Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([N:20](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[CH2:16][CH2:15]3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.CO>C(O)C.[OH-].[Pd+2].[OH-]>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:8]([O:13][C@H:14]3[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16][CH2:15]3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:5][CH2:6]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)[C@H]2CC[C@H](Oc3nccnc3C3=CCOCC3)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: N[C@H]1CC[C@H](Oc2nccnc2C2CCOCC2)CC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Palladium hydroxide (0.040 g, 0.057 mmol, 20 weight % on carbon) was added to a stirred mixture of trans-4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)-N,N-bis(4-methoxybenzyl)cyclohexanamine (0.40 g, 0.77 mmol) in ethanol (4 mL). The reaction mixture was placed under a hydrogen atmosphere (balloon) and stirred at 50° C. for 18 h. Additional palladium hydroxide (0.040 g) and methanol (1 mL) were added, and the reaction mixture was stirred at 50° C. for an additional 5 h. The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was purified via silica gel chromatography to give trans-4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)cyclohexanamine as a colorless oil.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=1[F:15])=[O:4].[C:18]([O:22][C:23]([N:25]1[C:36]2[C:28](=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32]C(C(O)=O)=[CH:30]3)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>>[C:18]([O:22][C:23]([N:25]1[C:36]2[C:28](=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:2]([C:3]([O:5][C:6]2[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=2[F:15])=[O:4])=[CH:30]3)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCc2c1ccc1[nH]c(C(=O)O)cc21
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2c1ccc1[nH]c(C(=O)Oc3c(F)c(F)cc(F)c3F)cc21
Reaction time: 4 h
Yield: 75 %

Procedure:
2,3,5,6-Tetrafluorophenyl trifluoroacetate (2.6 g, 10 mmol) was added dropwise to a solution of 3-(tertbutyloxycarbonyl)-1,2-dihydro-3H-pyrrolo (3,2-e]indole7-carboxylic acid (1.0 gi 3.7 mmol, D. L. Boger, R. S. Coleman, and B. J. Invergo. J. Org. Chem., 1987, Vol. 52, 1521-1530) and triethylamine (1.5 ml, 10 mmol) in 10 ml of anhydrous CH2cl2. After 4 hrs, CH2cl2 was removed by evaporation at reduced pressure. Flash chromatography (4×2O cm, hexane-ethyl acetate, 1:2) afforded 1b as a yellow crystalline solid (1.25 gr 75%): 1H NMR (Me2SO-d6, 200 MHz, ppm) 12.39 (d, 1H, J=1.4 Hz; NH), 8.02 (m, 1H, C6F4H), 7.9 (br s, 1H, C4H) i, 7.45 (d, 1Hj, J=1.4 Hz, C8-H), 7.33 (d, 1H, J=9 Hz, C5-H), 4.02 (t, 2H, J=9 Hz, NCH2CH2), 3.26 (t, 2H, J=9 Hz, NCH2CH2 2)″ 1.51 (s, 9H, C(CH3)3). Anal. Calcd. for C22H18N204F4: C, 58.67; HI 4.03; N, 6.22. Found: C, 58.45; HI 4eO9; N, 6*13a
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][C:9]=2[CH3:21])=[CH:4][CH:3]=1.[OH-].[NH4+].[H][H]>[Pd].C(O)C>[CH3:21][C:9]1[CH:10]=[C:11]([NH:14][NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:12]=[N:13][C:8]=1[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CCOC(=O)NNc1cc(C)c(-c2ccc(Br)cc2)nn1
Reactant: [H][H]
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)NNc1cc(C)c(-c2ccccc2)nn1

Procedure:
A 4.0 g. portion of ethyl 3-[6-(p-bromophenyl)-5-methyl-3-pyridazinyl]carbazate and 0.9 g. of 10% palladium on carbon catalyst in 100 ml. of ethanol and 50 ml. of ammonium hydroxide is shaken under 40 lb. of hydrogen pressure for 4 hours with external heating of the bottle by means of a heated jacket. The reaction mixture is suction filtered and the filtrate is concentrated to a light yellow oil which is scratched with petroleum ether to give a white solid, m.p. 142°-145° C.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9](Br)=[CH:8][N:7]=2)[N:3]=[CH:4][CH:5]=1.C[Sn](C)(C)[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][C@H:24]([CH2:26][C:27](=[O:31])[C:28]([NH2:30])=[O:29])[O:23][CH2:22]2)=[CH:17][C:16]=1[F:32]>>[N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:25][C@H:24]([CH2:26][C:27](=[O:31])[C:28]([NH2:30])=[O:29])[O:23][CH2:22]4)=[CH:17][C:16]=3[F:32])=[CH:8][N:7]=2)[N:3]=[CH:4][CH:5]=1
Reactant: Brc1ccc(-n2nccn2)nc1
Reactant: C[Sn](C)(C)c1ccc(N2CO[C@@H](CC(=O)C(N)=O)C2)cc1F
Product: NC(=O)C(=O)C[C@H]1CN(c2ccc(-c3ccc(-n4nccn4)nc3)c(F)c2)CO1

Procedure:
The same procedure as in Example 1 was conducted, except for adding 2-([1,2,3]triazol-2-yl)-5-bromopyridine and using (S)-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl acetamide as a starting material, to obtain the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:20]([OH:22])=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[NH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1>>[NH:29]1[C:28]([NH:27][C:20]([C:7]2[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[N:8]=2)=[O:22])=[N:32][N:31]=[N:30]1
Reactant: CCCCc1cc(C(=O)O)nc(-c2ccc([N+](=O)[O-])cc2)c1
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Product: CCCCc1cc(C(=O)Nc2nnn[nH]2)nc(-c2ccc([N+](=O)[O-])cc2)c1
Yield: 55.8 %

Procedure:
In the same manner as described in Example 13-(1), 4-n-butyl-6-(4-nitrophenyl)-2-pyridinecarboxylic acid (1.7 g), thionyl chloride (15 ml) and 5-aminotetrazole (0.67 g) are reacted to give N-(5-tetrazolyl)-4-n-butyl-6-(4-nitrophenyl)-2-pyridinecarboxamide (1.16 g). M.P. 278°-280° C. (decomp.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: [C:1]([OH:20])(=[O: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(=O)([O-])[O-].[K+:25].[K+]>>[C:1]([O-:20])(=[O: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].[K+:25]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]

Procedure:
To demonstrate the ability to obtain useful aqueous compositions wherein the anionic surface active agent is formed in situ, an aqueous dispersion containing 1.86 percent kerosene, 0.14 percent commercial oleic acid, and 2 percent potassium carbonate was prepared. The amount of oleic acid was calculated to provide approximately 0.16 weight percent potassium oleate. Alfalfa treated with the resulting dispersion dried to a 25 percent moisture content in 22.4 hours whereas the control (alfalfa treated with water only) required 47.25 hours to reach the same moisture level. This represents a 53 percent reduction in drying time.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[CH2:22](O)[C:23]#[CH:24].S(=O)(=O)(O)O>O>[CH2:24]([O:12][C:11](=[O:13])[CH2:10][CH2:9][C:8]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:14])[C:23]#[CH:22]
Reactant: C#CCO
Reactant: CC(CCC(=O)O)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: C#CCOC(=O)CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 41 %

Procedure:
A mixture of 21.2 grams of 4,4-bis(4-hydroxyphenyl)pentanoic acid, 50 ml. of propargyl alcohol and 0.3 ml. of concentrated sulfuric acid was stirred at room temperature for 40 hours. The mixture was then poured into 500 ml. of water, with stirring. The oily layer was allowed to settle and the aqueous layer was removed by decantation. The oily layer was washed with water two additional times. Finally, 500 ml. of water containing 10 grams of sodium bicarbonate was added to the oily layer, the product was extracted from the mixture into ether and chromatographed on a silica column (using 10/90 acetone/toluene, by volume, eluent) to give 96.9 grams (41%) of white solid, m.p. 99.5°-101.0° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:10][C:9]1[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[O:7][CH3:8]
Reactant: ClCCCCCBr
Reactant: COc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)ccc1OCCCCCCl

Procedure:
A mixture of 59.7 g (0.36 mole) of acetovanillone, 100 g (0.539 mole) of 1-bromo-5-chloropentane and 138 g (1 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure to give an oil which crystallized in petroleum ether (30°-60° C.). The solid was collected by filtration, washed with petroleum ether and dried to yield 81.4 g (84%) of fluffy, white solid. The solid was recrystallized from isopropyl ether, m.p. 57°-58° C.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:11]([O:13][C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:12].C(NC(C)C)(C)C.C([Li])CCC>>[CH2:11]([O:13][C:14](=[O:19])[CH:15]([C:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1)[CH:16]([CH3:18])[CH3:17])[CH3:12]
Reactant: CCOC(=O)CC(C)C
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(=O)c1cccnc1)C(C)C
Yield: 44 %

Procedure:
Nicotinic chloride hydrochloride (0.9 g), isovaleric acid ethyl ester (2.3 ml), diisopropylamine (2.1 ml) and butyllithium (1.6M hexane solution, 9.4 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 8(a) to obtain the title compound (0.78 g, 44%) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][Cl:25])=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20]
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1cc(CCl)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To the solution of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-(hydroxymethyl)benzonitrile (500 mg, 1.526 mmol) in DCM (30 mL), was added thionyl chloride (1.671 mL, 22.89 mmol) dropwise. The mixture was stirred at room temperature for 2 h. After removing the solvent, the residue was dissolved in DCM, then washed with water twice, dried over Na2SO4, concentrated and purified via flash chromatography to afford the title compound (479 mg, 89% yield) as a white solid. LCMS: rt=3.45 min
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1.N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O>C1(C)C(C)=CC=CC=1>[Cl:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH:3]([OH:11])[CH2:2][NH:1][C:16]1[NH:20][CH2:19][CH2:18][N:17]=1
Reactant: O=[N+]([O-])NC1=NCCN1
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: Cc1ccccc1C
Product: OC(CNC1=NCCN1)c1cccc(Cl)c1

Procedure:
A mixture of 9.5 parts of α-(aminomethyl)-m-chlorobenzyl alcohol, 7.15 parts of 2-(nitramino)-2-imidazoline and 40 parts of xylene is stirred in an oil-bath at 150°-160°C. while a great part of the xylene is distilled off. The resulting residue is diluted with a few parts of acetone and the product is allowed to crystallize. It is filtered off and crystallized from 4-methyl-2-pentanone, yielding m-chloro-α-(2-imidazolin-2-ylaminomethy)benzyl alcohol; m.p. 108.5°C.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:15](=[S:17])[NH2:16])[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O.C(O)(C)C>C(N(CC)CC)C>[CH2:18]([N:3]([CH2:1][CH3:2])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:15]3[S:17][CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:16]=3)[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:19]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCN(CC)c1ccc2cc(C(N)=S)c(=O)oc2c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCN(CC)c1ccc2cc(-c3nc(-c4ccccc4)cs3)c(=O)oc2c1
Yield: 80.6 %

Procedure:
8.3 parts of 7-diethylamino-3-thiocarbamoylcoumarin and 7 parts of ω-bromo-acetophenone in 30 parts by volume of isopropyl alcohol are boiled with 3 parts of triethylamine for 1 hour. The precipitate is filtered off and washed with isopropyl alcohol and water. 9.1 parts (80.6% of theory) of 7-diethylamino-3-(4-phenylthiazol-2-yl)-coumarin of melting point 127°-130° C. are obtained.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1[CH:10]=[C:9]([CH3:11])[NH:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:17](Cl)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>O.ClCCl>[C:17]([C:10]1[C:6]([CH3:5])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8][C:9]=1[CH3:11])(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)c1c(C)[nH]c(C(=O)OCC)c1C

Procedure:
1.46 g (11 mmol) of AlCl3 were added to a solution of 1.67 g (10 mmol) of ethyl 3,5-dimethylpyrrole-2-carboxylate a 2.63 g (12 mmol) of dodecanoyl chloride in 30 ml of absol. Dichloromethane and then stirred for 24 h. Addition of water and dilute HCl is followed by extraction twice with CH2Cl2. The organic phases are washed with dilute NaOH, dried over Na2SO4 and concentrated. The product is recrystallized from isopropanol.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.[SH:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].N12CCCN=C1CCCCC2>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:4]1[N:3]=[C:2]([S:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NCCSc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12

Procedure:
tert-Butyl (2-{[7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl]thio}ethyl)carbamate (Example 44A) is synthesized in analogy to the preparation of Example 42A from 5-chloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidine (Example 6A) (500 mg, 1.7 mmol), tert-butyl (2-mercaptoethyl)carbamate (445 mg, 2.5 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (382 mg, 2.5 mmol). The crude product is purified by flash chromatography (eluent: cyclohexane/ethyl acetate), and 422 mg (93% of theory) of the product are obtained after evaporation of the solvent.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[C:9]1=[N:10][NH:11][C:12]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[C:8]1[CH2:7]2.C(NC(C)C)(C)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]>C1COCC1>[CH:37]([O:36][C:34]([N:10]1[C:9]2[C:21]3[C:6]([CH2:7][C:8]=2[C:12]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[N:11]1)=[CH:5][C:4]([O:3][CH3:2])=[C:23]([O:24][CH3:25])[CH:22]=3)=[O:35])([CH3:39])[CH3:38]
Reactant: COc1cc2c(cc1OC)-c1n[nH]c(Nc3cccc(F)c3)c1C2
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc2c(cc1OC)-c1c(c(Nc3cccc(F)c3)nn1C(=O)OC(C)C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine HCl (Compound 14) (0.50 g, 0.0014 mole), THF (10 mL), and Diisopropyl amine (0.512 mL, 0.00295 mole) was stirred until the solid completely dissolved. Isopropyl chloroformate (1.5 mL, 0.0015 mole) was added slowly at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo from the resulting organics. Attempt to separate resulting isomers with reverse-phase chromatography was not successful. Placed isomer containing fractions in refrigerator. Much of major isomer crystallized. Filtered white crystals of title compound from solution (Compound 436). MS m/z 412 (M+H)+;
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=O)[CH2:3]1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14].O>CN(C=O)C>[CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[N:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3]1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(=NNC(=O)OC(C)(C)C)CC(C)(C)C1

Procedure:
3,3,5,5-Tetramethylcyclohexanone (7.7 g, 0.05 moles) was dissolved in DMF (50 mL) and t-butyl carbazate (6.6 g, 0.05 moles) was added to give a clear solution. Left to stand over the weekend. Poured into water and extracted into ethyl acetate. Washed with water and dried over anhydrous magnesium sulphate. Evaporated to give a white solid. Triturated with ether and dried in a desiccator to give the product as a white solid. (10.4 g, 78%). 1H NMR (300 MHz DMSO-d6) mixture of isomers 9.5 and 7.95 (brs, 1H), 2.95 (s, 1H), 2.75 (s, 1H), 2.1 (s, 2H), 1.95 (s, 2H), 1.4 (s, 9H), 0.9 (2s, 12H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:26])[CH2:24]Br)=[CH:19][CH:18]=1.O>CC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:24][C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:26]
Reactant: Oc1ccccc1Br
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)COc2ccccc2Br)cc1

Procedure:
44.3 g of potassium carbonate were added to a mixture of 34 ml of 2-bromo phenol, 150 ml of acetone and 75 g of 4'-methoxy-2-bromo acetophenone in 150 ml of acetone. The mixture was refluxed for 16 hours and the solution was poured into water. The aqueous phase was extracted with ethyl acetate, dried, filtered and brought to dryness to obtain 101 g of the desired product melting at 104° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[N:19]([S:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[C:18]([CH3:29])=[C:17](C(O)=O)[CH:16]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:6]=[C:7]([C:15]2[N:19]([S:20]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)(=[O:21])=[O:22])[C:18]([CH3:29])=[CH:17][CH:16]=2)[CH:8]=[C:9]([C:11]([CH3:13])([CH3:14])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(C(=O)O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1S(=O)(=O)N1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1S(=O)(=O)N1CCCCC1
Yield: 41.6 %

Procedure:
A solution of compound 4d (700 mg, 1.5 mmol) in TFA (5 mL) was heated to 100° C. for 30 min, evaporated and redissolved in EA, washed with aq. NaHCO3 (3×50 mL) and brine, dried with Na2SO4, concentrated and purified by CC (PE/EA=1/0 to 7/1) to get compound 4e (260 mg, 41%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:7][C@@:8]12[C@H:18]3[CH2:19][CH2:20][C@:21]4([CH3:31])[C@@:25]5([O:30]C(=O)CC5)[CH2:24][CH2:23][C@H:22]4[C@@H:17]3[CH:16]=[CH:15][C:14]1=[CH:13][C:11](=[O:12])[CH2:10][CH2:9]2.C[Si](Cl)(C)C>C(Cl)Cl.CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:9]1[C@@:8]2([CH3:7])[C:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:18]2[CH2:19][CH2:20][C@@:21]2([CH3:31])[C@H:22]3[CH2:23][CH2:24][C:25]2=[O:30])=[CH:13][C:11](=[O:12])[CH2:10]1
Reactant: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]21CCC(=O)O1
Reactant: C=CCCCBr
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@]12C(=CC(=O)C[C@@H]1CCCCCBr)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.25 h
Yield: 7 %

Procedure:
Cp2ZrHCl (206 mg, 0.80 mmol, 2.0 eq.) was added to a stirred, room temperature, solution of 5-bromo-1-pentene (0.12 mL, 1.0 mmol, 2.5 eq.) in CH2Cl2 (0.40 mL) under an argon atmosphere. After stirring for about 15 min, the resulting clear yellow solution was transferred via syringe over about 1 min to a clear colourless stirred solution of CuOTf-ligand complex (30.0 mg, 0.040 mmol, 0.10 eq.) in Et2O (2.0 mL) under an argon atmosphere. The resulting dark mixture was allowed to stir for an additional 10 min before Canrenone (136.0 mg, 0.40 mmol, 1.0 eq.) and TMSCl (0.26 mL, 2.00 mmol, 5.0 eq.) were added sequentially dropwise via syringe. Stirring at room temperature was continued arbitrarily for 15 h before the reaction was quenched by the addition of Et2O (ca 3 mL) and NH4Cl (1 M aq., ca 1.5 mL). The mixture was partitioned between the aqueous and Et2O layers and the former phase was extracted with Et2O (3×10 mL). The combined organic phase was washed with NaHCO3 (sat. aq., ca 10 mL), dried (Na2SO4), filtered and concentrated in vacuo to give an oil. Flash column chromatography of the yellow residue (30:70 EtOAc/petrol; SiO2) gave major diastereomer (4) (+)-7α-(5-bromopentyl)-17α-hydroxy-3-oxo-pregn-4-ene-21-carboxylic acid γ-lactone (64 mg, 0.13 mmol, 33%) and minor diastereomer (4a) (+)-1α-(5-bromopentyl)-4-androstene-3,17-dione (14 mg, 0.028 mmol, 7%). Diastereomeric ratio was determined by integration of 1H NMR spectra.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1.[CH:14]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][CH2:13][CH:4]1[CH2:3][NH:2][C:21]([CH:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:22]
Reactant: O=C(Cl)C1CCCCCC1
Reactant: NCC1CCc2ccccc2O1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NCC1CCc2ccccc2O1)C1CCCCCC1
Reaction time: 1 h

Procedure:
5.0 g (25 mmol) of 2-aminomethylchroman hydrochloride are dissolved in 50 ml of pyridine; 5.6 g (35 mmol) of cycloheptanecarbonyl chloride are added dropwise to this solution. After 1 hour at 50° C., the mixture is concentrated and the residue is partitioned between water and toluene/ethyl acetate 1:1. The organic phase is filtered over silica gel. The desired product is eluted with toluene/ethyl acetate 5:1. The amide obtained after concentration is further reacted directly.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9](OCC)=[O:10].[NH3:15]>CO>[CH3:1][C:2]1([CH3:14])[NH:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([NH2:15])=[O:10]
Reactant: CCOC(=O)CN1C(=O)CNC1(C)C
Reactant: N
Solvent: CO
Product: CC1(C)NCC(=O)N1CC(N)=O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
An ice-cold solution of ethyl 2,2-dimethyl-5-oxo-1-imidazolidineacetate (2 g) in methanol (150 ml) was saturated with gaseous ammonia). The solution was stirred at room temperature for 36 hours. After evaporation the residue was chromatographed on a silica gel column, eluting with dichloromethane/methanol 6:4. The selected fractions were collected, evaporated and the residue was crystallized from ethanol, to give 2,2-dimethyl-5-oxo-1-imidazolidineacetamide (1 g) as a white powder, m.p. 144°-146°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[CH2:15]([O:14][C:12]([C:11]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]2[CH:10]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cccc(Cl)n1
Solvent: CCO
Product: CCOC(=O)c1cn2c(Cl)cccc2n1
Yield: 67.7 %

Procedure:
A solution of 2-amino-6-chloropyridine (6.43 g, 50 mmoles) and ethyl bromopyruvate (9.75 g, 50 mmoles) in ethanol (150 ml) was heated at reflux for 4 hours. After the solvent was removed, chloroform was added to the residue, which was washed in turn with saturated sodium bicarbonate and saturated saline, and then dried over anhydrous magnesium sulfate. After the solvent was concentrated, n-hexane was added to the mixture. Then, the crystals precipitated were filtered off and washed with n-hexane to obtain 7.60 g of the desired product (67.6%, pale yellow crystals).