: C1CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)c1cc2c(cc1[N+](=O)[O-])OCO2

Procedure:
Reaction of 31.7 g of 4,5-methylenedioxy-2-nitrobenzoic acid and 31.2 g of phosphorus pentachloride in 250 ml of cylohexane at reflux for 30 minutes followed by treatment of the crude oil twice with carbon tetrachloride gave 4,5-methylenedioxy-2-nitrobenzoyl chloride. The acid chloride was dissolved in 50 ml of tetrahydrofuran and added to a warm solution of 30.9 g of 5-aminotetrazole monohydrate in 750 ml of tetrahydrofuran and 30 ml of water. The solution was stirred for 30 minutes and then diluted with 3 liters of water. The solid which formed was separated by filtration and dried to give 4,5-methylenedioxy-2-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 279° C. after recrystallization from a mixture of dimethylformamide and water.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]([OH:10])[CH2:6][CH2:7][CH2:8][Cl:9].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]([O:10][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:6][CH2:7][CH2:8][Cl:9]
Reactant: COC(=O)CC(O)CCCCl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CC(CCCCl)OS(C)(=O)=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In an atmosphere of nitrogen, 6-chloro-3-hydroxy-hexanoic acid methyl ester (2); 66.5 g {(GC purity; 79.1%, pure amount; 52.6 g (0.295 mol)}, triethylamine (44.7 g, 0.443 mol) and toluene (250 ml) were added to a 500 ml capacity flask, followed by cooling to 5° C. Methanesulfonyl chloride (37.0 g, 0.325 mol) was added dropwise thereto, followed by stirring at 5° C. for 0.5 hour to obtain a toluene solution of 6-chloro-3-methanesulfonyloxy-hexanoic acid methyl ester (3).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[S:12]1[CH:20]2[C:15]([CH2:16][NH:17][CH2:18][CH2:19]2)=[CH:14][C:13]1=[O:21].Br[CH:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])[C:24]([CH:26]1[CH2:28][CH2:27]1)=[O:25].C1COCC1.C1(C)C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C.O.C(#N)C>[CH:26]1([C:24](=[O:25])[CH:23]([N:17]2[CH2:18][CH2:19][CH:20]3[S:12][C:13](=[O:21])[CH:14]=[C:15]3[CH2:16]2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[CH2:28][CH2:27]1
Reactant: O=C1C=C2CNCCC2S1
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=C1C=C2CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S1

Procedure:
According to the process of the present invention the 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-on p-toluenesulfonate (HA=PTSA) of the formula (II) and the 2-bromo-1-cyclopropyl-2-(2-fluorphenyl)-ethanon of the formula (III) are stirred in an organic solvent, (preferably in DMF, THF, toluene, acetonitrile) by adding 1-3 mole equivalent, preferably 2-2.5 mole equivalents of amine, at 20-50° C., preferably 20-30° C., for 1-3, preferably 1-2 hours. The reaction mixture is then divided between water and ethyl acetate and the organic phase is dried and evaporated. The residual product is dissolved in an organic solvent (preferably in DMF, THF, toluene, acetonitrile) without isolating the crystalline 5-[2-cyclopropyl-1-(2-fluorphenyl)-2-oxoethyl]-5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-on of the formula (IV). Then 1-2 equivalent, preferably 1-1.5 equivalent of an amine and 1-3 equivalent, preferably 1-2 equivalent of acetic acid anhydride is added to the reaction mixture and it is further stirred at 20-50° C., preferably 20-30° C., for 1-3 hours, preferably 1-2 hours. The reaction mixture is then divided between water and ethylacetate and the organic phase is dried and evaporated. The remaining product is recrystallized from a suitable organic solvent (acetonitrile, diisopropylether, ethanol), from the mixture of an organic solvent and water or from mixture of suitable organic solvents (toluene-ethyl acetate, hexane-ethyl acetate).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=Cc1ccc(-c2ncccn2)cc1
Yield: 73.3 %

Procedure:
To a degassed suspension of 4-formylphenylboronic acid (100 mg), 2-bromopyrimidine (107 mg) and sodium carbonate (212 mg) in acetonitrile (2 ml)/water (2 ml) was added freshly prepared tetrakis(triphenylphosphine)palladium(0), (40 mg) and the mixture was refluxed under nitrogen, for 20 hrs. The cooled reaction mixture was diluted with water and extracted with ethyl acetate (×2). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with iso-hexane/ethyl acetate (75:25) to afford the sub-title compound as a solid (90 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccnc(Cl)c2)cc1
Temperature: 150 °C
Yield: 72.8 %

Procedure:
2-Chloro-4-iodopyridine (1.6 mmol), 4-cyanophenyl boronic acid (2.5 mmol), 2 M potassium carbonate (3.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.01 mmol) and dioxane (8 mL) were combined in a vial and heated by microwave for 10 min at 150° C. The crystallized product was filtered and subsequently dried in vacuo to yield 250 mg of 4-(2-chloropyridin-4-yl)-benzonitrile as yellow needles. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=5.1 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.2 Hz, 2H), 7.55 (m, 1H), 7.43 (dd, J=5.2, 1.4 Hz, 1H); EIMS 214 m/z (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]#[CH:21])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:22]([C@H:25]1[C:38]2[CH:37]=[CH:36][C:35]3[CH2:34][N:33]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])[CH2:32][CH2:31][C:30]=3[C:29]=2[CH2:28][CH2:27][CH2:26]1)=[N+:23]=[N-:24]>O1CCOCC1.CC(O)(C)C.O.CCOC(C)=O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]2[N:24]=[N:23][N:22]([C@H:25]3[C:38]4[CH:37]=[CH:36][C:35]5[CH2:34][N:33]([C:39](=[O:44])[C:40]([F:41])([F:43])[F:42])[CH2:32][CH2:31][C:30]=5[C:29]=4[CH2:28][CH2:27][CH2:26]3)[CH:21]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [N-]=[N+]=N[C@@H]1CCCc2c1ccc1c2CCN(C(=O)C(F)(F)F)C1
Reactant: C#CC[C@@H]1C(=O)NC=CN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1COCCO1
Product: O=C1NC=CN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)[C@@H]1Cc1cn([C@@H]2CCCc3c2ccc2c3CCN(C(=O)C(F)(F)F)C2)nn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-4-(3,4-dichlorophenylsulfonyl)-3-(prop-2-ynyl)-3,4-dihydropyrazin-2(1H)-one (345 mg, 1 mmol) and (R)-1-(7-azido-1,2,7,8,9,10-hexahydrobenzo[f]isoquinolin-3(4H)-yl)-2,2,2-trifluoroethanone (324 mg, 1 mmol) in dioxane (3 mL) and t-BuOH (4 mL) was added a solution of copper(2+) sulfate, pentahydrate (249 mg, 1 mmol) in water (0.5 mL), followed by a solution of (+)-sodium 1-ascorbate (198 mg, 1 mmol) in water (0.5 mL). The resulting solution was stirred at room temperature for 16 h. The reaction was diluted with EtOAc, washed with brine, dried over Na2SO4, and evaporated to dryness. Flash chromatography (SiO2, EtOAc/hexane=2:1 to pure EtOAc) afforded the title compound as a white solid.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[C:10]1([CH3:20])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17](O)=[O:18].O=P(Cl)(Cl)Cl>[Cl-].[Cl-].[Zn+2]>[OH:3][C:2]1[CH:4]=[CH:5][C:6]([C:17](=[O:18])[CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:20])=[CH:7][C:1]=1[O:8][CH3:9]
Reactant: COc1ccccc1O
Reactant: Cc1ccccc1CC(=O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(C(=O)Cc2ccccc2C)ccc1O
Temperature: 80 °C

Procedure:
To a mixture of guaiacol (1.24 g, 10 mmol), o-tolylacetic acid (1.50 9, 10 mmol), and ZnCl2 (5 g, 36.7 mmol) there was added POCl3 (15 mL, 161 mmol) and the resulting suspension was stirred and heated to 80° C. for 1.5 h. The reaction mixture was cooled and poured onto ice/water and the resulting suspension was stirred at room temperature for 1 h and then extracted with ethyl acetate. The organic layer was separated, washed with brine and dried with sodium sulphate. Volatiles were evaporated under reduced pressure and the residue was dissolved in diethylether. The solution was extracted twice with 50 mL of 2N aqueous solution of NaOH and the combined aqueous layers were combined and acidified with hydrochloric acid to pH=2. The emulsion formed was extracted by ethyl acetate, and the organic layer was washed with brine, dried, and the solvent was evaporated under diminished pressure. The residue was chromatographed on a column of silica gel with a mixture of petroleum ether and ethyl acetate to give 1-(4-hydroxy-3-methoxyphenyl)-2-(2-methylphenyl)-1-ethanone as off white crystals, m.p. 79 to 81° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[C:14]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:13][CH:12]=[C:11]([CH3:19])[N:10]=1.[F:20]F.C(OCC)(=O)C>C(#N)C>[F:20][N+:10]1[C:11]([CH3:19])=[CH:12][CH:13]=[C:14]([S:15]([O-:18])(=[O:17])=[O:16])[C:9]=1[CH3:8]
Reactant: FF
Reactant: Cc1ccc(S(=O)(=O)O)c(C)n1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)[O-])c(C)[n+]1F

Procedure:
To a mixture of acetonitrile (4 ml) and 2,6-dimethylpyridine-3-sulfonic acid (410 mg, 2 mmol), triethylamine (404 mg, 4 mmol) was added at room temperature while stirring, followed by evaporation to dryness under reduced pressure to obtain 2,6-dimethylpyridine-3-sulfonic acid triethylamine salt. The triethylamine salt was dissolved in acetonitrile (4 ml). To the resulting solution cooled with a cooling bath kept at -20° C., a mixed gas of 10% fluorine/ 90% nitrogen was introduced at a flow rate of 15 ml/min. The total amount of the fluorine gas was 6 mmol. Thereafter, the nitrogen gas alone was introduced for 30 minutes. Ethyl acetate was added to the reaction mixture. The precipitated crystal was recovered by filtration to obtain N-fluoro-2,6-dimethylpyridinium-3-sulfonate (257 mg). Yield, 63%. Decomposition point, 200°-210° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])(O)=O.[Na+].Cl[CH2:16][C:17](Cl)=[O:18]>CC(C)CC(=O)C.O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][CH2:16][C:17](=[O:18])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(Br)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C1COc2ccc(Br)cc2N1
Temperature: 80 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of 2-amino-4-bromophenol (25 g, 133.0 mmol), NaHCO3 (22.4 g, 266.0 mmol) in 4-methylpentan-2-one (50 mL) and water (50 mL) at 0° C. was added 2-chloroacetyl chloride (10.0 mL, 200.0 mmol) dropwise. The reaction mixture was stirred at 80° C. for 24 h then cooled to ambient temperature and filtered. The filtrate was washed with water (3×10 mL) and dried over anhydrous Na2SO4. After filtration, the organic phase was evaporated to give 6-bromo-4H-benzo[1,4]oxazin-3-one as a white solid (27 g, 89%). 1H NMR (CDCl3, 400 MHz): δ 8.49 (brs, 1H), 7.08 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 6.93 (d, J=2.0 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 4.61 (s, 2H).
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([N:10]3[CH2:15][CH2:14][N:13](C)[CH2:12][CH2:11]3)=[CH:8][CH:7]=[CH:6][C:5]=12.Cl[C:18]([O:20][CH:21]=[CH2:22])=[O:19].ClC(Cl)C>>[N:1]1[S:2][N:3]=[C:4]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([C:18]([O:20][CH:21]=[CH2:22])=[O:19])[CH2:12][CH2:11]3)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CN1CCN(c2cccc3nsnc23)CC1
Reactant: C=COC(=O)Cl
Solvent: CC(Cl)Cl
Product: C=COC(=O)N1CCN(c2cccc3nsnc23)CC1

Procedure:
To a 25 ml round-bottomed flask equipped with condenser and N2 inlet were added 620 mg (2.64 mmol) of 4-(2,1,3-benzothiadiazolyl)-N-methylpiperazine, 0.224 ml (2.64 mmol) vinyl chloroformate, and 15 ml dichloroethane. The reaction was refluxed 16 hours, cooled, and evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate as eluent, and the product fractions collected to give yellow solid 4-(2,1,3-benzothiadiazolyl)-N-vinyloxycarbonylpiperazine, 530 mg (69%). NMR (d, CDCl3): 3.6 (m, 4H), 3.8 (m, 4H), 4.4-5.0 (m, 2H), 6.6-7.6 (m, 4H).