Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:10]#[N:11])[C:5](O)=[N:6][C:7]=1[CH3:8].[ClH:13]>P(Cl)(Cl)(Cl)=O.CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:10]#[N:11])[C:5]([Cl:13])=[N:6][C:7]=1[CH3:8]
Reactant: Cl
Reactant: Cc1nc(O)c(C#N)c(C)c1Br
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(C#N)c(C)c1Br
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A mixture of 9.0 grams (0.040 mole) of 5-bromo-3-cyano-2-hydroxy-4,6-dimethylpyridine in 40 mL of phosphorus oxychloride is stirred, and one drop (catalyst) of N,N-dimethylformamide is added. The reaction mixture is then stirred at ambient temperature for about five hours, and then allowed to stand for about 72 hours. After this time, the reaction mixture is poured into 1000 mL of ice containing about one mL of concentrated hydrochloric acid. The mixture is stirred until the ice melts. The resultant precipitate is collected by filtration and washed with water. The solid is then dried under reduced pressure at about 60° C. An NMR spectrum of the solid indicates that it contains a large amount of starting material. The solid is then dissolved in 25 mL of phosphorus oxychloride, and two drops of N,N-dimethylformamide are added. The mixture is heated to reflux where it is stirred for about 18 hours. After this time, the reaction mixture is poured into 600 mL of ice containing about two mL of concentrated hydrochloric acid. The mixture is stirred until the ice melts. The resultant precipitate is collected by filtration, washed with water, and dried under reduced pressure at about 60° C., yielding 8.6 grams of 5-bromo-2-chloro-3-cyano-4,6-dimethylpyridine. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.C(N(C(C)C)CC)(C)C.[NH:42]1[CH2:47][CH2:46][CH2:45][C@@H:44]([NH:48][C:49]2[CH:54]=[CH:53][N:52]=[C:51]([C:55]3[CH:56]=[N:57][N:58]4[CH:63]=[CH:62][C:61]([C:64]#[N:65])=[CH:60][C:59]=34)[N:50]=2)[CH2:43]1>CN(C=O)C>[F:1][C:2]([F:8])([F:7])[CH2:3][C:4]([N:42]1[CH2:47][CH2:46][CH2:45][C@@H:44]([NH:48][C:49]2[CH:54]=[CH:53][N:52]=[C:51]([C:55]3[CH:56]=[N:57][N:58]4[CH:63]=[CH:62][C:61]([C:64]#[N:65])=[CH:60][C:59]=34)[N:50]=2)[CH2:43]1)=[O:5]
Reactant: O=C(O)CC(F)(F)F
Reactant: N#Cc1ccn2ncc(-c3nccc(N[C@@H]4CCCNC4)n3)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccn2ncc(-c3nccc(N[C@@H]4CCCN(C(=O)CC(F)(F)F)C4)n3)c2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 19.4 %

Procedure:
3,3,3-Trifluoropropanoic acid (0.03 mL, 0.29 mmol), N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate (0.12 g, 0.30 mmol) and diisopropylethylamine (0.21 mL, 1.21 mmol) were added to a stirred solution of 3-{4-[(3R)-piperidin-3-ylamino]pyrimidin-2-yl}pyrazolo[1,5-a]pyridine-5-carbonitrile (Preparation 7b, 0.11 g, 0.24 mmol) in N,N′-dimethylformamide (3 mL) and the mixture was stirred at room temperature for 20 hours. The reaction mixture was then partitioned between dichloromethane and 4% aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with 4% aqueous sodium hydrogen carbonate solution, dried (MgSO4) and the solvents were evaporated in vacuo. The crude product was purified by flash chromatography (200:1 to 10:1 chloroform/methanol) to give a residue that was repurified by flash chromatography (1:1 hexane/ethyl acetate to 100% ethyl acetate) to give the title compound (0.02 g, 19%) as a pale yellow solid.
Reaction SMILES: [N:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:17])=O.[S:18]([O-:21])([OH:20])=[O:19].[Na+].[OH-].[Na+]>O>[NH2:1][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[C:6]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:5][C:4]=1[OH:17]
Reactant: O=S([O-])O
Reactant: COC(=O)c1ccc2c(N=O)c(O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc2c(N)c(O)cc(S(=O)(=O)O)c2c1
Temperature: 40 °C
Yield: 64 %

Procedure:
92.4 g (0.4 mol) of crude 1-nitroso-6-methoxycarbonyl-β-naphthol were added at room temperature to a solution of 360 g (1.11 mol) of 40%-strength aqueous sodium hydrogen sulfite and 4.4 g (0.11 mol) or sodium hydroxide in 1610 ml of water. The suspension was heated for 24 h at 40° C. and then 2.4 g; (2.6% of the amount taken) of residue were separated off. The clear solution was then acidified at 25° C. with 142 g (1.39 mol) of 36%-strength sulfuric acid and the product was crystallized out for 48 hours at room temperature. After filtration by suction and drying, 76.0 g (64%) of product is obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11])=O.[NH2:12][CH2:13][C:14]([OH:16])=[O:15]>O>[OH:11][C:5]1[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=1[CH2:2][CH:1]=[N:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: NCC(=O)O
Solvent: O
Product: O=C(O)CN=CCc1ccc(O)cc1O

Procedure:
Ingredients. (1) Water 97.5 (2) Resacetophenone 1.5 (3) Glycine 1.0. Procedure. The mixture of all ingredients is heated at 90 to 95 C for 2 hours. A solution of N-[(2,4-dihydroxyphenyl)ethylidene]glycine in water is obtained. It is then hydrogenated over platinum (Pt) catalyst, filtered, and then acidified to pH 6.5. [RS]-N-[(2,4-dihydroxyphenyl)ethyl]glycine is thus obtained, which is then resolved into the corresponding [R] and [S] optical isomers, and used directly in cosmetic compositions of the present invention.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11](=[O:20])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2].S(Cl)(Cl)=O>C(Cl)Cl>[CH3:2][C:1]1[O:20][C:11]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:4]=1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)CCc1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nc(C)oc1CCc1ccccc1

Procedure:
To the entire oily residue obtained in Step A is added at 0° C., 60 ml. of thionyl chloride and the resulting mixture refluxed for 40 minutes. The reaction mixture is then cooled and evaporated (under vacuum) to obtain a residue. The residue is dissolved in methylene chloride, and the solution washed with 5% aqueous sodium bicarbonate (100 ml.). The organic layer is then dried over anhydrous sodium sulfate and evaporated (under vacuum) to obtain the title compound as a crude residue.
Reaction SMILES: [CH2:1]([N:8]([C@H:13]1[C@H:17]([OH:18])[CH2:16][CH2:15][C:14]1([F:20])[F:19])[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].C1COCC1>CC(O)(C)C>[CH2:1]([N:8]1[C:9](=[O:12])[CH2:10][O:18][C@@H:17]2[CH2:16][CH2:15][C:14]([F:20])([F:19])[C@@H:13]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)N(Cc1ccccc1)[C@H]1[C@H](O)CCC1(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=C1CO[C@@H]2CCC(F)(F)[C@H]2N1Cc1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a stirred solution of trans-N-benzyl-2-chloro-N-(2,2-difluoro-5-hydroxycyclopentyl)acetamide (750 mg, 2.46 mmol) in t-BuOH (20 mL) was added a 1M solution of KOtBu in THF (4.93 mL, 4.93 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 2 hours and then the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (20 mL), washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification of the residue on a silica gel column (0 to 40% EtOAc/hexanes) afforded trans-4-benzyl-5,5-difluorohexahydrocyclopenta[b][1,4]oxazin-3(2H)-one. MS ESI calc'd. for C14H15F2NO2 [M+H]+ 268. found 268.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:21](S(C)(=O)=O)=[N:22][N:23]=4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[CH3:29][NH2:30].O1CCCC1>CN1CCCC1=O>[F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:20][C:21]([NH:30][CH3:29])=[N:22][N:23]=4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3ncn(-c4ccc(OC(F)F)cc4)c3c2)o1
Reactant: CN
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CNc1nnc(-c2ccc3ncn(-c4ccc(OC(F)F)cc4)c3c2)o1
Yield: 67 %

Procedure:
In the same manner as in Example 433 and using 1-[4-(difluoromethoxy)phenyl]-6-[5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl]-1H-benzimidazole instead of 6-[5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl]-1-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole, using 2M methylamine-tetrahydrofuran solution instead of sodium methoxide, and using 1-methyl-2-pyrrolidone instead of N,N-dimethylformamide, the title compound (yield 67%) was obtained as colorless crystals.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][N:3]=1.[CH2:19]([C:21]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24])[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.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>[CH2:19]([C:21]1[C:22]([CH:23]=[O:24])=[CH:25][CH:26]=[CH:27][C:28]=1[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][N:3]=1)[CH3:20]
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Cc1ccc(-c2nnc(Br)s2)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(C=O)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 120 °C
Yield: 54.1 %

Procedure:
To a suspension of 5-(5-bromo-1,3,4-thiadiazol-2-yl)-2-(2-methylpropyl)benzonitrile (D26) (100 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (D5) (121 mg) and tripotassium phosphate (165 mg) in N,N-dimethylformamide (DMF) (4 mL) and water (1 mL) under nitrogen was added Pd(Ph3P)4 (35.9 mg). The reaction vessel was sealed and heated under microwave at 120° C. for 10 min. Water was added. The reaction mixture was extracted with EA for 3 times, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, the dried solution was concentrated, and purified by column chromatography to afford 5-[5-(2-ethyl-3-formylphenyl)-1,3,4-thiadiazol-2-yl]-2-(2-methylpropyl)benzonitrile (D27) (63 mg) as a yellow solid. MS (ES): C22H21N3OS requires 375. found 376.2 (M+H+).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@H:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[OH:6].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[I:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[O:37][C@@H:36]([C:41](O)=[O:42])[CH2:35][CH2:34]2>ClCCl>[OH:6][C@H:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][NH:3][C:41]([C@H:36]1[CH2:35][CH2:34][C:33]2[C:38](=[CH:39][CH:40]=[C:31]([I:30])[CH:32]=2)[O:37]1)=[O:42]
Reactant: O=C(O)[C@H]1CCc2cc(I)ccc2O1
Reactant: NC[C@H](O)c1cccnc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC[C@H](O)c1cccnc1)[C@H]1CCc2cc(I)ccc2O1
Reaction time: 18 h
Yield: 74 %

Procedure:
(1R)-2-Amino-1-(3-pyridinyl)ethanol dihydrochloride (U.S. Pat. No. 6,051,586) (5.73 g, 27.1 mmol), 1-hydroxybenzotriazole (6.67 g, 49.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcabodiimide hydrochloride (9.46 g, 49.3 mmol), and triethylamine (13.8 mL, 9.98 g, 98.7 mmol) were added successively to a stirred solution of (2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, Method A, 7.50 g, 24.7 mmol) in dichloromethane (100 mL). The reaction was stirred for 18 hours and then diluted with dichloromethane (300 mL). The solution was washed with saturated aqueous sodium bicarbonate (300 mL) and then the aqueous layer was back-extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 5-10% methanol/ethyl acetate gave the product (7.80 g, 74%) as a white solid: 1H NMR (acetone-d6, δ): 8.55 (d, J=1.6 Hz, 1 H), 8.44 (dd, J=4.7, 1.6 Hz, 1 H), 7.71 (ddd, J=7.9, 1.8, 1.8 Hz, 1 H), 7.59 (s, 1 H), 7.35-7.42 (m, 2 H), 7.27 (dd, J=7.9, 4.7 Hz, 1 H), 6.63 (d, 9.6 Hz, 1 H), 4.98 (d, J=4.2 Hz, 1 H), 4.85-4.93 (m, 1 H), 4.53 (dd, J=8.8, 3.4 Hz, 1 H), 3.38-3.70 (m, 2 H), 2.61-2.91 (m, 4 H), 2.16-2.28 (m, 2 H), 1.85-1.99 (m, 1 H); mass spectroscopy gave m/z=425.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]3[CH2:29][CH2:30][C:31](=O)[C:32]=3[C:24]=2[N:23]=[C:22]1[CH3:34])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.O>[CH2:14]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]3[CH2:29][CH2:30][C:31](=[CH:5][C:3]#[N:4])[C:32]=3[C:24]=2[N:23]=[C:22]1[CH3:34])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1nc2c3c(ccc2n1Cc1ccccc1)CCC3=O
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c3c(ccc2n1Cc1ccccc1)CCC3=CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a suspension of 60% sodium hydride (32 mg, 0.80 mmol) in tetrahydrofuran (5 mL) was added diethyl cyanomethylphosphonate (142 μL, 0.88 mmol), and the mixture was stirred at room temperature for 30 min. A solution of 3-benzyl-2-methyl-6,7-dihydroindeno[4,5-d]imidazol-8(3H)-one (73.4 mg, 0.27 mmol) in tetrahydrofuran (2 mL) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction solution was diluted with water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→80/20) to give the title compound (53.3 mg, yield 67%).
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.Br[C:30]1[CH:55]=[CH:54][C:33]([CH2:34][CH2:35][N:36]([CH3:53])[C:37]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([S:46]([CH2:49][CH3:50])(=[O:48])=[O:47])=[C:42]([C:51]#[N:52])[CH:41]=2)=[O:38])=[CH:32][CH:31]=1>>[C:51]([C:42]1[CH:41]=[C:40]([NH:39][C:37](=[O:38])[N:36]([CH2:35][CH2:34][C:33]2[CH:54]=[CH:55][C:30]([B:25]([OH:27])[OH:26])=[CH:31][CH:32]=2)[CH3:53])[CH:45]=[CH:44][C:43]=1[S:46]([CH2:49][CH3:50])(=[O:48])=[O:47])#[N:52]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(Br)cc2)cc1C#N
Product: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(B(O)O)cc2)cc1C#N
Yield: 78 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 25B (950 mg, 2.1 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 25C (679 mg, 78%) as an white solid. MS (ESI) m/z 415.93 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: O=C(Cl)C=Cc1ccc(Cl)cc1
Yield: 100.4 %

Procedure:
3-(4-chloro-phenyl)-acryloyl chloride was prepared as follows: To a stirred suspension of 4-chloro-trans-cinnamic acid (2.51 g, 13.77 mmol) in benzene was added thionyl chloride (1.1 mL, 15.14 mmol) and a catalytic amount of DMAP. The reaction mixture was heated at reflux for 1.5 h. The volatile materials were removed under reduced pressure. The white residue was dissolved in Et2O and concentrated again under reduced pressure, to give 3-(4-chloro-phenyl)-acryloyl chloride (2.78 g, quantitative) as a white solid: 1H NMR (CDCl3) δ 7.81 (d, 1H, J=15.6 Hz), 7.54 (d, 2H, J=8.6 Hz), 7.44 (d, 2H, J=8.6 Hz), 6.65 (d, 1H, J=15.6 Hz).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16](=[O:26])[NH:15][C:14]1=[O:27])=[O:6])[CH3:3].[CH2:28](Br)[CH2:29][CH2:30][CH3:31]>C(O)C>[CH2:28]([N:15]1[C:14](=[O:27])[CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16]1=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCBr
Reactant: CCCCCCCCN1C(=O)NC(=O)C1CCCCCCC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCN1C(=O)N(CCCC)C(=O)C1CCCCCCC(=O)OCC

Procedure:
To a solution of sodium (308 mg) in ethanol (40 ml) was added 5-(6-ethoxycarbonylhexyl)-1-octylhydantoin, followed by butyl bromide (1.8 g), and the solution was refluxed for 24 hours. The solvent was evaporated, water was added and the insoluble oil was extracted with ether. The washed and dried extract was evaporated to give 3-butyl-5-(6-ethoxycarbonylhexyl)-1-octyl hydantoin.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH:6](OCC)[O:7][CH2:8][CH3:9])=[O:5])[CH3:2].C=O.[C:27](O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][P:4]([CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH:6]1[CH2:27][CH2:9][CH2:8][O:7]1)=[O:5])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(OCC)P(=O)(CCCNCc1ccc(Cl)cc1)OCC
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(CCCNCc1ccc(Cl)cc1)C1CCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 g of 3-(p-chlorobenzylamino)propyl(diethoxymethyl)phosphinic acid ethyl ester are dissolved in 10 ml of methanol, 0.36 g (0.53 ml) of a 35% aqueous formaldehyde solution is added, and the mixture is stirred at room temperature for one hour. 0.4 g of glacial acetic acid and 0.40 g of sodium cyanoborohydride are added, and the mixture is stirred at room temperature for 2 hours, concentrated by evaporation under reduced pressure, taken up in dichloromethane and washed with 5% aqueous sodium hydrogen carbonate solution. The organic phase is separated off, dried over sodium sulfate and concentrated by evaporation under reduced pressure. The oily residue is purified by chromatography on silica gel, yielding 3-(p-chlorobenzylamino)propyl(tetrahydrofuran-2-yl)phosphinic acid ethyl ester in the form of a colourless oil.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][N:7]([CH3:37])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:34][C@@:32]3([CH3:33])[C@@H:28]([CH2:29][CH2:30][C:31]3=[O:35])[C@H:27]3[C:18]2=[C:19]2[C:24]([CH2:25][CH2:26]3)=[CH:23][C:22](=[O:36])[CH2:21][CH2:20]2)=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>ClCCl.N1C=CC=CC=1>[Cl:4][C:23]1[C:22](=[O:36])[CH2:21][CH2:20][C:19]2[C:24]=1[CH2:25][CH2:26][C@@H:27]1[C:18]=2[C@@H:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][N:7]([CH3:6])[CH3:37])=[CH:16][CH:15]=2)[CH2:34][C@@:32]2([CH3:33])[C@H:28]1[CH2:29][CH2:30][C:31]2=[O:35]
Reactant: O=S(=O)(Cl)Cl
Reactant: CN(C)CCOc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)CCOc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CCC4=C(Cl)C(=O)CCC4=C32)cc1
Reaction time: 0.5 h

Procedure:
6 ml of sulphuryl chloride at 10% in dichloromethane is added under an inert atmosphere, at ambient temperature to a solution of 1.08 g of 11β-[4-(2-(dimethylamino)ethoxy)phenyl]-estra-4,9-diene-3,17-dione in 11 ml of pyridine and agitation is carried out for 30 minutes at approximately −36° C. The reaction medium is poured into sodium bicarbonate, followed by extraction, washing, drying and evaporating under reduced pressure until 1.84 g of crude product is obtained, which is purified by chromatography, eluting with an ethyl acetate/triethylamine mixture 80/20. 616 mg of expected pure product is obtained. (Rf AcOEt/TEA 8/2=0.35).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[CH:11][N:10]([C:13]3[S:14][C:15]([C:25]([NH2:27])=[O:26])=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=4)[N:17]=3)[C:9]=2[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>[I-].[K+].CN(C)C=O>[Cl:24][C:20]1[CH:19]=[C:18]([C:16]2[N:17]=[C:13]([N:10]3[C:9]4[CH:28]=[C:5]([O:4][CH2:3][CH2:2][N:39]5[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]5)[CH:6]=[CH:7][C:8]=4[N:12]=[CH:11]3)[S:14][C:15]=2[C:25]([NH2:27])=[O:26])[CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCCCl)cc32)nc1-c1cccc(Cl)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(CCOc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Reaction time: 6 h
Yield: 76.5 %

Procedure:
A mixture of 0.043 g (0.1 mmole) of 2-[6-(2-chloro-ethoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.28a), 1 mL of dimethylformamide, 0.069 g (0.5 mmole) of potassium carbonate, 0.001 g of potassium iodide and 0.033 mL (0.3 mmole) of 1-methyl-piperazine was stirred at 100 degrees for 6 hours. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 30:70-100:0) to give 0.038 g of 4-(3-chloro-phenyl)-2-{6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-benzoimidazol-1-yl}-thiazole-5-carboxylic acid amide (I.28) as a white solid. MH+/Z=497
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH3:7][N:8]([CH3:20])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=O>C1(C)C=CC=CC=1>[CH3:7][N:8]([CH3:20])[C:9]([Cl:2])=[N:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1
Reactant: CN(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN(C)C(Cl)=Nc1ccc(Cl)c(Cl)c1
Yield: 100.2 %

Procedure:
10.4 g (0.05 mole) of phosphorus pentachloride and 11.6 g (0.05 mole) of N,N-dimethyl-N'-(3,4-dichlorophenyl)-urea in 74 ml of toluene are refluxed for 3 hours, and the volatile components are distilled off under 0.13 mbar to give 12.6 g of N,N-dimethyl-N'-(3,4-dichlorophenyl)-chloroformamidine in the form of an oil; nD25 : 1.6133.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8]3=[C:9]([C:14]([O:16][C:17](=[O:18])[C:7]3=[CH:6][CH:5]=1)=O)[CH:10]=[CH:11][CH:12]=2)([O-:3])=[O:2].O.S(O)(O)(=O)=O.[CH2:25]([N:27]([CH2:35][CH2:36][OH:37])[C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)[CH3:26].Cl>N1C=CN=C1>[CH2:25]([N:27]([CH2:35][CH2:36][OH:37])[C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:17](=[O:18])[C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[C:13]4[C:8]=3[C:9](=[CH:10][CH:11]=[CH:12]4)[C:14]2=[O:16])=[CH:30][CH:29]=1)[CH3:26]
Reactant: O=C1OC(=O)c2ccc([N+](=O)[O-])c3cccc1c23
Reactant: CCN(CCO)c1ccc(N)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: c1c[nH]cn1
Solvent: O
Product: CCN(CCO)c1ccc(N2C(=O)c3cccc4c([N+](=O)[O-])ccc(c34)C2=O)cc1

Procedure:
2.0 g (8.22 mmol) of 4-nitronaphthalene-1,8-dicarboxylic anhydride and 2.68 g (9.04 mmol) of N-ethyl-N-(2-hydroxyethyl)-p-phenylenediamine sulfate monohydrate were stirred in 12 g of molten imidazole at 130° C. under an argon atmosphere for 1 hour. After cooling, the mixture was poured into 400 mL of 2 N hydrochloric acid and the precipitate was suction-filtered off, washed with water and dried. The resulting product was used in Step 2 without further purification.