Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[C:8]#[N:9].C([N-]C(C)C)(C)C.[Li+].Br[CH2:28][Cl:29].[Cl-].[NH4+]>C1COCC1>[Cl:29][CH2:28][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[C:8]#[N:9]
Reactant: N#CC(CCOC1CCCCO1)c1ccccn1
Reactant: ClCBr
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC(CCl)(CCOC1CCCCO1)c1ccccn1
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 20 g of the compound obtained in Step 1 in 400 ml of THF was stirred at −78° C. under atmosphere of nitrogen, and then, 45 ml of 2M lithium diisopropylamide solution was slowly added thereto. The resulting mixture was stirred for one hour and thereto was slowly added a solution of 13.62 g of bromochloromethane in 30 ml of THF. After one hour, the resulting mixture was stirred at room temperature for four hours. After the reaction was completed, an aqueous ammonium chloride solution was added, the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue thus obtained was purified by a silica gel column chromatography using a mixture of ethyl acetate and n-hexane of 1:6 to obtain 19.14 g of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][CH3:14])=[C:7](Cl)[C:6]=2[CH:16]=1.[CH2:17]([N:19]([CH2:23][CH3:24])[C:20](=[S:22])[S-:21])[CH3:18].[Na+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][CH3:14])=[C:7]([S:22][C:20](=[S:21])[N:19]([CH2:23][CH3:24])[CH2:17][CH3:18])[C:6]=2[CH:16]=1
Reactant: CCCc1c(Cl)c2cc(Br)ccc2oc1=O
Reactant: CCN(CC)C(=S)[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(SC(=S)N(CC)CC)c2cc(Br)ccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-bromo-4-chloro-3-propyl-2H-1-benzopyran-2-one (0.5 g) in dimethylformamide (2 ml) was treated with sodium diethyldithiocarbamate (0.34 g). The mixture was stirred at room temperature under nitrogen overnight and then poured into water, extracted with diethyl ether and the extract washed with brine, dried and evaporated under reduced pressure to give 6-bromo-4-diethylthiocarbamoylthio-3-propyl-2H-1-benzopyran-2-one, m.p. 135-7°. (compound 16)
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20]CCCCCCCCCCO)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]#[C:42][C:43]#[C:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][OH:54]>>[Si:1]([O:18][CH2:19][CH2:20][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]#[C:42][C:43]#[C:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][OH:54])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCCCCCCC#CC#CCCCCCCCCCO
Reactant: CC(C)(C)[Si](OCCCCCCCCCCCCO)(c1ccccc1)c1ccccc1
Product: CC(C)(C)[Si](OCCCCCCCCCC#CC#CCCCCCCCCCO)(c1ccccc1)c1ccccc1
Yield: 26 %

Procedure:
This substance was synthesized following the same procedure as for (1) and obtained in comparable yields using 9.40 g of (3) (28.1 mmol) as diol component. 4.25 g of 1-(tert-Butyldiphenylsilyl)oxy-10,12-Docosadiyne-22-ol (7.24 mmol) was obtained in a yield of 26%. 1H NMR (250.13 MHz): δ (ppm)=1.05 (s, 9H, tert-butyl), 1.26 (br, 20H, —CH2—CH2—CH2—CH2—CH2—), 1.53 (m, 8H, —O—CH2—CH2— and —C≡CH2—CH2—), 2.24 (t, 4H, 3J=6.8 Hz, —C≡C≡CH2—), 3.64 (t, 2H, 3J=6.5 Hz, —Si—O—CH2—), 3.65 (t, 2H, 3J=6.5 Hz, HO—CH2—), 7.40 (m, 6H, phenyl), 7.69 (m, 4H, phenyl). 13C NMR (75.48 MHz): δ (ppm)=25.69, 25.72, 26.9, 28.30, 28.34, 28.8, 29.00, 29.04, 29.30, 29.34, 29.4, 32.5, 32.8, 63.1, 64.0, 127.5, 129.5, 134.1, 135.6.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([CH3:9])([CH3:8])[CH3:7])C.C[O-].[Na+].Cl.[NH2:23]O.Cl>CO>[C:6]([C:5]1[C:4]([OH:3])=[N:23][O:17][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: NO
Reactant: CCOC(=O)C(C(=O)c1ccccc1)C(C)(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1c(O)noc1-c1ccccc1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
2-Benzoyl-3,3-dimethylbutyric acid ethyl ester (2.0 g) was dissolved in methanol (20 ml), and sodium methoxide (28% methanol solution, 1.6 ml) was added dropwise thereto at 5° C. under a nitrogen atmosphere, followed by stirring of the resulting mixture for 10 minutes. The reaction mixture was cooled to -30° C., and a suspension of hydroxylamine hydrochloride (1.1 g) and sodium methoxide (28% methanol solution, 6.2 ml) in methanol (10 ml) was added dropwise to the reaction mixture. The resulting mixture was stirred at the same temperature for 30 minutes, and 6N hydrochloric acid (14 ml) was added to the reaction mixture, followed by stirring of the resulting mixture at 80° C. for one hour. After the reaction, the solvent was evaporated under reduced pressure. After the residue was poured into ice-cold water and extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was crystallized from isopropyl ether to obtain the title compound (0.35 g, 20%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:4][CH:3]=1.[CH:16](O)=[O:17]>O>[CH:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:6][CH:7]=1)=[O:17]
Reactant: O=CO
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Solvent: O
Product: O=CNc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 67 %

Procedure:
6.0 g (29.8 millimoles) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 8a) and 30 ml of formic acid are refluxed for 1 hour. The solution is then poured into 500 ml of water and the precipitate which separates out is filtered off, washed with water and recrystallized from a methanol/water mixture. 4.6 g (67% of theory) of 2-(p-formylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are isolated as almost colorless crystals, of melting point 239°-240° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([CH3:18])[C@H:13]2[CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)=[O:11])[CH:3]=1.[Si]([N:35]=[N+:36]=[N-:37])(C)(C)C>C1(C)C=CC=CC=1>[CH3:18][C@@H:14]1[CH2:15][CH2:16][CH2:17][N:12]([C:10]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:9]=[CH:8][C:5]=2[C:6]2[N:35]=[N:36][NH:37][N:7]=2)=[O:11])[C@@H:13]1[CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][N:22]=1
Reactant: Cc1ccc(C#N)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nn[nH]n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Temperature: 110 °C

Procedure:
A mixture of 4-methyl-2-((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidine-1-carbonyl)benzonitrile (obtained from Example A22, 0.098 g, 0.235 mmol), TMSN3 (0.06 mL, 0.47 mmol) and SnO(n-Bu)2 (0.006 g, 0.024 mmol) in toluene (2 mL) was heated at 110° C. overnight. The mixture was cooled to rt and filtered through a pad of diatomaceous earth, washing with methanol. The solvent was removed in vacuo and the resulting crude residue was purified by reverse-phase preparative HPLC to obtain the title compound. ESI-MS (m/z): 460 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[OH:10].[C:11](OC(=O)C)(=[O:13])[CH3:12].C(N(CC)CC)C>C1COCC1>[C:11]([O:10][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=1[F:1])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(F)c(F)c1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
To a mixture of 2,3,4-trifluorophenol (5.2 g) and acetic anhydride (3.98 mL) in THF (50 mL) was added triethylamine (5.87 mL) at room temperature, and the mixture was stirred for 1 hr and concentrated under reduced pressure. Water and ethyl acetate were added to the residue, the organic layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.70 g).
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].C[O-].[Na+].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([CH2:17][C:18]#[N:19])=O>C(O)C>[NH2:19][C:18]1[N:3]([C:4]([NH2:6])=[O:5])[N:2]=[C:15]([C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)[CH:17]=1
Reactant: N#CCC(=O)c1ccco1
Reactant: NNC(N)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=O)n1nc(-c2ccco2)cc1N
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To a stirred solution of 5.5 g of semicarbazide hydrochloride in 100 ml of absolute ethyl alcohol is added 3.0 g of sodium methoxide at room temperature. The reaction mixture is stirred for 30 minutes and 6.0 g of 2-furoyl acetonitrile is added. The reaction mixture is heated at reflux for 1 hour and concentrated in vacuo to a residue. The residue is suspended in water, filtered and dried to give 6.0 g of the desired product as a solid, m.p. 145° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:41])[C@@H:18]([N:27]([CH3:40])S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)[C:3]1=[O:42].SCC(O)=O.O.[OH-].[Li+]>CN(C)C=O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1([CH3:43])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:41])[C@@H:18]([NH:27][CH3:40])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:16]2)[C:3]1=[O:42]
Reactant: CN([C@@H](CCc1ccccc1)C(=O)N1CCC(N2C(=O)C(C)(C)c3ccccc32)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C(O)CS
Agent: O=C([O-])O
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN[C@@H](CCc1ccccc1)C(=O)N1CCC(N2C(=O)C(C)(C)c3ccccc32)CC1
Reaction time: 16 h
Yield: 27.8 %

Procedure:
To a solution of (S)—N-(1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-yl)-N-methyl-2-nitrobenzenesulfonamide (3.30 g, with triphenylphosphineoxide as impurity, EXAMPLE 73, Step 2) in dimethyl formamide (10 mL) were added mercaptoacetic acid (491 mg, 5.33 mmol) and lithium hydroxide monohydrate (447 mg, 10.7 mmol) at room temperature. After stirring for 16 h, the mixture was diluted with ethyl acetate and saturated sodium hydrogen carbonate aqueous solution. The organic layer was washed with saturated sodium hydrogen carbonate aqueous solution and brine, dried over sodium sulfate and concentrated in vacuo. The residue was diluted with dichloromethane (10 mL) and to the solution was added hydrogen chloride in methanol. Then the mixture was concentrated. The residue was diluted with methanol, and mixed with strong cation exchange gel (BondeSil(registered trademark) SCX, 40 g, Varian Inc.). The gel was filtered and washed with 1 mol/L ammonia in methanol, and the solution was concentrated to give the title compound (636 mg, 71%).
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C:8]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[C:13]([CH3:25])[C:9]=1[C:10]([OH:12])=[O:11])=O)([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH:1]([O:4][C:5]1[O:11][C:10](=[O:12])[C:9]2[C:13]([CH3:25])=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][C:8]=2[N:7]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(OCc2ccccc2)cc(NC(=O)OC(C)C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(OCc2ccccc2)cc2nc(OC(C)C)oc(=O)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.9 %

Procedure:
A mixture of 2-(isopropoxy)carbonylamino-4-benzyloxy-6-methyl-benzoic acid (97 mg, 0.000282 mol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI) (200 mg) in methylene chloride (20 ml) was stirred at room temperature for 2 days. The solution was diluted with methylene chloride and extracted with water. The methylene chloride was further washed with brine solution, dried over sodium sulphate and evaporated to give a yellow solid. This material was further purified by column chromatography (5% ethyl acetate: pet. ether 30-60) to give 2-isopropoxy-5-methyl-7-benzyloxy-4H-3,1-benzoxazin-4-one (55 mg), m.p. 137°-138° C., IR (CHCl3): 1755, 1640, 1605, 1569, 1460 cm-1. H--NMR (CDCl3): 1.4 (d, 6H, CH3CHCH3), 2.7 (s, 3H, CH3), 5.15 (s, 2H, OCH2Ph), 5.30 (p, 1H, CH), 6.8 (s, 1H, ArH), 7.40 (s, 5H, Ph).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].[Cl:28]N1C(=O)CCC1=O.ClCCl>C(O)(=O)C>[Cl:1][C:2]1[CH:22]=[C:21]([C:23]2[S:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(-c4cccs4)cc3Cl)c2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(-c4ccc(Cl)s4)cc3Cl)c2n1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a suspension of methyl 3-[2-chloro-4-(thiophen-2-yl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (50 mg, 0.126 mmol) in acetic acid (1 ml) was added N-chlorosuccinimide (19 mg, 0.138 mmol) at room temperature. Thirty minutes later, dichloromethane (0.5 ml) was added to the reaction mixture to give a clear transparent solution. Four hours later, N-chlorosuccinimide (19 mg, 0.138 mmol) was further added. The reaction mixture was left standing overnight and concentrated. The residue was purified by p-TLC (chloroform/methanol=40/1) to give the object compound (52 mg, 95.7%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=2[O:27][CH3:28])=[CH:16][CH:15]=1>CCCCCCC>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:24][C:23]1[CH:25]=[CH:26][C:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[C:21]([O:27][CH3:28])[CH:22]=1)=[O:8])=[O:5]
Reactant: COc1cc(N)ccc1-c1ccc(Cl)cc1
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: CCCCCCC
Product: COc1cc(NC(=O)NC(=O)c2ccccc2Cl)ccc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 2-chlorobenzoylisocyanate (0.2 g, 1.1 mmol) in xylenes (40 ml) was added a solution of 4-(4-chlorophenyl)-3-methoxyaniline (0.2 g, 0.9 mmol) in xylenes (ml). The mixture was stirred at ambient temperature for 2.5 hours then diluted with n-heptane (60 ml) and stirred for an additional one-half hour. The resulting precipitate was collected by filtration and washed with cold pentane to provide 2-chloro-N-[{(2-methoxy4'-chloro[1,1'-biphenyl]-4-yl)amino}carbonyl]benzamide, m.p. 178-179° C. (Compound A).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.I[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20])[CH2:6][CH2:5]2
Reactant: Cc1ccc2c(c1)CCNC2=O
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)CCN(c1cnccc1C)C2=O
Yield: 31.9 %

Procedure:
6-Methyl-3,4-dihydroisoquinolin-1(2H)-one (I-69f: 2 g, 12.422 mmol) was reacted with 3-iodo-4-methyl-pyridine (2.72 g, 12.422 mmol), 1,4-dioxane (70 mL), copper iodide (236 mg, 1.2422 mmol), trans-N,N′-dimethyl-cyclohexyl-1, 2-diamine (530 mg, 3.727 mmol) and potassium phosphate (6.58 g, 31.055 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM) afforded 1 g of the product (31.8% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:20][NH2:21])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)C(=NN)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a hot solution of 10 g 4,4'-dimethylbenzil in 20 ml of ethanol is added 2.1 g of hydrazine hydrate. After a few minutes at reflux, a solid begins to crystallize. Heating is continued for 10 min. and the solution cooled slowly to 0° C. The solid is filtered off and washed with cold ethanol. The product is recrystallized from ethanol. Yield 7.1 g. M.P. 137°-140°.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([O:19]CC)=[O:18])[N:15]=1.[OH-].[Na+]>C(O)C.C1COCC1>[Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[N:15]=1
Reactant: CCOC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2Br)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1Br
Yield: 94.6 %

Procedure:
A mixed solution of the compound (2.55 g, 6.85 mmol) obtained in step 6 and 1N aqueous sodium hydroxide solution (10.27 mL, 10.27 mmol) in ethanol (10 mL) and THF (10 ml) was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. 1N Hydrochloric acid was added thereto, and the precipitate was collected by filtration, and washed with diethyl ether and hexane to give 2-(2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid (2.23 g, 6.48 mmol, 95%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C:17]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:12][C@H:11]1[F:38].[H][H]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C:17]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:12][C@H:11]1[F:38]
Reactant: CCCCCC(C)(/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@H](F)C[C@H]1OC1CCCCO1)OC1CCCCO1
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: CCCCCC(C)(/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@H](F)C[C@H]1OC1CCCCO1)OC1CCCCO1

Procedure:
A solution of 400 mg of (5Z,13E)-(9R, 11R,15RS)-11,15-bis(tetrahydropyran-2 -yloxy)-9-fluoro-15-methyl-5,13-prostadienoic acid methyl ester in 50 ml of ethyl acetate is shaken with 40 mg of pa 11adium/10% strength on carbon under a hydrogen atmosphere at 0° C. After absorption of 1 equivalent of hydrogen, the product is filtered off from the catalyst and evaporated under vacuum. The residue is absorbed on silica gel. With hexane/5-20% diethyl ether, 300 mg of the title compound is eluted as a colorless oil.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[F:55][C:56]1[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([NH2:63])[CH:57]=1>[Cl-].[Na+].O.CN(C=O)C>[CH:10]1[C:11]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:62][C:59]3[CH:60]=[CH:61][C:56]([F:55])=[CH:57][C:58]=3[NH2:63])=[O:24])=[O:16])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(F)ccc1NC(=O)CCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.9 %

Procedure:
6-(2-(9H-fluoren-9-ylidene)acetamido)hexanoic acid (335 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-fluoro-o-phenylenediamine (151 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (350 mg, 79% yield) as a brown solid. 1H NMR (DMSO-d6) δ1.39 (m, 2H, CH2), 1.57 (m, 2H, CH2), 1.63 (m, 2H, CH2), 2.31 (t, J=8.0 Hz, 2H, CH2CO), 3.26 (m, 2H, NCH2), 5.13 (s, 2H, benzene-NH2), 6.26 (t, J=8.0 Hz, 1H, Ar—H), 6.46 (d, J=8.0 Hz, 1H, Ar—H), 7.08 (s, 1H, ═CH—CO and Ar—H), 7.33 (m, 2H, Ar—H), 7.40 (m, 2H, Ar—H), 7.76 (d, J=8.0 Hz, 1H, Ar—H), 7.82 (m, 2H, Ar—H), 8.53 (t, J=4.0 Hz, 1H, CONH), 8.69 (d, J=8.0 Hz, 1H, Ar—H), 9.03 (s, 1H, benzene-NH). LC-MS (m/z) 444 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:11]([N:18]1[CH2:27][CH2:26][C:21]2([O:25][CH2:24][CH2:23][O:22]2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>CCOCC.O>[CH2:11]([N:18]1[CH2:19][CH2:20][CH:21]([O:22][CH2:23][CH2:24][OH:25])[CH2:26][CH2:27]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(CN2CCC3(CC2)OCCO3)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: OCCOC1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
106.8 g of (0.8 mole) of aluminum chloride were added to a 2 liter, 3-neck flask and then 800 ml of anhydrous ether were added thereto with strong cooling. The mixture was stirred for 30 minutes and then a suspension of 7.6 g (0.2 mole) of lithium aluminum hydride in 200 ml of ether was added thereto. The mixture was stirred for 30 minutes and then a solution of 93.2 g (0.4 mole) of 8-benzyl-1,4-dioxa-8-aza-spiro [4,5] decane in 400 ml of anhydrous ether was added thereto dropwise. After the addition, stirring was continued at room temperature for 2 hours and 1 liter of water was then slowly added with strong cooling. The mixture was made alkaline with 90 g of sodium hydroxide pellets and the ether phase was decanted off. The aqueous layer was extracted again with ether and the combined ether phases were dried and the ether removed by distillation. The residue was distilled to obtain 63 g (67% yield) of 2-[1-benzyl-4-piperidyloxy]-ethanol in the form of a clear oil boiling at 140° C at 0.1 mm Hg and having a refractive index nD20 = 1.633.