Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[C:3]=1[CH2:10][C:11]([OH:13])=O.C(N(CC)CC)C.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.Cl.[OH:44][CH2:45][C@H:46]1[CH2:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][C:53]=2[CH2:56][CH2:57][C:58]([CH3:61])([OH:60])[CH3:59])[C@H:48]([CH3:62])[NH:47]1>C(#N)C>[Cl:1][C:2]1[C:3]([CH2:10][C:11]([N:47]2[C@@H:46]([CH2:45][OH:44])[CH2:55][C:54]3[C:49](=[CH:50][CH:51]=[CH:52][C:53]=3[CH2:56][CH2:57][C:58]([OH:60])([CH3:59])[CH3:61])[C@@H:48]2[CH3:62])=[O:13])=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]#[N:9]
Reactant: N#Cc1cccc(Cl)c1CC(=O)O
Reactant: C[C@@H]1N[C@@H](CO)Cc2c(CCC(C)(C)O)cccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1c2cccc(CCC(C)(C)O)c2C[C@H](CO)N1C(=O)Cc1c(Cl)cccc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.6 %

Procedure:
In a vial slurry 2-(2-chloro-6-cyano-phenyl)acetic acid (75.4 mg, 0.37 mmol) in acetonitrile (0.3 mL). Add triethylamine (114 μL, 0.82 mmol) and stir until the solids dissolve. Add 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (165 mg, 0.51 mmol) and stir at ambient temperature for 10 min. In a separate flask slurry 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol hydrochloride (102 mg, 0.34 mol) in acetonitrile (0.3 mL). Add triethylamine (227 μL, 1.63 mmol) and a precipitate forms. Stir 10 min at ambient temperature. Transfer the 2-(2-chloro-6-cyano-phenyl)acetic acid, acetonitrile, triethylamine, and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate reaction mixture from the vial to the flask containing the 4-[(1S,3R)-3-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol hydrochloride, acetonitrile and triethylamine reaction mixture. Rinse with acetonitrile (0.9 mL) and stir the homogeneous reaction mixture at ambient temperature overnight. Dilute the reaction mixture with water and extract with ethyl acetate. Wash the ethyl acetate extracts with water, saturated sodium bicarbonate solution and brine. Dry the extracts over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (0-60% gradient) to give a residue. Purify by reverse phase chromatography on C18 modified silica to yield the title compound as a green oil (34 mg, 0.08 mmol): (m/z): 441.2 (M+1).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)=[O:3].Br[C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][NH2:20])=[CH:16][CH:15]=1.C1(C)C=CC=CC=1.CCO>COCCOC>[NH2:20][CH2:19][CH2:18][C:17]1[CH:21]=[CH:22][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=2)=[CH:15][CH:16]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: NC(=O)c1cccc(B(O)O)c1
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: NCCc1ccc(-c2cccc(C(N)=O)c2)cc1

Procedure:
The title compound was prepared from 3-(aminocarbonyl)-phenyl boronic acid and 4-bromophenethylamine. according to the procedure described for intermediate I-VII-1 with the exceptions that 4:1 PhMe/EtOH was sued as organic solvent (instead of DME) and the chromatographic purification step was omitted. LC/MS (method E) 0.53 min; m/z 241 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25]>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: Oc1ccccc1Cl
Product: Clc1ccccc1Oc1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-chloro-phenol to give [1-(2-chloro-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[NH2:37][C@H:38]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=2)=[CH:46][CH:45]=1)[CH2:39][C:40]([OH:42])=[O:41].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([NH:37][C@H:38]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=2)=[CH:46][CH:45]=1)[CH2:39][C:40]([OH:42])=[O:41])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Reactant: N[C@@H](CC(=O)O)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
A solution of succinic acid mono-benzyl ester (71.1 mg, 0.342 mmol), EDCI (65.5 mg, 0.342 mmol) and HOAt (46.5 mg, 0.342 mmol) in DMF (1 ml), which is allowed to stir at room temperature for 1 hour, is added to a solution of (R)-3-amino-4-(3′-chlorobiphenyl-4-yl)butanoic acid (66 mg, 0.228 mmol) and DIPEA (0.080 ml, 0.456 mmol) in a mixed solvent DMF (2 ml) and water (2 ml). The reaction mixture is allowed to stir for 3 hours, and then diluted with H2O. The products are extracted twice with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated to give crude. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-3-(4-(benzyloxy)-4-oxobutanamido)-4-(3′-chlorobiphenyl-4-yl)butanoic acid (42.4 mg) as a white solid; HPLC retention time=1.22 minutes (condition B); MS (m+1)=480.35; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.44-2.75 (m, 6 H) 2.86-2.99 (m, 2 H) 4.48-4.56 (m, 1 H) 5.11 (s, 2 H) 6.29 (br d, J=8.6 Hz, 1 H) 6.97-7.07 (m, 10 H) 7.25-7.36 (m, 2 H) 7.42-7.50 (m, 2 H) 7.54 (br t, J=1.6 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:21][CH2:20][CH2:19][CH2:18][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Oc1ccc(F)cc1OCc1ccccc1
Reactant: ClCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: Fc1ccc(OCCCCl)c(OCc2ccccc2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred mixture of 2.5 parts of 4-fluoro-2-(phenylmethoxy)phenol, 2.3 parts of 1-bromo-3-chloropropane, 10 parts of water and 0.39 parts of tetrabutylammonium hydrogen sulfate was added dropwise a solution of 0.7 parts of sodium hydroxide in 5 parts of D at 60° C. (exothermic reaction: temperature rose to 70°). The whole was stirred for 2 hours at 70° C. After cooling, the product was extracted twice with methylbenzene. The combined extracts were dried, filtered and evaporated, yielding 3.4 parts (100%) of 1-(3-chloropropoxy)-4-fluoro-2-(phenylmethoxy)benzene as a residue (intermediate 78).
Reaction SMILES: O1C[CH2:4][CH2:3][CH2:2]1.C[Mg]Br.C([C:12]12[CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)(=O)C>C(OCC)C>[C:3](=[C:14]1[CH2:13][CH:12]2[CH2:18][CH:15]1[CH2:16][CH2:17]2)([CH3:4])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(=O)C12CCC(CC1)C2
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(C)=C1CC2CCC1C2

Procedure:
Next, 1 L of tetrahydrofuran solution (concentration: approximately 2 mols/liter) of methylmagnesium bromide was placed in a three-liter four-necked flask, and the mixture of 260 g of acetyl norbornane obtained above and 500 ml of ethyl ether was added dropwise while stirred. After completion of the reaction, the reaction mixture was post treated by the ordinary method, and distilled, to obtain 210 g of isopropylidene norbornane with a purity of 90%.
Reaction SMILES: [C:1]([OH:5])(=O)[C:2]#[CH:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>ClCCl.C(O)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:1](=[O:5])[C:2]#[CH:3])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: C#CC(=O)O
Reactant: COc1ccc(-c2ccc(N)cc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: C#CC(=O)Nc1ccc(-c2ccc(OC)cc2)cc1

Procedure:
Prepared analogously to Example 1.1.b. from propynoic acid and 4′-methoxybiphenyl-4-ylamine. Yield: 1.3 g (17.2% of theory); C16H13NO2 (M=251.28); calc.: molecular ion peak (M+H)+: 252; found: molecular ion peak (M+H)+: 252; Rf value: 0.6 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21]>C(O)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Yield: 81.9 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 3.75 g (25.8 mmol) 3-chloro-4-fluoroaniline was heated to reflux under N2. Removed heat at 3.5 hours and added a solution of saturated sodium bicarbonate until mixture was basic. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solids, washed with water and dried in vacuo. Dissolved solids in 250 ml boiling ethyl acetate, stirred with Darco, and filtered. Stripped solvent and dried in vacuo, giving 6.036 g of yellow solid: mass spectrum (electrospray m/e): M+H=343.1, 345.1.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1(C)[C:19]2[C:18](=[O:20])[N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16](=[O:27])[N:15]([CH2:28][C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[C:14]=2[S:13][CH:12]1[C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-])=O)=[CH:39][CH:38]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O.NCCO>C(O)(=O)C.[Cl-].[Ti+3].[Cl-].[Cl-].CC(=O)CC>[NH2:43][C:40]1[CH:39]=[CH:38][C:37]([C:12]2[S:13][C:14]3[N:15]([CH2:28][C:29]4[C:30]([F:36])=[CH:31][CH:32]=[CH:33][C:34]=4[F:35])[C:16](=[O:27])[N:17]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:18](=[O:20])[C:19]=3[C:11]=2[CH2:10][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:9])=[CH:42][CH:41]=1
Reactant: CN(Cc1ccccc1)CC1(C)c2c(n(Cc3c(F)cccc3F)c(=O)n(-c3ccccc3)c2=O)SC1c1ccc([N+](=O)[O-])cc1
Agent: [Ti+3]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Solvent: NCCO
Product: CN(Cc1ccccc1)Cc1c(-c2ccc(N)cc2)sc2c1c(=O)n(-c1ccccc1)c(=O)n2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-5-methyl-6-(4-nitrophenyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione (3.00 g, 4.80 mmol) was dissolved in acetic acid (6.00 ml). A 20% titanium (III) chloride solution (22.22 g, 28.82 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour (slight exothermic). Citric acid monohydrate (7.07 g) was added to the reaction solution to dissolve it, and water (30 ml) and 2-butanone (50 ml) were added thereto. 2-aminoethanol (15 ml) was added thereto while the temperature of the solution was maintained below 40° C., and the mixture was stirred at room temperature for 20 minutes. The organic layer was separated, and the aqueous layer was reverse-extracted with 2-butanone (30 ml). The organic layers were combined, which was washed by addition of an aqueous saturated sodium hydrogen carbonate solution (40 ml) and sodium chloride (7.00 g). Active carbon (0.3 g) was added to the organic layer, and the mixture was stirred at room temperature for 10 minutes. After active carbon was filtered, the organic solvent was distilled off under reduced pressure, acetonitrile (15 ml) was added thereto, and the mixture was heated to reflux for 40 minutes. The mixture was allowed to cool to room temperature for 1 hour, and water (9 ml) was slowly added dropwise. The mixture was stirred at room temperature for 30 minutes, and stirred at 0° C. for 30 minutes. The crystals were filtered and washed with cold acetonitrile/water=5/3(5 ml). The resulting crystals were dried under vacuum at 50° C. to give 6-(4-aminophenyl)-5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione (2.51 g, 4.23 mmol, 88.1%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([NH:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Product: CCOC(=O)c1cnc(Cl)cc1NC(C)(C)C
Yield: 60 %

Procedure:
A solution of ethyl 4,6-dichloronicotinate (10 g, 45.7 mmol) in tert-butylamine (100 mL) was stirred at 50° C. for 10 h. The solvent was removed under reduced pressure and the residue was suspended in H2O and extracted with EtOAc (3×100 mL). The organics were washed with brine, dried (MgSO4), concentrated in vacuo and purified by silica gel chromatography to provide ethyl 4-(tert-butylamino)-6-chloronicotinate (7 g, 60% yield). 1HNMR (400 MHz, DMSO-d6): δ 8.53 (s, 1 H), 8.39 (s, 1 H), 6.80 (s, 1 H), 4.25 (d, J=7.2 Hz, 2H), 1.37 (s, 9 H), 1.27 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][CH2:36][O:37][CH3:38]>CN(C)C=O.O.C(Cl)Cl>[CH:23]([N:18]1[C:17]([C:11]2[S:12][C:13]3[CH2:14][CH2:15][O:16][C:7]4[CH:6]=[C:5]([CH:3]5[CH2:4][N:1]([CH2:35][CH2:36][O:37][CH3:38])[CH2:2]5)[CH:27]=[CH:26][C:8]=4[C:9]=3[N:10]=2)=[N:21][C:20]([CH3:22])=[N:19]1)([CH3:25])[CH3:24]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COCCN1CC(c2ccc3c(c2)OCCc2sc(-c4nc(C)nn4C(C)C)nc2-3)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, from Example 519, (0.300 g, 0.786 mmol) and Cesium Carbonate (0.384 g, 0.00118 mol) in N,N-Dimethylformamide (7.9 mL) was added 1-bromo-2-methoxyethane, (0.0739 mL, 0.786 mmol) dropwise. The reaction was stirred at room temperature overnight. The mixture was diluted with water and methylene chloride and extracted 3 times with methylene chloride. The crude was purified by column chromatography followed by reverse-phase HPLC to obtain 518 as a white solid (66.3 mg). MS (ESI+) 440.2. 1H NMR (400 MHz, DMSO) δ 8.28 (d, J=8.2 Hz, 1H), 7.19 (dd, J=8.2, 1.5 Hz, 1H), 7.02 (d, J=1.5 Hz, 1H), 5.76 (hept, J=6.6 Hz, 1H), 4.38-4.32 (m, 2H), 3.66-3.52 (m, 3H), 3.41 (t, J=5.0 Hz, 2H), 3.34-3.29 (m, 2H), 3.23 (s, 3H), 3.15-3.07 (m, 2H), 2.58 (t, J=5.9 Hz, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[Mg].BrC1C=CC=CC=1OC.[CH3:21][C:22]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:30]2[CH:26]([CH2:27][N:28]([C:31](=[O:41])[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[CH2:29]2)[C:25](=[O:42])[CH2:24][CH2:23]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:21][C:22]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:30]2[CH:26]([CH2:27][N:28]([C:31](=[O:41])[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[CH2:29]2)[C:25]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])([OH:42])[CH2:24][CH2:23]1
Reactant: COc1ccccc1[Mg]Br
Reactant: COc1ccccc1CC(=O)N1CC2C(=O)CCC(C)(c3ccccc3)C2C1
Agent: COc1ccccc1Br
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccccc1CC(=O)N1CC2C(C1)C(O)(c1ccccc1OC)CCC2(C)c1ccccc1
Temperature: 30 °C

Procedure:
To a suspension of 2-methoxyphenylmagnesium bromide, prepared from 0,576 g of magnesium and 4.5 g of 2-bromoanisole in 25 cm3 of tetrahydrofuran, is added dropwise, with stirring and at 30° C., a solution of 1.6 g of (3aRS,7SR,7aRS)-7-methyl-7-phenyl-2-[(2methoxyphenyl)acetyl]-4-perhydroisoindolone in 40 cm3 of tetrahydrofuran. The reaction mixture is stirred at room temperature for 18 hours, treated with 100 cm3 of saturated aqueous ammonium chloride solution, taken up in 100 cm3 of ethyl acetate and washed with 100 cm3 of water and then with 100 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 16 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 35 cm3 fractions. Fractions 8 to 16 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). The residue is crystallized in 4 cm3 of ethyl acetate. 0.6 g of (3aRS,4RS,7SR,7aRS)-7-methyl-7-phenyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-4perhydroisoindolol is obtained, in the form of white crystals melting at 234° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:18]=[CH:19][C:20]2[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][S:22][C:21]=2[CH:29]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([C:25]([F:26])([F:27])[F:28])=[CH:23][S:22][C:21]=4[CH:29]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: FC(F)(F)c1csc2cc(Br)ccc12
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccc3c(C(F)(F)F)csc3c2)CCN1c1cnccc1C1CC1
Yield: 4.4 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 170 mg, 0.837 mmol) was reacted with 6-bromo-3-(trifluoromethyl)benzo[b]thiophene (259 mg, 0.921 mmol), 1,4-dioxane (8 mL), copper iodide (15.9 mg, 0.083 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (11.9 mg, 0.083 mmol) and potassium phosphate (533 mg, 2.51 mmol) to afford the crude product. Purification by column chromatography on silica gel (0.4% methanol in CHCl3) afforded 15 mg of the product (4% yield).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:27][C:28]2[O:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH:32]=2)[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:25][CH:24]([CH3:26])[CH2:23][CH2:22][N:21]([CH2:27][C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[CH:32]=1)[CH:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1
Reactant: CC(C)CCN(Cc1cc2ccccc2o1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCN(Cc1cc2ccccc2o1)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Trifluoroacetic acid (15 ml, 195 mmol) is added to a solution of 4-{[(benzofuran-2-yl)methyl]-(3-methylbutyl)-amino}-piperidine-1-carboxylic acid tert-butyl ester (1.17 g, 2.92 mmol) in dichloromethane (15 ml). The reaction is stirred overnight at room temperature. The reaction is concentrated and water added to the residue. The solution is loaded onto a SCX-2 (10 g) column and washed with water (20 ml) and methanol (20 ml). The product is then eluted off with 2M ammonia in methanol (30 ml) and concentrated on a rotary evaporator to yield (0.77 g) of N-(3-methylbutyl)-N-[(benzofuran-2-yl)methyl]piperidin-4-amine: mass spectrum (ion spray): m/z=301 (M+1); 1H NMR (CDCl3): δ=7.52-7.43 (2H, m), 7.25-7.16 (2H, m), 6.56 (1H, s), 3.81 (2H, s), 3.14 (2H, brd), 2.72-2.52 (5H, m), 1.86-1.75 (3H, brm), 1.64-1.34 (5H, m), 0.92-0.83 (6H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].[CH:11]([NH2:13])=[O:12].BrBr.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:11][O:12][CH:9]=1
Reactant: NC=O
Reactant: CC(=O)c1ccccc1F
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1ccccc1-c1cocn1
Temperature: 60 °C
Yield: 21.9 %

Procedure:
1-(2-Fluoro-phenyl)-ethanone (2.24 g, 16.23 mmol) and formamide (3.9 mL 97.4 mmol) were added to a flame-dried flask, stirred, and heated to 60° C. Bromine (832 μL, 16.23 mmol) was added dropwise. Upon completion of the bromine addition, the reaction was stirred for 30 minutes, and then the temperature was increased to 125° C. After 3.5 hour further stirring, the reaction mixture was cooled and diluted with 100 mL water. 1N sodium hydroxide was added to increase the pH to about 10. The aqueous layer was extracted twice with diethylether, the combined ether layers were washed with water, dried with magnesium sulfate and concentrated under vacuum. The crude material obtained was chromatographed on silica gel (ISCO MPLC purification, 40 minutes, 0-50% ethyl acetate gradient, Biotage flash 40 m column) to provide 580 mg (22%) of the title compound. 1H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 8.22 (d, 1H, J=9.9 Hz), 8.0 (m, 1H), 7.3 (m, 3H).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH:12]([CH2:13][N:14]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C@H:15](C(OC)=O)[CH3:16])[CH2:11][CH2:10][C@H:9]1[CH2:31][CH:32]=[CH2:33])=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>Cl>[CH2:24]([O:23][C:21]([N:14]1[C@@H:15]([CH3:16])[C:6](=[O:5])[N:8]2[CH:9]([CH2:31][CH:32]=[CH2:33])[CH2:10][CH2:11][C@H:12]2[CH2:13]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=CC[C@@H]1CCC(CN(C(=O)OCc2ccccc2)[C@@H](C)C(=O)OC)N1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCC1CC[C@H]2CN(C(=O)OCc3ccccc3)[C@@H](C)C(=O)N12
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.5 %

Procedure:
A solution of (S)-2-allyl-5-{[benzyloxycarbonyl-((S)-1-methoxycarbonyl-ethyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (298 mg, 0.65 mmol) in hydrogen chloride solution (4 M in 1,4-dioxane, 3 mL) was stirred at room temperature for 2 h, then evaporated. The residue was taken up in MeOH (3 mL), then after addition of potassium carbonate (268 mg, 1.94 mmol) the suspension was stirred at room temperature for 16 h, then partitioned between sat. aq. ammonium chloride solution and EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to afford the title compound (221 mg, 100%). Light brown solid, MS: 329.4 (M+H)+.