Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH2:14][F:15])([CH2:12][F:13])[CH2:8][C@@H:7]2O.N12CCCN=C1CCCCC2.C1(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:42]([C@H:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[O:10][C:9]([CH2:14][F:15])([CH2:12][F:13])[CH2:8]1)=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O[C@H]1CC(CF)(CF)Oc2c(Cl)cccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@@H]1CC(CF)(CF)Oc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of Example 2B (7.75 g, 31.2 mmol) and THF (116 mL) was cooled to <5° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (7.91 mL, 53.0 mmol) and diphenylphosphoryl azide (10.09 mL, 46.8 mmol) were added. The yellow slurry was warmed slowly to ambient temperature, becoming a brown solution. After 14 hours, the mixture was concentrated, diluted with MTBE (200 mL), and washed with 2N NaOH (50 mL×2), brine (50 mL), 2N HCl (50 mL×2), and brine (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to give the title compound. This material was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C[Al](C)C.C[O:13][C:14]([C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[N:19]=[C:18]([CH3:30])[N:17]=1)=O>O1CCOCC1.CCCCCC>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:14]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)[N:19]=[C:18]([CH3:30])[N:17]=2)=[O:13])[S:3][CH:4]=1
Reactant: Cc1csc(N)n1
Reactant: COC(=O)c1cc(-c2cc(F)cc(F)c2)nc(C)n1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: C1COCCO1
Product: Cc1csc(NC(=O)c2cc(-c3cc(F)cc(F)c3)nc(C)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a solution of 156 mg (1.37 mmol, 1.8 equiv.) of 2-Amino-4-methylthiazole in 4 ml of dry dioxane were added 0.68 μl (1.37 mmol, 1.8 equiv.) of a 2M solution of trimethylaluminium in hexane. The solution was stirred for 1 h at room temperature. Then 200.0 mg (0.76 mmol) of 6-(3,5-Difluoro-phenyl)-2-methyl-pyrimidine-4-carboxylic acid methyl ester were added and the reaction was heated to 90° C. for 4 h. The reaction was quenched by cautious addition of 0.2 ml of water. Then approximately 1 g of anhydrous sodium sulfate were added to bind the water and the mixture was stirred vigorously for 5 min. The mixture was diluted by addition of 10 ml of methylenene chloride and filtered over Speedex filter aid which was washed with methylene chloride. The filtrate was concentrated in vaccuo and the residue was purified by flash chromatography (heptane/ethyl acetate 4:1) and recristallised from diisopropyl ether to yield the title compound (152.0 mg, 58%) as a white solid, MS (ISP): m/e=347.1 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=CC=2F)=[CH:10][C:9]=1[NH:22][C:23](=[O:35])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=O)(C)(C)C.[C:37](O)([C:39]([F:42])(F)F)=O>C(Cl)Cl>[F:42][C:39]1[CH:37]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=3)[C:33]#[N:34])[CH2:24][C:23](=[O:35])[NH:22][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(F)ccc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4cc(F)ccc4F)cc3NC(=O)C2)c1

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2′,5′-difluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K92) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (49 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15]([CH2:19][NH:20][C:21](=O)OCC)([OH:18])[CH2:14][CH2:13]2)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15]([CH2:19][NH:20][CH3:21])([OH:18])[CH2:14][CH2:13]2)=[CH:2]1
Reactant: CCOC(=O)NCC1(O)CCN(CCc2coc3ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCC1(O)CCN(CCc2coc3ccccc23)CC1

Procedure:
A solution of 13.4 g of the product obtained in Step C in 130 ml of tetrahydrofuran is added, at a reaction mixture temperature of 20° C., to a suspension of 3.63 g of lithium aluminium hydride in 20 ml of tetrahydrofuran. After 9 hours' reflux and then 12 hours at room temperature, the reaction mixture is hydrolysed, filtered and then concentrated under reduced pressure, enabling the expected product to be isolated.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][C:20]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:16]1)=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:34]([O:33][C:20]1[CH:21]=[C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][C:19]=1[CH:17]1[CH2:18][NH:15][CH2:16]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COc2ccc(C3CNC3)c(OCc3ccccc3)c2)cc1
Reaction time: 2 h
Yield: 90 %

Procedure:
In a 25 ml round-bottomed flask, 1 g of 3-(2,4-bis(benzyloxy)phenyl)azetidine-1-carboxylic acid tert-butyl ester is dissolved in 10 ml of dichloromethane and then 2.5 ml of trifluoroacetic acid are added. The reaction mixture is stirred for 2 hours. The solvents are evaporated off and the residue is then taken up in isopropyl ether. 0.92 g of 3-(2,4-bis(benzyloxy)phenyl)azetidine trifluoroacetate is obtained. Yield=90%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[C:21](O)=[CH:20][CH:19]=[C:18]1O)(=[O:16])=[O:15].ClC1C=C(C=CC=1)C(OO)=[O:29].O1CCCC1>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:18][C@@H:19]2[C@@H:20]([O:29]2)[CH2:21]1)(=[O:16])=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)n1c(O)ccc1O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1C[C@@H]2O[C@@H]2C1
Reaction time: 3 h

Procedure:
To a stirring suspension of 5-bromo-3-(2,5-dihydroxy-1H-pyrrol-1-ylsulfonyl)-1H-indole-2-carboxamide (10 mg, 0.027 mmol, 1.0 equiv.) in 2 mL of acetone was added m-chloroperoxybenzoic acid (6.5 mg, 0.038 mmol, 1.4 equiv.). After stirring for 3 hours, 3 mL of tetrahydrofuran and m-chloroperoxybenzoic acid (6.5 mg, 0.038 mmol, 1.4 equiv.) were added. After stirring an additional 72 hours, more m-chloroperoxybenzoic acid (13 mg, 0.076 mmol, 2.8 equiv.) was added and, after 3 hours, the solvent was removed in vacuo. The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 385.96 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[C:15]([CH3:24])[C:14]=3[CH3:25])[CH:10]=1)[NH:7][C:6]([CH3:27])([CH3:26])[CH2:5]2.[H-].[Na+].[CH3:30]I>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[C:15]([CH3:24])[C:14]=3[CH3:25])[CH:10]=1)[N:7]([CH3:30])[C:6]([CH3:27])([CH3:26])[CH2:5]2
Reactant: CI
Reactant: Cc1c(CCC(=O)O)ccc(OCc2cc(F)cc3c2NC(C)(C)C3)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CCC(=O)O)ccc(OCc2cc(F)cc3c2N(C)C(C)(C)C3)c1C
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of (310) (20 mg, 0.05 mmol) in DMF (3 mL) was added sodium hydride (4.3 mg, 2 eq.) and the reaction mixture was stirred at 40° C. for 1 hour. The solution was warmed to room temperature, an excess of methyl iodide was added and the reaction was sealed and warmed to 40° C. overnight. The reaction was quenched with water and extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford compound (311). 1H NMR (400 MHz, CDCl3) δ 6.97 (d, J=8.2 Hz, 1H), 6.93-6.91 (m, 2H), 6.78 (d, J=8.2 Hz, 1H), 4.99 (s, 2H), 3.83 (s, 2H), 3.68 (s, 3H), 2.94-2.90 (m, 2H), 2.56-2.52 (m, 2H), 2.20 (s, 3H), 2.12 (s, 3H), 1.54 (s, 6H). LC-MS ESI m/z: found 384.5 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[Br:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:15]3[CH:14]=[CH:13][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)[CH:3]=2)[CH:8]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Brc1ccc2cc(Br)ccc2c1
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: COCCOC
Product: Brc1ccc2cc(-c3ccc4ccccc4c3)ccc2c1
Reaction time: 16 h
Yield: 68.7 %

Procedure:
Under an argon gas atmosphere, 246 g (860 mmol) of 2,6-dibromonaphthalene, 163 g (950 mmol) of 2-naphthalene boronic acid, 20 g (17.0 mmol) of tetrakis(triphenylphosphine)palladium(0), 3 L of dimethoxyethane (DME) and 1.5 L of 2M sodium carbonate solution were mixed, and stirred for 16 hours while being refluxed. After the completion of the reaction, precipitated crystal was separated by filtration. Then, the obtained solid was cleansed with water, methanol and hexane. The obtained solid was dried under reduced pressure, and 197 g of 2-bromo-6-(2-naphthyl)naphthalene was obtained at an yield of 69%.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)([CH3:3])[CH3:2].[C:10]([CH2:12][C:13]1([N:27]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]4[NH:38][CH:39]=[CH:40][C:33]=34)[CH:29]=[N:28]2)[CH2:16][N:15]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=2[F:26])[CH2:14]1)#[N:11].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CC(N)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:10]([CH2:12][C:13]1([N:27]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]4[NH:38][CH:39]=[CH:40][C:33]=34)[CH:29]=[N:28]2)[CH2:16][N:15]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:22])=[CH:19][C:18]=2[F:26])[CH2:14]1)#[N:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CN(c2ccc(C(=O)O)cc2F)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(C)N
Product: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (63 μL, 0.36 mmol) was added to a mixture of 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluorobenzoic acid (50.0 mg, 0.120 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (64 mg, 0.14 mmol) and 2-propanamine (11 mg, 0.18 mmol) in methylene chloride (10 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with aqueous NaHCO3, and extracted with dichloromethylene (2×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=458.1.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([Cl:23])=[CH:17][C:16]=3[F:24])=O)=[C:9]([CH2:25][CH2:26][CH3:27])[CH:8]=2)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([Cl:23])=[CH:17][C:16]=3[F:24])=[N:31]/[OH:32])=[C:9]([CH2:25][CH2:26][CH3:27])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(=O)c1cc(OC)c(Cl)cc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1/C(=N/O)c1cc(OC)c(Cl)cc1F
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A mixture of the product from Step 3 (1.4 g, 3.2 mmol), hydroxylamine hydrochloride (2.2 g, 32 mmol) and sodium acetate (2.6 g, 32 mmol) in ethanol (30 mL) was stirred in a sealed tube at 60° C. for 72 h. The precipitate was filtered off and the filtrate was concentrated. The residue was purified by chromatography on silica gel to give the oxime product.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:4][CH3:5])[CH3:2]>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH2:4]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[C:19]([C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:18][CH:17]=[N:16][CH:15]=3)[CH2:1][CH3:2])[CH3:5]
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCNC3
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3cnccc3c2c1-c1ccc(OC)c(OC)c1
Reaction time: 11.5 h
Yield: 30.8 %

Procedure:
A mixture of the compound obtained in Example 5A (10.16 g), activated manganese dioxide (30.93 g) and toluene (200 ml) was stirred under refluxing conditions for 11.5 hours. The reaction mixture was filtered; the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane-methanol (20:20:1, v/v) to yield ethyl 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)thieno[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below) (3.1 g, 31%), which was then recrystallized from ethyl acetate to yield colorless needle crystals having a melting point of 163 to 165° C. ##STR47##
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:18]2[CH2:23][NH:22][CH2:21][CH2:20][CH:19]=2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16].I[CH:25]([CH3:27])[CH3:26]>C(#N)C>[CH3:26][CH:25]([N:22]1[CH2:23][C:18]([C:11]2[CH:12]=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:9]([O:8][CH3:7])[CH:10]=2)=[CH:19][CH2:20][CH2:21]1)[CH3:27]
Reactant: COc1cc(C2=CCCNC2)ccc1[N+](=O)[O-]
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C2=CCCN(C(C)C)C2)ccc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a pressure vessel containing acetonitrile (40 mL) and potassium carbonate (4.0 g, 29.2 mmol) was added 5-[3-(methyloxy)-4-nitrophenyl]-1,2,3,6-tetrahydropyridine (1.7 g, 7.3 mmol) and 2-iodopropane (1.85 g, 10.9 mmol). The reaction was stirred at 85° C. overnight. After removal of the solvent under reduced pressure the residue was diluted with ethyl acetate (30 mL) and washed with water (40 mL). After partitioning and extraction of the aqueous layer (Ethyl acetate 2×15 mL), the organic layer was dried over sodium sulfate, filtered, concentrated and purified via chromatography on SiO2 to afford 1-(1-methylethyl)-5-[3-(methyloxy)-4-nitrophenyl]-1,2,3,6-tetrahydropyridine (1.6 g, 80% yield.) ESIMS (M+H)+=277.1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.CCN(CC)CC.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].C([O-])(O)=O.[Na+]>ClCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6][CH:7]=1
Reactant: Nc1ccc(I)cn1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(I)cn1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 106.3 %

Procedure:
5-Iodopyridin-2-amine (5 g, 22.7 mmol) was dissolved in 50 ml of dichloromethane and Et3N (6.3 ml, 45.5 mmol, 2 equiv.) was added at room temperature. The mixture was cooled to 0-5° C. and pivaloyl chloride (3.4 ml, 27.3 mmol, 1.2 equiv.) was added dropwise. The reaction mixture was stirred for 1 hour at 0-5° C. Saturated NaHCO3-solution was added and the mixture was extracted with dichloromethane. The organic extracts were dried with sodium sulfate, filtered and evaporated to dryness. The desired N-(5-iodopyridin-2-yl)pivalamide (7.34 g, 99.8% yield) was obtained as a brown oil, MS: m/e=305.0 (M+H+).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:42]=[CH:43][CH:44]=1)[CH2:7][O:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]1)=[O:3].[CH3:45][O:46][CH2:47][CH2:48][NH:49][CH3:50]>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][O:25][CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:14]2[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][CH:9]2[O:8][CH2:7][C:6]2[CH:42]=[CH:43][CH:44]=[C:4]([C:2](=[O:3])[N:49]([CH2:48][CH2:47][O:46][CH3:45])[CH3:50])[CH:5]=2)=[CH:16][CH:17]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(C(=O)Cl)c2)cc1
Reactant: CNCCOC
Product: COCCN(C)C(=O)c1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1

Procedure:
Analogously to Example 127a, 0.355 g tert-butyl 3-(3-chlorocarbonylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.106 g of 2-methoxy-N-methylethylamine are reacted. The title compound is obtained as a colourless oil. Rf=0.10 (1:1 EtOAc-heptane); Rt=5.65.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O.[F-:13].[K+]>C(#N)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([F:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)F)cc1

Procedure:
A 25.0 gm (0.13 mole) portion of p-toluenesulfonyl chloride was dissolved in 100 ml of acetonitrile and combined in a 250 ml round bottom flask with 25.0 ml of water containing 1.5 gm (0.196 mole) of potassium fluoride. This mixture was stirred and heated under reflux for one hour. Acetonitrile was then removed under reduced pressure in a rotary evaporator. This resulted in crystallization of p-toluenesulfonyl fluoride which was removed by filtration, washed twice with water, and dried, giving 20.7 gm (91% yield) of product with mp 41°-41.2° C; (literature is 41°-42° C; W. Davies and J. H. Dick, J. Chem. Soc., 2104, 1931). The NMR and IR spectra were in agreement with the assigned structure.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH:19]2[O:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[O:21][CH2:20]2)[CH2:13]1)=O)C.O>C1COCC1>[O:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[O:21][CH2:20][CH:19]1[CH2:18][N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([CH2:10][OH:9])[CH2:13]1
Reactant: CCOC(=O)C1CCCN(CC2COc3ccccc3O2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CCCN(CC2COc3ccccc3O2)C1

Procedure:
To a suspension of LiAlH4 (0.11 g, 2.78 mmol) in dry THF (1 ml) was added 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine-3-carboxylic acid ethyl ester (0.17 g, 0.55 mmol) in dry THF (10 ml). The reaction mixture was refluxed for 2 h. Water was slowly added under cooling and the reaction mixture was extracted with EtOAc (3×20 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:11]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([C:23]([C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)=[O:24])=[CH:16]2)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC(C1C(OC)=CC=C2C=1C=CC(C(C1N=CN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=1)=O)=C2)C)([C:33](C)([CH3:35])[CH3:34])(C)C.Cl.N1C=CC=CC=1>CO>[Si:1]([O:8][CH:9]([C:11]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([C:23]([C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)([OH:24])[CH:33]([CH3:35])[CH3:34])=[CH:16]2)[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COc1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1C(C)O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc2cc(C(=O)c3c[nH]cn3)ccc2c1C(C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1C(C)O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Production of [5-[1-(tert-Butyldimethylsilyloxy)-ethyl]-6-methoxynaphthalen-2-yl]-(1H-imidazol-4-yl)ketone. [5-[1-(tert-butyldimethylsilyloxy)ethyl]-6-methoxynaphthalen-2-yl]-(1-trityl-1H-imidazol-4-yl)ketone (5.18 g) and pyridine hydrochloride (1.59 g) were dissolved in methanol (50 ml). The solution was stirred at 50° C. for 1 h. The reaction mixture was concentrated, and water and ethyl acetate were added. The organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate and saturated sodium chloride solution, dried and concentrated. The obtained residue was washed with ether to give the titled compound (2.71 g) as a colorless solid.
Reaction SMILES: C1(S[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH:18]([N:20]([OH:24])[C:21]([NH2:23])=[O:22])C)[CH:9]=2)C=CC=CC=1.C(O)(=O)C1C(=CC=CC=1)S.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>>[N:10]1([CH2:17][CH2:18][N:20]([OH:24])[C:21]([NH2:23])=[O:22])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: CC(Cn1cc(Sc2ccccc2)c2ccccc21)N(O)C(N)=O
Agent: O=C(O)c1ccccc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)N(O)CCn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-[1-(3-phenylthioindol-1-yl)prop-2-yl]-N-hydroxy urea from Example 3 (100 mg, 0.34 mmol), thiosalicylic acid (208 mg, 1.4 mmol) and trifluoroacetic acid (3 mL) was stirred at r.t. for one hour. The reaction mixture was then poured onto an aqueous saturated NaHCO3 solution and extracted with EtOAc. The combined organic phase was then washed with 1N NaOH, brine, dried and evaporated to dryness. Separation of two products by flash chromatography using 90% EtOAc in hexanes gave the N-[2-(indol-1-yl)eth-1-yl]-N-hydroxy urea, m.p.: 150°-152° C., and the N-[2-(2-phenylthioindole-1-yl)eth-1-yl]-N-hydroxy urea, m.p.: 57°-60° C.
Reaction SMILES: [F:1][C@@H:2]1[CH2:19][C@@:18]2([CH3:20])[C:5]([C:6]([O:22]C)=[CH:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[OH:21])=[CH:4][C:3]1=[O:24]>C1COCC1.Cl>[F:1][C@@H:2]1[CH2:19][C@@:18]2([CH3:20])[C:5]([C:6](=[O:22])[CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[OH:21])=[CH:4][C:3]1=[O:24]
Reactant: COC1=C[C@H]2[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]2[C@@]2(C)C[C@@H](F)C(=O)C=C12
Agent: Cl
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC(=O)C4=CC(=O)[C@H](F)C[C@@]43C)[C@@H]1CC[C@@H]2O
Yield: 101 %

Procedure:
To a solution of 2α-fluoro-6-methoxy-17β-hydroxyandrosta-4,6-dien-3-one (610 mg) in THF (10 ml), 3N HCl (2 ml) was added and the mixture refluxed for 1 h. After cooling, Na2HPO4 5% was added and the reaction mixture was extracted with EtOAc. The organic phase was washed with H2O and brine, dried over Na2SO4 and evaporated to dryness. The crude reaction mixture was purified by flash chromatography (SiO2, n-hexane/DCM/acetone 5/3/2) to give 2α-fluoro-17β-hydroxyandrost-4-en-3,6-dione (590 mg, 84% yield).