Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH2:26][CH2:25][C:24]4[C:19](=[CH:20][C:21]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:23]=4)[CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[I:34].[C:35](OCC)(=O)C>CN(C=O)C>[I-:34].[C:27]1([C:21]2[CH:20]=[C:19]3[C:24]([CH2:25][CH2:26][CH:17]([C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([CH2:7][N+:1]5([CH3:35])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:13][CH:12]=4)=[O:16])[CH2:18]3)=[CH:23][CH:22]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Nc1ccc(CN2CCCCC2)cc1)C1CCc2ccc(-c3ccccc3)cc2C1
Reactant: CCOC(C)=O
Reactant: CI
Solvent: CN(C)C=O
Product: C[N+]1(Cc2ccc(NC(=O)C3CCc4ccc(-c5ccccc5)cc4C3)cc2)CCCCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To N-[4-(piperidinomethyl)phenyl]-7-phenyl-1,2,3,4-tetrahydronaphthalene-2-carboxamide (300 mg) dissolved in DMF (3 ml) was added methyl iodide (132 μl), and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was mixed with ethyl acetate (100 ml), and the resulting precipitate was collected by filtration to obtain 1-[4-(7-phenyl-1,2,3,4-tetrahydronaphthalene-2-carboxamido)benzyl]-1-methylpiperidinium iodide (compound 83) (374 mg) as colorless crystals.
Reaction SMILES: C1(C(C)C)C=CC=CC=1.[CH:10]([C:13]1[C:14]([CH:22]([CH3:24])[CH3:23])=[C:15](C(C)C)[CH:16]=[CH:17][CH:18]=1)([CH3:12])[CH3:11].B(F)(F)F>F>[CH:22]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:10]([CH3:12])[CH3:11])([CH3:24])[CH3:23]
Reactant: CC(C)c1cccc(C(C)C)c1C(C)C
Agent: F
Agent: FB(F)F
Solvent: CC(C)c1ccccc1
Product: CC(C)c1ccccc1C(C)C
Reaction time: 2 h
Yield: 36 %

Procedure:
12 g (0.1 mol) cumene and 10 g (0.05 mol) triisopropylbenzene are dissolved in 150 ml of anhydrous hydrogen fluoride at a temperature between -20° and 0°. While stirring the reaction mixture at this temperature, it is saturated with boron trifluoride and stirring is continued for two hours. After workup, as in Example 5, 36% diisopropylbenzene was obtained, comprised of 99.2% of the meta and 0.8% of the para isomer.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[N+:13]([O-])([O-:15])=[O:14].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:13]([C:12]1[C:2]([OH:1])=[C:3]([CH:9]=[CH:10][CH:11]=1)[CH:4]=[CH:5][C:6]([OH:8])=[O:7])([O-:15])=[O:14]
Reactant: O=C(O)C=Cc1ccccc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)C=Cc1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 52.3 %

Procedure:
2-Hydroxycinnamic acid (3.00 g, 18.3 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (2.21 g, 26.1 mmol). The addition of sulfuric acid (30 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(2.0 g, 52%). 1H NMR (CD3COCD3): d 8.21 (d, 1H), 8.16 (d, 1H), 8.05 (d, 1H), 7.19 (t, 1H), 6.72 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:11])[C:9]=1[NH2:10])=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[C:26](Cl)=[N:27][C:28]([Cl:31])=[N:29][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:11])[C:9]=1[NH:10][C:26]1[C:25]([Cl:24])=[CH:30][N:29]=[C:28]([Cl:31])[N:27]=1)=[O:4]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COC(=O)c1sc(-c2ccccc2)c(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(-c2ccccc2)c(C)c1Nc1nc(Cl)ncc1Cl
Yield: 2 %

Procedure:
A solution of 3-amino-4-methyl-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.25 g, 5.06 mmol), potassium carbonate (0.7 g, 5.06 mmol) and trichloropyrimidine (2.78 g, 15.2 mmol) was heated at 50° C. in DMF (10 mL) for 16 hours. The mixture was diluted with ethyl acetate, washed with brine and water, and dried over sodium sulfate. Evaporation of solvent and column chromatography (hexane and ethyl acetate (9:1)) gave 39 mg of 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-5-phenyl-thiophene-2-carboxylic acid methyl ester in 2% yield: 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 7.5 (m, 5H), 3.82 (s, 3H), 2.37 (s, 3H); MS (m/e): 393.9 (M+1).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:14]([N:21]1[CH2:11][C:5]2[C:4](=[CH:9][C:8]([Cl:10])=[CH:7][CH:6]=2)[C:3]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2cc(Cl)ccc2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
A mixture of 2-bromomethyl-5-chloro-benzoic acid methyl ester (0.200 g, 0.76 mmol), benzylamine (0.135 mL, 1.25 mmol), and K2CO3 (0.276 g, 3.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-6-chloro-2,3-dihydro-isoindol-1-one (0.118 g, 60%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.23 (s, 2H), 4.68 (s, 2H), 7.29 (m, 7H), 7.76 (d, 1H). GC-MS: m/z 257 (M)+, 180 (M−77)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Br[CH2:18][CH2:19][CH2:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][C:22]1=[O:31]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][C:22]2=[O:31])[CH2:13][CH2:12]1
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: O=C1CCc2ccccc2N1CCCBr
Product: Cl
Product: O=C1CCc2ccccc2N1CCCN1CCC(c2c[nH]c3ccc(Cl)cc23)CC1

Procedure:
from 5-chloro-3-(piperidin-4-yl)-1H-indole and 1-(3-bromopropan-1-yl)-3,4-dihydroquinolin-2(1H)-one. Mp 142-146° C. 1H NMR (DMSO-d6): 1.95-2.15 (m, 6H); 2.60 (t, 2H); 2.90 (t, 2H); 2.95-3.15 (3H); 3.15-3.20 (m, 2H); 3.55 (d, 2H); 3.95 (t, 2H); 7.00-7.10 (m, 2H); 7.20-7.30 (m, 4H); 7.35 (d, 1H); 7.75 (s, 1H), 11.30 (broad s, 1H); 11.15 (s, 1H). MS m/z: 422 (MH+), 188.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1[CH:29]=[CH:28][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:11][C@@H:10]2[CH3:27])=[O:8])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]([C@H:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:30])=[CH:29][CH:28]=3)[C@@H:10]([CH3:27])[CH2:11]2)[C:40](=[O:42])[CH3:41])=[CH:25][CH:24]=1
Reactant: CC(=O)Cl
Reactant: C[C@H]1C[C@@H](Nc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc(N(C)C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N(C)C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To a solution of (±)-cis-1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-4-(N-4-chlorophenyl)aminoquinoline (120 mg, 0.29 mmol) in methylene chloride (2 mL) was added diisopropylethylamine (37 mg, 0.051 mL, 0.29 mmol) followed by acetyl chloride (2 mL). The mixture was stirred at rt 4 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over sodium sulfate. The drying agent was removed by filtration under reduced pressure, concentrated and purified by silica gel chromatography (100% hexanes-25/75 hexanes/ethyl acetate gradient) to afford pure (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (45 mg, 34%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]=O)=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)([O-])=O.CO.[CH3:20][NH:21][CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[H][H]>O1CCCC1.CO.[Pd].C(O)(=O)C>[CH3:20][N:21]([CH3:22])[CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=1[C:14]([F:17])([F:16])[F:15]
Reactant: [H][H]
Reactant: CNC
Reactant: O=CCCc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCCc1ccc(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 6 mL of tetrahydrofuran, 100 mg (0.41 mmol) of 3-(4-nitro-2-(trifluoromethyl)phenyl)propionaldehyde was dissolved, and 405 μL (0.81 mmol) of a 2N dimethylamine methanol solution, 171 mg (0.81 mmol) of sodium triacetoxy borohydride and 100 μL of acetic acid were added thereto and the mixture solution was stirred at room temperature overnight. The reaction solution was partitioned between water and ethyl acetate and the organic layer was washed with a saturated sodium chloride solution and concentrated to form an intermediate. This intermediate was dissolved in 10 mL of methanol and stirred on 10 mg of Pd/C (10%) in a hydrogen atmosphere for 20 hours. The catalyst was removed by filtration and the filtrated was concentrated and the obtained residue was purified by a silica gel column (n-hexane:ethyl acetate=5:1) to obtain 109 mg (quantitative) of a target object as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1C=[C:11]([C:15]([OH:17])=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:19]1[C:27]2[N:26]=[N:25][NH:24][C:23]=2[CH:22]=[CH:21][CH:20]=1.C1CCC([N:34]=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[N:34]=[C:11]([C:15]([O:17][N:26]2[C:27]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[N:24]=[N:25]2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cccc2[nH]nnc12
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)O
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)OC(C)(C)C)nc1C(=O)On1nnc2ccccc21
Reaction time: 24 h
Yield: 85 %

Procedure:
The Boc-pyrrole-acid 8 (31 g, 129 mmol) was dissolved in 500 ml DMF and hydroxybenzotriazole (17.4 g, 129 mmol) was added followed by DCC (34 g, 129 mmol). The reaction was allowed to stir for 24 hours and then filtered dropwise into a well stirred solution of 5 liters of water (0° C.). The precipitate was allowed to sit for 15 minutes at 0° C. and then collected by filtration. The wet cake was dissolved in 500 ml of dichloromethane, washed with 200 ml brine, and added slowly to a stirred solution of petroleum ether at −20° C. After 4 hours at −20° C. the precipitate was collected by vacuum filtration and dried in vacuo to give (39 g, 85% yield) of a finely divided white powder. (A yellowish impurity may be observed, which can be removed by flash chromatography (acetone:dichloromethane), followed by precipitation in petroleum ether). TLC (7:2 benzene/ethyl acetate v/v) Rf 0.6; 1H NMR (DMSO-d6) δ9.43 (s, 1H), 8.12 (d, 1H, J=8.4 Hz), 7.80 (d, 1H, J=8.2 Hz), 7.64 (t, 1H, J=7.0 Hz), 7.51 (m, 2H), 7.18 (s. 1H), 3.83 (s, 3H), 1.45 (s. 9H); 13C NMR (DMSO-d6) δ156.5, 153.3, 143.2, 129.6, 129.2, 125.7, 125.2, 124.6, 120.3, 112.8, 110.3, 109.8, 79.5, 36.8, 28.6.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:10]O)[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>COCCOC.[Fe](Cl)Cl>[Cl:1][C:2]1[N:7]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(Cc1cccc(Cl)n1)c1ccc(F)cc1
Agent: Cl[Fe]Cl
Solvent: COCCOC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2cc3cccc(Cl)n3n2)cc1
Temperature: 15 °C
Reaction time: 1.5 h
Yield: 68.3 %

Procedure:
To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (109.2 g, 414 mmol) in 1,2-dimethoxyethane (500 mL) at 0° C. was added trifluoroacetic anhydride (59 mL, 414 mmol), keeping the temperature below 10° C. After the addition was complete, the reaction was warmed to 15° C. The solution was then cooled to 4° C. and a solution of triethylamine (116 mL, 828 mmol) in 1,2-dimethoxyethane (60 mL) was added over 0.5 hours. After warming to room temperature, the mixture was stirred for 1.5 hours. To this was added iron(II) chloride (0.52 g, 4.1 mmol) and the reaction was heated to reflux for 3 hours. The reaction was concentrated and the resulting solid was recrystallized from ethyl acetate-hexanes to give 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (69.7 g. 68%) as off-white needles. 1H NMR (CDCl3): δ 8.03 (m, 2 H), 7.54 (d, 1 H), 7.16 (m, 3 H), 6.93 (d, 1 H), 6.91 (s, 1 H); MS m/z 247 (M+1); mp 156–157° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].N1C=CC=C[CH:16]=1.[C:21]1(C)[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:23]1([CH3:16])[C:24]([S:27]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:28])=[O:29])=[CH:25][CH:26]=[CH:21][CH:22]=1
Reactant: c1ccncc1
Reactant: COc1ccccc1CCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1CCOCCOS(=O)(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The solution of 7.50 g of 2-[2-(2-methoxyphenyl)ethoxy]ethanol in 75 ml of dichloromethane is admixed successively % with 8.5 ml of pyridine, 0.519 g of 4-dimethylaminopyridine and 9.10 g of p-toluenesulphonyl chloride, and stirred at room temperature over 16 hours. The reaction mixture is washed with brine (2×200 ml). The organic phase is dried with sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.26 (1:2 EtOAc-heptane); Rt=5.02.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1.C1C[O:30]CC1>>[C:20]([OH:25])(=[O:26])[CH2:21][CH2:22][C:23]([OH:30])=[O:24].[CH2:1]([NH-:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C1CCOC1
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Product: CCCCCCCC/C=C\CCCCCCCC[NH-]
Product: O=C(O)CCC(=O)O
Temperature: 68 °C

Procedure:
Oleyl amide succinic acid was synthesised using the following procedure. To a solution of 50 of oleyl amine in 100 ml THF was added 22 g, that is to say 1.2 mole equivalents, of succinic anhydride. The solution was then refluxed at a temperature of 68° C. for 48 hours to ensure the complete reaction shown in the FIG. 12. THF was removed under vacuum and 50 ml of petroleum ether was added. The excess succinic anhydride not soluble in petroleum ether was removed by filtration on Whatman paper 43. The petroleum ether solution was cooled down and maintained at −10° C. overnight using a refrigerated centrifuge. The white solid was then collected by centrifuging for 30 min at 9000 rpm. The product was washed with cold petroleum ether and dried under vacuum.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([OH:7])[CH:4]=[CH:3][C:2]=1[OH:8].[H-].[Na+].[Br:11][C:12]1[CH:13]=[C:14]([N+]([O-])=O)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1.[CH3:23]I>CN(C)C=O.O>[Br:11][C:12]1[CH:13]=[C:14]([O:7][C:5]2[CH:4]=[CH:3][C:2](=[O:8])[N:1]([CH3:23])[CH:6]=2)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1
Reactant: Oc1ccc(O)nc1
Reactant: CI
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(Oc2cc(Br)cnc2C#N)ccc1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a solution of pyridine-2,5-diol (1.0 g, 9.0 mmol) in dimethylformamide (150 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.30 g, 9.0 mmol) in portions, and the reaction stirred at 0° C. for 1 hour. To this reaction was added 5-bromo-3-nitropicolinonitrile (2.05 g, 9.00 mmol) and the reaction stirred overnight at ambient temperature. Sodium hydride (60% dispersion in mineral oil, 0.30 g, 9.0 mmol) was added to the reaction mixture in portions, followed by methyl iodide (2.56 g, 18.00 mmol), and the reaction was stirred at ambient temperature for 3 hours. The reaction was poured into water and the aqueous layer extracted with ethyl acetate. The organics were washed with 1N HCl, 1M NaOH, water, brine, dried over magnesium sulfate and concentrated in vacuo. The material purified over silica gel (2% ethyl acetate/dichloromethane) to afford 5-bromo-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yloxy)picolinonitrile (1.5 g, 54%).
Reaction SMILES: Cl[P:2]([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[CH:9]([Mg]Br)=[CH2:10].C1C[O:16]CC1>>[CH:3]([P:2](=[O:16])([CH:6]([CH3:8])[CH3:7])[CH:9]=[CH2:10])([CH3:5])[CH3:4]
Reactant: C1CCOC1
Reactant: CC(C)P(Cl)C(C)C
Reactant: C=C[Mg]Br
Product: C=CP(=O)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Chlorodiisopropylphosphine (6.00 g, 39.3 mmol) was dissolved in THF (150 mL) and cooled to −78° C. Vinylmagnesium bromide (1 M in THF, 43.2 mL, 43.2 mmol) was added dropwise. The dry ice bath was then removed, and the reaction was allowed to warm to room temperature. After 2 h at room temperature, the reaction was quenched with saturated NH4Cl, and 30% H2O2 (75 mL) was added. The mixture was vigorously stirred at room temperature for 2 h. It was then extracted with CH2Cl2 (2×), dried (MgSO4), and evaporated. Flash chromatography (0-10% MeOH/EtOAc) afforded diisopropyl(vinyl) phosphine oxide as a colorless oil. 1H NMR (CDCl3, 600 MHz) δ 6.31 (td, J=18.6, 2.2 Hz, 1H), 6.24 (ddd, J=34.8, 12.8, 2.3 Hz, 1H), 6.03 (ddd, J=27.3, 18.7, 12.8 Hz, 1H), 2.01-1.92 (m, 2H), 1.15 (dd, J=15.0, 7.0 Hz, 6H), 1.06 (dd, J=15.9, 7.4 Hz, 6H). MS: cal'd 161 (MH+), exp 161 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC(O)C>[CH2:18]([NH:25][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: NCc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1cc(NCc2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.3 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (1.5 g, 10 mmol) in iPrOH (40 mL) and DIPEA (1.55 g, 12 mmol) was added a solution of benzylamine (1.28 g, 12 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2.5 hours. Water was added and the mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by flash chromatography on silica to obtain the title compound (1.5 g, yield: 68%) as a white solid. H NMR (300 MHz, CDCl3) δ 8.35 (br s, 1H), 7.20-7.38 (m, 5H), 6.35 (s, 1H), 4.52 (s, 2H); MS (ESI): 220 [M+H]+.
Reaction SMILES: O[C:2]1[C:3](=[O:23])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:5][CH2:6][C:7]=1[C:8](=[O:13])C(F)(F)F.Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1.C(N(CC)CC)C.Cl>C1COCC1>[OH:13][C:8]1[C:7]2[CH2:6][CH2:5][N:4]([C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)[C:3](=[O:23])[C:2]=2[N:33]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[N:34]=1
Reactant: O=C1C(O)=C(C(=O)C(F)(F)F)CCN1c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(O)c3c2C(=O)N(c2ccc([N+](=O)[O-])cc2)CC3)cc1

Procedure:
Part C. A mixture of the 3-hydroxy-1-(4-nitrophenyl)-4-(trifluoroacetyl)-5,6-dihydro-2(1H)-pyridinone made above (4.91 g, 12.94 mmol), p-methoxyphenylhyrazine HCl salt (2.37 g, 13.59 mmol) in 100 mL of THF was treated with 3.62 mL of triethylamine at rt overnight. To the reaction mixture was added 100 mL of 1N HCl. The resulting mixture was refluxed for 2 h. After cool to rt the title compound was collect by filtration (4.5 g, 92%). 1H NMR (DMSO-d6, 300 MHz) δ 8.24 (2H, d, J=9.2 Hz), 7.64 (2H, d, J=9.0 Hz), 7.39 (2H, d, J=9.0 Hz), 6.94(2H, t, J=9.2 Hz), 4.13 (2H, t, J=6.6 Hz), 3.77 (3H, s), 2.85 (2H, t, J=6.6 Hz) ppm.
Reaction SMILES: [O:1]=[CH:2][C:3](Cl)(Cl)Cl.[NH2:7][OH:8].[NH2:9][C:10]1[C:11](O)=[CH:12][C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[CH:19]=1.Cl.C([O-])(=O)C.[Na+]>O>[O:1]1[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:10]=2[N:9]=[C:2]1[CH:3]=[N:7][OH:8])[CH2:17][CH2:16][CH2:15][CH2:14]3
Reactant: Nc1cc2c(cc1O)CCCC2
Reactant: O=CC(Cl)(Cl)Cl
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: ON=Cc1nc2cc3c(cc2o1)CCCC3

Procedure:
Chloral (10.7 g in 20 ml of water) and hydroxylamine hydrchloride (4.5 g in 10 ml of water) was added simultaneously to a solution of 5,6,7,8-tetrahydro-3-amino-2-naphthol (7 g) in 50 ml of water containing 3.8 ml of concentrated HCl at 60°-70° C. The reaction mixture was neutralized with sodium acetate (25 g) to keep the PH 4.5 over a period of 1 hour. The reaction mixture was cooled, filtered, and dried thoroughly to give 8.5 g of 5,6,7,8-tetrahydronaphth[2,3-d]oxazole-2-aldoxime as dark solid product.
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].C([Li])CCC.[NH2-].[Li+].[C:20]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[O:35]1CCCC1>>[CH2:1]([N:4]([C@@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@@H:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@H:21]([OH:35])[C:20]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:2]=[CH2:3]
Reactant: C1CCOC1
Reactant: C=CCN[C@@H](C)c1ccccc1
Reactant: CC(C)(C)OC(=O)C=Cc1ccccc1
Agent: [Li+]
Agent: [Li]CCCC
Agent: [NH2-]
Product: C=CCN([C@@H](C)c1ccccc1)[C@@H](c1ccccc1)[C@H](O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of (S)-N-allyl-α-methylbenzylamine (2) (1.94 g, 12.1 mmol) in anhydrous tetrahydrofuran (25 ml) was cooled to -78° C. and 1.6M butyllithium (6.03 ml, 9.6 mmol) was added dropwise via a syringe. The resulting orange lithium amide solution was stirred at -78° C. for 1 hour. A solution of t-butyl cinnamate (7) (1.64 g, 8.1 mmol) in anhydrous tetrahydrofuran (15 ml) was then added via a cannula and the solution was stirred for a further 1 hour. The resulting yellow enolate solution was then diluted with anhydrous tetrahydrofuran (30 ml) and solid (+)-(camphorsulphonyl)-oxaziridine (2.76 g, 12.1 mmol) was added. After stirring for a further 6 hours at -78° C., the mixture was warmed to 0° C. (15 minutes) and quenched by the addition of saturated aqueous ammonium chloride solution. Ethyl acetate (50 ml) was added, followed by brine (10 ml). The organic layer was separated, dried (magnesium sulphate) and filtered and the solvent was evaporated under reduced pressure to afford an oily solid residue. Treatment of this with diethyl ether precipitated the oxaziridine/sulfonimine which was removed by filtration and the resulting oil was purified by flash chromatography on silica gel [ethyl acetate/petroleum ether (1:19)] affording the title compound (Rf 0.20) as a colourless oil (2.89 g, 95%). δH (300 MHz: CDCl3) 7.50-7.21 (10H, m, Ph), 5.89 (1H, m, NCH2CH=CH2), 5.12 (1H, app. dd, J=17.2 and 41.4, trans CH=CH2), 5.04 (1H, app. dd, J=17.2 and 1.4, cis CH=CH2), 4.53 (1H, d, J=3.8, CHOH), 4.23 (1H, d, J=3.8, NCHCH), 4.13 (1H, q, J=6.8, PhCHCH3), 3.47 (1H, app. dd, J=15.6 and 7.1, NCH2), 3.03 (1H, bs, OH), 1.29 (9H, s, (CH3)3CH), 1.21 (3H, d, J=6.8, PhCHCH3).