Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[Na].[C:5]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][N:8]=1)#[N:6].[Cl-:14].[NH4+:15].C(O)(=O)C>CO>[ClH:14].[C:5]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][N:8]=1)(=[NH:15])[NH2:6]
Reactant: N#Cc1ncccc1F
Reactant: [NH4+]
Reactant: [Cl-]
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: Cl
Product: N=C(N)c1ncccc1F
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A sodium methoxide solution made from 0.40 g (17.391 mmol) of sodium and 65 ml of methanol is added to a solution of 10.30 g (84.355 mmol) of the compound from Example II in 30 ml of methanol, and the mixture is stirred at 20° C. for 72 hours. 5.44 g (101.682 mmol) of ammonium chloride (powdered) and 17.39 mmol (1.04 ml) of acetic acid are added, and the mixture is stirred at 40° C. for 28 hours and cooled. Insoluble salt is filtered off with suction (1.78 g), and the filtrate is concentrated, concentrated with acetone and then stirred with acetone, filtered off with suction and washed.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13].S(=O)(=O)(O)[OH:15]>O>[Cl:1][C:2]1[C:7]([C:8]([NH2:9])=[O:15])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13]
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=S(=O)(O)O
Solvent: O
Product: NC(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
In a preferred embodiment of the invention, pentachlorobenzonitrile is interacted with a molar excess of sulfuric acid having at least 75% by weight H2SO4 at a temperature of between about 130° and 160° C. for about fifteen (15) to ninety (90) minutes. The reaction mixture is then cooled and diluted with water to form a solid pentachlorobenzamide precipitate. The resultant pentachlorobenzamide is recovered in yields on the average of above about 90%.
Reaction SMILES: [CH:1]1([CH2:5][OH:6])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>ClCCl>[S:14]([O:6][CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: OCC1CCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Temperature: 25 °C

Procedure:
Cyclobutanemethanol(5 g, 58 mmol) was dissolved in dichloromethane (150 ml) and cooled in an ice water bath. Triethylamine (10.5 ml,-75.5 mmol) was added followed by the dropwise addition of a solution of tosyl chloride (13.3 g, 69.8 mmol) in dichloromethane (50 ml). The cooling bath was removed and the mixture allowed to warm to room temperature over 16 hours. The mixture was washed with water (2×100 ml) dried (MgSO4) and concentrated in vacuo to give cyclobutanemethanol tosylate as a yellow oil which was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8][O:9][CH:10]=1)=[O:5])C.O.[OH-].[Li+].CO>C1COCC1.O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=1
Reactant: CCOC(=O)c1conc1-c1ccccn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1conc1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a suspension of 3-pyridin-2-yl-isoxazole-4-carboxylic acid ethyl ester (9.52 g, 44 mmol) in THF (530 mL) was added a solution of lithium hydroxide monohydrate (11.0 g, 263 mmol) in water (265 mL) followed by methanol (265 mL) at 0° C. and the resulting mixture stirred at room temperature for 1 h. The mixture was then evaporated to half volume and then acidified to pH 4 with HCl (1N) and cooled to 0° C. for 30 min. A solid precipitated and was filtered off and dried to afford the title compound (6.55 g, 79%) which was obtained as an off white solid. MS: m/e=189.3 [M−H]−.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH:24][CH2:25][C@H:26]1[O:30][C:29](=[O:31])[CH:28]=[CH:27]1>CN(C)C=O>[Si:6]([O:24][CH2:25][C@H:26]1[O:30][C:29](=[O:31])[CH:28]=[CH:27]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1C=C[C@@H](CO)O1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@@H]1C=CC(=O)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Imidazole (1.22 g, 17.6 mmol) and tert-butyl(diphenyl)silyl chloride (3.95 mL, 15.4 mmol) were added to a solution of (5S)-5-(hydroxymethyl)furan-2(5H)-one (1.60 g, 14.0 mmol) in N,N-dimethylformamide (50 mL), and the reaction mixture was stirred at room temperature for 18 hours. It was then partitioned between tert-butyl methyl ether and water; the organic layer was washed twice with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 5% to 30% ethyl acetate in heptane) afforded the product as a white solid. Yield: 5.20 g, quantitative. 1H NMR (400 MHz, CDCl3) δ 7.63-7.66 (m, 4H), 7.38-7.49 (m, 7H), 6.19 (dd, J=5.7, 2.0 Hz, 1H), 5.06-5.10 (m, 1H), 3.93 (dd, half of ABX pattern, J=10.9, 4.5 Hz, 1H), 3.88 (dd, half of ABX pattern, J=10.8, 5.0 Hz, 1H), 1.05 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
To a solution of 3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (9.41 g, 0.048 mol) in dichloromethane (200 mL) at room temperature was added iPr2NEt (14.1 g, 0.110 mol), followed by MsCl (5.5 g, 0.048 mol). The reaction mixture was allowed to stir for one hour before concentrating and purifying the resulting residue by silica gel chromatography (1:1 hexane:ethyl acetate). The desired compound was obtained as an oil (11.06 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl.O>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1NC(=O)C(C)(C)C
Yield: 93 %

Procedure:
A biphasic solution of o-toluidine (107.2 g, 1.0 mol) in methylene chloride (500 ml) and water (150 ml) containing sodium carbonate (69 g, 0.65 mol) was treated with trimethylacetyl chloride (120.6 g, 1.0 mol). The rate of addition of trimethylacetyl chloride was adjusted so as to maintain the reaction at gentle reflux. After 45 minutes the addition was complete. The organic layer was separated, washed with water, and concentrated in vacuo. The crude N-[(2-methyl)phenyl]-2,2-dimethylpropanamide was slurried in 2% aqueous HCl, filtered and washed with H2O until the filtrate was neutral. After drying in vacuo (50° C., 20 mm), N-[(2-methyl)phenyl]-2,2-dimethylpropanamide (178 g, 0.93 mol) was obtained in 93% yield. (mp 109°-110° C.).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][OH:17]>O1CCCC1>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([O:17][CH2:16][CH2:15][N:14]([CH3:18])[CH3:13])=[N:5][CH:6]=1)([O-:12])=[O:11]
Reactant: CN(C)CCO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride and oil bath heating. To a mixture of sodium hydride (189 mg, 4.73 mmol) in anhydrous tetrahydrofuran (2 mL) at 0° C. a solution of 2-chloro-5-nitropyridine (500 mg, 3.16 mmol) and 2-(dimethylamino)ethanol (353 mg, 3.96 mmol) in anhydrous tetrahydrofuran (4 mL) was added dropwise. The reaction was warmed to room temperature and stirred for 16 h. The THF was evaporated, and water (100 mL) and EtOAc (200 mL) were added. The aqueous layer was extracted with EtOAc (200 mL), and the organic layers combined, washed with brine, dried over sodium sulfate and concentrated to give a brown oil. Purification column chromatography on silica gel using 5% methanol/methylene chloride yielded 2-(5-nitropyridin-2-yloxy)-N,N-dimethylethanamine as a light yellow solid (233=mg, 35%). LC/MS (m/z): 212.2 (MH+), Rt 1.28 minutes.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=2)=[CH:12][CH:11]=1
Reactant: Fc1cccc(F)n1
Reactant: NCc1ccc(Cl)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Fc1cccc(NCc2ccc(Cl)cc2)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To 2,6-difluoro-pyridine (20, 3.80 g, 33.0 mmol) in 20.0 mL of N-methylpyrrolidone, 4-chloro-benzylamine (21, 5.6 mL, 46.0 mmol) and N,N-diisopropylethylamine (10.0 mL, 57.4 mmol) were added. The reaction was stirred at 90° C. overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 25% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum, and the resulting material was washed with ethyl acetate/hexane to provide the desired compound as a white solid (22, 5.30 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:27][OH:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:29](Cl)(=[O:31])[CH3:30]>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]([CH2:27][O:28][C:29](=[O:31])[CH3:30])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)NC(COC(C)=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 68.4 %

Procedure:
To a mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (2.35 g) in pyridine (30 ml), was dropwise added a solution of acetyl chloride (942 mg) in methylene chloride (5 ml) under stirring and ice-cooling over the period of 7 minutes. The mixture was further stirred for 70 minutes at room temperature. The pyridine was distilled off under reduced pressure and ethyl acetate was added to the residue. The resultant mixture was washed twice with water and adjusted to pH 4 with hydrochloric acid and then an aqueous solution of sodium chloride, dried and concentrated under reduced pressure to give an oily substance. This oily substance was crystallized by treating with a mixture of diethyl ether and a small amount of n-hexane, and collected crude crystals (2.5 g) were washed with n-hexane and thus obtained crystals were recrystallized from diethyl ether to give pure crystals (1.78 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-acetoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 89° to 90° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([N:26]4[CH2:25][CH2:24][NH:23][CH:22]([CH3:21])[CH2:27]4)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1CNCCN1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNC(C)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
A mixture of 0.75 g (2.68 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 1.07 g (10.4 mmol) of 2-methylpiperazine and 30 ml of acetonitrile was refluxed for five hours, then stirred at room temperature overnight. The precipitate was filtered, washed with water/ethanol and acetonitrile, and dried to give 0.42 g of the title compound, mp 189°-192° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])=[N:6][CH:7]=1.[C:15](=[O:18])([O-])[O-].[Na+].[Na+].[CH2:21]1[CH2:25]O[CH2:23][CH2:22]1>C(OCC)(=O)C>[CH3:7][N:6]1[C@H:5]2[C@@:21]([CH3:25])([C:21]3[CH:25]=[CH:12][C:11]([C:2]4[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])=[N:6][CH:7]=4)=[CH:9][C:22]=3[CH2:23][CH2:4]2)[CH2:22][CH2:23][C:15]1=[O:18]
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cn1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(NC(=O)C(C)(C)C)nc4)cc3CC[C@@H]12
Yield: 32 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 5-bromo-2-(t-butylcarbonylamino)pyridine (167 mg, 0.65 mmol), 0.65 mL of 2M aqueous sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 84 mg (32%) of the title compound as a brown solid. mp 248°-250°. FDMS: m/e=405. α[D]589 =+70.74 (c=0.45, chloroform)
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:9])C=CC=CC=1.[OH:10][C:11]1C2C=CC=CC=2C=CC(=O)[CH:12]=1.[OH:23][C:24]1[C:34](=[O:35])[CH:33]=[CH:32][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:26]=2[CH:25]=1>>[CH2:11]([O:10][C:2](=[O:1])[C:3]([O:23][C:24]1[C:34](=[O:35])[CH:33]=[CH:32][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:26]=2[CH:25]=1)=[O:9])[CH3:12]
Reactant: O=c1ccc2ccccc2c(O)c1
Reactant: O=c1ccc2cnccc2cc1O
Reactant: O=c1cccccc1O
Product: CCOC(=O)C(=O)Oc1cc2ccncc2ccc1=O

Procedure:
In the same manner using the appropriate compound of formula III and replacing 2-hydroxy-2,4,6-cycloheptatrien-1-one with an equivalent amount of 5-hydroxy-7H-benzocyclohepten-7-one, 6-hydroxy-7H-cyclohepta[c]pyridin-7-one, 2-hydroxy-3H-6,7-dihydrocyclobutacyclohepten-3-one, 1-hydroxy-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-3-one, and 2-hydroxy-3H-6,7,8,9,10,11,12,13-octahydrocycloheptacyclodecen-3-one, the following compounds are obtained respectively: [(7H-7-oxobenzocyclohepten-6-yl)oxy]oxo-acetic acid methyl ester (I; R1, R5 and R6 = H, R3 and R4 together form a --CH=CH--CH=CH-- chain and R2 = O--CO--COOCH3), [(7-oxo-7H-cyclohepta[c]pyridin-6-yl)oxy]oxo-acetic acid ethyl ester (I; R1, R2 and R5 = H, R3 and R4 together form a --CH2 =CH2 --N=CH-- chain and R6 = O--CO--COOC2H5), [(3-oxo-3H-6,7-dihydrocyclobutacyclohepten-2-yl)oxy]oxo-acetic acid ethyl ester (I; R2, R5 and R6 = H, R3 and R4 together form a --CH2 --CH2 -- chain and R1 = O--CO--COOC2H5), [(3-oxo-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-1-yl)oxy]oxo-acetic acid ethyl ester (I; R1, R2 and R6 = H, R3 and R4 together form a --(CH2)6 -- chain and R5 = O--CO--COOC2H5) and [(3H-6,7,8,9,10,11,12,13-octahydro-3-oxocycloheptacyclodecen-2-yl)oxy]-oxo-acetic acid methyl ester (I; R1, R2 and R5 = H, R3 and R4 together form a --(CH2)8 -- chain and R6 = O--CO--COOCH3).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Li])CCC.[Si]([O:21][CH2:22][C@@H:23](/[N:28]=[CH:29]/[C:30]([F:33])([F:32])[F:31])[CH2:24][CH:25]([CH3:27])[CH3:26])(C(C)(C)C)(C)C>CCOCC>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C@H:29]([NH:28][C@@H:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:21])[C:30]([F:32])([F:31])[F:33])=[CH:3][CH:4]=1
Reactant: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)/N=C/C(F)(F)F
Reactant: Clc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)C[C@@H](CO)N[C@@H](c1ccc(Cl)nc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-2-chloropyridine (2.5 g, 13 mmol) in ether (30 mL) at −78° C. was added n-butyllithium (13 mmol, 2.5 M in hexane). The mixture was stirred at −78° C. for 1 h. (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-N-[(1E)-2,2,2-trifluoroethylidene]pentan-2-amine (3.64 g, 11.7 mmol, see Step 2, Example 8) was added. The mixture was stirred at −78° C. for 2 h. Saturated aqueous NH4C1 was added to the reaction mixture and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhyd. MgSO4 and concentrated to an oil (5.3 g). The crude oil (2.0 g) was then treated with (Bu)4NF (6 mL, 1M in THF). The mixture was stirred at rt for 1 h, saturated aqueous NH4C1 was added and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhyd. MgSO4 and concentrated to an oil. Chromatography (20% EtOAc/hexane) afforded the title compound.
Reaction SMILES: Br[C:2](Br)=[CH:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([Li])(CC)C.[Cl-].[NH4+]>C1COCC1.CCOCC>[C:3]([C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[CH:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=C(Br)Br
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 538A (6.11 g, 17.21 mmol) in THF (150 mL) at −78° C. was treated with sec-butyl lithium (24.6 mL, 34.41 mmol) dropwise via syringe and stirred for 30 minutes at −78° C. The solution was then treated with a saturated ammonium chloride solution (100 mL), allowed to warm to room temperature, diluted with ether and extracted. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to provide the desired product in quantitative yield. MS (ESI(+)) m/e 196 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+].C(OC(=O)C)C.O>C1COCC1>[CH2:10]([O:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OCc2ccccc2)nc1
Temperature: 0 °C

Procedure:
20 mmol of 6-Chloro-nicotinonitrile were dissolved in THF. 1.1 eq. of benzyl alcohol were added. The reaction mixture was cooled to 0° C. and flushed with argon. 4 eq of NaH were added slowly. After 15 min the product was isolated via extraction from ethylacetate/water.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=1.CO.O>CN1C(=O)CCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[NH:20][C:1](=[O:2])[NH:21][C:16]=2[CH:15]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CO
Product: O=c1[nH]c2ccc(Br)cc2[nH]1
Temperature: 100 °C

Procedure:
1,1′-Carbonyldiimidazole (2.1 g) in NMP (5 ml) was added to a solution of 4-bromo-o-phenylenediamine (CAS Reg. No. 1575-37-7, 2 g) in NMP (5 ml). The mixture was heated to 100° C. for 2 h and then allowed to cool to 60° C. MeOH (3 ml) was added, and the mixture was allowed to cool to room temperature. Water (50 ml) was added. The mixture was filtered. The residue was washed with isopropanol and then dried in vacuo to give the title compound (1.65 g) as a dark brown solid. MS (m/e, ISP neg. ion)=213.1 [M−H+].
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Br:13][C:14]1[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=1>CN(C=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[NH:20][C:1](=[O:2])[NH:21][C:16]=2[CH:15]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc(Br)cc2[nH]1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
4.29 g (26.46 mmol) of carbonyldiimidazole (CDI) is added to a solution of 4.5 g (24.05 mmol) of 4-bromobenzene-1,2-diamine in 95 mL of DMF and the reaction mixture is stirred for 5 hours at 80° C. Then the reaction mixture is poured onto water and the precipitate formed is filtered off. The precipitate is washed three times with water and dried in the circulating air dryer at 60° C. Yield: 4.6 g (90% of theoretical); C7H5BrN2O (M=213.03); calc.: molpeak (M+H)+: 213/215; found: molpeak(M+H)+: 213/215; Rf value: 0.5 (silica gel, DCM/MeOH 10:1).
Reaction SMILES: C([O-])=O.[NH4+].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=1[F:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(C)C=CC=CC=1>[Fe].O>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[F:22])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(OCc2ccccc2)c(F)c1
Yield: 101.3 %

Procedure:
A mixture of iron powder (45.2 g, 0.809 g atoms), ammonium formate (53.6 g, 0.850 mol), 1-benzyloxy-2-fluoro-4-nitrobenzene (50.0 g, 0.200 mol), toluene (400 mL) and water (400 mL) was heated to reflux overnight. The mixture was filtered through Celite and washed with hot ethyl acetate. The combined organic layers were washed with water and brine, then dried over sodium sulfate and concentrated to afford 4-benzyloxy-3-fluoroaniline (44 g, 100%). 1H NMR (400 MHz, d6-DMSO): δ 7.43-7.26 (m, 5H), 6.90 (dd, 1H), 6.49 (dd, 1H), 6.34 (m, 1H), 4.99 (br s, 2H), 4.98 (s, 2H); 13C NMR (100 MHz, d6-DMSO): 6171.1, 155.1, 152.7, 144.9, 138.0, 137.2, 129.6, 129.0, 128.5, 118.9, 110.0, 102.9, 72.5; IR (cm−1): 1510, 1454, 1277, 1215, 1126, 1007, 957, 843, 800, 789, 739, 694, 604; LC/MS (M+H=218).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[N:1]1([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:21])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6]1
Reactant: C1=CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CC=CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
Into a solution of 1,2,3,6-tetrahydropyridine (1.00 g, 12.0 mmol) and triethylamine (3 mL) in CH2Cl2 (30 mL), benzoyl chloride (1.69 g, 12.0 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 hrs and washed with saturated Na2CO3 (20 mL×3) and brine solution (20 mL), dried over Na2SO4 and concentrated under vacuum to afford crude product. The crude product was purified by silica gel column chromatography using hexane/ethyl acetate (10/3, v/v) to afford target product as a colorless oil (2.27 g, 100%). 1H NMR (CDCl3): δ 2.16-2.25 (m, 2H), 3.46-4.20 (m, 4H), 5.53-5.91 (m, 2H), 7.29-7.53 (m, 5H).