Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].C(N(CC)CC)C.[CH2:20]([NH2:23])[CH:21]=[CH2:22]>ClCCl>[CH2:20]([NH:23][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH:21]=[CH2:22]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: C=CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 2 °C
Reaction time: 16.5 h
Yield: 90.8 %

Procedure:
Step 1′ A 2-L, three-necked, round-bottomed flask equipped with a magnetic stirring bar, a 24/40 adapter fitted with a thermometer, an argon inlet adapter, and a 250-mL pressure-equalizing addition funnel fitted with a glass stopper was purged with argon. The flask was charged with 3-nitrobenzoyl chloride (J) 112.0 g (0.6035 mol) and 850 mL of dichloromethane, and then cooled with an ice-water bath. The addition funnel was charged with triethylamine 93.0 mL (0.667 mol) and allylamine (K) 50.0 mL (0.666 mol), and this solution was then added dropwise to the reaction mixture over ca. 2.5 h while the reaction temperature was maintained at 0-4° C. The addition funnel was then rinsed with two 5-mL portions of dichloromethane. The resulting turbid pale orange-pink reaction mixture was allowed to slowly warm to and stir at room temperature. After 16.5 h, 600 mL of 1N HCL was added to the turbid bright yellow solution over 30 sec and the biphasic mixture was transferred to a separatory funnel. The reaction flask was rinsed with three 100-mL portions of 1:1 CH2Cl2: 1N HCl and the organic phase was separated and washed with 500 mL of saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 122 g (98% crude yield) of a pale yellow solid. The crude product was recrystallized from 450 mL of toluene to afford 113 g (91 % yield) of N-allyl-3-nitrobenzamide (L) as a powdery pale yellow solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@:7]([Cl:28])([C@H:8]([Cl:27])[CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.[F:33]C(F)(F)C([O-])=O.[Na+].FF>FC(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@:7]([Cl:28])([C@H:8]([Cl:27])[CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@@:11]3([F:33])[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)=O)CC[C@H]4[C@@H]3C[C@@H](Cl)[C@@]2(Cl)C1
Agent: FF
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: FC(Cl)(Cl)Cl
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)=O)CC[C@@]4(F)[C@@H]3C[C@@H](Cl)[C@@]2(Cl)C1

Procedure:
3β-Acetoxy-5α,6β-dichloropregnan-20-one (1.4g) was dissolved in fluorotrichloromethane (250 ml) and chloroform (200 ml) containing sodium trifluoroacetate (ca. 2g) and sodium fluoride (ca. 2g). The resulting solution was cooled to -78° and vigourously stirred, whereupon fluorine from four 750 cc bottles (10% v/v fluorine in nitrogen) was bubbled through the solution over a period of 8 hours. The reaction solution was then poured into aqueous sodium thiosulphate and the organic layer was separated, washed with water, dried over potassium carbonate and evaporated to dryness to yield crude 3β-acetoxy-5α,6β-dichloro-14α-fluoropregnan-20-one.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:22]([O:26][C:27](=[O:36])[NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])([CH3:25])([CH3:24])[CH3:23]>ClCCl.C(OCC)C.CCCCC>[C:22]([O:26][C:27](=[O:36])[NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[O:35])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCCCCCO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCCCC
Product: CC(C)(C)OC(=O)NCCCCCC=O
Reaction time: 24 h
Yield: 79.9 %

Procedure:
Pyridinium dichromate (13.5 g, 0.036 mol) is added to a solution of t-butyl-(6-hydroxyhexyl)carbamate (5.88 g, 24 mmol) in dichloromethane (40 ml). After stirring for 24 hours, the reaction mixture is diluted with diethylether/pentane (1:1), filtered through Florisil and concentrated to yield t-butyl-(5-formylpentyl)carbamate (4.13 g, 80%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Li])CCC.[Br-].[Mg+2].[Br-].[Br:24][C:25]1[CH:26]=[C:27]([CH:30]=[O:31])[S:28][CH:29]=1>O1CCCC1.CCCCCC.ClCCl>[Br:24][C:25]1[CH:26]=[C:27]([CH:30]([OH:31])[C:2]2[CH:15]=[CH:14][CH:13]=[C:4]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:3]=2)[S:28][CH:29]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(O)c2cc(Br)cs2)c1
Temperature: -78 °C
Yield: 48.2 %

Procedure:
3-Bromophenoxy-tert-butyldimethylsilane (30.2 g, 0.105 mol), prepared as in Example 1, was dissolved in 300 mL of dry tetrahydrofuran under nitrogen and cooled to -78° C. A solution of 1.6M n-butyllithium in hexane (66 mL, 0.105 mol) was added dropwise at a rate to maintain a temperature below -65° C. The reaction was stirred for thirty minutes after the addition was complete and the cold solution was transferred to another vessel containing a room temperature solution of magnesium bromide (20.2 g, 0.11 mol) in 400 mL of dry tetrahydrofuran under nitrogen. The resulting solution was allowed to warm to 15° C. while stirring. After one hour a solution of 4-bromo-2-thiophenecarboxaldehyde (20.0 g, 0.105 mol) in 100 mL of dry tetrahydrofuran was added slowly at a rate to maintain a temperature below 25° C. The resulting solution was stirred for three hours at room temperature, then washed three times with aqueous ammonium chloride, dried over sodium sulfate and evaporated to give a yellow oil. Chromatography on silica gel with dichloromethane:hexane/50:50 gave 20.23 g (48.2%) of α-(4-bromo-2-thienyl)-3-((tert-butyldimethylsilyl)-oxy)benzyl alcohol as a viscous yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:51]=[CH:50][C:32]([CH2:33][N:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=[C:35]2[NH:43][CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C.C(N(CC)CC)C>C(#N)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:47]2[CH2:48][CH2:49][CH:44]([NH:43][C:35]3[N:34]([CH2:33][C:32]4[CH:50]=[CH:51][C:29]([F:28])=[CH:30][CH:31]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:45][CH2:46]2)([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: CS(=O)(=O)OCCC1(Cc2ccccc2)CCN(Cc2ccccc2)C1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: O=C1N(Cc2ccccc2)CCC1(CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)Cc1ccccc1
Reaction time: 12 h

Procedure:
Combine 1-benzyl-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.99 g, 2.57 mmol), (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.80 g, 2.57 mmol), and N,N-diisopropylethylamine (0.73 g, 5.65 mmol) in acetonitrile (37 mL). Heat to reflux. After 12 hours, cool and partition the reaction mixture between dichloromethane and water. Separate the layers and extract the organic layer with brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on a short column of silica gel eluting with 2% triethylamine/10% methanol/ethyl acetate to give a residue. Partition the residue between dichloromethane and brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give the title compound: Rf=0.22 (silica gel, 2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[F:12].[CH3:13][OH:14]>C1(C)C=CC=CC=1.[Ag-]=O>[F:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][O:14][CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Reactant: CO
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: COCc1cc([N+](=O)[O-])ccc1F
Temperature: 60 °C

Procedure:
30 g (128 mmol) of the compound from example 26A are dissolved in 1.3 l of anhydrous toluene and admixed with 45 g (192 mmol) of silver(I) oxide and 24.6 g (769 mmol) of anhydrous methanol. The mixture is heated to 60° C. for 16 h. It is then allowed to cool and filtered through silica gel. The product is fractionally eluted with a gradient of cyclohexane and 25:1 cyclohexane/ethyl acetate. The product fractions are concentrated to dryness under reduced pressure and dried under reduced pressure. This affords 17 g (72% of theory) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH:5]=[CH:6]C(O)=O.C([N:16]([CH2:19]C)CC)C.ClC(OCC)=[O:23].[N-]=[N+]=[N-].[Na+]>CC(C)=O.O.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:19](=[O:23])[NH:16][CH:6]=[CH:5]2
Reactant: CCN(CC)CC
Reactant: Cc1ccc(C=CC(=O)O)cc1F
Reactant: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: Cc1cc2c(=O)[nH]ccc2cc1F
Temperature: 150 °C
Yield: 41.7 %

Procedure:
To a solution of 10.0 g (55.5 mmol) of 3-fluoro-4-methyl-cinnamic acid in 80 ml of acetone were subsequently added at 0° C. 6.74 g (66.6 mmol) of triethylamine in 10 ml of acetone followed by 7.83 g (72.2 mmol) of ethyl chloroformate. After stirring for 2 h at 0 to 5° C. a solution of 4.0 g (61.1 mmol) of sodium azide in 9.5 ml of water was added. After stirring for 1 additional h the reaction mixture was poured onto 200 ml of ice water and extraced twice with chloroform. The organic phase was dried over magnesium sulfate, 40 ml diphenylether were added and the chloroform was cautiously removed in vacuo. The residue was then added dropwise into 50 ml of diphenylether, which had been preheated to 245° C. After complete addition it was stirred further for 1 h at 230-250° C. After cooling down to 150° C. the reaction mixture was poured into 270 ml of heptane and after further cooling in an ice bath the precipitated product was filtered by suction and 4.1 g 6-fluoro-7-methyl-2H-isoquinolin-1-one were obtained.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:13]([OH:16])([OH:15])=[O:14])([P:9]([OH:12])([OH:11])=[O:10])[OH:8])[CH:2]=1.CN(C=O)C.[OH-].[Na+:23].O>CO>[CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:9]([O-:12])([O-:11])=[O:10])([P:13]([O-:15])([OH:16])=[O:14])[OH:8])[CH:2]=1.[Na+:23].[Na+:23].[Na+:23]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: O=P([O-])([O-])C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C
Yield: 84 %

Procedure:
A 250 ml flask was loaded with Zoledronic acid form XII (5.0 g), Sodium hydroxide (1.4 g), Methanol (50 ml) and water (2.5 ml) [=5% v/v water in Methanol]. The reaction mixture was heated to reflux temperature for 22 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with Methanol (2×50 ml) and dried in a vacuum oven at 50° C. for 24 hours to give 5.4 g (84%) of Zoledronate trisodium crystal form XI in a mixture with crystal form IX (LOD by TGA=10.5%).
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:13]([OH:16])([OH:15])=[O:14])([P:9]([OH:12])([OH:11])=[O:10])[OH:8])[CH:2]=1.CN(C=O)C.[OH-].[Na+:23].O>C(O)C>[CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:9]([O-:12])([O-:11])=[O:10])([P:13]([O-:15])([OH:16])=[O:14])[OH:8])[CH:2]=1.[Na+:23].[Na+:23].[Na+:23]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: O=P([O-])([O-])C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C
Yield: 86 %

Procedure:
A 250 ml flask was loaded with Zoledronic acid form XII (5.0 g), Sodium hydroxide (1.4 g), absolute Ethanol (50 ml) and water (2.5 ml) [=5% v/v water in Ethanol]. The reaction mixture was heated to reflux temperature for 20 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with absolute Ethanol (2×25 ml) and dried in a vacuum oven at 50° C. for 24 hours to give 5.4 g (86%) of Zoledronate trisodium crystal form XI (LOD by TGA=8.9%).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:8]1(O)[CH2:13][CH2:12]C[CH2:10][CH2:9]1>C([Sn](=O)CCCC)CCC.CO>[C:1]([O:6][CH:7]1[CH2:12][CH2:13][CH2:8][CH2:9][CH2:10]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC
Reactant: OC1CCCCC1
Agent: CCCC[Sn](=O)CCCC
Solvent: CO
Product: C=C(C)C(=O)OC1CCCCC1
Yield: 62.8 %

Procedure:
Using a reflux apparatus equipped with a 20-plates Oldershaw column as the distillation column, a 3-liter four-necked flask with a side arm was charged with 1,401 g (14 moles) of methyl methacrylate, 701 g (7 moles) of cyclohexanol, 12.6 g of dibutyltin oxide, and 1.18 g (corresponding to 0.1% of the theoretical yield of the product) of IB as a polymerization inhibitor. This mixture was subjected to an ester exchange reaction. The methanol formed as a by-product during reaction was removed from the system together with the methyl methacrylate. The resulting reaction product was purified by simple distillation using an empty column having a length of 20 cm, so that 740 g of cyclohexyl methacrylate was obtained. During the course of the reaction and distillation, polymerization occurred neither in the reactor nor the column. The cyclohexyl methacrylate thus obtained had a color number (APHA) of not greater than 5.
Reaction SMILES: Cl.[C:2]1([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17](OC(C)=O)=[O:18]>C(Cl)Cl>[C:8]([CH:10]1[CH2:15][CH2:14][N:13]([C:17](=[O:18])[CH3:16])[CH2:12][CH2:11]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(c1ccccc1)C1CCNCC1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of phenyl(piperidin-4-yl)methanone hydrochloride (743 mg, 3.29 mmol, Apollo Scientific) in DCM (13.2 mL) and TEA (1.10 mL, 7.90 mmol) was treated with Ac2O (0.373 mL, 3.95 mmol) dropwise over 1 min on an ice bath under argon, and the resulting translucent mixture was immediately removed from the ice bath and stirred at room temperature overnight. The reaction was then partitioned with 1 M HCl (1×8 mL) and 1 M NaOH (1×8 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated to provide the title compound as a translucent beige oil that crystallized upon standing.
Reaction SMILES: C1COCC1.[NH:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.C1C=CC2N(O)N=NC=2C=1.[NH:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:33]([C:35](O)=[O:36])[CH3:34]>CN(C=O)C>[NH:32]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[C@H:33]([C:35]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:36])[CH3:34]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
THF (200 ml), H-Pro-OBzl.HCl (48.3 g, 0.2 M) and HOBT (27.0 g, 0.2 M) were added to BOC-Ala-OH (37.8 g, 0.2 M); DMF (100 ml) was added, and WSCI (36.6 ml, 0.2 M) was added dropwise at 0° C. After stirring at 0° C. for one hour and at room temperature overnight, the solvent was distilled off in vacuo. The residue was dissolved in ethyl acetate (500 ml), washed three times with 5% sodium bicarbonate solution, three times with 1 N HCl and three times with water, in that order, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in a small amount of benzene and charged on a column of silica gel (250 g) packed with benzene. Elution was carried out with benzene (1 l.), benzene-ethyl acetate (10:1) (1 l.) and benzene-ethyl acetate (1:1) (1 l.), and the corresponding fractions were collected and checked by TLC and concentrated in vacuo to obtain the oily substance [24] (75.55 g, yield: 100%).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[C:7]([CH3:22])[C:6](=[O:23])[CH2:5][CH2:4]2.[C:24]([O:27]C(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([OH:27])(=[O:26])[CH3:25].[OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[C:7]([CH3:22])[C:6](=[O:23])[CH2:5][CH2:4]2
Reactant: CC(=O)OC(C)=O
Agent: CC1=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(CO)CCC1=O
Solvent: c1ccncc1
Product: CC(=O)O

Procedure:
19-Hydroxy-4-methyl-4-androstene-3,17-dione is stirred under nitrogen with acetic anhydride and pyridine for about 16 hours. The yellow solution is poured onto water and the precipitate collected by suction filtration and washed well with water. Crystallization from acetone-hexane yield the desired 19-hydroxy-4-methyl-4-androstene3,17-dione acetate.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[CH:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[C:22][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
Iodobenzene (135 μl, 1.2 mmols), 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (209 mg, 1 mmols) and triethylamine (167 μl, 1.2 mmols) were dissolved in acetonitrile (6 ml). Dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmols) and Cul (10 mg, 0.05 mmols) were added, and reaction mixture was stirred at room temperature overnight and continued to stir at 50 C. for two more hours before partitioning between ethyl acetate and water. Organic layer was isolated, washed with 1 N HCl, brine and dried (MgSO4). Solvents were removed and residue was purified by column chromatography on silica gel using solutions of ethyl acetate in hexanes (1:4; 1:2) to yield the title compound (74 mg). LCMS m/e (230, M−t-Bu+2H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl>[Br:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1
Reactant: Cc1ccnc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: Fc1cc(CBr)ccn1
Temperature: 25 °C
Yield: 21.1 %

Procedure:
A solution of 2-fluoro-4-methylpyridine (0.5 g) in chloroform (50 ml) was treated with N-bromosuccinimide (1.35 g) and azobisisobutyronitrile (0.25 g). The mixture was heated at reflux for 30 hours, cooled to room temperature and washed with water (30 ml). The chloroform solution was evaporated and the resulting brown oil purified by flash chromatography on silica eluting initially with a mixture of ethyl acetate and pentane (1:9, v/v) then with a mixture of ethyl acetate and pentane (15:85, v/v). Fractions homogenous in the required product were combined and evaporated affording the title compound (0.18 g) as a yellow oil.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:5][C:6]1[CH:11]=[C:10]([CH2:12][Br:13])[CH:9]=[CH:8][N:7]=1
Reactant: Cc1ccnc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccn1
Temperature: 50 °C
Reaction time: 16 h
Yield: 33.2 %

Procedure:
0.073 ml of acetic acid is added to a solution of 0.111 g of 2-fluoro-4-methylpyridine in 2.5 ml of carbon tetrachloride, under an inert atmosphere of argon at a temperature in the region of 20° C. The mixture is brought, with stirring, to a temperature of 50° C. 0.356 g of N-bromosuccinimide and 0.048 g of benzoyl peroxide are successively added at this temperature. The mixture is brought to 80° C. over about 16 hours. After cooling, the reaction medium is placed on a cartridge 20 mm in diameter packed with 10 g of 20-40 μm silica not conditioned beforehand, and then eluted with dichloromethane at a flow rate of 5 ml/minute. The fractions between 28 and 38 ml are concentrated to dryness under reduced pressure. 0.063 g of 2-fluoro-4-(bromomethyl)pyridine is thus obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2([C:14]#[N:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N#CC1(c2ccc(Cl)cc2)CCNCC1
Reaction time: 20 h

Procedure:
To a solution of 4-(4-chlorophenyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester (1.000 g, 3.12 mmol) in methanol (5 ml) at rt was added 4M HCl in dioxane (15 ml). After stirring for 20 h the solution was concentrated to give the deprotected amine as the hydrochloride salt (0.785 g, 98%). LC-MS (LCT2) m/z 221 [M+H4], Rt 2.84 min.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([OH:11])[CH:9]=[CH2:10].C(N(CCCC)CCCC)CCC.CCCCCCCCCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:2]1([CH2:10][CH2:9][CH:8]=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCO
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCN(CCCC)CCCC
Product: O=CCCc1ccccc1
Yield: 62 %

Procedure:
0.1 g Palladium acetate, 10.2 g iodobenzene, 4.4 g allyl alcohol, 9.3 g tributylamine were heated together with 20 ml diphenyl ether as solvent and 2 g tridecane as internal standard. After 45 minutes at 135° the iodobenzene was 91% reacted to produce 62% 3-phenylpropanal and 13% hydratropic aldehyde based on conversion.