Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[CH3:2][N:3]([CH3:9])[C:4](=[NH:8])[N:5]([CH3:7])[CH3:6].C[O-].[Na+]>ClCCl>[Cl-:1].[CH3:2][N:3]([CH3:9])[C:4](=[NH2+:8])[N:5]([CH3:7])[CH3:6]
Reactant: CN(C)C(=N)N(C)C
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C(=[NH2+])N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
600 ml of dichloromethane and 400 g (2.34 mol) of (N,N-dimethylimidazolidino) chloride were initially charged. Subsequently, 552 g of tetramethylguanidine (2 eq., 4.8 mol) were added with cooling within 2 hours. Subsequently, the solvent was removed and 600 ml of methanol were added to the solid residue. Afterwards, 432 g (2.4 mol) of 30% sodium methoxide solution (in methanol) were added to the suspension with cooling and the mixture is stirred at room temperature for one hour. The solvents were removed and 200 ml of dichloromethane are then added to the residue. The precipitate was filtered off and discarded. The filtrate was concentrated to dryness. 449 g (1.80 mol) of (N,N-dimethylimidazolidino) tetramethylguanidinium chloride (CNC catalyst of the formula (III-1)) were isolated. Yield: 94%; m.p.: 145-147° C.
Reaction SMILES: C([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25](=O)[NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)(C)(C)C.CC1C=CC2C(NC3C=CC=C(C(F)(F)F)C=3)=[N:45][CH:44]=[CH:43]C=2C=1N.NC1C=CC=CC=1>>[NH2:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[C:20]([CH3:38])=[CH:21][CH:22]=[C:23]4[C:24]=3[CH:43]=[CH:44][N:45]=[C:25]4[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=3)=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Reactant: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1N
Solvent: Nc1ccccc1
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1NC(=O)c1cccc2c(N)nccc12
Yield: 2 %

Procedure:
The procedures of Steps (3) and (4) of Example 2 were repeated step by step, except for using 6-methyl-N1-(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine obtained in Step (2) above instead of aniline in Step (3) of Example 1 to obtain the title compound (1.0 mg, 2%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[N:23]=[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[O:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1>C(Cl)Cl.CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:26]2[CH2:27][CH2:28][CH2:29][CH:24]([C:22]3[O:21][N:20]=[C:19]([C:15]4[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=4)[N:23]=3)[CH2:25]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Fc1cccc(-c2noc(C3CCCNC3)n2)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCCC(c2nc(-c3cccc(F)c3)no2)C1
Yield: 50 %

Procedure:
The compound was prepared following the procedure described in the Example 3 (D), using 4-Fluoro-benzoyl chloride as the acyl chloride of choice and the 3-[3-(3-Fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidine hydrochloride (already prepared before in the Example 9). Yield: 50% (yellow oil); Mp=86-89° C. (beige powder); Rf=0.28 (DCM/MeOH: 98/2); LCMS (Tr): 4.88 min (Method C); MS (ES+) gave m/z: 370.3; 1H-NMR (CDCl3), δ (ppm): 8.05-7.90 (m, 2H), 7.30-7.23 (m, 2H), 7.25-7.15 (m, 3H), 7.00 (m, 1H), 3.65-3.32 (m, 4H), 2.53 (m, H), 1.86-1.45 (m, 4H).
Reaction SMILES: [CH2:1]([S:13][CH2:14][CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCOCC.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>N1C=CC=CC=1>[CH:22]1([C:25]([O:16][CH2:15][CH2:14][S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:26])[CH2:24][CH2:23]1
Reactant: O=C(Cl)C1CC1
Reactant: CCCCCCCCCCCCSCCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCCCCCCSCCOC(=O)C1CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 2.0 g. 2-hydroxyethyl dodecyl sulfide, 60 ml. anhydrous ether and 1.27 g. cyclopropyl carboxylic acid chloride at 0° is added 1.3 ml. pyridine. The mixture is allowed to warm to room temperature and is stirred for three days. The product is isolated using the procedure of Example 3 to yield 3-thiapentadecyl cyclopropanecarboxylate, boiling point 131°-137° (0.03 mm.).
Reaction SMILES: Cl[P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)=O.Br[C:19]([F:22])([F:21])[F:20].C(N(CC)P(N(CC)CC)N(CC)CC)C>CC(C)=O.ClCCl>[C:3]1([P:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:19]([F:22])([F:21])[F:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)Br
Agent: CCN(CC)P(N(CC)CC)N(CC)CC
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: FC(F)(F)P(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
A flask equipped with a dry ice condenser was flame dried under a nitrogen stream, and charged with 3.1 mL (17 mmol) of chlorodiphenylphosphine and 10 mL of dichloromethane. After cooling the resulting solution to -78° C. and charging the condenser with dry ice and acetone, 4 mL (43 mmol) of bromotrifluoromethane (Freon 13B1) that had been condensed into a graduated tube was warmed to room temperature and allowed to distill into the flask. The cold solution was treated dropwise with 7 mL (26 mmol) of hexaethylphosphorous triamide, allowed to stir at "78° C. for 1 hour, and allowed to stir at room temperature overnight. Dilution with 50 mL of dichloromethane, water washing (three 50 mL portions), drying (MgSO4), and concentration afforded a brown liquid which was purified by flash chromatography on 50g of silica gel (230-400 mesh) eluted with petroleum ether to give 2.9g (68% yield) of diphenyltrifluoromethylphosphine as a colorless liquid. 19F NMR (CDCl3, relative to CFCl3) -55.60 ppm (d, JPF =73 Hz); 31P NMR (CDCl3, relative to H3PO4) 3.11 ppm (quartet of pentets, JPF =73 Hz, JPH =8 Hz); mass spectrum (70 eV) m/z (relative intensity) 254 (41, M+), 185 (74), 183 (100), 127 (23), 107 (40), 77 (26), 69 (65), 51 (54).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[I:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1>[Cu]I.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.C1COCC1>[I:7][C:8]1[CH:13]=[CH:12][C:11]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:10][CH:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(I)cc1
Temperature: 40 °C
Yield: 130.9 %

Procedure:
To a mixture of (trimethylsilyl)-acetylene (2.0 mL, 14 mmol) and 1,4-diiodobenzene (9.4 g, 28 mmol) in freshly distilled TEA (40 mL) and THF (20 mL) in a 100 mL Schlenk flask were added CuI (0.19 g, 1.0 mmol) and PdCl2(PPh3)2 (0.30 g, 0.43 mmol) with stirring. The flask was then evacuated and purged with argon (3 times) on a Schlenk line. The mixture was heated at 40° C. (oil bath), sealed and stirred for 4 h. The solvents were removed under reduced pressure. The residue was dissolved in ethyl ether (150 mL), washed with H2O (3×100 mL), dried (MgSO4) and filtered. The solvent removed under reduced pressure. The resulting residue was purified by column chromatography (silica, petroleum ether/ethyl ether, 10:1) to afford 5.5 g (85%) of an off-white solid. mp 57-59° C. (lit.25 56-58° C.); 1H NMR δ 0.33 (s, 9H), 7.18, 7.64 (AA′BB′, J=8.7 Hz, 2×2H); 13C NMR δ 0.24, 94.2, 96.1, 102.6, 123.4, 133.5, 137.8; FAB-MS obsd 299.9821, calcd exact mass 299.9882 (C11H13ISi).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[C:23]3[N:24]=[C:25]([NH:27][C:28](C)([CH3:31])[CH2:29]O)[S:26][C:22]=3[CH2:21][CH2:20][O:19][C:18]=2[CH:33]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[C:23]3[N:24]=[C:25]([N:27]4[C:28]([CH3:29])([CH3:31])[CH2:7][O:6][C:5]4=[O:11])[S:26][C:22]=3[CH2:21][CH2:20][O:19][C:18]=2[CH:33]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(CO)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)COC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reaction time: 3 h

Procedure:
Triphosgene (148 mg, 0.500 mmol) was added to a mixture of 185 mg (0.500 mmol) of 2-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine-2-ylamino)-2-methylpropan-1-ol and 0.522 ml (3.00 mmol) of diisopropylethylamine in 7.0 ml of methylene chloride. The reaction mixture was stirred for 3 hours and concentrated in vacuum. The residue was partitioned between ethyl acetate and 5% aqueous citric acid. The organic extracts were washed with water, brine, dried over magnesium sulfate and concentrated in vacuum. Yield 194 mg (98%). MS (ESI+): 396.3
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21]SCCC1C=CC=CC=1.BrCC1[C:42]2[C:37](=[CH:38][CH:39]=[C:40](C3C=CC=CC=3OC)[CH:41]=2)[NH:36]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+]>C1(CCS)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])([CH3:20])[CH:13]=[C:12]2[CH2:21][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSCCc1ccccc1)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: SCCc1ccccc1
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
6-(2-Methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline 80 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 30 μL of benzeneethanethiol (phenethyl mercaptan) reacted to give 15 mg of the title compound as a foam.
Reaction SMILES: [CH:1](=[C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[N:9]=[CH:10][CH:11]=2)[CH2:6][O:5][CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(O)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH2:1]([C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[N:9]=[CH:10][CH:11]=2)[CH2:6][O:5][CH:4]=1)[CH3:2]
Reactant: CC=C1COCc2c1ccnc2OC
Agent: [Rh]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCCO
Product: CCC1=COCc2c1ccnc2OC
Reaction time: 2 h

Procedure:
A warmed solution of 4-ethylidene-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine, prepared as in example 3 (0.35 g, 1.83 mmol) in 30 mL of n-propanol is purged with a stream of nitrogen for 20 minutes prior to the addition of tris(triphenylphosphine)rhodium(I) chloride (0.025 g, 0.027 mmol). The reaction mixture is stirred at reflux for 15 hours under nitrogen and again treated with tris(triphenylphosphine)rhodium(I) chloride (0.025 g). After 2 hr, the flask is charged with potassium carbonate (0.50 g, 3.60 mmol), and heated for 2 hr. The mixture is then treated with tris(triphenylphosphine)rhodium(I) chloride (0.025 g). The mixture is heated to reflux for an additional 2 hr, filtered through Celite 545® and the filtrate is concentrated in vacuo. 1H NMR analysis shows an 1:8.3 ratio of exo-(4-ethylidene-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine) to endocyclic (4-ethyl-8-methoxy-1H-pyrano[3,4-c]pyridine) product. The dark residue is chromatographed on silica gel using 5% EtOAc/hexanes to provide 4-ethyl-8-methoxy-1H-pyrano[3,4-c]pyridine, the endocyclic form, as a colorless oil. 1H-NMR (CDCl3, 400 MHz): δ1.13 (t, J=7.4 Hz, 3H, --CH3); 2.30 (q, J=7.4 Hz, 2H, --CH2 --); 3.95 (s, 3H, --OCH3); 5.04 (s, 2H, --CH2O); 6.55 (d, J=5.4 Hz, 1H, Aromatic); 8.04 (d, J=5.4 Hz, Aromatic). Anal. Calcd for C11H13NO2.0.10CHCl3.0.05C3H8O: C, 65.54; H, 6.60; N,6.79. Found: C, 65.48; H, 6.57; N, 6.89. Mass Spectrum (FAB+): m/e 192 (M+1,100%).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[H-].[Na+].[Br:9][C:10]1[CH:11]=[CH:12][C:13](F)=[C:14]([CH:17]=1)[C:15]#[N:16]>CN(C=O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])=[C:14]([CH:17]=1)[C:15]#[N:16]
Reactant: CC(C)(C)CO
Reactant: N#Cc1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc(Br)cc1C#N

Procedure:
After 2,2-dimethyl-1-propanol and sodium hydride were stirred at 0° C. in DMF, 5-bromo-2-fluorobenzonitrile was added thereto, followed by reaction at room temperature to obtain 5-bromo-2-(2,2-dimethylpropoxy)benzonitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9](OCC)=[O:10].[NH3:15]>CO>[CH3:1][C:2]1([CH3:14])[NH:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([NH2:15])=[O:10]
Reactant: CCOC(=O)CN1C(=O)CNC1(C)C
Reactant: N
Solvent: CO
Product: CC1(C)NCC(=O)N1CC(N)=O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
An ice cold solution of ethyl 2,2-dimethyl-5-oxo-1-imidazolidineacetate (2 g) in methanol (150 ml) was saturated with gaseous ammonia. The solution was stirred at room temperature for 36 hours. After evaporation the residue was chromatographed on a silica gel column, eluting with dichloromethane/methanol 6:4. The selected fractions were collected, evaporated and the residue was crystallized from ethanol, to give 1 g of the title compound, as a white powder, m.p. 144°-146° C.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=O)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:7]=[C:8](/[CH:9]=[CH:22]/[CH:23]=[O:24])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cccc(-n2cccn2)c1
Product: O=C/C=C/c1cccc(-n2cccn2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-(1H-pyrazol-1-yl)-benzaldehyde (prepared as described in Reference Example 3) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 199 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[CH2:19][C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si](C(C)(C)C)(C)C)/[C:9]1=[O:32])=O)(C)(C)C.[Cl:33][C:34]1[C:35]([F:47])=[C:36](/[CH:40]=[N:41]/[CH2:42][Si](C)(C)C)[CH:37]=[CH:38][CH:39]=1.C(O)(=O)C.O>CN(C)P(N(C)C)(N(C)C)=O>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:32])[C:10]3([CH:18]([CH2:19][C:20]([CH3:30])([CH3:31])[CH2:21][OH:22])[CH2:42][NH:41][CH:40]3[C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([Cl:33])[C:35]=3[F:47])[C:11]2=[CH:12][CH:13]=1
Reactant: CC(C)(C/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21)CO[Si](C)(C)C(C)(C)C
Reactant: C[Si](C)(C)C/N=C/c1cccc(Cl)c1F
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(CO)CC1CNC(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of E/Z-3-[4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 31 (2.5 g, 5.2 mmol) in hexamethylphosphoramide (30 mL) was added [1-(3-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-trimethylsilanylmethyl-amine prepared in Example 5 (2.9 g, 12 mmol), acetic acid (0.75 g, 12 mmol) and H2O (0.25 g, 14 mmol) sequentially. The reaction mixture was stirred at room temperature for 24 h. Water was added. The mixture was extracted with ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water twice, dried over MgSO4, then concentrated. The residue was dissolved into dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and aqueous saturated NaHCO3 solution. The organic layer was separated, dried over MgSO4, then concentrated. The residue was dissolved into tetrahydrofuran (5 mL), and saturated aqueous NaHCO3 solution was added (5 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4, then concentrated. The residue was purified by chromatography (3% MeOH in EtOAc) to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(3-hydroxy-2,2-dimethyl-propyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one as a white solid (Yield, 0.25 g, 11%).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[C:12]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>ClCCl>[C:8]([NH:20][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])[CH3:9]
Reactant: NCCc1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCCc1ccccc1
Reaction time: 2 h

Procedure:
Triethylamine (1.26 ml, 9.08 mmol), followed by acetyl chloride (0.64 ml, 9.08 mmol) was added to a solution of 2-phenylethylamine (1.04 ml, 8.25 mmol) in dichloromethane (16 ml) at 0° . After 2 hours, the solution was poured into water and extracted thoroughly with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified on silica using 80% ethyl acetate/hexane. The title amide was obtained as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH2:12][CH2:11][CH2:10][NH:9][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCNc1nc(Cl)ncc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccccc1OCCCNc1nc(Cl)ncc1Br
Reaction time: 21 h

Procedure:
A solution of 500 mg (1.29 mmol) of (5-bromo-2-chloro-pyrimidin-4-yl)-[3-(2-nitro-phenoxy)-propyl]-amine in 20 ml of THF is mixed at room temperature with 6.0 ml of an approximately 10% solution of Ti(III)Cl in 20-30% hydrochloric acid. After 21 hours, another 2.0 ml of the Ti(III)Cl solution is added. Renewed additions of the Ti(III)Cl solution are carried out after 4 hours (3.0 ml) or 16 hours (4.0 ml). After another 6 hours, the batch is diluted with ethyl acetate and made basic with 1N NaOH solution. It is filtered on Celite, and the filter cake is washed with ethyl acetate. The organic phase is separated, dried (Na2SO4), filtered and concentrated by evaporation. The residue that is obtained is purified by chromatography (hexane/ethyl acetate 7:3). 290 mg (0.81 mmol, corresponding to 62% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][O:19][CH3:20])=[C:5]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][O:13][C:12]2=[O:16])[CH:10]=1)[CH:6]=O>C(O)(=O)C.C(O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([N:11]2[CH2:15][CH2:14][O:13][C:12]2=[O:16])[CH:8]=[C:5]([CH3:6])[C:4]=1[O:17][CH2:18][O:19][CH3:20]
Reactant: COCOc1c(C=O)cc(N2CCOC2=O)cc1OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COCOc1c(C)cc(N2CCOC2=O)cc1OC
Temperature: 25 °C

Procedure:
3-Methoxy-2-methoxymethoxy-5-(2-oxo-oxazolidin-3-yl)benzaldehyde (0.5 g, 1.79 mmol) was dissolved in a solvent mixture of acetic acid (5 ml) and ethanol (5 ml) and 10% palladium carbon (0.05 g) was added thereto to perform catalytic reduction at 1 atm at 50° C. for 4 hours. The reaction mixture was cooled to room temperature and filtrated by cerite. The filtrate was concentrated under reduced pressure. The residue was dissolved in acetic acid (10 ml) and 10% palladium carbon (0.05 g) was added thereto to perform catalytic reduction at 1 atm at 50° C. for 6 hours. The solvent was removed under reduced pressure to obtain 3-(3-methoxy-4-methoxymethoxy-5-methylphenyl)oxazolidin-2-one as a crude product, which was subjected to the next reaction as it was.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][CH:10]([OH:20])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:5][CH:4]=1)#[N:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:23][S:24]([O:20][CH:10]([CH2:11][NH:12][C:13]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:19])[CH2:9][CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:22][CH:21]=1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)NCC(O)CCOc1ccc(C#N)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(CCOc1ccc(C#N)cc1)OS(C)(=O)=O
Temperature: 0 °C
Yield: 58.5 %

Procedure:
tert-Butyl 4-(4-cyanophenoxy)-2-hydroxybutylcarbamate (38.1 g, 120 mmol; from step (f) above) and 4-(dimethylamino)pyridine (10 mol %) was dissolved in pyridine (200 mL). The mixture was cooled to 0° C. Methanesulfonyl chloride (10.7 mL, 0.136 mol) was added dropwise at 0° C. The mixture was allowed to reach r.t before the pyridine was evaporated. DCM was added, the solution was washed with 2 M HCl and water, dried and then evaporated. The compound was purified by chromatography on silica, eluting with DCM:ethyl acetate (95:5) to give 27 g of the sub-title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C@@H:14]2[CH2:16][C@H:15]2[C:17]([N:19]2[CH2:24][CH2:23][CH:22]([CH2:25][NH2:26])[CH2:21][CH2:20]2)=[O:18])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:27][C:28]1[CH:29]=[N:30][C:31](Cl)=[N:32][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Br:27][C:28]1[CH:29]=[N:30][C:31]([NH:26][CH2:25][CH:22]2[CH2:21][CH2:20][N:19]([C:17]([C@@H:15]3[CH2:16][C@H:14]3[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:18])[CH2:24][CH2:23]2)=[N:32][CH:33]=1
Reactant: NCC1CCN(C(=O)[C@@H]2C[C@H]2c2ccccc2)CC1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCC(CNc2ncc(Br)cn2)CC1
Temperature: 100 °C

Procedure:
A mixture of (1-{[(1R,2R)-2-phenylcyclopropyl]carbonyl}piperidin-4-yl)methylamine trifluoroacetate salt (1.00 g, 2.69 mmol), 5-bromo-2-chloro-pyrimidine ([32779-36-5 ], 0.519 g, 2.69 mmol) and cesium carbonate (1.75 g, 5.37 mmol) in DMF (7 mL) was heated at 100° C. for 1.5 h. The reaction mixture was cooled to RT, diluted with ethyl acetate (200 mL), washed with water (5×20 mL), and brine (10 mL), then dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60, eluting with 10:1–20:89–70 CH2Cl2:2-propanol:hexane to give the title compound. (0.31 g, 28.1%). M.S. (M+1): 416.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>C(#N)C>[N:26]1([CH2:2][C:3]([NH:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([NH:14][C@H:15]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH2:17][CH2:16]4)[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: O=C(Cn1ccnc1)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 73.5 %

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3 step A) (100 mg, 0.281 mmol) and imidazole (96 mg, 1.405 mmol) in acetonitrile (1 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (80 mg, 73%), MS (ISP) m/e=388.3 [(M+H)+].