Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Br)C.[CH2:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][CH:9]=1)[CH2:6][CH3:7].[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=1)[CH3:17]>CCOCC>[CH2:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:16][CH3:17])=[N:20][CH:21]=2)=[CH:12][CH:13]=1)[CH2:6][CH3:7]
Reactant: C#Cc1ccc(CCC)cc1
Reactant: CCOc1ccc(Br)cn1
Agent: CC[Mg]Br
Solvent: CCOCC
Product: CCCc1ccc(C#Cc2ccc(OCC)nc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.05 m of ethylmagnesium bromide in ether are added to a mixture of 0.05 m of 4-propylphenylacetylene at 0°-10°. The mixture is stirred for 4 hours at room temperature and then a solution of 0.05 m of 2-ethoxy-5-bromopyridine and 0.5 g of NiCl2 (Ph3P)2 in ether is added. After stirring for 6 hours at room temperature and customary work-up 1-(4-propylphenyl)-2-(2-ethoxy-pyridine-5-yl)-acetylene is obtained.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH:11]([NH:24][OH:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>[OH-].[Na+]>[CH:11]([N:24]([OH:25])[CH:1]=[O:3])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ONC(c1ccccc1)c1ccccc1
Reactant: O=CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: O=CN(O)C(c1ccccc1)c1ccccc1
Temperature: 55 °C
Reaction time: 0.08 h
Yield: 65.8 %

Procedure:
Formic acid (0.53 mL, 14.1 mmol) was added dropwise to acetic anhydride (1.07 mL, 11.3 mmol) at 0° C., stirred for 5 mins. and then warmed to 55° C. for 5 mins prior to cooling back down to room temperature. N-benzhydrylhydroxylamine 41 (225 mg, 1.13 mmol) was added, and stirred at room temperature for 3 days. The reaction mixture was diluted with aqueous NaOH solution (to pH=7), the solution was stirred for 5 mins, and then acidified with aqueous HCl solution (to pH=4). Following extraction with ethyl acetate, the combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated. The crude material was concentrated and purified by silica gel column chromatography with gradient of ethyl acetate (0-75%) in hexane to afford compound 42 as a tan solid (169 mg, 66%). 1H NMR: (DMSO-d6) 8.41 (br s, 1H), 7.44-7.28 (m, 11H). LRMS (ESI): (calc.) 227.3 (found) 228.2 (MH)+.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])=[O:12])=[CH:9][N:10]=2)[CH2:2]1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>C(O)C>[C:20]([NH:24][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])=[O:12])=[CH:9][N:10]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)N
Reactant: C=CCCCCNC(=O)c1cnc(OCC2CO2)s1
Solvent: CCO
Product: C=CCCCCNC(=O)c1cnc(OCC(O)CNC(C)(C)C)s1
Temperature: -20 °C
Reaction time: 12 h

Procedure:
This example illustrates method for preparing the compounds of the present invention. In this example a mixture containing 12 g. (0.037 mole) of 1,2-epoxy-3-[5-(hex-5-enylaminocarbonyl)thiazol-2-yloxy]propane, 12 g. (0.164 mole) of t-butylamine and 20 ml. of ethanol is allowed to stand at room temperature for 12 hours. The mixture is then evaporated under vacuum to remove the ethanol solvent and the resulting residue dissolved in 50 ml. of ethyl acetate and cooled to -20° C, and maintained at this temperature for two hours. The mixture is then filtered and the resulting filter cake washed with cold (about 0° C) ethyl ether and then recrystallized from ethyl acetate affording 1-t-butylamino-3-[5-(hex-5-enylaminocarbonyl)thiazol-2-yloxy]propan-2-ol, m.p. 80°-81° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:9]1[N:14]=[C:13]([C:15](OC)=[O:16])[CH:12]=[C:11]([N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1>[C:37]([O:36][C:34]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[C:11]([N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[N:10]=1)=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: COC(=O)c1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cc(CO)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 56.5 %

Procedure:
Methyl 2,6-di(bis(tert-butoxycarbonyl)amino)pyrimidine-4-carboxylate Crude methyl 2,6-diaminopyrimidine-4-carboxylate (2.52 g, 15 mmol) was suspended in dry tetrahydrofuran (200 ml) then treated sequentially with di-tert-butyl dicarbonate (19.6 g, 90 mmol), triethylamine (16.7 ml, 120 mmol), and 4-dimethylaminopyridine (0.092 g, 0.75 mmol). This mixture was refluxed gently for 16 h, evaporated, dissolved in diethyl ether, washed with water and brine, dried and evaporated to give a dark red gum. This residue was purified by flash chromatography, eluting with 0–18% ethyl acetate in petroleum ether, to give the title compound as an off-white foam (4.58 g, 54%); m/z (APCI+) 569 [MH]+ 100%.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[Br:20]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:14][O:13][CH2:12][O:11][C:9]1[C:8]([Br:20])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1cc(CC(=O)OC)cc(OCOC)c1
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(CC(=O)OC)c(Br)c(OCOC)c1
Temperature: 4 °C
Reaction time: 3 h

Procedure:
Methyl 3,5-bis(methoxymethoxy)phenylacetate (43 g, 0.16 mol) obtained in Example 1, Step 1 was dissolved in N,N-dimethylformamide (0.68 L). After the solution was cooled to 4° C., N-bromosuccinimide (28 g, 0.16 mol) was added thereto, followed by stirring for 3 hours, while the temperature of the reaction mixture was raised to room temperature. To the reaction mixture was added water (0.50 L), and the mixture was extracted with a mixed solvent of hexane and ethyl acetate (hexane/ethyl acetate=1/2, 0.40 L×4). The organic layer was washed with a saturated aqueous solution of sodium chloride (50 mL) and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-1/2) to obtain a quantitative yield of methyl 3,5-bis(methoxymethoxy)-2-bromophenyl-acetate.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[N:16]=1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[N:16]=1)=[O:11]
Reactant: CCOC(=O)[C@H](Cc1cccc(OC)n1)NC(=O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](Cc1cccc(OC)n1)NC(=O)CN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 100-mL round-bottomed flask was added ethyl N-(tert-butoxycarbonyl)glycyl-3-(6-methoxy-2-pyridinyl)alaninate (1.28 g, 3.36 mmol) and trifluoroacetic acid (5 mL, 67.3 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo to give the crude ethyl glycyl-3-(6-methoxy-2-pyridinyl)alaninate as a colorless viscous oil, which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>CN(C)C=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([C:19]([F:18])([F:28])[F:29])[CH:21]=2)=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
To a solution of 2.28 g (15 mmol) of 4-hydroxy-benzoic acid methyl ester in 30 mL of dimethylformamide (DMF) was added 5.38 g (16.5 mmol) of cesium carbonate (Cs2CO3), followed by 2.75 mL (18 mmol) of 3-(trifluoromethyl)-benzyl bromide, and the resulting heterogeneous mixture was stirred at rt overnight. The reaction mixture was filtered and concentrated, diluted with water and extracted with ethyl acetate, and the combined organic extracts were washed with water and brine, and concentrated to give 4.75 g of desired 4-(3-trifluoromethyl-benzyloxy)-benzoic acid methyl ester as indicated by 1H NMR and 19F-NMR (containing traces of residual 3-(trifluoromethyl)-benzyl bromide).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][OH:10].[Cl:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C:17]2[N:18]=[C:19]([O:35][CH2:36][CH2:37][CH3:38])[C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[C:30]([CH3:32])[C:29]([OH:33])=[C:28]([CH3:34])[CH:27]=4)[O:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1>CN(C)C=O>[Cl:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C:17]2[N:18]=[C:19]([O:35][CH2:36][CH2:37][CH3:38])[C:20]3[N:25]=[C:24]([C:26]4[CH:27]=[C:28]([CH3:34])[C:29]([O:33][CH2:8][CH2:9][OH:10])=[C:30]([CH3:32])[CH:31]=4)[O:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCCO)c(C)c3)nc12
Temperature: 60 °C
Yield: 4.9 %

Procedure:
130 mg of potassium carbonate and 32.4 mg of 2-bromo-ethanol were added to a solution of 100 mg of 4-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]2,6-dimethyl-phenol in 3 ml of dimethylformamide. The reaction mixture was heated to 60° C. for 3 h. After filtration, the solvent was removed in vacuo. Preparative HPLC (method HPLC1) of the residue yielded 5.4 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[CH3:12])=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>>[Br:13][CH2:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc2ccc(F)cc12
Reactant: O=C1CCC(=O)N1Br
Product: Fc1ccc2cccc(CBr)c2c1

Procedure:
Using general procedure A (Exp. 1.3.), 7-fluoro-1-methyl-naphthalene was reacted with N-bromosuccinimide to give 1-bromomethyl-7-fluoro-naphthalene as white solid. MS: 238.1 ([M]+).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[CH2:26][NH2:27].C(N(CC)C(C)C)(C)C>CS(C)=O>[Br:8][C:6]1[N:7]=[C:2]([NH:27][CH2:26][C:19]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=2[O:17][CH3:16])[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)CNc1ncc(Br)nc1NCc1ccc(OC)cc1OC
Temperature: 150 °C
Yield: 47.8 %

Procedure:
Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example 1.C) (1.06 g, 3.13 mmol), (2,4-dimethoxyphenyl)methanamine (0.601 g, 3.60 mmol), N,N-diisopropylethylamine (1.63 mL, 9.38 mmol) and dimethylsulfoxide (1.6 mL) were combined in a microwave vial with a stirbar and heated in a microwave reactor at 150° C. for 2 h. The resulting mixture was purified using flash chromatography (5-60% ethyl acetate in hexane). Fractions containing the desired product were combined and concentrated nearly to dryness under reduced pressure. Ethyl acetate (2 mL) and hexane (18 mL) was added. The resulting solids were collected by vacuum filtration, washed with hexane and dried under high vacuum to give the desired product (0.636 g, 1.495 mmol, 48% yield) as a light pink solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm) 7.24 (s, 1H), 7.19 (d, J=8.52 Hz, 1H), 7.11 (t, J=5.63 Hz, 1H), 6.84 (t, J=4.81 Hz, 1H), 6.59 (d, J=2.47 Hz, 1H), 6.50 (dd, J=2.20, 8.24 Hz, 1H), 4.37 (d, J=4.67 Hz, 2H), 3.96-4.15 (m, 4H), 3.81 (s, 3H), 3.75 (s, 3H), 1.17 (t, 3H); MS (ESI) m/z 425.3 [M]+, 426.9 [M+2]+.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[F:8][C:9]1[CH:10]=[C:11]([C:33](O)=[O:34])[C:12]2[CH2:13][C:14]([CH3:32])([CH3:31])[CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:20]=3)[NH:16][C:17]=2[CH:18]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:8][C:9]1[CH:10]=[C:11]([C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34])[C:12]2[CH2:13][C:14]([CH3:31])([CH3:32])[CH:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[CH:20]=3)[NH:16][C:17]=2[CH:18]=1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)Cc2c(cc(F)cc2C(=O)O)NC1c1cccc(N2CCOCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(cc(F)cc2C(=O)NS(C)(=O)=O)NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a suspension of 60% sodium hydride (200 mg, 5.0 mmol) in N,N-dimethylformamide (1.5 mL) was added methanesulfonamide (494 mg, 5.2 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 7-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (200 mg, 0.52 mmol) and 1,1′-carbonyldiimidazole (170 mg, 1.04 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[7-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carbonyl]-methanesulfonamide (48 mg, 20%) as a white solid: LC/MS m/e calcd for C23H28FN3O4S (M+H)+: 462.56, observed: 462.1.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[O:24]([C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1)[N+:25]([O-:27])=[O:26]>O1CCCC1>[O:24]([C@H:28]1[CH2:29][CH2:30][C@H:31]([NH:34][C:7](=[O:9])[C@@H:2]2[CH2:3][CH2:4][C:5](=[O:6])[NH:1]2)[CH2:32][CH2:33]1)[N+:25]([O-:27])=[O:26]
Reactant: N[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CC[C@@H](C(=O)N[C@H]2CC[C@H](O[N+](=O)[O-])CC2)N1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
2.1 g (0.016 mol) (S)-pyroglutamic acid (2-pyrrolidinone-5-carboxylic acid) are dissolved in 50 ml abs. tetrahydrofuran and 2.5 ml (0.018 mol) triethylamine. With cooling to about 5° C., 2 ml (0.016 mol) pivaloyl chloride in 10 ml abs. tetrahydrofuran are added dropwise thereto. After 15 min stirring at 5° C., one adds dropwise thereto a solution of 3.9 g trans-4-nitroxycyclohexylamine in 40 ml abs. tetrahydrofuran and 2.8 ml (0.02 mol) triethylamine. Thereafter, one allows to stir for 2 d at room temperature, filters off with suction and removes the solvent in a vacuum. The residue is dissolved in ethyl acetate and shaken out with sodium hydrogen carbonate. After drying of the ethyl acetate phase with sodium sulphate, distilling off in a vacuum, trituration with ether and suction filtration, there remain 1.5 g of the title compound of the melting point 166° C., i.e. 35% of theory.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si](C)(C)C)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].FC(F)(F)S(O[C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[C:28]([CH:33]=[O:34])[CH2:29][O:30]2)=[C:25]([F:35])[CH:24]=1)(=O)=O>CN(C=O)C.[Cu](Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:35][C:25]1[CH:24]=[C:23]([C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=2)[CH:32]=[C:31]2[C:26]=1[CH:27]=[C:28]([CH:33]=[O:34])[CH2:29][O:30]2
Reactant: O=CC1=Cc2c(F)cc(OS(=O)(=O)C(F)(F)F)cc2OC1
Reactant: CC(C)Cc1ccc(C#C[Si](C)(C)C)cc1
Agent: Cl[Cu]Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(C#Cc2cc(F)c3c(c2)OCC(C=O)=C3)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 23.8 %

Procedure:
To a solution of copper chloride (10 mg) and Pd(PPh3)4 (60 mg) in DMF (2 mL) were added [(4-isobutylphenyl)ethynyl](trimethyl)silane (288 mg) and 5-fluoro-3-formyl-2H-chromen-7-yl trifluoromethanesulfonate (340 mg) at room temperature, followed by stirring at 80° C. for 12 hours. The reaction liquid was concentrated and the residue was purified by silica gel column chromatography (CHCl3) to obtain 5-fluoro-7-[(4-isobutylphenyl)ethynyl]-2H-chromene-3-carbaldehyde (83 mg) as a yellow solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:20]([NH:29][CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][NH:32]2)[C:19]([C:36]([OH:38])=O)=[N:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[N:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[Cl:10])[N:18]=[C:19]3[C:20]=2[NH:29][CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][N:32]2[C:36]3=[O:38])=[CH:23][CH:24]=1
Reactant: O=C(O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1NCC1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2NCC2CCCN12
Reaction time: 5 h
Yield: 30.1 %

Procedure:
Diisopropylethylamine (250 microliters, 2 mmol) was added to a mixture of 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-[(pyrrolidin-2-ylmethyl)-amino]-1H-pyrazole-3-carboxylic acid (I-5b, 160 mg, 0.37 mmol) and HATU (380 mg, 1 mmol) in DMF (50 ml) at room temperature. The reaction mixture was stirred for 5 hours, quenched with saturated aqueous NaCl, and extracted twice with EtOAc. The combined organic extracts were washed with 0.5 M citric acid, 1 M K2CO3, and saturated aqueous NaCl, dried, and concentrated in vacuo. The residue was slurried in CH2Cl2 and the solvent decanted, a process repeated once more with EtOAc. The combined organic solutions were concentrated under vacuum and the residue was purified on a chromatogram using 4 mm plates and a solvent gradient of 10:1 EtOAc/MeOH to 5:1 EtOAc/MeOH to give 4A-1 as a white solid (46 mg): +ES MS (M+1) 413.4; 1H NMR (CD3OD) δ 7.58 (bs, 1H), 7.52–7.44 (m, 3H), 7.34 (d, 2H, J=7.6 Hz), 7.22 (d, 2H, J=7.6 Hz), 3.93–3.82 (m, 2H), 3.64–3.50 (m, 2H), 3.10–2.99 (m,1 H), 2.38–2.29 (m,1 H), 2.04–1.96 (m, 1H), 1.95–1.74 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:14]([CH3:16])([CH3:15])[CH2:13][CH:12]([NH2:17])[CH2:11][C:10]1([CH3:19])[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:20]([CH:32]1[CH2:37][C:36](=O)[O:35][C:33]1=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:1]([O:8][N:9]1[C:14]([CH3:16])([CH3:15])[CH2:13][CH:12]([N:17]2[C:36](=[O:35])[CH2:37][CH:32]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:33]2=[O:34])[CH2:11][C:10]1([CH3:18])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCON1C(C)(C)CC(N)CC1(C)C
Reactant: CCCCCCCCCCCCC1CC(=O)OC1=O
Product: CCCCCCCCCCCCC1CC(=O)N(C2CC(C)(C)N(OCCCCCCC)C(C)(C)C2)C1=O

Procedure:
The procedure of Example 75 is repeated using 1-heptyloxy-4-amino-2,2,6,6-tetramethylpiperidine and n-dodecyl succinic anhydride to afford the title compound.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=[O:13])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:15]C1C=CC=C([N+]([O-])=O)C=1Cl>>[Cl:15][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=[O:13])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1cnc2cccc(Br)c21
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Product: O=C(O)Cn1cnc2cccc(Cl)c21

Procedure:
Alternatively, the title compound was synthesised according to the procedure described for the synthesis of (7-bromo-1H-benzimidazol-1-yl)acetic acid (parts A-D) starting from 1,2-dichloro-3-nitrobenzene. The new intermediates isolated were:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C@@H:11]3[CH2:28][CH2:29][CH2:30][N:10]3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[N:22]1([CH2:21][CH2:20][CH2:19][O:18][C:14]2[CH:13]=[C:12]3[C:17]([C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[CH:3]=4)[CH2:9][N:10]4[CH2:30][CH2:29][CH2:28][C@H:11]43)=[CH:16][CH:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Ic1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a high-pressure reaction vial was added cis-6-(3-iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline (Example 32, 40.0 mg, 0.08 mmol), trimethylsilylacetylene (9.0 mg, 0.093 mmol), Pd(PPh3)2Cl2 (6.0 mg, 0.008 mmol), CuI (2.0 mg, 0.008 mmol), PPh3 (4.0 mg, 0.016 mmol), Et2NH (0.12 mL, 1.2 mmol), and DMF (0.1 mL). The sealed vial was placed in a 120° C. preheated oil bath for 30 min, cooled to rt, concentrated under a stream of nitrogen, and purified by reverse-phase HPLC to give 27.0 mg (47%) of the desired product as a TFA salt. MS: exact mass calcd for C31H42N2OSi, 486.3; m/z found, 487.6 [M+H]+. 1H NMR (acetone-d6): 7.46 (m, 2H), 7.36 (m, 2H), 6.97 (d, J=2.5, 1H), 6.80 (dd, J=2.6, 8.7, 1H), 6.65 (d, J=8.7, 1H), 4.92 (m, 1H), 4.63 (m, 1H), 4.14 (t, J=6.0, 2H), 3.95 (m, 1H), 3.66 (m, 3H), 3.51 (m, 1H), 3.41 (m, 1H), 3.31 (m, 2H), 2.95 (m, 3H), 2.32 (m, 5H), 1.89 (m, 5H), 1.50 (m, 1H), 0.22 (s, 9H).
Reaction SMILES: [CH2:1]([N:4]1[C@H:18]2[C@@H:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[CH:15][NH:14]4)[CH2:7][C@H:6]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:5]1)[CH2:2][CH3:3].S(Cl)([Cl:30])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Cl:30][C:15]1[NH:14][C:13]2[C:19]3[C:16]=1[CH2:17][C@@H:18]1[C@@H:8]([C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:7][C@H:6]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:5][N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCN1C[C@@H](NC(=O)C(C)(C)C)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCN1C[C@@H](NC(=O)C(C)(C)C)C[C@@H]2c3cccc4[nH]c(Cl)c(c34)C[C@H]21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1 g silica gel are added to 2 g 6-n-propyl-8α-pivaloylamino-ergoline (example 2) in 50 ml methylene chloride, pre-cooled to 0° C. 0.503 ml sulfurylchloride are added drop-wise and the reaction mixture stirred for 4 hours. 1N potassium carbonate solution is added, the mixture extracted with methylene chloride, dried over Na2SO4 and concentrated. The residue is chromatographed on 50 g silica gel using toluene/ethylacetate (2:1) as eluant to yield the title compound. M.P.=146°-147° C.