Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]=[C:26]1[C:38]2[C:37]3[C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:34]=[CH:33][C:32]=3[NH:31][C:30]=2[CH2:29][NH:28][CH2:27]1.[CH2:43]([O:50][C:51]([NH:53][C:54]([CH3:59])([CH3:58])[C:55](O)=[O:56])=[O:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:43]([O:50][C:51]([NH:53][C:54]([CH3:59])([CH3:58])[C:55]([N:28]1[CH2:27][C:26](=[O:25])[C:38]2[C:37]3[C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:34]=[CH:33][C:32]=3[NH:31][C:30]=2[CH2:29]1)=[O:56])=[O:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CNC3
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(C(=O)C(C)(C)NC(=O)OCc1ccccc1)C3

Procedure:
A solution of HATU (86 mg) in DMF (2 ml) was added to a mixture of methyl 4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate (36 mg), 2-(((benzyloxy)carbonyl)amino)-2-methylpropanoic acid (21 mg), diisopropylethylamine (58) and DMF (8 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The DMF was evaporated to give methyl 2-(2-(((benzyloxy)carbonyl)amino)-2-methylpropanoyl)-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate which was used in the next step without further purification.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[C:10]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Br[C:23]1[C:28]([Br:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(Cl)Cl>CC(N(C)C)=O.[Zn].[Cu]I>[Br:29][C:28]1[C:23]([CH:19]2[CH2:20][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:18]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Brc1cccnc1Br
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(c2ncccc2Br)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
A 5 L 3-neck round bottom flask fitted with a magnetic stirrer under nitrogen was charged with zinc dust (138 g, preactivated according to the above Preparation 1, 2.11 mol, 2 eq.) and DMA (370 mL, anhydrous). 1,2-dibromoethane (13 mL, 0.158 mol, 0.15 eq, Aldrich) was then added over 5 min, followed by TMSCl (20 mL, 0.158 mol, 0.15 eq, Acros) over 5 min. The reaction mixture was stirred for 20 min at RT. A solution of N-Boc-3-iodoazetidine (2) (448 g, 1.583 mol, 1.5 eq, CNH Technologies) in DMA (925 mL, anhydrous) was added over 25 min keeping the internal temperature below 65° C. using a water bath. The suspension was stirred for 1 h at RT at which point it was degassed with nitrogen. Stirring was stopped and the suspension was allowed to stand. A 12 L 3-neck round bottom flask fitted with a mechanical stirrer was charged with 2,3-dibromopyridine (1) (250 g, 1.055 mol, 1.0 eq, Frontier Scientific), PdCl2dppf.CH2Cl2 (25.8 g, 31.65 mmol, 0.03 eq, Aldrich), CuI (12.5 g, 65.41 mmol, 0.062 eq, Aldrich), and DMA (925 mL, anhydrous). The solution was degassed with nitrogen. The clear zinc reagent solution above the residual solid zinc was poured into the 12 L flask under nitrogen. The brown solution was degassed with nitrogen and heated to 80° C. for 17 h at which point LCMS indicated complete conversion of 2,3-dibromopyridine (1). The reaction mixture was transferred to brine (2 L) in 22 L separatory funnel. Water (2 L) and EtOAc (4 L) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×3 L). The combined organics were washed with water (3×3 L) and brine (2 L), dried over sodium sulfate and evaporated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=9:1 to 5:1) to obtain 289 g of impure tert-butyl 3-(3-bromopyridin-2-yl)azetidine-1-carboxylate (3) which was distilled under high vacuum to remove the impurity (N-Boc-azetidine) to give 281 g of pure tert-butyl 3-(3-bromopyridin-2-yl)azetidine-1-carboxylate. Yield: 85%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH:9]=O)=[CH:5][CH:4]=1.N1CCC[C@@H:14]1C(O)=O.ClN1C(=O)CCC1=O.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:41]=[N:40][C:39]([NH2:42])=[N:38][CH:37]=2)=[CH:32][C:31]=1[F:43]>C(Cl)(Cl)Cl>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[N:38][C:39]3[N:40]([C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH2:1][CH3:14])=[CH:12][CH:11]=4)=[CH:9][N:42]=3)[N:41]=2)=[CH:32][C:31]=1[F:43]
Reactant: O=C(O)[C@H]1CCCN1
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Reactant: COc1ccc(OCC=O)cc1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(Oc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)cc1
Temperature: 25 °C

Procedure:
To a cooled (0° C.) mixture of (4-methoxyphenoxy)acetaldehyde (33.2 mg, 0.2 mmol) and D-proline (4.6 mg, 0.04 mmol) in chloroform (1.0 mL) was added N-chlorosuccinimide (26.7 mg, 0.2 mmol) with stirring. The mixture was stirred at 0° C. for 30 min, then gradually warmed to ambient temperature for 2 h. To the reaction mixture was added 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (26.9 mg, 0.1 mmol). The reaction mixture was stirred for 1 h and then the solvent was removed under reduced pressure. The residue was dissolved in isopropanol (2 mL) and heated to 100° C. overnight. After cooling, the mixture was filtered and the filtrate was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=415.0/416.9.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[CH2:15]=O.Cl.[CH3:18][NH:19][CH3:20]>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:18][N:19]([CH3:15])[CH3:20])[CH:10]=[CH:9]2
Reactant: CNC
Reactant: C=O
Reactant: COCCOc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: CC(=O)O
Product: COCCOc1ccc2c(ccn2CN(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of 5-(2-methoxy-ethoxy)-indole (2.06 g, 11.0 mmol) in acetic acid (7 ml) and 40% aqueous dimethylamine (2.1 ml) is cooled to 0° C., and 36% aqueous formaldehyde (1.38 ml) (pre-cooled to 0° C.) is added drop wise. The mixture is stirred at room temperature overnight, 2 M hydrochloric acid is added, and the mixture is washed with dichloromethane. The aqueous layer is made alkaline with 10% NaOH, and is extracted with dichloromethane. The combined organic layer is washed with water, is dried and concentrated. The residue is purified by column chromatography (dichloromethane-methanol, 4:1→dichloromethane-methanol-water-aqueous ammonia, 10:20:1:1) to afford [5-(2-methoxy-ethoxy)-1H-indol-ylmethyl]-dimethyl-amine (2.42 g, 90%). M.p. 163-164° C. (from toluene-N,N-dimethylformamide).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[N:24]C(C(C)=C)=[CH:22][N:21]=3)[C@H:16]([CH3:29])[CH2:15]2)=[C:10]([CH3:30])[C:9]=1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([OH:36])([CH3:35])([CH3:34])[CH3:33].O.C[N+]1([O-])CC[O:42]CC1>CC(C)=O>[CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[N:24][C:33]([C:32]([OH:36])([CH3:35])[CH2:34][OH:42])=[CH:22][N:21]=3)[C@H:16]([CH3:29])[CH2:15]2)=[C:10]([CH3:30])[C:9]=1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c(C)c3C)C[C@H]2C)cn1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)(C)O
Solvent: CC(C)=O
Solvent: O
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(c3cnc(C(C)(O)CO)cn3)[C@H](C)C2)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-5′-isopropenyl-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (example 143, 120 mg, 0.290 mmol) is suspended in acetone (2 mL), tert-butanol (1 mL), and H2O (1 mL). To this suspension is added K2OsO4 (9.6 mg, 0.029 mmol) and NMO (37.4 mg, 0.319 mmol). The reaction is stirred at room temperature for 16 h. Concentrate in vacuo. Add H2O and extract with EtOAc. Wash the combined organics with brine and concentrate in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (49.2 mg, 38%).
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:26][C:27]([F:35])([F:34])[CH:28]([CH3:33])[CH2:29][C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C1COCC1>[F:26][C:27]([F:35])([F:34])[CH:28]([CH3:33])[CH2:29][C:30]([CH:20]1[NH:19][CH2:18][C:16]2=[C:15]3[C:11](=[C:10]([C:22]([F:25])([F:24])[F:23])[C:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:17]2)[CH:12]=[CH:13][N:14]3[CH2:21]1)=[O:31]
Reactant: CC(CC(=O)O)C(F)(F)F
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CC(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1)C(F)(F)F
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A mixture of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 64 mg, 0.17 mmol), 3-(trifluoromethyl)butanoic acid (27 mg, 0.18 mmol), HATU (73 mg, 0.2 mmol) and triethylamine (85 mg, 0.84 mmol) in THF (7 mL) was stirred overnight. The resulting mixture was partitioned between ethyl acetate and water, and the organic layer was washed sequentially with NaHCO3 (sat'd) and brine, then dried and concentrated. The residue was purified by reverse-phase chromatography (CH3CN-water/TFA) to yield 4,4,4-trifluoro-3-methyl-1-(6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-2(1H)-yl)butan-1-one (78 mg).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl:12][C:13]1[CH:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:24][CH2:23]2)[C:19]([N+:35]([O-:37])=[O:36])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].IC>O>[CH3:1][O:16][C:15](=[O:17])[C:14]1[CH:18]=[C:19]([N+:35]([O-:37])=[O:36])[C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:24][CH2:23]2)=[CH:21][C:13]=1[Cl:12]
Reactant: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)O)cc2[N+](=O)[O-])CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(c3ccccc3C)CC2)cc1Cl
Yield: 92.8 %

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stir bar, the potassium carbonate (2.06 g, 14.91 mmol) was suspended in clean, dry N,N-dimethylformamide (50.00 ml, 645.74 mmol) and the mixture was stirred together under nitrogen at room temperature as the 2-chloro-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid 1d (2.54 g, 6.76 mmol) was added in one portion. The mixture was stirred until it appeared all the organic solids were in solution and then iodomethane (0.46 ml, 7.39 mmol) was added. The reaction was diluted with 100 ml of water and the product was extracted from the aqueous using ethyl acetate (3×100 ml). The layers were separated and the organic phases were combined, washed with brine (1×150 ml) and saturated aqueous lithium chloride solution (2×150 ml). The solution was then dried over Na2SO4; the solution was decanted and the solvent was removed under reduced pressure. The compound was purified using silica gel column chromatography, eluting a gradient of 100% heptanes to 75% ethyl acetate in heptane. 2-Chloro-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid methyl ester 10a (2.45 g, 6.27 mmol) was isolated as a yellowish-white solid and was carried on without further purification. LCMS (m/e)=390 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][O-:12].[Na+].CO>CO.C(Cl)Cl.O>[Br:1][C:2]1[CH:9]=[C:8]([O:12][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(F)cc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C=O)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-fluorobenzaldehyde (50 g, 246 mmol), in MeOH (500 mL) in a 15° C. water bath was added a 25% solution of NaOMe/MeOH (88 mL). The mixture was stirred at r.t. for 1 hour followed by 2 hours at reflux. The solid was filtered and the filtrate was concentrated to dryness to give a second crop of solid. Both crops were taken up in CH2Cl2/H2O. After washing with H2O, the organic phase was dried (MgSO4), filtered, and evaporated to give an off-white solid (52.2 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.I[CH2:29][C:30]#[N:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:29][C:30]#[N:31])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(O)nc3)n2)n1
Reactant: N#CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(OCC#N)nc3)n2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.8 %

Procedure:
A mixture of 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridin-2-ol (Intermediate 136, 0.150 g, 0.414 mmol), 2-iodoacetonitrile (0.036 mL, 0.497 mmol), cesium carbonate (0.270 g, 0.827 mmol) in DMF (2 mL) was stirred at 90 C in a pressure tube for 18 h. A further 0.6 equivalent of 2-iodoacetonitrile was added and the mixture was stirred overnight at 90 C. The reaction mixture was cooled to room temperature, diluted with water, the precipitate was collected by filtration, washed with water and dried under vacuum. The resulting solid was purified by preparative HPLC to afford the title compound (3 mg, 2%).
Reaction SMILES: [OH-:1].[K+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].Cl.[NH2:14]O>C(O)C>[OH:1][NH:8][C:7](=[NH:14])[C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[O:4][CH3:3]
Reactant: [OH-]
Reactant: COc1ccccc1C#N
Reactant: NO
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: COc1ccccc1C(=N)NO
Yield: 77.2 %

Procedure:
Add potassium hydroxide (30.3 g, 225 mmol) to a solution of 2-methoxybenzonitrile (25.0 g, 187 mmol) and hydroxylamine hydrochloride (15.77 g, 225 mmol) in ethanol (500 mL) at room temperature under nitrogen and heat the mixture at reflux for 12 hours. Remove the solvent under reduced pressure, triturate the residue with ethyl acetate/hexanes (1:9, 300 mL) and collect by vacuum filtration to provide N-hydroxy-2-methoxybenzamidine (24.0 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ru].C1CCCCC1>[CH:2]1([NH2:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:2]1([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Nc1ccccc1
Agent: [Ru]
Solvent: C1CCCCC1
Product: C1CCC(NC2CCCCC2)CC1
Product: NC1CCCCC1

Procedure:
It has now surprisingly been found that aniline can be efficiently hydrogenated over a ruthenium catalyst to produce cyclohexylamine with a minimum amount of byproduct dicyclohexylamine or cyclohexane by operating at a temperature of from 160° to 180° C. and by including from about 1 to about 8 parts by weight of ammonia per 100 parts aniline by weight in the charge. Moderate hydrogen pressures of from about 2 MPa to 5 MPa can be employed, and the reaction proceeds smoothly to completion in one half hour to four hours, with no rapid rise in temperature or localized heating. The ruthenium catalyst does not appear to be poisoned by the ammonia, and can be recycled a number of times.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2([CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH:21]4[CH2:24][CH:19]3[C:20]4([CH3:26])[CH3:25])[CH2:12][CH2:11]2)[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:6]1.[CH3:33][NH2:34].CCO>O.CCOC(C)=O.[I-].[Na+]>[CH3:26][C:20]1([CH3:25])[CH:19]2[CH2:24][CH:21]1[CH2:22][CH2:23][CH:18]2[CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][C:8]2([N:7]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:34][CH3:33])[C:9]2=[O:10])[CH2:15][CH2:14]1
Reactant: CN
Reactant: CC1(C)C2CCC(CCN3CCC4(CC3)C(=O)N(CCCCl)CN4c3ccccc3)C1C2
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCCCN1CN(c2ccccc2)C2(CCN(CCC3CCC4CC3C4(C)C)CC2)C1=O
Temperature: 70 °C
Reaction time: 72 h
Yield: 52.2 %

Procedure:
The crude spiro compound (23) (162.8 g; 0.36 mol) was dissolved in methylamine/EtOH solution (Fluka, 8M; 1154 ml; 9.23 mol). Sodium iodide (2.16 g; 0.014 mol) was added and the solution was stirred at 70° C. under N2-atmosphere for 3 days. After cooling the reaction mixture was diluted with water and EtOAc (500 ml each). The aqueous layer was extracted with EtOAc (3×800 ml). The organic layer was washed with brine (500 ml). After drying on Na2SO4 the solvent was evaporated to yield a yellow oil. This oil was purified by column chromatography (SiO2; CH2Cl2/MeOH 90:10; containing 1% 7N NH3/MeOH) to yield 30 g of (24) with a purity of 93% (according to HPLC/MS) and 85 g of (24) with a purity of 96% (115 g; 0.25 mol; 70%).
Reaction SMILES: [OH:1][C:2]1([CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][CH:10]1[O:16][CH3:17])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[H-].[Na+].[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C(Cl)Cl>[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([O:1][C:2]1([CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][CH:10]1[O:16][CH3:17])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)=[O:23]
Reactant: COC1C=CC(Br)=CC1(O)Cc1cnccn1
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COC1C=CC(Br)=CC1(Cc1cnccn1)OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.6 g of 2-(1-hydroxy-2'methoxy-5'-bromobenzyl)pyrazine were dissolved in 15 ml of methylene chloride. At 0° C., 0.2 g of NaH were added, resulting in the evolution of a gas and formation of a precipitate. 0.4 ml of trimethylacetyl chloride were added in one portion. The reaction mixture was stirred at room temperature overnight. The solvent was then stripped from the reaction mixture, and the residue was extracted with ice water and methylene chloride. The methylene chloride layer was washed with water, dried (MgSO4), filtered and stripped of the solvent to yield 0.9 g of 3-(1-trimethylacetoxy-2'-methoxy-5'-bromobenzyl)-pyrazine.
Reaction SMILES: C([Li])CCC.CCCCCC.C[Si](C)(C)[N:14]1[CH2:19][CH2:18][C:17]2[S:20][CH:21]=[CH:22][C:16]=2[CH2:15]1.[B:25](OCCCC)([O:31]CCCC)[O:26]CCCC.Cl>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[S:20]1[C:17]2[CH2:18][CH2:19][NH:14][CH2:15][C:16]=2[CH:22]=[C:21]1[B:25]([OH:31])[OH:26]
Reactant: C[Si](C)(C)N1CCc2sccc2C1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cc2c(s1)CCNC2
Temperature: -20 °C
Reaction time: 2 h

Procedure:
45.4 cc. of a 12% solution of butyl lithium in hexane (0.084 mol) are added dropwise, under an atmosphere of nitrogen, to a solution, cooled to -20° C., of 15 g. (0.07 mol) 5-trimethylsilyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, prepared as in Example 7, in 150 cc. of THF. The reaction mixture is allowed to return to 0° C. and 3 cc. HMPT are added thereto. After cooling this mixture to -50° C., a solution of 19.3 g. (0.084 mol) tributyl borate in 30 cc. THF is added dropwise. Stirring is continued for 2 hours, whilst allowing the mixture to return to ambient temperature. 28 cc. 3N hydrochloric acid (0.084 mol) are then added and the precipitate formed is filtered off. The crystals are washed with acetone and with diisopropyl ether and then dried in vacuo. Off white crystals are obtained in quantitative yield; m.p.>260° C.; NMR (D2O): 6.75 (s,1H); 4.10 (m,2H); 2.80-3.50 (m,4H).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH2:19]([N:22]1[CH:26]=[C:25]([C:27]2[CH:28]=[C:29]([CH:38]=[CH:39][CH:40]=2)[CH2:30][CH2:31][O:32][CH2:33][CH2:34][C:35]([OH:37])=O)[CH:24]=[N:23]1)[CH2:20][CH3:21].[CH3:41][O:42][CH:43]([O:51][CH3:52])[CH2:44][NH:45][CH:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1.C(=O)([O-])O.[Na+]>C1COCC1.C(#N)C.C(N(CC)CC)C>[CH:46]1([N:45]([CH2:44][CH:43]([O:51][CH3:52])[O:42][CH3:41])[C:35](=[O:37])[CH2:34][CH2:33][O:32][CH2:31][CH2:30][C:29]2[CH:38]=[CH:39][CH:40]=[C:27]([C:25]3[CH:24]=[N:23][N:22]([CH2:19][CH2:20][CH3:21])[CH:26]=3)[CH:28]=2)[CH2:47][CH2:48][CH2:49][CH2:50]1
Reactant: CCCn1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Reactant: COC(CNC1CCCC1)OC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCn1cc(-c2cccc(CCOCCC(=O)N(CC(OC)OC)C3CCCC3)c2)cn1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
A solution of T3P (0.637 mL, 1.57M) dissolved in THF was added to a stirred solution of 3-(3-(1-propyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 18, Step ii)] (151 mg), triethylamine (0.906 mL) and N-(2,2-dimethoxyethyl)cyclopentanamine [Preparation 9] (106 mg) in acetonitrile (2 mL) at 22° C. under air. The resulting solution was stirred at 22° C. for 30 min. The reaction mixture was neutralised with saturated sodium hydrogen carbonate and extracted with DCM. The organic was filtered through a phase separator cartridge and evaporated to afford crude product. The crude product was purified by flash silica chromatography using elution gradient 0 to 100% ethyl acetate in isohexane to the subtitled compound (150 mg) as an oil. MS [M+H-MeOH]+=426 (MultiMode+) 1H NMR (300 MHz, CD3OD) δ 8.00 (s, 1H), 7.83 (s, 1H), 7.43 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 4.60 and 4.41 (2×t, J=5.2 Hz, 1H), 4.31-4.18 (m, 1H), 4.14 (t, J=7.0 Hz, 2H), 3.80-3.67 (m, 4H), 3.39 and 3.26 (2×d, J=5.3 Hz, 2H), 3.38 (s, 3H), 3.36 (s, 3H), 2.88 (t, J=6.6 Hz, 2H), 2.69 (t, J=6.2 Hz, 2H), 1.92 (sextet, J=7.2 Hz, 2H), 1.85-1.47 (m, 8H), 0.95 (t, J=7.4 Hz, 3H), a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]#[N:23])=[CH:17][CH:16]=1.[H][H].[CH:26]1(Br)[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C=O)C>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:22]#[N:23])=[CH:17][CH:16]=1
Reactant: N#CCc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: [H][H]
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Temperature: 25 °C

Procedure:
0.6 g (80 % pure) of sodium hydride (0.02 mol) is suspended in 40 ml of absolute DMF at 0° C., and 5.5 g (0.02 mol) of the compound from Example I in 20 ml of DMF are added dropwise. Evolution of hydrogen starts. During this process, the temperature rises to room temperature. The mixture is subsequently stirred at room temperature for a further hour and then cooled to 0° C., and 3 g (0.02 mol) of cyclopentyl bromide are added dropwise. The mixture is allowed to react further overnight and then concentrated to dryness in vacuo, and the residue is extracted by stirring with 180 ml of water/methylene chloride (1: 1) . The organic phase is separated off, dried and concentrated to a small volume, and the residue is separated by column chromatography (silica gel 60, mobile phase: toluene/ethyl acetate 9:1).