Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(OCC)C>ClCCl>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(C#Cc2cn(-c3ccc(F)cc3)c(C)n2)ccn1
Reaction time: 8 h

Procedure:
2-Methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (II-1) (200 mg, 1.01 mmol) was dissolved in 10 mL dichloromethane. Powdered molecular sieves (3 Å, 200 mg), 4-fluorobenzene boronic acid (284 mg, 2.02 mmol) and [Cu(OH)TMEDA]2Cl2 (47 mg, 0.10 mmol) were added. Oxygen was bubbled through the reaction mixture for 5 min and stirring was continued at RT overnight. The reaction mixture was filtered through a dicalite speed plus pad and washed with 50 mL dichloromethane. The filtrate was washed with 50 ml water, dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0→85:15 gradient) and a mixture of 2 regioisomers was isolated. The desired compound was obtained by recrystallization from diethylether as a white solid (151 mg, 51%), mp=151° C., MS: m/e=292.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]2[NH:7][CH2:8][CH2:9][C@@H:4]2[CH2:3]1.[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.CCN(C(C)C)C(C)C>FC(F)(F)CO>[CH3:1][N:2]1[CH2:6][C@@H:5]2[N:7]([C:21]3[C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]([NH:17][C:14]4[N:13]=[C:12]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[C:11]([Cl:10])=[CH:16][N:15]=4)=[C:19]([O:28][CH3:29])[CH:20]=3)[CH2:8][CH2:9][C@@H:4]2[CH2:3]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: CN1C[C@H]2CCN[C@H]2C1
Solvent: OCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 49.6 %

Procedure:
(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,2-c]pyrrole (Intermediate 37, 91 mg, 0.72 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 250 mg, 0.60 mmol) and DIPEA (0.334 mL, 1.93 mmol) in 2,2,2-trifluoroethanol (3 mL) and the mixture was heated at 140° C. in a microwave for 0.5 h. The mixture was then absorbed onto silica. Purification by FCC, eluting with 2% 7N methnaolic ammonia in CH2Cl2 gave material that was concentrated in vacuo and dissolved in CH3OH. The resulting solution was absorbed onto an SCX column and the column was washed with CH3OH then eluted with 7N methanolic ammonia. Appropriate fractions were concentrated in vacuo to give the title compound (155 mg, 49%) as a orange/red gummy solid; 1H NMR: (CDCl3) 1.89 (1H, dd), 2.04-2.19 (1H, m), 2.24 (3H, s), 2.30-2.39 (1H, m), 2.40-2.57 (2H, m), 2.68 (1H, t), 2.98-3.11 (1H, m), 3.23 (1H, t), 3.51-3.63 (1H, m), 3.97 (3H, s), 4.36-4.48 (1H, m), 6.46 (1H, s), 6.90-7.02 (1H, m), 7.31-7.43 (2H, m), 8.38 (1H, s), 8.48 (1H, dd), 8.53-8.57 (1H, m), 8.82 (1H, s), 8.93 (1H, s); m/z: ES+ MH+ 521.45.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Li+].[Br-].[CH2:27]([OH:32])[CH2:28][CH2:29][C:30]#[CH:31]>N1CCCCC1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:31]#[C:30][CH2:29][CH2:28][CH2:27][OH:32])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: C#CCCCO
Reactant: O=S(=O)(Oc1ccc2c(ccn2-c2ccc(Br)cc2)c1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCNCC1
Product: OCCCC#Cc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 30.3 %

Procedure:
To 8.4 g (20 mmol) Trifluoro-methanesulfonic acid 1-(4-bromo-phenyl)-1H-indol-5-yl ester in 30 ml piperidine were added 2.08 g (24 mmol) LiBr, 580 mg (0.05 eq) [1,2-Bis(diphenylphosphino)ethane]dichloropalladium(II) and 2.8 ml (30 mmol) 4-pentyn-1-ol. The mixture was stirred at 60° C. for 3 h, further 0.5 ml (5.4 mmol) 4-pentynol were added and stirred at 70° C. for 1 h. The reaction mixture was concentrated and dissolved in ether and water. 2M HCl was added and the inorganic phase was extracted with ether. The combined organic phases were washed with water and concentrated. The residue was dissolved in 50 ml EtOH and treated with 5 ml conc. NaOH at 50° C. for 30 min. The solution was concentrated and dissolved in water and ether. The organic phase was washed with water, dried over Na2SO4 and concentrated. Column chromatography with CH2Cl2 yielded 2.15 g (30%) 5-[1-(4-Bromo-phenyl)-1H-indol-5-yl]-pent-4-yn-1-ol as colorless viscous oil, MS: 353 (M, 1Br).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6](O)[CH2:7][O:8][C:4]=2[CH:3]=1.Cl>C1COCC1.[Cl-].[Na+].O>[O:8]1[C:4]2[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=2[CH:6]=[CH:7]1
Reactant: Oc1ccc2c(c1)OCC2O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc2ccoc2c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-hydroxy-2,3-dihydrobenzofuran-3-ol (35.2 g, 0.2 mol) in THF (1.3 L) was added hydrochloric acid (323 mL, 1.0 N). The mixture was stirred at 65° C. for 2 h. After cooling to room temperature, it was diluted with brine (2.0 L), extracted with ethyl acetate (4.0 L), dried over magnesium sulfate, filtered and concentrated. The crude product was purified on a silica gel column, eluting with ethyl acetate (1-30%) in heptane. The final product was collected as light brown solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6]([CH:7]=[O:8])[C@:5]1([CH3:23])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1.CC12C(C)(C)C(C(OC[C@@H]3[C@H](COC)[C@]3(C)C3C=CC4C(C)(C)CCC(C)(C)C=4C=3)=O)(CC1)OC2=O>>[CH3:1][O:2][CH2:3][C@H:4]1[C@@H:6]([CH:7]=[O:8])[C@@:5]1([CH3:23])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([CH3:20])([CH3:19])[CH2:14][CH2:13][C:12]([CH3:22])([CH3:21])[C:11]=2[CH:10]=1
Reactant: COC[C@@H]1[C@H](C=O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC[C@H]1[C@@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: COC[C@H]1[C@@H](C=O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 99 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 12a but using Intermediate 9a as the starting material afforded the title compound (42 mg, 99% yield) as a colorless oil:
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=1)[O:11][CH2:10][CH2:9]2.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:19])[C@@:3]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:27](=[O:28])[C:24]4[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=4)[CH:16]=3)[O:11][CH2:10][CH2:9]2)[N:4]=1
Reactant: NC1=N[C@@]2(CCOc3ccc(N)cc32)C(F)(F)CO1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: NC1=N[C@@]2(CCOc3ccc(NC(=O)c4ccc(Cl)cn4)cc32)C(F)(F)CO1
Yield: 56 %

Procedure:
The condensation of (R)-5′,5′-difluoro-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazine]-2′,6-diamine (intermediate B7.1) and 5-chloropicolinic acid yielded the title compound (56% yield) as a white solid. MS (ISP): m/z=409.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:14]([O:16]C)=[O:15])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:18][C:19]([NH2:21])=[O:20].C(O)C.[OH-].[Li+].Cl>C(OCC)(=O)C.CO.C1COCC1>[NH2:21][C:19]1[O:20][CH:2]=[C:3]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]3)=[CH:9][CH:10]=2)[N:18]=1
Reactant: NC(N)=O
Reactant: COC(=O)C1(c2ccc(C(=O)CCl)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nc(-c2ccc(C3(C(=O)O)CC3)cc2)co1

Procedure:
A mixture of methyl 1-[4-(chloroacetyl)phenyl]cyclopropanecarboxylate (0.20 g, 0.00079 mol, example 243, steps 1 & 2) and urea (0.095 g, 0.0016 mol) in ethanol (5.0 mL, 0.086 mol) was refluxed overnight. The mixture was diluted with ethyl acetate and washed with sat'd. NaHCO3, brine, dried and concentrated. The methyl ester was purified by CombiFlash using CH2Cl2/EtOAc (max. EtOAc 100%). The ester was hydrolyzed using lithium hydroxide (6.0 eq.) in methanol/THF and then acidified by adding 1 N HCl. The solvent was removed under vacuum and the crude product was used in the next step. LC-MS: 259.2 (M+H+) methyl eater; 245.2 (M+H+) acid
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.O.[CH3:12][N:13](C=O)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[NH:8]1[C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:12]#[N:13])[C:3]=2[CH:10]=[CH:9]1
Reactant: Brc1cncc2[nH]ccc12
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Solvent: O
Product: N#Cc1cncc2[nH]ccc12
Temperature: 120 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A mixture of 4-bromo-1H-pyrrolo[2,3-c]pyridine (320 mg, 1.62 mmol), Pd(dppf)Cl2 (131 mg, 0.179 mmol), zinc cyanide (190 mg, 1.62 mmol), and zinc powder (21 mg, 0.324 mmol) in DMF (20 mL) was stirred at 120° C. for 2 h. The reaction mixtue was cooled to RT and H2O (100 mL) was added. The reaction mixture extracted with EtOAc (3×50 mL). The organic layers were concentrated tinder reduced pressure and the crude residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (1:1) to afford 232 mg (99.8%) of 1H-pyrrolo[2,3-c]pyridine-4-carbonitrile as yellow solid: MS (ESI) m/z: 144.2 [M+1]+.
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][C:5]1([CH3:22])[CH:9]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])[N:8]2[C:18](=[O:21])[CH:19]([NH2:20])[C@H:7]2[S:6]1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[C:41]([C:42](Cl)=[O:43])=[C:40]([CH3:45])[O:39][N:38]=1>C(Cl)Cl>[Br:2][CH2:3][CH2:4][C:5]1([CH3:22])[CH:9]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])[N:8]2[C:18](=[O:21])[CH:19]([NH:20][C:42]([C:41]3[C:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[Cl:30])=[N:38][O:39][C:40]=3[CH3:45])=[O:43])[C@H:7]2[S:6]1
Reactant: CC1(CCBr)S[C@@H]2C(N)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)(CCBr)S[C@H]12
Reaction time: 33 h
Yield: 70.2 %

Procedure:
A solution of 2,2,2-trichloroethyl 2-bromoethyl-2-methyl-6-aminopenam-3-carboxylate hydrochloride (6.95 g) and triethylamine (3.0 g) in dried methylene chloride (100 ml) was cooled at -25° C. To this solution was added dropwise a solution of 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl chloride (4.5 g) in dried methylene chloride (30 ml), and the mixture was stirred for 33 hours at the same temperature. After the reaction was completed, the reaction mixture was post-treated in the similar manner as described in Example 1 to give oily 2,2,2-trichloroethyl 2-bromoethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate (6.75 g).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12](O)([CH3:14])[CH3:13])[C:4]=2[S:5][C:6]=1[CH3:7].CCN(CC)CC.CS(Cl)(=O)=O>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([CH3:14])=[CH2:13])[C:4]=2[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc2c(C(C)(C)O)cccc2c1Br
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)c1cccc2c(Br)c(C)sc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.1 %

Procedure:
A solution of 2-(3-bromo-2-methyl-benzo[b]thiophen-7-yl)-propan-2-ol (0.98 g, 3.45 mmol) in CH2Cl2 910 mL) is treated with Et3N (0.72 mL, 5.18 mmol) and MsCl (0.29 mL, 3.80 mmol) at) 0° C. The reaction is stirred at 0° C. for 10 min, and at RT overnight. It is diluted with EtOAc (50 mL), washed with 0.1 M HCl (10 m), H2O (20 mL); dried with Na2SO4, filtered and concentrated. Purification of the crude material by silica gel chromatography gives the title compound (0.36 g, 1.35 mmol, 39%). 1H NMR (CDCl3): δ) 2.23 (s, 3H), 2.56 (s, 3H), 5.40 (s, 1H), 5.49 (s, 1H), 7.28 (s, 1H), 7.41 (t, J=7.1 Hz, 1H), 7.64 (d, J=7.9 Hz, 1H) ppm.
Reaction SMILES: [C:1]([C:3]([C:18]1[S:22][C:21]([Br:23])=[CH:20][CH:19]=1)([CH:15]([CH3:17])[CH3:16])[CH2:4][CH2:5][CH2:6]O[Si](C(C)(C)C)(C)C)#[N:2].C(C(C1SC(Br)=CC=1)(C(C)C)CCCO)#N.[C:40]([C:42]1[CH:43]=[C:44]([CH:54]=[CH:55][CH:56]=1)[O:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)#[N:41].C(C(C1C=CSC=1)(C(C)C)CCCN1CCN(CCOC2C=CC=C(F)C=2)CC1)#N>>[C:1]([C:3]([C:18]1[S:22][C:21]([Br:23])=[CH:20][CH:19]=1)([CH:15]([CH3:16])[CH3:17])[CH2:4][CH2:5][CH2:6][N:51]1[CH2:50][CH2:49][N:48]([CH2:47][CH2:46][O:45][C:44]2[CH:54]=[CH:55][CH:56]=[C:42]([C:40]#[N:41])[CH:43]=2)[CH2:53][CH2:52]1)#[N:2]
Reactant: N#Cc1cccc(OCCN2CCNCC2)c1
Reactant: CC(C)C(C#N)(CCCO[Si](C)(C)C(C)(C)C)c1ccc(Br)s1
Agent: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(F)c2)CC1)c1ccsc1
Agent: CC(C)C(C#N)(CCCO)c1ccc(Br)s1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(C#N)c2)CC1)c1ccc(Br)s1

Procedure:
By using [4-cyano-5-methyl-4-(2-bromo-5-thienyl)hexyloxy]-tert-butyldimethylsilane (700 mg) which was obtained in Example 114-5) described in JP-A 11-206862, 4-cyano-5-methyl-4-(2-bromo-5-thienyl)hexanol (371 mg, 80%) was synthesized as a yellow oil in accordance with Example 114-8) described in JP-A 11-206862. From 105 mg of the resulting compound and 96 mg of 2-(3-cyanophenoxy)ethylpiperazine, the title compound was synthesized as a colorless oil in accordance with the production method described in Example 84 (138 mg, 62%).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[NH:13][C:12](=[O:14])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:17]([N:13]1[CH:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:10][CH2:11][C:12]1=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCCCOC1CCC(=O)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCOC1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a mixture of 4 g of 5-(n-heptyloxy)-pyrrolidin-2-one, 1.68 g of potassium hydroxide hydrated to 85% and 0.4 g of tetra-n-butylammonium bromide in 55 cm3 of tetrahydrofuran, there is added a solution of 3.43 g of benzyl bromide in 20 cm3 of tetrahydrofuran, operating at 20° C. to 25° C. After agitating for 1 hour at ambient temperature, filtering, and evaporating the solvent to dryness under reduced pressure, the residue is chromatographed on silica (eluent: ethyl acetate--n-hexane, 1-2), and 4.54 g of the expected product is obtained.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH2:7].[CH3:16][CH2:17][CH2:18][C:19](=O)[CH2:20][CH2:21][CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.O.C(N(CC)CC)C>[Br:2][C:3]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH:7][CH:19]([CH2:20][CH2:21][CH3:22])[CH2:18][CH2:17][CH3:16]
Reactant: CCCC(=O)CCC
Reactant: NCCc1ccc(C(F)(F)F)cc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCC(CCC)NCCc1ccc(C(F)(F)F)cc1Br
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
Added to a suspension of 1 g of 2-bromo-4-trifluoromethylphenethylamine hydrocloride in 25 cm3 of dichloroethane and under an inert atmosphere is 0.5 cm3 of triethylamine. After stirring for 30 min at a temperature close to 20° C., 5 cm3 of distilled water are added and the stirring is continued for 30 min. The two phases are separated and the organic phase is dried. Added to the solution obtained are successively 375 mg of 4-heptanone and 970 mg of sodium triacetoxyborohydride. The reaction mixture is stirred for 15 h at a temperature close to 20° C. 20 cm3 of a saturated solution of sodium hydrogen carbonate are then added to the reaction medium. The organic phase is decanted and separated from the aqueous phase then washed successively with 15 cm3 of distilled water and 15 cm3 of a saturated solution of sodium chloride. The organic phase is dried then concentrated using a rotary evaporator under reduced pressure (5 kPa). 1.16 g of N-[2-(2-bromo-4-trifluoromethylphenyl)ethyl]heptan-4-amine are obtained in the form of a colorless oil.
Reaction SMILES: Br[CH:2]=[C:3]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[Cl:32][C:33]1[CH:41]=[CH:40][C:39]2[NH:38][C:37]3[CH2:42][CH2:43][N:44]([CH3:46])[CH2:45][C:36]=3[C:35]=2[CH:34]=1>CN(C=O)C.[Cu]I>[Cl:32][C:33]1[CH:41]=[CH:40][C:39]2[N:38](/[CH:2]=[C:3](\[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)/[C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[C:37]3[CH2:42][CH2:43][N:44]([CH3:46])[CH2:45][C:36]=3[C:35]=2[CH:34]=1
Reactant: BrC=C(c1ccccc1)c1ccncc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2/C=C(\c2ccccc2)c2ccncc2)C1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
4-(2-Bromo-1-phenylvinyl)pyridine (310 mg, 1.1 mmol) was dissolved in DMF (5 mL) and potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (220 mg, 1 mmol) was added and the mixture purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the solid mass was filtered under vacuum. The crude compound was purified on silica gel (100-200 mesh) using 0-10% MeOH:DCM as eluent. The compound was further purified through reverse phase HPLC. Yield: 20 mg (TFA salt). 1HNMR (CDCl3, TFA salt) δ (ppm): 8.78 (d, 2H), 7.64 (d, 2H), 7.40-7.28 (m, 5H), 7.10 (m, 2H), 6.92 (d, 2H), 4.65 (m, 1H), 4.0 (m, 1H), 3.60 (m, 1H), 3.05 (m, 1H), 2.84 (s, 3H), 2.76 (m, 2H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C@@H:13]([OH:24])[CH2:12][C@H:11]1[OH:25])=[O:7].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH2:8][CH2:9][C@H:10]1[C:11](=[O:25])[CH2:12][C@H:13]([OH:24])[C@@H:14]1[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:7]
Reactant: CCCCCC(=O)CC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCCCCC(=O)CC[C@H]1C(=O)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O

Procedure:
Carboxylic acid (8) was deketalized according to the usual method to give 13,14-dihydro-15-keto-PGF2 α (10). The resultant (10) was oxidized with Jones reagent to give 13,14-dihydro-15-keto-PGD2 (11), R=H.
Reaction SMILES: CI.[Br:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([OH:11])=[C:6]([Cl:12])[CH:5]=1.[C:13](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([O:11][CH3:13])=[CH:8][C:9]=1[Cl:10]
Reactant: Oc1cc(Cl)c(Br)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1cc(Cl)c(Br)cc1Cl
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 75.2 %

Procedure:
Methyl iodide (1.861 mL, 29.76 mmol) was added to a stirred suspension of 4-bromo-2,5-dichlorophenol (4.8 g, 19.84 mmol) and potassium carbonate (8.23 g, 59.53 mmol) in DMF (20 mL) at ambient temperature under air. The resulting suspension was stirred at 50° C. for 90 minutes. The reaction mixture was allowed to cool and diluted with EtOAc (200 mL), and washed sequentially with saturated brine (2×150 mL) and water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 1-bromo-2,5-dichloro-4-methoxybenzene (3.82 g, 75%) as a brown solid.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.I[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28].[CH:32]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([CH:41]=1)[C:39]#[N:40])=[CH2:33]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[C:27]([C:26]1[CH:25]=[C:24]([CH:33]=[CH:32][C:34]2[CH:35]=[N:36][CH:37]=[C:38]([CH:41]=2)[C:39]#[N:40])[CH:31]=[CH:30][CH:29]=1)#[N:28]
Reactant: N#Cc1cccc(I)c1
Reactant: C=Cc1cncc(C#N)c1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: N#Cc1cccc(C=Cc2cncc(C#N)c2)c1
Yield: 59 %

Procedure:
Prepare essentially as described in EXAMPLE 15 using palladium(II) acetate (0.009 g, 0.04 mmol), tri-o-tolylphosphine (0.024 g, 0.08 mmol), copper (I) iodide (0.004 g, 0.02 mmol), 3-iodobenzonitrile (0.9 g, 3.93 mmol) and 5-vinylnicotinonitrile, (prepared essentially as described in PREPARATION 51), (0.715 g, 5.5 mmol) at 110° C. for 5 h. Add diethyl ether and wash with water three times. Filter the organic layer and concentrate to give the title compound (0.530g, 59%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]([O:29][CH2:30][C:31]([NH:33][CH2:34][CH3:35])=[O:32])[C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[CH:12]=[CH:13][CH:14]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]([C@@H:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[O:29][CH2:30][C:31]([NH:33][CH2:34][CH3:35])=[O:32])[CH:12]=[CH:13][CH:14]=1
Reactant: CCNC(=O)COC(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)COC(c1cccc(Cl)c1)[C@@H]1CCCNC1
Yield: 912.7 %

Procedure:
To a stirred solution of TFA in CH2Cl2 (20% v/v, 5 mL) was added (3R)-tert-butyl 3-((3-chlorophenyl)(2-(ethylamino)-2-oxoethoxy)methyl)piperidine-1-carboxylate (57.9 mg, 0.0141 mmol). The reaction was monitored by tlc (elution solvent: 5:1 petroleum ether/EtOAc). When the reaction was complete, the mixture was washed with satd aq NaHCO3 and water, dried over Na2SO4 and concentrated to give 2-((3-chlorophenyl)((R)-piperidin-3-yl)methoxy)-N-ethylacetamide (40 mg, 91%). MS (E/Z): 311 (M+H+).
Reaction SMILES: [N:1]1([CH:6]2[CH2:9][N:8]([CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:20]>C(OCC)C.O1CCOCC1>[ClH:20].[ClH:20].[N:1]1([CH:6]2[CH2:9][N:8]([CH2:10][CH2:11][NH2:12])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)NCCN1CC(N2CCCC2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCCN1CC(N2CCCC2)C1

Procedure:
460 mg of tert-butyl {2-[3-(pyrrolidin-1-yl)azetidin-1-yl]ethyl}carbamate (Example 220A, 1.7 mmol, 1 equivalent) were initially charged in 8.54 ml of 2 N hydrochloric acid in diethyl ether and 1 ml of dioxane, and the mixture was stirred at RT overnight. The precipitated solid was filtered off, washed with diethyl ether and dried under reduced pressure. This gave 390 mg (94% of theory) of the title compound.