Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:5]=2[O:4][CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[CH:17]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[C:31]1=[O:40])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.ClCCCl>[C:24]1([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([OH:39])([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[C:10]=3[OH:11])[C:31]2=[O:40])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1cccc2c1OCCO2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1O)OCCO2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69.3 %

Procedure:
To a solution of 2,3-dihydro-1,4-benzodioxin-5-ol (3.60 g, 23.7 mmol) in anhydrous tetrahydrofuran (80 mL) at 0° C. was added isopropylmagnesium chloride (11.8 mL, 2 M solution in tetrahydrofuran, 23.7 mmol). The mixture was stirred at 0° C. for 45 min, concentrated in vacuo, and 1,2-dichloroethane (60 mL) was added. The mixture was cooled to 0° C. and a solution of 1-benzhydrylindoline-2,3-dione (4.94 g, 15.8 mmol) in 1,2-dichloroethane (70 mL) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 60 h, and heated to 83° C. and stirred for 3.5 h. The reaction mixture was allowed to cool to ambient temperature, concentrated in vacuo and saturated aqueous ammonium chloride (250 mL) was added. The mixture was extracted with ethyl acetate (250 mL followed by 2×100 mL). The organic phase was washed with water (150 mL) and brine (150 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and a solid was precipitated by the addition of hexanes to afford 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (5.10 g, 69%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ9.14 (s, 1H), 7.43-7.30 (m, 9H), 7.22 (d, J=8.7 Hz, 1H), 6.97-6.79 (m, 3H), 6.52 (s, 1H), 6.44 (d, J=8.7 Hz, 1H) 6.26 (d, J=7.8 Hz, 1H), 4.22 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([N+:20]([O-])=O)=[C:4]([NH:23][C:24](=[O:26])[CH3:25])[CH:3]=1>CO.C(Cl)Cl.[Pd]>[NH2:20][C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)=[N:7][C:2]([Cl:1])=[CH:3][C:4]=1[NH:23][C:24](=[O:26])[CH3:25]
Reactant: CC(=O)Nc1cc(Cl)nc(NCc2ccc3ncccc3c2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1cc(Cl)nc(NCc2ccc3ncccc3c2)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(6-chloro-3-nitro-2-(quinolin-6-ylmethylamino)pyridin-4-yl)acetamide (220 mg, 0.593 mmol) in methanol (5 mL) and CH2Cl2(5 mL) was added 10% catalytical amount Pd/C. The reaction mixture was stirred at room temperature under 1 atm of H2 for 1 h, then filtered. The filtrate was concentrated to afford the title compound, which was used for the next step without further purification. MS (m/z): 342 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:15]3[CH:16]=[CH:17][C:18]4[C:22]([CH:23]=3)=[N:21][N:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=4)[CH:6]=2)[CH2:2]1.[CH3:31][N:32]([CH3:37])[CH2:33][C:34](O)=[O:35].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:24]([N:20]1[CH:19]=[C:18]2[C:22]([CH:23]=[C:15]([C:7]3[CH:6]=[C:5]([CH:3]4[CH2:4][N:1]([C:34](=[O:35])[CH2:33][N:32]([CH3:37])[CH3:31])[CH2:2]4)[N:13]4[C:8]=3[C:9]([NH2:14])=[N:10][CH:11]=[N:12]4)[CH:16]=[CH:17]2)=[N:21]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ncnn2c(C3CNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.4 %

Procedure:
A mixture of 7-azetidin-3-yl-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (20 mg, 0.051 mmol), N,N-dimethylglycine (5.7 mg, 0.056 mmol), EDCl (11.6 mg, 0.061 mmol), HOBt (8.2 mg, 0.061 mmol), and N,N-diisopropylethylamine (26 μL, 0.15 mmol) in DMF (1 mL) was stirred at rt for 16 h. The crude reaction mixture was purified via preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 5 mg (21%) of the desired product. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1 H), 7.79-7.85 (m, 2 H), 7.67 (s, 1 H), 7.29-7.37 (m, 5 H), 7.25 (d, 1 H), 6.81 (s, 1 H), 5.65 (s, 2 H), 4.70 (t, 1 H), 4.25-4.54 (m, 4 H), 3.18 (s, 2 H), 2.38 (s, 6 H); ES-MS m/z 481.10 [M+H]+, HPLC RT (min) 2.07.
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])(=O)=O.O>CC(C)=O>[I:1][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CS(=O)(=O)OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCI
Yield: 93.2 %

Procedure:
Sodium iodide (10.32 g, 68.88 mmol) was added to a solution of 1-methanesulfonyloxy-5,5,6,6,7,7,8,8,8-nonafluorooctane (8.5 g, 22.96 mmol) in acetone (300 ml), followed by heating under reflux for 12 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with 1% aqueous sodium thiosulfate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give 1-iodo-5,5,6,6,7,7,8,8,8-nonafluorooctane (8.6 g, Yield 93%).
Reaction SMILES: C(OC(N1C[CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[O:31](CCN)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[O:31]([CH2:11][CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCCOc1ccccc1
Product: O=C(NCCOc1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-phenoxyethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 379 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93 (1H, br. s.) 10.42 (1H, s) 8.34 (1H, t, J=5.47 Hz) 8.04 (1H, d, J=6.15 Hz) 7.85 (1H, d, J=5.37 Hz) 7.42 (1H, d, J=5.37 Hz) 7.37 (1H, d, J=3.51 Hz) 7.21-7.28 (2H, m) 6.89-6.97 (1H, m) 6.87 (2H, dd, J=8.74, 1.02 Hz) 6.77 (1H, d, J=6.25 Hz) 6.58 (1H, d, J=3.32 Hz) 4.04 (2H, t, J=5.95 Hz) 3.60 (2H, q, J=5.92 Hz)
Reaction SMILES: [CH2:1](OC(=O)C(OC1C=C(C(F)(F)F)C=C(N)C=1)(C)C)C.[CH2:21]([O:23][C:24](=[O:47])[C:25]([O:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:30]=1)([CH3:27])[CH3:26])[CH3:22].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH2:21]([O:23][C:24](=[O:47])[C:25]([O:28][C:29]1[CH:34]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:32]=[C:31]([N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH3:1])[CH:30]=1)([CH3:27])[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Oc1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C(C)(C)Oc1cc(N)cc(C(F)(F)F)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Oc1cc(N(C)C(=O)OC(C)(C)C)cc(C(F)(F)F)c1

Procedure:
In analogy to the procedures described in example 5D], 5E] and 5F], 2-(3-amino-5-trifluoromethyl-phenoxy)-2-methyl-propionic acid ethyl ester was converted into 2-(3-tert-butoxycarbonylamino-5-trifluoromethyl-phenoxy)-2-methyl-propionic acid ethyl ester by treatment with di-tert-butyl dicarbonate and sodium hydrogen carbonate in dioxane/water at r.t., methylated at nitrogen to yield 2-[3-(tert-butoxycarbonyl-methyl-amino)-5-trifluoromethyl-phenoxy]-2-methyl-propionic acid ethyl ester and deprotected again to yield the title compound as light yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[F:20][C:21]1[C:28]([F:29])=[C:27]([CH3:30])[C:26]([F:31])=[C:25]([F:32])[C:22]=1[CH2:23]Br.C([O-])([O-])=O.[K+].[K+]>>[F:20][C:21]1[C:28]([F:29])=[C:27]([CH3:30])[C:26]([F:31])=[C:25]([F:32])[C:22]=1[CH2:23][N:8]([CH2:7][C:6]1[CH:18]=[CH:19][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[C:9]1[CH:17]=[CH:16][C:12]2[NH:13][CH:14]=[N:15][C:11]=2[CH:10]=1
Reactant: Cc1c(F)c(F)c(CBr)c(F)c1F
Reactant: CCc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(CN(Cc2c(F)c(F)c(C)c(F)c2F)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-ethylbenzyl)benzimidazol-5-amine (251 mg; 1 mmol; 1 eq.), 2,3,5,6-tetrafluoro-4-methylbenzylbromide (283 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.051 g (11.9%); MS m/z: 428.4 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.11 (t, 3H, 3J=7.6 Hz); 2.18 (s, 3H); 2.50-2.54 (m, 2H); 4.47 (s, 2H); 4.70 (s, 2H); 6.87-6.91 (m, 2H); 7.07 (d, 2H, 3J=7.9 Hz); 7.14 (d, 2H, 3J=7.9 Hz); 7.37 (d, 1H, 3J=8.9 Hz), 7.96 (s, 1H); 12.05 (br s, 1H); HPLC (METHOD [A]): rt 19.03 min (93.3%)
Reaction SMILES: CN(CCN(C)C)C.[C:9]1([N:15]2[CH:19]=[CH:18][CH:17]=[CH:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([Li])CCC.[C:25]12([P:35]([C:37]34[CH2:46][CH:41]5[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]5)[CH2:38]3)[CH2:44]4)Cl)[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2>CCCCCC.O>[C:9]1([N:15]2[CH:19]=[CH:18][CH:17]=[C:16]2[P:35]([C:37]23[CH2:38][CH:39]4[CH2:40][CH:41]([CH2:42][CH:43]([CH2:45]4)[CH2:44]2)[CH2:46]3)[C:25]23[CH2:26][CH:27]4[CH2:33][CH:31]([CH2:30][CH:29]([CH2:28]4)[CH2:34]2)[CH2:32]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Reactant: c1ccc(-n2cccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: c1ccc(-n2cccc2P(C23CC4CC(CC(C4)C2)C3)C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1.6 ml of TMEDA (15 mmol.) are added to a suspension of 1.43 g (10 mmol.) of N-phenylpyrrole in 30 ml of hexane. 6.25 ml of 1.6 molar n-butyllithium solution (10 mmol.) are added at room temperature. The mixture is then heated for 2.5 hours at reflux temperature (solution 1). In another flask, 3.36 g (10 mmol.) of di-1-adamantylchlorophosphane are mixed with 40 ml of hexane and heated to 76° C. (solution 2). The boiling solution 1 is then slowly transferred into solution 2, which is at 76° C., by means of a cannula. The mixture is then boiled for a further 2 hours at reflux, the solution is cooled, and 20 ml of water are added thereto. The organic phase is filtered off over magnesium sulfate. The solution is concentrated in vacuo; 15 ml of toluene are added thereto, and the mixture is heated to 60° C. and then cooled. After one day at room temperature, the product is filtered off. Yield: 3.3 g (75%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].C(N(CC)CC)C>C(Cl)Cl>[CH3:25][O:24][C:22]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([Cl:26])[CH:28]=1)=[CH:10][CH:9]=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:23]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1c(CNC(=O)c2cccc(Cl)c2)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3-(aminomethyl)-7-methoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylate (intermediate K) (30 mg, 0.089 mmol), 3-chlorobenzoyl chloride (35 mg, 0.200 mmol), and triethylamine (40 mg, 0.305 mmol) in methylene chloride (4 mL) was stirred at 0° C. for 1 hr. After this time, the reaction mixture was concentrated, and the crude material was triturated with diethyl ether. The product 3-[(3-chloro-benzoylamino)-methyl]-7-methoxy-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was obtained without further purification. MS calcd. for C26H21ClN2O5 [(M+H)+] 477.1, obsd. 476.9.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[CH:11]1([N:17]([C@H:35]2[CH2:40][CH2:39][C@H:38]([CH3:41])[CH2:37][CH2:36]2)[C:18](=[O:34])[NH:19][C:20]2[S:21][C:22]([S:25]([N:28]([CH2:30][C:31](O)=[O:32])[CH3:29])(=[O:27])=[O:26])=[CH:23][N:24]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCN=C=NCCCN(C)C.[CH:53]([N:56](C(C)C)[CH2:57][CH3:58])(C)[CH3:54].C(NCC)C>CN(C=O)C>[CH:11]1([N:17]([C@H:35]2[CH2:36][CH2:37][C@H:38]([CH3:41])[CH2:39][CH2:40]2)[C:18](=[O:34])[NH:19][C:20]2[S:21][C:22]([S:25]([N:28]([CH3:29])[CH2:30][C:31]([N:56]([CH2:57][CH3:58])[CH2:53][CH3:54])=[O:32])(=[O:27])=[O:26])=[CH:23][N:24]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(CC(=O)O)S(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)CN(C)S(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An equimolar mixture of HOBt, ({2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-methyl-amino)-acetic acid was added EDAC (1.5 eq) and diisopropylethyl amine (1.2 eq) and dry DMF (10 mL/mmol). The solution was stirred 30 min at rt and then diethyl amine (1.5 eq) was added and stirring was continued over night.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[CH3:10][O:11][C:12]1[CH:23]=[CH:22][C:15]([C:16]([NH:18][C:19](=[O:21])[CH3:20])=S)=[CH:14][CH:13]=1.Cl.Cl.[NH2:26][CH:27]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:28]([NH:30][C:31]1([C:38]#[N:39])[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)=[O:29].C(N(CC)C(C)C)(C)C>ClCCl>[C:19]([N:18]=[C:16]([NH:26][CH:27]([CH2:40][CH:41]1[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1)[C:28]([NH:30][C:31]1([C:38]#[N:39])[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]1)=[O:29])[C:15]1[CH:22]=[CH:23][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)(=[O:21])[CH3:20]
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: COc1ccc(C(=S)NC(C)=O)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=NC(C)=O)NC(CC2CCCCC2)C(=O)NC2(C#N)CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Chloro-N-methylpyridinium iodide (660 mg, 2.58 mmol), was added to a solution of N-(4-methoxy-thiobenzoyl)acetamide (420 mg, 2.01 mmol), 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt (730 mg, 2.00 mmol), and N,N-diisopropylethylamine (1.05 mL, 6.02 mmol) in dichloromethane (8.0 mL). The reaction mixture was stirred at room temperature for 2 h, then diluted with dichloromethane (100 mL)and washed with 2×150 mL of saturated sodium bicarbonate. The organic phase was dried (MgSO4) and concentrated. The resulting residue was chromatographed over 100 g of flash silica first using EtOAc, then dichloromethane/methanol 9:1 as the eluant to provide the desired product as an off white solid (377 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ 0.70-0.90 (m, 2H), 1.00-1.30 (m, 4H), 1.35-1.65 (m, 8H), 1.72 (s, 3H), 1.85-2.20 (m, 6H), 2.48-2.60 (m, 1H), 3.78 (s, 3H), 4.20-4.35 (m, 1H), 6.95-6.99 (m, 2H), 7.33 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H). MS, m/z 468=M+1.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CN(C=O)C>C(Cl)Cl>[CH2:5]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][Cl:3])=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCOc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(CCl)cc1
Reaction time: 0.12 h

Procedure:
Thionyl chloride (38.8 g, 328 mmol) was added dropwise to a 0° C. solution of 4-Dodecyloxybenzyl alcohol (80.0 g, 274 mmol) in dry CH2Cl2 (900 mL) with a catalytic amount of DMF. Upon addition, reaction was allowed to stir for 5-10 minutes, while monitoring through TLC (CH2Cl2) for completion. Reaction mixture was concentrated under reduced pressure and the resulting residue re-crystallized from acetone to give the title benzyl chloride, decomposes upon melting. 77g (92%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C(O)(C(F)(F)F)=O.[H-].[Na+]>>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][O:7]2)[N:3]=1
Reactant: Cc1cc[nH]n1
Reactant: C1=COCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn(C2CCCCO2)n1
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A mixture of 3-methylpyrazole (3.0 g, 35.4 mmol), 3,4-dihydro-2H-pyrane (4.97 mL, 53.2 mmol) and TFA (0.02 mL, 0.260 mmol) was stirred at 85° C. for 6 h under an argon atmosphere. The RM was cooled to RT and NaH 60% in mineral oil (0.061 g, 1.524 mmol) was and the RM was stirred for 10 min. The RM was purified by bulb-to-bulb distillation to give 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (b.p. 150-170° C., 12 mbar). A solution of n-1.6 M BuLi in n-hexane (3.38 mL, 5.41 mmol) was added dropwise over 10 min to a solution of 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.0 g, 5.41 mmol) in THF (12 mL) at −70° C. under a nitrogen atmosphere and The RM was stirred for 10 min and then treated dropwise with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.898 g, 5.69 mmol) and stirred at −70° C. for 1 h. The RM was allowed to warm to RT, treated with n-hexane and the product was filtered, dissolved in water (10 mL) and acidified to pH 6 with 10% aqueous citric acid. The water was evaporated off under reduced pressure and the aqueous residue extracted with EtOAc, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as a yellow resin. UPLC-MS (Condition 3) tR=0.56 min, m/z=211.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[C:5]#[N:6].Cl.[NH2:12][OH:13].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])/[C:5](=[N:12]/[OH:13])/[NH2:6]
Reactant: NO
Reactant: N#Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N/C(=N\O)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 3,4-dichlorobenzonitrile (2.000 g, 11.63 mmol), hydroxylamine hydrochloride (1.649 mL, 12.79 mmol) and sodium hydroxide (4.15 mL, 12.4 mmol) in ethanol (40 mL) was stirred at rt for 1 h. Concentrated and refluxed in hexane for 30 min and concentrated in vacuo. The product Intermediate 1A was used directly for the next step. HPLC/MS (Method C) RT=1.24 min [M+H]+ 204.9.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[CH:3]=1.C(Cl)(Cl)Cl.[Br:26]N1C(=O)CCC1=O.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][Br:26])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[CH:3]=1
Reactant: Cc1ccc2nc(-c3ccccc3[N+](=O)[O-])cc(Cl)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1ccccc1-c1cc(Cl)c2cc(CBr)ccc2n1
Temperature: 25 °C
Yield: 44.3 %

Procedure:
To 27.6 g (92.4 mmol) of the 4-chloro-6-methyl-2-(2-nitrophenyl)quinoline obtained in Example 1, 110 ml of chloroform was added. After stirring, 15.6 g (87.8 mmol) of N-bromosuccinimide (NBS) was added thereto. Then, 15 ml of chloroform containing 0.78 g of 2,2'-azobis(2,4-dimethylvaleronitrile) was added dropwise thereto, and the thus-prepared mixture was heated under reflux for 1 hour. After cooling to room temperature, the mixture was poured into 220 ml of water and separated out, and the organic layer was washed with 110 ml of water twice. Next, the washed organic layer was evaporated and dried in an evaporator and recrystallized from toluene to obtain 14.7 g of 4-chloro-6-(bromomethyl)-2-(2-nitrophenyl)quinoline.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH2:17]([NH:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][C:28]([OH:32])=[CH:29][CH:30]=2)[N:25]([CH3:33])[C:24]=1[CH3:34])=[O:22])[CH2:18][CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:17]([NH:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][C:28]([O:32][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:29][CH:30]=2)[N:25]([CH3:33])[C:24]=1[CH3:34])=[O:22])[CH2:18][CH3:19]
Reactant: CCCNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc12

Procedure:
This material was prepared from 7-chloro-2-(1-methyl-1H-imidazol-2-yl]thieno[3,2-b]pyridine 1e with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid propylamide 58b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CDCl3) δ 8.42 (1H, d, J=5.5 Hz), 7.82 (1H, d, J=8.7 Hz), 7.76 (1H, s), 7.37 (1H, d, J=1.8 Hz), 7.30 (1H, s), 7.08 (1H, s), 7.03 (1H, dd, J=1.8, 8.7 Hz), 6.65 (1H, d, J=5.5 Hz), 4.01 (3H, s), 3.70 (3H, s), 3.39 (2H, m), 2.64 (3H, s), 1.70 (2H, m), 1.03 (3H, m). LCMS (ESI+) [M+H]/z Calc'd 460. found 460.
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: CCOCC
Solvent: CCOC(C)=O
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)).