Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.[O:60]1[CH2:65][CH2:64][CH2:63][CH2:62][CH:61]1[CH2:66][NH2:67]>>[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:7])=[O:50])=[C:33]2[S:53]([NH:67][CH2:66][CH:61]1[CH2:62][CH2:63][CH2:64][CH2:65][O:60]1)(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: NCC1CCCCO1
Agent: CN
Agent: Cl
Product: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)NCC1CCCCO1

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with (±)-1-tetrahydro-2H-pyran-2-ylmethanamine, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 415.93 [M+H]+.
Reaction SMILES: C([O:5][NH:6][C:7](=[N:60]S(C1C(C)=C(C)C2OC(C)(C)CC=2C=1C)(=O)=O)[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:42][C:43](=[O:59])OCC1C2C=CC=CC=2C2C1=CC=CC=2)[C:14](=[O:41])[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)=[CH:28][C:27]([C:37]([F:40])([F:39])[F:38])=[N:26]2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])(C)(C)C.[C:78](OC(=O)CC)(=O)[CH2:79]C>>[OH:5][N:6]=[C:7]([NH2:60])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:42][C:43](=[O:59])[CH2:78][CH3:79])[C:14]([NH:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:29]([C:30]3[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=3)=[CH:28][C:27]([C:37]([F:40])([F:38])[F:39])=[N:26]2)=[CH:23][CH:24]=1)(=[O:17])=[O:18])=[O:41]
Reactant: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)NC(=O)[C@H](CCCCNC(=NS(=O)(=O)c3c(C)c(C)c4c(c3C)CC(C)(C)O4)NOC(C)(C)C)NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)cc1
Reactant: CCC(=O)OC(=O)CC
Product: CCC(=O)N[C@@H](CCCCNC(N)=NO)C(=O)NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(C)cc2)cc1

Procedure:
Compound (20a) is treated according to the methods of Example 16, with substitution of propionic anhydride as the acylating agent, to afford the title compound.
Reaction SMILES: C([O:3][C:4](=[O:34])[C@H:5]([CH3:33])[CH2:6][C@H:7]([NH:21][C:22](=[O:32])[C:23]1[CH:28]=[C:27]([F:29])[C:26]([OH:30])=[C:25]([F:31])[CH:24]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>CO>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]([CH2:8][C@@H:7]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[C:27]([F:29])[C:26]([OH:30])=[C:25]([F:31])[CH:24]=2)[CH2:6][C@@H:5]([CH3:33])[C:4]([OH:34])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(F)c(O)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(F)c(O)c(F)c1)C(=O)O
Reaction time: 1 h
Yield: 60.8 %

Procedure:
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester (30 mg, 0.064 mmol) in MeOH (2 mL) at room temperature is added aqueous 1M NaOH (4 mL, 4.0 mmol). After stirring for 1 hour the reaction is quenched with aqueous 1M HCl (4 mL, 4.0 mmol). The mixture is concentrated under reduced pressure and filtered to remove NaCl salt. The obtained residue is purified by preparative silica gel thin-layer chromatography (7% MeOH in DCM) to give 17.1 mg of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid. HPLC Retention time 1.56 minutes (condition B); MS 440 (M+1); 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 1.19 (d, J=7.07 Hz, 3H) 1.55 (ddd, J=14.27, 10.74, 3.79 Hz, 1H) 1.90-1.96 (m, 1H) 2.54-2.71 (m, 1H) 2.91 (dd, J=6.69, 3.16 Hz, 2H) 4.25-4.43 (m, 1H) 6.49 (d, J=9.60 Hz, 2H) 6.93 (d, J=8.84 Hz, 1H) 7.33-7.42 (m, 3H) 7.49 (t, J=7.71 Hz, 2H) 7.61 (d, J=8.34 Hz, 2H) 7.67 (dd, J=8.34, 1.26 Hz, 2H).
Reaction SMILES: C[Mg+].[Br-].[CH3:4]COCC.[OH:9][C:10]1[C:15]2[C:16]([CH3:25])=[C:17]([CH2:21][CH2:22][CH2:23][OH:24])C(=O)OC=2C=[C:12]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:11]=1.[CH3:31][CH2:32][O:33][C:34]([CH3:36])=O>C1COCC1>[OH:9][C:10]1[C:15]2[C:16]([CH3:25])=[C:17]([CH2:21][CH2:22][CH2:23][OH:24])[C:32]([CH3:31])([CH3:4])[O:33][C:34]=2[CH:36]=[C:12]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:11]=1
Reactant: CCOCC
Reactant: CCCCCc1cc(O)c2c(C)c(CCCO)c(=O)oc2c1
Reactant: CCOC(C)=O
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCCO)=C2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Alternate Synthesis A solution of 15 mL of a 1M solution of MeMgBr (Aldrich) diluted with 60 mL of anhy. Et2O and 15 mL of anhy. THF was brought to a boil under reflux and under argon. A solution of 1.0 g of 5-Hydroxy-3-(3-hydroxypropyl)-4-methyl-7-pentyl-2H-1-benzopyran-2-one in 60 mL of dry THF was then added dropwise over 1 hr to the reaction and boiling continued for a total of 4 hr. The reaction was allowed to cool to RT overnight, brought back to a boil and boiling resumed for a further 2 hr. Heating was then stopped and the reaction cooled to RT, then in an ice-bath, and quenched by careful addition of 120 mL of ice-cold 1N HCl with vigorous stirring. The reaction turned yellow, then purplish in color with considerable precipitation of solids, before turning yellow again with clearing of the solution. 40 mL of ice-cold 6N HCl was then added and the mixture stirred in the ice-bath for 15 min. Cooling was then removed, the mixture allowed to attain RT with continuous stirring and the resulting deep yellow solution extracted with EtOAc (1×200 mL, 1×100 mL). The combined organic layers were washed with half-sat. aq. NaCl (3×100 mL), sat. aq. NaCl (1×100 mL), dried (Na2SO4) and evaporated under reduced pressure to give a discolored syrup. The residue was swirled with about 20 mL EtOAc to give a clear pale colored solution containing off-white solids. The mixture was filtered to give 274 mg of recovered starting material, and a filtrate which was stripped of solvent under reduced pressure to give 760 mg of a material containing product. The material was again triturated with a little EtOAc and filtered again to give a further 159 mg of recovered starting material as a solid, and a filtrate which was stripped of solvent to give 600 mg of a residue which was subjected to PLC, eluting with 1:1 CHCl3 -EtOAc. The product band approximately halfway up the plate was isolated, the silica washed with 10% MeOH-EtOAc and the washings evaporated under reduced pressure to give 243 mg of the desired product 5-Hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3 -propanol.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH:30]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[Li+].[OH-].O>C1COCC1.O.CO>[OH:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([N:10]([C:11]([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]2)=[O:12])[C:9]2[CH:8]=[C:7]([C:27]3[CH2:32][CH2:31][CH:30]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:29][CH:28]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:21][CH2:22]1
Reactant: COC(=O)c1sc(C2=CCC(Oc3ccccc3)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCC(Oc4ccccc4)CC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4-phenoxy-cyclohex-1-enyl)-thiophene-2-carboxylic acid methyl ester (30 mg, 0.05 mmol) in THF:H2O:MeOH (3:1:2) (2 mL), was added LiOH in water (1N) (0.2 mL, 0.2 mmol). The reaction mixture was stirred at 70° C. for 4 h. The reaction mixture was concentrated under reduced pressure on a rotary evaporator. The mixture was partitioned between ethyl acetate and water. The water layer was acidified using 0.1 N HCl. The EtOAc layer was separated and dried over Na2SO4. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by HPLC purification afforded 3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(4-phenoxy-cyclohex-1-enyl)-thiophene-2-carboxylic acid (3 mg, 10%) as a foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.Cl.[C@H:13]12[CH2:19][C@H:16]([NH:17][CH2:18]1)[CH2:15][N:14]2[C:20]([C@@:22]1([CH2:36][CH:37]([F:39])[F:38])[CH2:26][CH2:25][C@@H:24]([NH:27][C@@H:28]2[C@H:33]([O:34][CH3:35])[CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23]1)=[O:21].C(N(CC)CC)C>CS(C)=O.O1CCOCC1>[F:39][CH:37]([F:38])[CH2:36][C@:22]1([C:20]([N:14]2[CH2:15][C@@H:16]3[CH2:19][C@H:13]2[CH2:18][N:17]3[C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)=[O:21])[CH2:26][CH2:25][C@@H:24]([NH:27][C@@H:28]2[C@H:33]([O:34][CH3:35])[CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23]1
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@](CC(F)F)(C(=O)N2C[C@@H]3C[C@H]2CN3)C1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@](CC(F)F)(C(=O)N2C[C@@H]3C[C@H]2CN3c2nccc(C(F)(F)F)n2)C1
Temperature: 100 °C
Yield: 58 %

Procedure:
Prepared as described in example 24 using 2-chloro-4-(trifluoromethyl)pyrimidine in place of 4-chloro-6-(trifluoromethyl)pyrimidine and modifying step 9 as follows. The HCl salt of 1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-{[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-(2,2-difluoroethyl)cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol (175 mg, 0.41 mmol) was placed in flask with 1,4-dioxane (3 ml). Triethylamine (0.2 ml, 1.43 mmol) was added as well as 2-chloro-4-(trifluoromethyl)pyrimidine (237 mg, 1.30 mmol). DMSO (0.3 ml) was added for solubility and the reaction was heated to 100° C. for 14.5 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organics were washed with brine, dried over MgSO4, concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate 15 column volumes) to give 1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-(2,2-difluoroethyl)-3-({(1S,4S)-5-[4-(trifluoromethyl)pyrimidin-2-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol as a brown foam (126 mg, 58%). LC/MS (M+H)=534.2504 exp, 534.2452 obs; 1H NMR (400 MHz, CDCl3) δ ppm 8.48-8.45 (1H), 6.79-6.78 (1H), 5.96-5.58 (1H), 5.10-4.71 (2H), 4.07-4.01 (1H), 3.93-3.87 (1H), 3.69-3.55 (4H), 3.39-3.32 (4H), 3.30-3.21 (3H), 2.77-2.66 (1H), 2.52-2.40 (1H), 2.23-1.82 (7H), 1.70-1.39 (5H)
Reaction SMILES: C([O:3][C:4](=[O:11])[CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)C.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[N+:17]([C:9]1[CH:8]=[N:7][N:6]([CH2:5][C:4]([OH:3])=[O:11])[CH:10]=1)([O-:19])=[O:18]
Reactant: CCOC(=O)Cn1cccn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)Cn1cc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
Six conical flasks were charged with pyrazol-1-yl-acetic acid ethyl ester (6×9.66 g, 6×62.6 mmol) and concentrated sulphuric acid (6×20 ml) was added. The solutions were cooled to 0° C. and concentrated nitric acid (6×10 ml) was added dropwise. The reaction mixtures were allowed to warm to room temperature and left standing for 18 hours. The combined organic mixtures were poured into ice (50 ml) and extracted with ethyl acetate (5×500 ml). The combined organic extracts were washed with brine (500 ml), dried (MgSO4), filtered and concentrated under reduced pressure to leave a yellow solid. Recrystallisation from ethyl acetate afforded the title compound as an off-white solid (20.97 g, 33% yield).
Reaction SMILES: [Cl-:1].[C:2]([C:5]1[C:14](=[O:15])[C:13]2[C:12]([N+]#N)=[C:11]3[O:18]C[O:20][C:10]3=[CH:9][C:8]=2[N:7]([CH2:21][CH3:22])[CH:6]=1)([OH:4])=[O:3].O>OS(O)(=O)=O>[Cl:1][C:12]1[C:11]([OH:18])=[C:10]([OH:20])[CH:9]=[C:8]2[C:13]=1[C:14](=[O:15])[C:5]([C:2]([OH:4])=[O:3])=[CH:6][N:7]2[CH2:21][CH3:22]
Reactant: CCn1cc(C(=O)O)c(=O)c2c([N+]#N)c3c(cc21)OCO3
Reactant: [Cl-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2c(Cl)c(O)c(O)cc21
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A solution of 7-carboxy-5-ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5-g]quinoline-9-diazonium chloride (7.5 g, 23.17 mmol) (Mixture of 16c and 16d) in 50% H2SO4 (60 mL) was heated at 95° C. for 4 h. The reaction mixture was cooled down to r.t. and then poured into 450 mL of water. The precipitates were collected by filtration and dried to afford 5-chloro-1-ethyl-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (6 g, 18.61 mmol, 80% yield) as a yellow brown solid. LCMS: (M+H)+: 284.1.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[CH2:31]([N:35]=[C:36]=[O:37])[CH2:32][CH2:33][CH3:34]>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:36]([NH:35][CH2:31][CH2:32][CH2:33][CH3:34])=[O:37])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reactant: CCCCN=C=O
Product: CCCCNC(=O)NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-butyl-urea is prepared as described in Example 26 using cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and n-butyl isocyanate (Fluka, Buchs, Switzerland). Analytical HPLC: tR=6.54 min (Grad 2); ES-MS: m/eo=499.0.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]Cl)=[CH:15][CH:14]=1>C(Cl)(Cl)(Cl)Cl.[Fe]>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)=[CH:15][CH:14]=1
Reactant: ClSc1ccc(Cl)cc1
Reactant: c1ccc(-c2cccs2)cc1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Sc2ccc(-c3ccccc3)s2)cc1
Reaction time: 168 h
Yield: 52.8 %

Procedure:
A solution of 40 g (0.250 mole) of 2-phenylthiophene in 200 ml of carbon tetrachloride was treated at room temperature with 45 g (0.252 mole) of p-chlorobenzenesulfenyl chloride. Iron powder (0.1 g) was added and the reaction mixture was allowed to stand for seven days at room temperature. Filtration removed a small amount of insoluble material. Evaporation of the filtrate gave a residue of 79.8 g of crude product, m.p. 85°-87° C. Recrystallization of the residue from 400 ml of absolute ethanol gave 40 g (53%) of 2-(p-chlorophenylthio)-5-phenylthiophene, m.p. 101°-103° C.
Reaction SMILES: CCN(CC)CC.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1.Cl.FC1C=CC(N2[C:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:28]=3[C:27]([CH2:35][OH:36])=N2)=CC=1>CCO>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:27]([CH2:35][OH:36])=[C:28]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:29]3=[N:16]2)=[CH:11][CH:10]=1
Reactant: NNc1ccc(F)cc1
Reactant: OCc1nn(-c2ccc(F)cc2)c2c1CCCCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: OCc1c2c(nn1-c1ccc(F)cc1)CCCCC2
Reaction time: 8 h

Procedure:
The crude diketone was dissolved in 60 mL of absolute EtOH and combined with 3.07 mL (22 mmol, 2.23 g) of Et3N and 3.45 g (21.1 mmol) of 4-fluorophenylhydrazine.HCl. The resulting solution was stirred under N2 overnight and refluxed for 4 h. A 30 mL portion of 1N aqueous HCl was added and the mixture was refluxed for an additional hour. The mixture was cooled and extracted with 200 mL of Et2O. The organic phase was washed with water, saturated aqueous NaHCO3, and brine and dried over Na2SO4. The solution was concentrated to give 5.50 g of a 1.2:1 mixture of 1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydrocycloheptapyrazole-3-methanol and the title compound as a brown oil. The crude product was crystallized from EtOAc:Et2O to afford 0.97 g (18%) of the title compound as an off-white solid, m.p. 177°-178° C.; 1H NMR (CDCl3, 300 MHz) 1.72 (m, 4), 1.85 (m, 2), 2.60 (m, 2), 2.80 (m, 2), 4.51 (d, 2, J=5 Hz), 7.15 (m, 2), 7.60 (m, 2); IR (KBr) 3240 (broad), 1513, 1223 cm-1 ; MS (DCI) m/z 261 (base). Anal. Calcd. for C15H17FN2O: C, 69.21; H, 6.58; N, 10.76. Found: C, 69.15; H, 6.77; N, 10.63.
Reaction SMILES: [CH:1]1([CH2:10][C:11]#[C:12][CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H][H]>N1C=CC=CC=1.[Pd]>[CH:14]1([CH2:13]/[CH:12]=[CH:11]\[CH2:10][CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1
Reactant: C(#CCC1C=Cc2ccccc21)CC1C=Cc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccncc1
Product: C1=CC(C/C=C\CC2C=Cc3ccccc32)c2ccccc21
Yield: 112.4 %

Procedure:
A solution is prepared of 20 g (0.0532 moles) of 1,4-bis-(1-indenyl)-but-2-ine in 200 ml of pyridine. The alkyne is then hydrogenated with hydrogen at 1 atm., in the presence of 1.0 g of Pd on BaSO4 (ALDRICH). After 3 hours the absorption of hydrogen stops. The reddish solution is filtered, diluted with water and extracted with diethyl ether. The extract, after evaporation of the solvent, is purified by chromatography on a silica gel column with petroleum ether as eluant. 17 g of 1,4-bis-(1-indenyl)-Z-but-2-ene are obtained with a yield of 85%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[CH3:33][O:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](O)=[O:38]>>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][N:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=3[O:34][CH3:33])[CH:22]=[CH:21][N:20]=2)=[CH:31][CH:30]=1
Reactant: COc1ccccc1C(=O)O
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: COc1ccccc1C(=O)NCCCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)S(C)(=O)=O

Procedure:
Compound 2, was coupled with 2-methoxybenzoic acid following procedure K. LC-MS showed the product had the expected M+H+ of 590. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.2 (d, 1H) 8.0 (s, 1H) 7.9 (s, 1H) 7.7 (t, 1H) 7.5 (m, 5H), 7.1 (d, 1H), 6.9 (d, 2H), 6.8 (d, 2H), 4.5 (s, 2H), 3.8 (s, 3H), δ 3.7 (t, 2H), 3.5 (t, 2H), 3.3 (t, 2H), 2.9 (t, 2H), δ 2.8 (s, 3H), δ 1.8 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:16]([CH3:17])=[C:15](Br)[CH:14]=[C:13]([N+:19]([O-])=O)[C:12]=1[NH2:22])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>[Ni]>[CH2:1]([N:8]([CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([NH2:19])[C:12]=1[NH2:22])[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cc([N+](=O)[O-])c(N)c1CN(C)Cc1ccccc1
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(N)c(N)c1CN(C)Cc1ccccc1
Yield: 99.6 %

Procedure:
2-[(Benzyl-methyl-amino)-methyl]-4-bromo-3-methyl-6-nitro-phenylamine (6 g, 16.5 nmnol) was hydrogenated (Ra Ni, 3 g) in the presence of KOH (0.498N). Reaction mixture filtered and extracted in CHCl3 (200 mL) and washed with water and dried (MgSO4). Solvent evaporated to give a dark oil 4.19 g=99%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12].[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([SH:25])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>CN(C)C=O.C1(C)C=CC=CC=1>[F:27][C:18]([F:17])([F:26])[C:19]1[CH:20]=[C:21]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH:11]=[O:12])[CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1ccccc1CCCCCCCBr
Reactant: FC(F)(F)c1cccc(S)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1CCCCCCCSc1cccc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To N,N-dimethylformamide (30 ml) and 2-(7-bromoheptyl) benzaldehyde (1.5 g, 5 mmoles) was added a solution of 3-trifluoromethylthiophenol (1.0 ml, 8 mmoles) and triethylamine (3.0 ml, 0.02 mole) in N,N-dimethylformamide (20 ml). The reaction mixture was heated to (35 90° C. for 1 hour and then stirred for 11/2 hours while slowly cooling to room temperature. The mixture was diluted with toluene and evaporated, followed by dilution with methylene chloride. The solution was evaporated and flash chromatographed using 8% ethyl acetate in hexane to give the desired product.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:20]([SH:22])[CH3:21]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([S:22][CH2:20][CH3:21])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: CCS
Product: CCCCOC(=O)c1nc(SCC)c2ccccc2c1O
Temperature: 70 °C
Reaction time: 48 h

Procedure:
52 mg of 1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester, Example D-20c, was dissolved in 2 ml of ethanethiol and heated in a sealed tube at 70° C. for 24 h, and 100° C. for 48 h. The resultant solution was concentrated under vacuum and the residue (54 mg) was purified by chromatography on silica gel using a gradient of 0 to 20 percent ethyl acetate in hexanes to elute the product. 25 mg of product was obtained; MS (+): m/z 306.06 (M+1)
Reaction SMILES: [C:1]([N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:25](C(CN)O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].[CH3:36][CH2:37][N:38]=C=NCCCN(C)C.Cl.O>ClCCl.CN(C)C1C=CN=CC=1>[NH2:38][CH2:37][CH2:36][O:16][C:15](=[O:17])[C@:9]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCCN)C(=O)O
Reactant: CC(C)(C)OC(=O)C(O)CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@](CCCCN)(C(=O)OCCN)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
Di-Boc lysine (770 grams, 2.2 mol) was dissolved in dichloromethane (4 liters). Bocethanolamine (340 grams, 2.1 mol) was added to the solution, along with 4-dimethylaminopyridine (50 grams.) EDC-HCl (450 grams, 2.35 mol) was added and the mixture was allowed to stir overnight at room temperature. Water (2 liters) was added and the mixture was stirred for 30 minutes. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organics were washed with saturated sodium bicarbonate, 1N HCl solution, and brine. Solvent was removed under reduced pressure to give an oil. Mass recovery was 770 grams (68% yield).