Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([NH2:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.CO[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#N)[CH:24]=1)=[NH:22]>CO>[C:21]([C:23]1[CH:24]=[C:25]([C:29]2[NH:10][CH2:9][C:8]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:11]=2)[CH:26]=[CH:27][CH:28]=1)#[N:22]
Reactant: COC(=N)c1cccc(C#N)c1
Reactant: NCC(N)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CO
Product: N#Cc1cccc(C2=NC(c3ccc(F)cc3)(c3ccc(F)cc3)CN2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
To a solution of 1,1-bis(4-fluorophenyl)-1,2-ethanediamine (500 mg) in methanol (10 mL) was added 3-cyanobenzeneimidic acid methyl ester (792 mg), and the mixture was stirred at room temperature for 18 hrs. After concentrating the reaction mixture, the residue was dissolved in ethyl acetate (30 mL), washed with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=3:1→2:1) to give the objective compound (370 mg).
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH:7]1[CH2:10][N:9]([C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-])=O)=[N:15][CH:16]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>C(O)C.[Fe]>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH:7]1[CH2:8][N:9]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CN(c2ccc([N+](=O)[O-])nc2)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC1CN(c2ccc(N)nc2)C1
Temperature: 80 °C
Yield: 93.7 %

Procedure:
To a suspension of 5-[3-(tert-butyl-dimethyl-silanyloxy)-azetidin-1-yl]-2-nitro-pyridine (124 mg, 0.401 mmol) in 5 mL of ethanol is added iron powder (206 mg, 3.68 mmol) then 2 mL of NH4Cl solution. The resulting mixture is heated at 80° C. for 3 h and filtered through celite and concentrated. The resulting dark solid is divided between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate (2×50 mL). The combine organic layers are ished with brine, dried over Na2SO4 and concentrated to give 5-[3-(tert-butyl-dimethyl-silanyloxy)-azetidin-1-yl]-pyridin-2-ylamine (105 mg, 94%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH2:13][CH:12](OS(C)(=O)=O)[CH2:11][CH2:10]2)(=[O:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([CH:12]1[CH2:13][C:14]2[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:10][CH2:11]1)=[N+:21]=[N-:22]
Reactant: CC(=O)Nc1cccc2c1CC(OS(C)(=O)=O)CC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc2c1CC(N=[N+]=[N-])CC2
Temperature: 50 °C
Yield: 96.9 %

Procedure:
A mixture of methanesulfonic acid 8-acetylamino-1,2,3,4-tetrahydronaphthalen-2-yl ester (3.8 g, 13 mmol) and sodium azide (1.7 g, 27 mmol) in dimethylformamide (70 mL) was heated at 50° C. for 6 h. The solvent was removed by rotoevaporation in vacuo and the residue partitioned between methylene chloride and water. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to give a dark solid. The product was purified by column chromatography on silica gel (1:1 ethyl acetate:hexane as eluant) to give a white solid (2.9 g) in 97% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:25][C:26](=[O:28])[CH3:27])([CH2:23][OH:24])[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:12]=2)[CH2:7][CH:6]1O.C1(C)C(S(O)(=O)=O)=CC=CC=1.O.C(=O)(O)[O-]>C1(C)C=CC=CC=1>[OH:24][CH2:23][C:3]([NH:25][C:26](=[O:28])[CH3:27])([CH2:2][OH:1])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:12]=2)[CH2:7][CH:6]=1
Reactant: CCCCCCCCc1ccc2c(c1)CC(O)C2CC(CO)(CO)NC(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCc1ccc2c(c1)CC=C2CC(CO)(CO)NC(C)=O

Procedure:
Compound 18 (85 mg, 022 mmol) is dissolved in toluene (10 mL), toluenesulphonic acid (˜5 mg) is added, and the reaction heated to reflux for 3 hours with continuous removal of water from the condensed azeotrope. The reaction is cooled, then poured into aqueous bicarbonate (5% w/w, 10 mL) and the aqueous layer extracted with ether (5 mL) twice. The organic layers are combined and removed in vacuo to provide the crude residue that upon silica gel chromatography provide 19.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[CH3:21])=[NH:12].Cl.N([O-])=O.[Na+].[N-:27]=[N+:28]=[N-].[Na+].N#N.[OH-].[Na+]>O>[CH3:21][C:15]1[CH:16]=[C:17]([N:20]=[N+:27]=[N-:28])[CH:18]=[CH:19][C:14]=1[NH:13][C:11]([NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH3:3])=[NH:12]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccccc1NC(=N)Nc1ccc(N)cc1C
Agent: Cl
Agent: N#N
Agent: O=N[O-]
Solvent: O
Product: Cc1ccccc1NC(=N)Nc1ccc(N=[N+]=[N-])cc1C

Procedure:
N-(2-Methylphenyl)-N'-(2-methyl-4-aminophenyl)guanidine dihydrochloride (112 mg, 0.341 mmol) were dissolved in 2 ml H2O and 100 ul conc. HCl (1.2 mmol). The solution was cooled in an ice bath, and a solution of NaNO2 (42 mg, 0.61 mmol) in 450 ul H2O were added. The reaction mixture turned yellow, and was stirred for 45 min before solid NaN3 (43 mg, 0,661 mmol) was added in a single portion. After N2 evolution was caused, a foamy solid (11 mg) was removed and discarded. Solid NaOH (96 mg, 2.41 mmol) was added, and the bright yellow precipitate was extracted with Et2O (3×5 ml). Evaporation of the combined Et2O layers gave a yellow solid which was crystallized from EtOH/H2O: NMR (CD3OD) 2.279 (s, 3H), 2.284 (s, 3H), 6.864 (dd, 1H, J=2.4 Hz, 8.4 Hz), 6.914 (d, 1H, J=2.1 Hz), 7.055 (td, 1H, J=1.8 Hz, 7.2 Hz), 7.136-7.229 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2].[NH2:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([C:40]([F:43])([F:42])[F:41])[CH:33]=1.N1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>>[C:36]([C:35]1[CH:38]=[CH:39][C:32]([NH:31][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C:5]3[CH:6]=[N:7][C:8]([O:10][CH2:11][C:12]4[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=4)=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])=[CH:21][C:22]=2[F:30])=[CH:33][C:34]=1[C:40]([F:41])([F:42])[F:43])#[N:37]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a solution of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (1 g, 2.431 mmol) and 4-amino-2-(trifluoromethyl)benzonitrile (0.452 g, 2.431 mmol) in pyridine (3.93 mL, 48.6 mmol) was added T3P® (4.64 g, 7.29 mmol) slowly. The mixture was stirred at rt for 0.5 h. The reaction was quenched with H2O (10 mL) and extracted with DCM (20 mL×5). The combined organic extracts were dried, filtered, and concentrated. Purification by column chromatography (PE/EA=511, Rf=0.6) provided N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (870 mg, 1.351 mmol, 55.6% yield). 1H NMR (400 MHz, CDCl3-d): δ 8.02 (s, 1H), 7.98 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.30-7.45 (m, 5H), 6.93 (d, J=8 Hz, 2H), 6.33 (s, 1H), 5.33 (d, J=8 Hz, 2H), 4.09 (q, J=6.8 Hz, 2H), 3.83 (s, 5H), 1.41 (t, J=6.8 Hz, 3H); LCMS (m/z): 580.0 (M+H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][CH:8]=1)#[N:2].C([Li])CCC.[CH3:20][N:21]1[C:25]([Cl:26])=[C:24]([C:27](Cl)=[O:28])[C:23]([Cl:30])=[N:22]1.Cl>C1COCC1>[CH3:20][N:21]1[C:25]([Cl:26])=[C:24]([C:27]([OH:28])=[C:3]([C:4]2[N:5]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:7][CH:8]=2)[C:1]#[N:2])[C:23]([Cl:30])=[N:22]1
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1Cl
Reactant: N#CCc1csc(-c2ccccc2)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nc(Cl)c(C(O)=C(C#N)c2csc(-c3ccccc3)n2)c1Cl
Temperature: -60 °C
Reaction time: 0.33 h
Yield: 63.4 %

Procedure:
0.72 g of 4-cyanomethyl-2-phenylthiazole was dissolved in 10 ml of dry THF, and 4.6 ml of n-butyl lithium (1.56 M hexane solution) was dropwise added thereto at -60° C. or lower in an argon atmosphere. After the resulting product was stirred at -60° C. or lower for 20 minutes, 0.84 g of 1-methyl-3,5-dichloropyrazole-4-carbonyl chloride as dissolved in 3 ml of dry THF was dropwise added thereto at -60° C. or lower. Then, the resulting product was gradually heated, and stirred for 4 hours at room temperature. The reaction mixture was poured into ice water, acidified with diluted hydrochloric acid, extracted with ethyl acetate, and washed with saturated saline. The resulting product was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through silica gel column chromatography to obtain the intended product from the fraction eluted with chloroform. The resulting product was crystallized and washed with diethyl ether to obtain 0.86 g of 3-(1-methyl-3,5-dichloropyrazol-4-yl)-2-(2-phenylthiazol-4-yl)-3-hydroxyacrylonitrile.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.O>[CH2:24]([O:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:4][CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1ccc(OCc2ccccc2)cc1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To a solution of 1.11 g (4.70 mmol) of tert-butyl 4-hydroxyphenethylcarbamate in 20 mL of DMF at 22° C. was added 1.3 g (9.4 mmol) of potassium carbonate and 0.700 mL (5.87 mmol) of benzyl bromide. The mixture was stirred for about 16 h at 22° C., diluted with 100 mL of water and extracted with ethyl acetate (3×75 mL). The organic layers were combined, washed with 100 mL of 1 N HCl, dried (Na2SO4), and evaporated. The residue was purified by flash chromatography on silica gel eluting with a mixture of hexane and ethyl acetate to give tert-butyl 4-(benzyloxy)phenethylcarbamate as an oil which later solidified under vacuum. Transformation of tert-butyl 4-(benzyloxy)phenethylcarbamate to tert-butyl 4-(benzyloxy)phenethyl(methyl)carbamate was accomplished in a manner analogous to Method B Step 1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(OCC)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CCOCC
Product: O=C(CN1CCCC1)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 95.3 %

Procedure:
2-bromo-1-(4-bromophenyl)ethanone (5.0 g, 18 mmol) was dissolved in 10 mL diethyl ether and added dropwise over 15 min to a solution of pyrrolidine (3.0 mL, 36 mmol) in 20 mL diethyl ether cooled to 0° C. in an ice bath. The resulting solution was allowed to warm to room temperature and maintained for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in 100 mL of EtOAc and washed with sodium bicarbonate (100 mL) and then brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4.6 g (96%) of the title compound as a yellow/orange solid. MS (ES) m/e 268/270 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C:14]([CH:17]([OH:19])[CH3:18])=[CH:15][S:16][C@H:11]12)=[O:8].CC(C)=O.[Cr](O)(O)(=O)=O>C(O)(C)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[CH:13]([C:20]([O:22][CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:21])[C:14]([C:17](=[O:19])[CH3:18])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=[Cr](=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC(=O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
To a stirred solution of 2.98 g. of benzhydryl 7-(2-thienylacetamido)-3-(1-hydroxyethyl)-2-cephem-4-carboxylate in 200 ml. of acetone was added dropwise 2.83 ml. of a 2.26 molar chromic acid solution. The reaction mixture was allowed to stir at room temperature for ten minutes, after which time approximately 10 ml. of isopropanol was added. The reaction mixture was stirred for 5 minutes and then evaporated in vacuo to dryness. The residue was taken up in a mixture of ethyl acetate and water and transferred to a separatory funnel with the aid of ethyl acetate. The organic layer was separated and washed successively with brine (4X), sodium bicarbonate solution, water, 1N.HCl, and brine (2X) and then dried over anhydrous sodium sulfate. The residue obtained upon evaporation in vacuo of the solution thereby obtained was chromatographed on a silica gel column using a toluene-ethyl acetate gradient to provide 2.11 g. (71.2 percent) of the title product:
Reaction SMILES: [CH2:1]([OH:8])[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].C([O:12][C@@H:13]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[C@@H:16]([CH2:27][O:28]C(=O)C)[O:15][C@H:14]1[O:32][C:33]1[C:37]([CH2:38][C:39]2[CH:44]=[CH:43][C:42](/[CH:45]=[CH:46]/[C:47](O)=[O:48])=[CH:41][CH:40]=2)=[C:36]([CH:50]([CH3:52])[CH3:51])[NH:35][N:34]=1)(=O)C.C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1OC1C(CC2C=CC(/C=C/CC(O)=O)=CC=2)=C(C(C)C)NN=1)(=O)C>>[C@@H:14]1([O:32][C:33]2[C:37]([CH2:38][C:39]3[CH:44]=[CH:43][C:42](/[CH:45]=[CH:46]/[C:47](=[O:48])[NH:7][C:2]([CH2:5][OH:6])([CH2:3][OH:4])[CH2:1][OH:8])=[CH:41][CH:40]=3)=[C:36]([CH:50]([CH3:52])[CH3:51])[NH:35][N:34]=2)[O:15][C@H:16]([CH2:27][OH:28])[C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:13]1[OH:12]
Reactant: NC(CO)(CO)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(/C=C/C(=O)NC(CO)(CO)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 26 using tris(hydroxymethyl)aminomethane and 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]phenyl}methyl)-5-isopropyl-1H-pyrazole instead of ammonium chloride and 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole, respectively.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[CH3:22][C:23]1([CH3:35])[CH2:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:31]([CH2:32][CH2:33]Cl)[C:25]=2[O:24]1>O>[CH3:22][C:23]1([CH3:35])[CH2:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:31]([CH2:32][CH2:33][O:1][C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[CH:4][CH:3]=3)[C:25]=2[O:24]1
Reactant: CC1(C)Cc2cccc(CCCl)c2O1
Reactant: CON(C)C(=O)Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)Nc1ccc(OCCc2cccc3c2OC(C)(C)C3)cc1
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
2.6 g of 1-(4-hydroxyphenyl)-3-methoxy-3-methylurea was dissolved into 20 ml of dried N,N-dimethylformamide, and 0.6 g of 60% sodium hydride was added thereto. After the mixture was stirred for 30 minutes, 1.7 g of 2-(2,3-dihydro-2,2-dimethyl-7-benzofuranyl)ethyl chloride was added dropwise thereto under cooling with ice. After the mixture was stirred at room temperature for 5 hours, it was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/1) as a developer to obtain 2.0 g of Compound No. 10 shown in Table 1.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])([O-])=O.O1CCCC1>C(O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cccc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cccc2c(N)cccc12

Procedure:
A solution of ethyl 5-nitro-1-naphthoate (3.304 g, 13.47 mmol) in ethanol (10 ml)-tetrahydrofuran (20 ml) was hydrogenated under normal temperature and normal pressure using 10% palladium/carbon (containing water by 50%) (0.5 g) as a catalyst until the starting material disappeared. The catalyst was filtered off and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: CCOCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([OH:30])/[CH:12]=[CH:13]/[C@@H:14]1[C@@H:18]([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C@@H:17]([OH:28])[CH2:16][C@H:15]1[OH:29].[H][H]>[Pd].C(OCC)(=O)C>[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([OH:30])/[CH:12]=[CH:13]/[C@@H:14]1[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C@@H:17]([OH:28])[CH2:16][C@H:15]1[OH:29]
Reactant: [H][H]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1O

Procedure:
Refer to Chart 36. The mixed formula-CC bis(THP ether) of the PGF2α compounds (Example 36, 1.5 g.) in 60 ml. of ethyl acetate are reduced at C5 -C6 by hydrogenation at about 25° C. in the presence of 200 mg. of 5% palladium-on-carbon with slightly over the theory for one equivalent of hydrogen. The solids are filtered off and the filtrate concentrated to yield the corresponding formula-CCXII bis(THP ether) of the PGF1α compounds having Rf 0.28 (TLC on silica gel in acetone-Skellysolve B (1:2)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]([F:16])[F:15])[C@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:20]([C:24]1[N:25]=[N:26][C:27](Cl)=[CH:28][C:29]=1[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:32][CH:31]=1)[CH2:21][CH2:22][CH3:23]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]([F:15])[F:16])[C@H:10]([O:17][C:27]2[N:26]=[N:25][C:24]([CH2:20][CH2:21][CH2:22][CH3:23])=[C:29]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:34][CH:35]=3)[CH:28]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(F)F)[C@H](O)C1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nnc(O[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2C(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
To a stirred solution of (±)-trans-4-difluoromethyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.52 mmol, 0.13 g) in anhydrous THF (1 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (1.08 mmol, 0.043 g) and continued stirring for 10 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.43 mmol, 0.15 g) in anhydrous THF (1 mL). After completion of addition, the reaction mixture was warmed to room temperature and stirred for 12 hours. The reaction was quenched with water (2 mL). The reaction was then extracted with ethyl acetate (5 mL). The ethyl acetate layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 12 g SiO2 cartridge using a gradient of ethyl acetate/hexanes to give (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-4-difluoromethyl-piperidine-1-carboxylic acid tert-butyl ester (0.18 g). LCMS: m/z 561 [M+1].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.[CH:15]1([C:18]2[C:19]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:20][CH:21]=[C:22]([CH:24]3[CH2:26][CH2:25]3)[CH:23]=2)[CH2:17][CH2:16]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:30]2[CH2:31][CH2:32][N:27]([C:19]3[C:18]([CH:15]4[CH2:16][CH2:17]4)=[CH:23][C:22]([CH:24]4[CH2:26][CH2:25]4)=[CH:21][N:20]=3)[CH2:28][CH2:29]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Product: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 73 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 38 and using 4-bromo-2-methanesulfonylbenzoic acid (2.29 g) and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (2 g) described in Preparation Example 62, the title compound (3.02 g) was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([NH2:10])=[CH:8][CH:9]=1)=O.[NH4+:11].[OH-]>>[NH2:10][C:7]1[S:6][C:5]([C:3]([NH2:11])=[O:2])=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(N)s1
Agent: [OH-]
Product: NC(=O)c1ccc(N)s1
Temperature: 60 °C
Yield: 47.4 %

Procedure:
A 18 ml vial was loaded with 5-amino-thiophene-2-carboxylic acid methylester (250 mg, 1.59 mmole) and 5 ml of 30% NH4OH. The vial was sealed and the mixture was heated at 60° C. for 24 hours. The mixture was cooled down and concentrated to give 200 mg crude product, 47.4% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][CH2:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=1.C[Si](C)(C)[N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.[F-].[Cs+].CCCCCC>CN(C=O)C.C(OCC)(=O)C>[Cl:13][C:11]1[CH:10]=[C:9]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[N:8]=[C:7]([CH2:6][CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([Cl:1])[CH:3]=2)[N:12]=1
Reactant: Clc1cccc(CCc2nc(Cl)cc(Cl)n2)c1
Reactant: C[Si](C)(C)n1ccnc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Clc1cccc(CCc2nc(Cl)cc(-n3ccnc3)n2)c1
Yield: 62.7 %

Procedure:
A solution of 2-(3-chlorophenethyl)-4,6-dichloropyrimidine (286 mg, 1 mmol) 91 in 3 mL of dry DMF was treated with 1-trimethylsilylimidazole (140 mg, 1 mmol) and CsF (152 mg, 1 mmol) at RT overnight. Aqueous work up and chromatography (silica gel, hexane:ethyl acetate, 1:1) gave 200 mg of 4-chloro-2-(3-chlorophenethyl)-6-(1-imidazolyl)pyrimidine (92).