Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:12])[C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.Cl[CH2:14][CH:15]=O>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:12])[C:9]2[S:10][CH:14]=[CH:15][N:11]=2)=[CH:6][CH:7]=1
Reactant: CN(C(N)=S)c1ccc(F)cc1
Reactant: O=CCCl
Solvent: CCO
Product: CN(c1ccc(F)cc1)c1nccs1

Procedure:
A solution of 2.0 g (11 mmol) of 1-(4-fluorophenyl)-1-methylthiourea in 20 mL of EtOH was treated with 4.1 mL (33 mmol) of a 50% (w/v) aqueous solution of chloroacetaldehyde and heated at reflux for 18 h. The solvent was removed in vacuo and the residue purified by flash chromatography eluting with a linear gradient of 10% EtOAc in hexane to 100% EtOAc to deliver the title compound. MS (M+H)+ 209.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]OCC2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.[O:51]1[CH2:55]CCN1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:55][O:51]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CNOC1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CCCO2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and isoxazolidine hydrochloride and isolated as white solid (13.1 mg, 74%). MS(m/e): 373.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:3]=1[O:4][CH2:5][CH:6]1[CH:10]=[CH:9][CH2:8][N:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C([SnH](CCCC)CCCC)CCC.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:2]2[CH:10]3[CH:6]([N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9]3)[CH2:5][O:4][C:3]=2[CH:18]=1
Reactant: COc1ccc(Br)c(OCC2C=CCN2C(=O)OC(C)(C)C)c1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)OCC1C2CCN1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Tert-butyl 2-[(2-bromo-5-methoxyphenoxy)methyl]-2,5-dihydro-1H-pyrrole-1-carboxylate (16.4 g, 0.43 mol) was dissolved in toluene (790 mL) and heated at 50° C. for 20 min. To this solution was added AlBN (781 mg, 0.047 mol) and tributyltin hydride (17.9 mL, 0.67 mol). The reaction mixture was stirred at 80° C. for 16 h, cooled to RT, and DBU (10.7 g, 0.70 mol) was added. The resulting suspension was filtered through a pad of silica gel (100 g), and the solids washed with methyl tert-butylether. The filtrate was evaporated and the resulting oil triturated with heptane (10 mL). The crude product was collected via filtration and purified using an ISCO instrument (330 g RediSep® column), eluting with a gradient of ethyl acetate in heptane (from 5%-20%) to afford the title product. MS m/z 249 [M−tBu+H]+
Reaction SMILES: [Cl:1][CH2:2][CH2:3]Cl.CN(C=O)C.C(Cl)(C(Cl)=O)=O.OC1C=[C:19]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:20]2[C:25]([CH3:26])=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)[C:21]=2[N:22]=1>O>[Cl:1][C:2]1[CH:3]=[C:19]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:20]2[C:25]([CH3:26])=[N:24][N:23]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:32][CH:33]=3)[C:21]=2[N:22]=1
Reactant: ClCCCl
Reactant: CCOC(=O)c1cc(O)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Cl)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(see, e.g., Sercel, A. D., et al., Synthetic Communications 2007, 37, 4199-4208). Fresh Vilsmeier's reagent was prepared as follows: to a stirring solution of 1.2 DCE (4 mL) was added DMF (0.2 mL, 2.6 mmol). The resulting solution was cooled down to 0° C. and (COCl)2 (0.22 mL, 2.6 mmol) was added dropwise. The viscous suspension was stirred at room temperature for 10 min, and then 49 (104 mg, 0.26 mmol) was added to the mixture. The suspension was heated to reflux overnight. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL×2). The organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to provide the title compound (120 mg, quantitative yield) as a yellow oil. Crude was used in the next reaction without further purification. 1H NMR (500 MHz, CDCl3) δ 7.56 (s, 1H), 7.31 (t, J=8.2 Hz, 4H), 7.08 (t, J=7.4 Hz, 1H), 6.97 (d, J=7.7 Hz, 2H), 6.93 (d, J=8.5 Hz, 2H), 5.59 (s, 2H), 4.48 (q, J=7.1 Hz, 2H), 2.69 (s, 3H), 1.46 (t, J=7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 164.34, 157.00, 156.91, 151.20, 150.30, 141.77, 135.67, 131.25, 129.71, 129.54, 123.37, 119.00, 118.78, 117.69, 110.41, 62.31, 50.03, 16.16, 14.20.
Reaction SMILES: [CH2:1]([C:8]1[C:9](N(C2CC2)C)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1[C:32](C#N)=[N:33][C:34]2[C:39](N=1)=[CH:38]C=C(Cl)C=2)C1C=CC=CC=1.C1([Mg]Br)CC1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C:8]1[C:9]([CH2:32][NH:33][CH:34]2[CH2:39][CH2:38]2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1nc2cc(Cl)ccc2nc1Cc1ccccc1
Reactant: CN(c1nc2cc(Cl)ccc2nc1Cc1ccccc1)C1CC1
Agent: Br[Mg]C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2nc(Cc3ccccc3)c(CNC3CC3)nc2c1
Temperature: -60 °C
Reaction time: 0.67 h

Procedure:
(±)-(3-Benzyl-7-chloroquinoxalin-2-yl)-cyclopropyl-methylamine (16): To a stirred solution of 3-benzyl-7-chloro-2-cyanoquinoxaline (4.0 g, 14.3 mmol) in anhydrous CH2Cl2 (80 mL) at −64° C. under nitrogen was added dropwise cyclopropylmagnesium bromide (0.76 M in THF, 52 mL, 39.5 mmol). The reaction mixture was stirred at −68˜−30° C. for 40 min. It was cooled to −60° C. and TFA (12 mL) was added to the reaction mixture followed by NaBCNH3 (1.25 g, 18.9 mmol). The mixture was slowly warmed to −20° C. over 20 min, and then cooled to −30° C. and quenched with aq. NaHCO3 and extracted with CH2Cl2 (2×100 mL). The organic solution was washed with brine (60 mL), dried over MgSO4 and concentrated. Purification by flash column (SiO2, EtOAc/hexane MeOH/NH4OH 30:70:3:0.3) gave C-(3-Benzyl-7-chloro-quinoxalin-2-yl)-cyclopropyl-methylamine (16) as an oil (1.8 g). This oily product was slightly contaminated by impurities, but it was used directly for the next step without any further purification. 1H NMR (CDCl3) δ 8.02 (m, 1H), 7.96 (m, 1H), 7.67 (m, 1H), 7.19 (m, 5H), 4.52 (m, 1H), 4.41 (m, 2H), 1.37(m, 1H), 0.61 (m, 1H), 0.36 (m, 1H), 0.12 (m, 1H), 0.01 (m, 1H); MS (ESI), (M+H)+323.26, 325.26.
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]([NH:13][NH2:14])([CH3:12])([CH3:11])[CH3:10].[CH3:15][O:16][C:17](=[O:28])[C:18]([C:23]([CH:25]1[CH2:27][CH2:26]1)=O)=[CH:19]N(C)C>C(O)C>[CH3:15][O:16][C:17]([C:18]1[CH:19]=[N:14][N:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:23]=1[CH:25]1[CH2:27][CH2:26]1)=[O:28]
Reactant: CC(C)(C)NN
Reactant: COC(=O)C(=CN(C)C)C(=O)C1CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1cnn(C(C)(C)C)c1C1CC1
Yield: 36.3 %

Procedure:
Triethylamine (4.8 mL, 34.2 mmol) and tert-butyl hydrazine hydrochloride (1.4 g, 11.4 mmol) were added sequentially to a solution of crude 2-cyclopropanecarbonyl-3-dimethylamino-acrylic acid methyl ester (2.4 g, 11.4 mmol) in ethanol (24 mL). The resulting suspension was mixed well and divided equally into two 25 mL Personal Chemistry Microwave Process Tubes (Biotage AB, Sweden). The tubes were sealed with a septum and submitted to 150 W microwave irradiation using a Personal Chemistry Microwave Synthesis System (Biotage AB, Sweden) at 160° C. for 30 minutes. The reaction mixtures in the two tubes were combined and ethanol was evaporated under reduced pressure. The remaining mixture was partitioned between dichloromethane and water, and the water phase was extracted three times with dichloromethane. The organic phases were combined, concentrated in vacuo, and purified by silica chromatography eluting with a gradient of 10-20% ethyl acetate/hexanes, then 20% ethyl acetate/hexanes to give 1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (921 mg, 36%). LRMS m/z calcd for C12H18N2O2 (M+H) 223.1, found 223.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([SH:8])=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:13])[O:12][CH2:11][CH2:10]1>C(#N)C>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:11][CH2:10][C:9]([OH:13])=[O:12]
Reactant: O=C1CCO1
Reactant: Cc1ccccc1S
Solvent: CC#N
Product: Cc1ccccc1SCCC(=O)O
Reaction time: 2 h
Yield: 58.8 %

Procedure:
A solution of acetonitrile (30 mL) and o-thiocresol (5.0 g, 40 mmol) was heated to reflux. Neat β-propiolactone (2.8 mL, 40 mmol) was added dropwise over 5 min. Heating was continued at reflux for 20 h at which time additional β-propiolactone (2.8 mL, 40 mmol) was added in one portion. After heating for an additional 24 h, the reaction mixture was concentrated in vacuo. The resultting solid-oil mixture was treated at 23° C. with 2N aqueous NaOH (150 mL). This basic solution was washed with Et2O (2×200 mL). The separated aqueous layer was acidified with conc. aqueous HCl until pH<1. This heterogenous solution was concentrated in vacuo to half of its original volume. Then it was allowed to stand at 23° C. for 2 h. The solid product was collected by vacuum filtration, washed with H2O (20 mL), and dried under vacuum at 65° C. for 2 h to afford 3-[(2-methylphenyl)sulfanyl]propanoic acid (4.62 g, 59%) as a white powder. 1H NMR (CHCl3, 300 MHz) δ7.31 (d, 1H, J=7.0 Hz), 7.20-7.15 (m, 3H), 3.14 (t, 2H, J=7.3 Hz), 2.69 (t, 2H, J=7.4 Hz), 2.39 (s, 3H) ppm.
Reaction SMILES: [F:1][CH:2]([F:4])Cl.[NH2:5][C:6]1[N:11]=[C:10]([SH:12])[N:9]=[C:8]([O:13][CH3:14])[N:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:5][C:6]1[N:11]=[C:10]([S:12][CH:2]([F:4])[F:1])[N:9]=[C:8]([O:13][CH3:14])[N:7]=1
Reactant: COc1nc(N)nc(S)n1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc(N)nc(SC(F)F)n1

Procedure:
10.0 g of gaseous difluorochloromethane are introduced, during a period of 90 minutes at a temperature of 70° to 75° C., into a suspension of 5.0 g of 2-amino-4-mercapto-6-methoxy-1,3,5-triazine and 4.8 g of potassium carbonate in 100 ml of dimethylformamide. The reaction mixture is concentrated by evaporation, the residue is stirred up with water, and the solid precipitate is separated. The yield is 1.6 g of 2-amino-4-difluoromethylthio-6-methoxy-1,3,5-triazine, m.p. 146° to 150° C. (compound No. 1.14).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:18][CH2:17][C:12]3([NH:16][CH2:15][CH2:14][CH2:13]3)[CH2:11]2)[CH:7]=[N:8][CH:9]=1)[CH3:2].C=O.[C:21](=O)(O)[O-].[Na+]>C(O)=O>[CH3:21][N:16]1[C:12]2([CH2:17][CH2:18][N:10]([C:6]3[CH:7]=[N:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH2:11]2)[CH2:13][CH2:14][CH2:15]1
Reactant: CCOc1cncc(N2CCC3(CCCN3)C2)c1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CCOc1cncc(N2CCC3(CCCN3C)C2)c1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a stirring solution of 7-(5-ethoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane (360.4 mg, 1.4 mmol) in 37% aqueous solution of formaldehyde (4 mL) was added 98% formic acid (2 mL) under nitrogen. The reaction mixture was heated to reflux for 8 h. The reaction mixture was cooled to room temperature, then basified with saturated aqueous sodium bicarbonate to pH 8-9 and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to afford a viscous brown liquid. This was distilled using a Kugelrohr apparatus (2 mm, 180° C.) to give a very light cream-colored syrup (340 mg, 89.3%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:9][CH:10]([CH2:14][CH2:15][Br:16])[C:11](Cl)=[O:12].[OH-].[Na+]>ClCCl.O>[Br:9][CH:10]([CH2:14][CH2:15][Br:16])[C:11]([NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:12]
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)C(Br)CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)C(Br)CCBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a stirred mixture of ethyl 2-aminoacetate hydrochloride (1.568 g, 11.24 mmol) in dichloromethane (9 mL) and water (2 mL) at 0° C. was added a solution of 2,4-dibromobutanoyl chloride (3.0 g, 10.21 mmol) in dichloromethane (2 mL). A solution of sodium hydroxide in water (11.5 M, 2 mL) was then added slowly. The reaction was stirred 1 hour at 0° C. and then 15 minutes at room temperature. The reaction was then treated with dichloromethane (40 mL) and water (25 mL). The layers were separated, and the organic layer was brine-washed, dried over sodium sulfate, filtered, concentrated down, and dried under vacuum to afford the crude title racemic compound (3.165 g in 90% purity, 84% yield) as a clear oil. 1H NMR (400 MHz, chloroform-d) δ ppm 6.81 (br s, 1H), 4.58 (dd, J=8.84, 4.80 Hz, 1H), 4.21-4.31 (m, 2H), 4.07 (d, J=5.56 Hz, 2H), 3.51-3.63 (m, 2H), 2.62-2.75 (m, 1H), 2.44-2.57 (m, 1H), 1.28-1.36 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([O:15][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: Cc1cn2c3ccc(Br)cc3c3cc(O)cc(c1=O)c32
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1cc2c(=O)c(C)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
10-bromo-2-hydroxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (400 mg) obtained in Example 49 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (0.34 g) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and ethyl bromoacetate (0.16 ml) was added. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was poured into ice water (50 ml). The crystals precipitated were recovered by filtration. The resulting crude crystals were washed with water, ethanol and ether in succession, and recovered by filtration to obtain the title compound (360 mg, 71%).
Reaction SMILES: C[Zn]C.[CH:4]([Mg]Br)=[CH2:5].[F:8][C:9]1[CH:10]=[C:11]([CH:20]=[C:21]([I:23])[CH:22]=1)/[CH:12]=[N:13]/[S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15]>C1COCC1>[F:8][C:9]1[CH:10]=[C:11]([C@H:12]([NH:13][S@@:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])[CH:4]=[CH2:5])[CH:20]=[C:21]([I:23])[CH:22]=1
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)[S@@](=O)/N=C/c1cc(F)cc(I)c1
Agent: C[Zn]C
Solvent: C1CCOC1
Product: C=C[C@@H](N[S@](=O)C(C)(C)C)c1cc(F)cc(I)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Dimethyl zinc (1.2M in toluene) (7.29 mL, 8.75 mmol) and vinylmagnesium bromide (45.5 mL, 45.5 mmol) was mixed at room temperature for 20 min under argon before cooling down to −78° C., then (R,E)-N-(3-fluoro-5-iodobenzylidene)-2-methylpropane-2-sulfinamide in dry THF (117 mL) as added dropwise about 30 min. The internal temperature between −74 C to −72° C., after addition the reaction mixture was stirred at −78° C. for 1 h, sample was taken quenched by Water, LCMS showed the desired product along with unreacted starting material. More vinylmagnesium bromide (12 mL, 12.0 mmol)) was added and reaction monitored by LCMS and after 30 min, reaction was deemed complete. The reaction mixture was poured over ice-cold by sat.NH4Cl and water, THF was removed in vacuo and the product extracted by EtOAc. The organic layer was washed by water and Brine, dried over anhydrous Na2SO4, filtered and concentrated and the crude product was purified by flash chromatography (0-70% EtOAc/heptane) to provide 8.99 g of (R)—N—((R)-1-(3-fluoro-5-iodophenyl)allyl)-2-methylpropane-2-sulfinamide as the desired product as a colorless yellow syrup. Yield (67.4%). The yield is for the 4 step sequence. Note: The major side-product corresponds to de-iodinated desired product. LCMS (m/z): 382.5 (MH+), 0.96 min; 1H NMR (400 MHz, CDCl3)) δ ppm 7.48 (s, 1H), 7.37 (dt, J=7.6, 1.9 Hz, 1H), 7.06 (d, J=9.0 Hz, 1H), 5.85 (ddd, J=17.0, 10.0, 7.4 Hz, 1H), 5.25-5.47 (m, 3H), 4.90 (d, J=7.0 Hz, 1H), 3.23-3.66 (m, 1H), 1.26 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2Br)[C@H:10]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22]C=2O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](=[O:31])([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>O1CCOCC1.[Cu]I>[Cl:26][C:24]1[CH:23]=[CH:22][C:28]2[O:31][C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C@H:11]3[CH2:12][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][C@@H:10]3[C:20]=2[CH:25]=1
Reactant: Oc1ccc(Cl)cc1[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1Br
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: [Cs+]
Solvent: C1COCCO1
Product: Clc1ccc2c(c1)[C@H]1CN(Cc3ccccc3)C[C@@H]1c1ccccc1O2

Procedure:
A mixture of racemic trans-2-(1-benzyl-4-(2-bromophenyl)pyrrolidin-3-yl)-4-chlorophenol (1.8 g, 4.07 mmol), cesium carbonate (2.65 g, 8.13 mmol, 2.0 eq.), N,N-dimethylglycine (165 mg, 1.6 mmol; 0.4 eq.) and CuI (310 mg, 1.6 mmol; 0.4 eq.) in dioxane (20 ml) was heated to reflux temperature while stirring under inert nitrogen atmosphere. After one hour the title product was formed according to mass analysis (M+1=362, 364 found), but the conversion was not yet complete. Heating was continued overnight to give 98% conversion according to LC-MS. The reaction mixture was cooled to room temperature and was then filtered over a glass filter. The residual salts were washed with dioxane (25 ml). The combined filtrates were concentrated under vacuum to give the crude product as a brown oil. Toluene (150 ml) was added and the resulting solution was washed with concentrated aqueous ammonia (25 ml; 25%). The toluene layer was separated and dried with Na2SO4. Concentration under vacuum gave the title compound (1.47 g, 4.06 mmol) in quantitative yield as a brown oil, with ca. 78% purity according to LC-MS analysis. The product was used without further purification. MS: M+1=362, 364 found.
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.[F:9][C:10]([F:19])([F:18])[C:11]([CH3:17])([CH3:16])[C:12](OC)=[O:13]>C1COCC1>[F:9][C:10]([F:19])([F:18])[C:11]([CH3:17])([CH3:16])[C:12](=[O:13])[CH2:1][C:2]#[N:3]
Reactant: COC(=O)C(C)(C)C(F)(F)F
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C(=O)CC#N)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To a mixture of MeCN (13.9 mL, 264 mmol) in THF (500 mL) cooled to −78° C. was added n-BuLi (106 mL, 264 mmol). The mixture was stirred at −30° C. for 0.5 h. Then to the mixture was added methyl 3,3,3-trifluoro-2,2-dimethylpropanoate (30 g, 176 mmol) dropwise. The mixture was stirred at 25° C. for 10 h. The mixture was quenched with aqueous NH4Cl (50 mL), extracted with EA (300 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated to yield a crude product of a yellow oil of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (22 g, 122.9 mmol, 70% yield): 1H NMR (400 MHz, CDCl3) δ 3.75 (s, 2H), 1.41 (s, 6H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]([C:7]([O:9][C@@H:10]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:8])[CH3:6].C(N(CC)CC)C.[O:29]1[CH2:34][CH2:33][N:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1>C(Cl)Cl>[CH3:6][N:5]([C:7]([O:9][C@@H:10]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:8])[CH2:4][CH2:3][N:2]([C:35]([N:32]1[CH2:33][CH2:34][O:29][CH2:30][CH2:31]1)=[O:36])[CH3:1]
Reactant: CNCCN(C)C(=O)O[C@@H](Cc1ccccc1)C(=O)OC
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)OC(=O)N(C)CCN(C)C(=O)N1CCOCC1
Yield: 88.8 %

Procedure:
Methyl 2(S)-[N-(2-methylaminoethyl)-N-methylaminocarbonyloxy]- 3-phenylpropionate (8.0 g) was dissolved in methylene chloride (40 ml), and triethylamine (4.13 g) was added thereto under cooling. Thereto was dropwise added morpholinocarbonyl chloride (4.07 g) at 0°-10° C. over 30 minutes. After the dropwise addition, the mixture was stirred at said temperature for 60 minutes, washed with 5% hydrochloric acid, water, an aqueous solution of 6% sodium hydrogencarbonate, and water in this order, and the solvent was evaporated under reduced pressure to give 9.83 g of methyl 2(S)-[N-methyl-N-[2-{N-(morpholinocarbonyl)-N-methylamino}ethyl]aminocarbonyloxy]-3-phenylpropionate (yield 88.8%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]12[CH:13]([CH2:14][N:15]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[C:25]([F:35])[CH:24]=3)[C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[O:17])[CH:12]1[CH2:11][NH:10][CH2:9]2.[CH:36](=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH2:36]([N:10]1[CH2:11][CH:12]2[CH:8]([CH:13]2[CH2:14][N:15]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[CH2:9]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(c1cccs1)N(CC1C2CNCC21)c1ccc(N2CCOCC2)c(F)c1
Reactant: O=Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccs1)N(CC1C2CN(Cc3ccccc3)CC21)c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of the Thiophene-2-carboxylic acid (3-aza-bicyclo[3.1.0]hex-6-ylmethyl)-(3-fluoro-4-morpholin-4-yl-phenyl)-amide trifluoroacetic acid salt prepared above (100 mg, 0.16 mmol) in 4 mL of CH2Cl2 at room temperature was added benzaldehyde (0.02 mL, 0.24 mmol) and NaHB(OAc)3 (50 mg, 0.24 mmol). The reaction stirred at room temperature for 2 hours. The reaction was quenched by the addition of saturated NaHCO3, the layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting crude material was purified via flash chromatography with 75% EtOAc/hexanes. The product containing fractions were collected and concentrated to yield 32 mg of the desired product. 400 MHz 1H NMR (CDCl3) δ 7.17-7.29 (m, 6H), 6.94-6.98 (m, 4H), 6.78-6.80 (m, 1H), 3.86-3.88 (m, 4H), 3.65 (d, J=7.47 Hz, 2H), 3.52 (brs, 2H), 3.09-3.12 (m, 4H), 2.86-2.88 (m, 2H), 2.26-2.28 (m, 2H), 1.63 (brs, 1H), 1.47 (brs, 1H), 1.21-1.25 (m, 1H); MS (M+1) 492.2.