Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH3:13])=[C:2]=[O:3].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>C1(C)C=CC=CC=1>[CH3:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[NH:1][C:2](=[O:3])[O:19][CH2:18][CH2:17][CH2:16][CH2:15][Cl:14]
Reactant: OCCCCCl
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)OCCCCCl

Procedure:
17.8 g (0.10 mol) 4-isocyanato-3-methyl-1-nitro-benzene are placed in 750 ml of toluene and a solution of 11.7 ml (0.10 mol) 4-chloro-butan-1-ol in 50 ml of toluene is added dropwise. Then the reaction mixture is heated for 16 hours to 75° C., then evaporated down i. vac. and twice taken up with toluene and concentrated by evaporation completely i. vac. The residue is purified by recrystallisation from cyclohexane.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1.C(OCC)(=O)C>[Cl:15][C:14]1[N:13]=[C:20]([Cl:21])[N:19]=[C:17]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)[N:16]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Temperature: 2.5 °C
Yield: 100 %

Procedure:
A solution of 4-trifluoromethoxyaniline (XII) (14.66 mL, 108 mmol) in dry tetrahydrofuran (THF; 120 mL) was added, dropwise, to a cold (0-5° C.) stirred suspension of cyanuric chloride (II) (20.0 g, 108 mmol) and potassium carbonate (15 g, 108 mmol) in dry THF (400 mL). The reaction mixture was stirred for 3 h while slowly warming to ambient temperature. After stirring for 14 h at ambient temperature, the reaction mixture was diluted with ethyl acetate (400 mL) and then acidified with 1 N aqueous hydrochloric acid. The organic phase was separated, rinsed successively with water, saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum on a rotary evaporator. The residue, an off white solid, was recrystallized from hot hexanes to afford (4,6-dichloro-1,3,5-triazin-2-yl)-(4-trifluoromethoxyphenyl)amine (XIII) (35.1 g, 99% yield): m.p. 119-122° C.; 1H NMR (CDCl3) δ 7.62 (d, J=3.3 Hz, 2H), 7.58 (d, J=2.2 Hz, 2H); ESI/MS 325 (M+H), 323 (M−H); Anal. Calcd. For C10H5Cl2F3N4O: C, 36.95; H, 1.55; N, 17.53. Found: C, 36.80; H, 1.53; N, 16.98.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([S:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)(=[O:25])=[O:24])[CH:17]=2)=[C:10]([Cl:31])[CH:9]=1)=[O:6])C.Cl>O.CO.[OH-].[K+]>[Cl:14][C:12]1[CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]([OH:32])=[O:3])[CH:9]=[C:10]([Cl:31])[C:11]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([S:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:25])=[O:24])[CH:17]=1
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)N3CCCC3)c2)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)Nc1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)N3CCCC3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-{3,5-dichloro-4-[4-hydroxy-3-(pyrrolidine-1-sulfonyl)-phenoxy]-phenyl}-oxamic acid ethyl ester (10 mg, 0.02 mmol) in a mixture of H2O (0.5 mL) and MeOH (0.5 mL) was added 2 drops of 3N KOH. The reaction mixture was stirred at RT for 2 h, acidified with 1N HCl and extracted with EtOAc (4×5 mL). The combined organic extracts were dried and concentrated to afford the title compound as an off-white solid. NMR (400 MHz, CD3OD) d 7.96 (s, 2H), 7.02-7.06 (m, 2H), 6.95-6.98 (d, 1H), 3.28-3.31 (m, 4H), 1.78-1.81 (m, 4H). MS Calc.: 474.3 Found: 473.1 (M−1).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][C@@H:6]([C:8]([O:10]C)=[O:9])[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]2)[CH2:2]1.O[Li].O>C(O)C.O>[C:15]([O:14][C:12]([N:5]1[C@H:6]([C:8]([OH:10])=[O:9])[CH2:7][C:3]2([CH2:2][CH2:1]2)[CH2:4]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)[C@@H]1CC2(CC2)CN1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(CC2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 102.4 %

Procedure:
To a solution of (S)-5-tert-butyl 6-methyl 5-azaspiro[2.4]heptane-5,6-dicarboxylate (0.436 g, 1.708 mmol) in ethanol (4 mL) was added a solution of LiOH.H2O (86.0 mg, 2.049 mmol, 1.2 eq) in H2O (2 mL) at room temperature. The mixture was stirred at room temperature for 20 hours. EtOH was removed by rotavapor. The aqueous residue was diluted with H2O and extracted with Et2O. The aqueous layer was cooled with an ice bath and acidified to pH ˜2 with 1 N HCl. The resulting milky solution was extracted with a mixed solvent of EtOAc and CH2Cl2. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was dried under vacuum to afford the desired product as an off-white solid (0.422 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([CH3:19])[C:11]=1[CH3:20].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:20][C:11]1[C:12]([CH3:19])=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1C
Reactant: Nc1cc(O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(Oc2ccnc(N)c2)ccc([N+](=O)[O-])c1C
Temperature: 75 °C

Procedure:
To a stirred solution of 2-aminopyridin-4-ol (600 mg, 5.5 mmol) and 1-fluoro-2,3-dimethyl-4-nitrobenzene (570 mg, 3.37 mmol) in DMSO (4.0 mL) was added K2CO3 (1.00 g, 7.20 mmol) and the reaction mixture heated to 75° C. for 3 days. The resulting mixture was cooled to RT and was partitioned between water (50 mL) and EtOAc (75 mL). The aq layer was separated and extracted with EtOAc (75 mL) and the combined organic extracts were washed with water (3×50 mL) and brine (50 mL) and then dried and evaporated in vacuo. The residue was recrystallized from DCM to afford the title compound, Intermediate C2, as a tan solid (25 mg, 28%): Rt 1.40 min (Method 2); m/z 260 (M+H)+ (ES+).
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[C:13]([O-:16])(O)=O.[Na+]>C1CCCCC1>[CH3:12][C@@H:2]1[CH:7]=[CH:6][CH2:5][C:4]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[C@H:3]1[C:13](=[O:16])/[CH:3]=[CH:2]/[CH3:12]
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Product: C/C=C/C(=O)[C@H]1[C@H](C)C=CCC12CCCC2
Temperature: 0 °C
Yield: 79 %

Procedure:
At −70° C., a solution of diisopropylamine (0.5 g, 4.93 mmol) in tetrahydrofuran (4 ml) was treated with n-butyl lithium (3.3 ml, 1.6M in hexane, 5.14 mmol). The resulting solution was stirred at −70° C. for 20 min. and treated with a solution of 1-(rel-(6S,7R)-7-methylspiro[4.5]dec-8-en-6-yl)ethanone (0.79 g, 4.11 mmol) in tetrahydrofuran (4 ml). The resulting solution was stirred 20 min. at −70° C. warmed to 0° C., cooled to −70° C., and treated with a solution of acetaldehyde (0.9 g, 20.5 mmol) in tetrahydrofuran (4 ml). After 20 min. stirring, the reaction mixture was warmed to −5° C., treated with a 1:1 mixture of a 2N aqueous HCl solution and saturated aqueous NaCl solution (25 ml) and extracted three times with MTBE (60 ml). The combined organic phases were washed with a saturated solution of NaHCO3, with a saturated solution of NH4Cl, and with water, dried (MgSO4), and concentrated. Fluid chromatography (FC, SiO2, hexane/MTBE 35:1) of the crude product (1.3 g) gave the desired intermediate β-hydroxyketone (0.47 g, 1.98 mmol, 48%) which was dissolved in cyclohexane (1 ml). The resulting solution was treated with para-toluene sulfonic acid monohydrate (13 mg, 6.7 mmol) and refluxed 1.5 h. The reaction mixture was cooled to 0° C., treated with a saturated aqueous solution of NaHCO3 and the aqueous phase was extracted twice with MTBE. The combined organic phases were washed with water, dried (MgSO4) and concentrated. FC (SiO2, hexane/MTBE 50:1) of the crude product (0.42 g) gave (E)-1-(rel-(6S,7R)-7-Methylspiro[4.5]dec-8-en-6-yl)but-2-en-1-one (0.34 g, 79%).
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH2:16][CH2:15][N:14]=[C:13]1S(O)(=O)=O>CC#N>[C:1]1([N:11]=[C:13]2[NH:14][CH2:15][CH2:16][NH:12]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)C1=NCCN1
Reactant: Nc1cccc2c1CCCC2
Solvent: CC#N
Product: c1cc2c(c(N=C3NCCN3)c1)CCCC2
Temperature: 155 °C
Yield: 13.7 %

Procedure:
5,6,7,8-Tetrahydro-1-naphthylamine (Aldrich, 159 mg, 1.06 mmol), imidazoline-2-sulfonic acid (147.0 mg, 1.0 mmol, Compound 7 obtained as described above) and CH3CN (5ml) were placed in a thick-walled cap which was sealed with a TEFLON™ screw and heated to 155° C. for 1.25 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in CHCl3 and washed with aq. 1N NaOH (to pH 13). The organic layer was separated, washed with brine, dried over Na2CO3 and concentrated in vacuo to yield a brown oil. The crude material was purified by flash chromatography (SiO2 ; 80:20 CHCl3 /CH3OH saturated with NH3) to yield 29.5 mg (14%) of the title compound as a white solid: mp 138°-141° C.; 1H NMR (300 MHz, CDCl3) & 7.05 (t, 1H) 6.82 (m, 2 H); 5.41 (br, 2H); 3.50 (s, 4H); 2.79 (m, 2H); 2.62 (m, 2H); 1.80 (m, 4H); Mass spectrum m/e 214.1339 (C13H16N3 requires 214.1344). Alternatively and preferably alcohols, most preferably isobutanol, are used instead of CH3CN in this reaction.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=2)=[CH:7][C:6]=1[C:30]([F:33])([F:32])[F:31])#[N:4].I[CH3:35]>CN(C=O)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:25][C:26]([F:29])([F:27])[F:28])[CH2:12][CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]([CH3:35])[C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=2)=[CH:7][C:6]=1[C:30]([F:31])([F:33])[F:32])#[N:4]
Reactant: CI
Reactant: CC(=O)Nc1ccc(SCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(SCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 0.1 %

Procedure:
NaH (60% in oil, 0.003 g, 0.075 mmol) was added to a solution of N-[4-({2-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]ethyl}thio)phenyl]acetamide (0.026 g, 0.056 mmol) in DMF (2 mL) under N2. After 5 min, iodomethane (0.009 g, 0.063 mmol) was added and stirred at rt for 30 min. The mixture was partitioned between Et2O and water. The organic phase was washed with water and brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel chromatography (5-80% EtOAc/hexanes gradient) to give the title compound (0.018 mg, 66% yield): MS (ES) m/z 476 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:37]=4[C:38]([NH2:40])=[O:39])[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][C@@H:7]1[CH3:48])=[O:5].[OH-].[Na+].[Na+].[Cl-]>O1CCOCC1.CCOC(C)=O>[CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:37]=4[C:38]([NH2:40])=[O:39])[N:17]=3)[CH:13]=2)[CH2:8][C@@H:7]1[CH3:48])=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)[C@@H](C)C2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)[C@@H](C)C2
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A solution of 2-({2-{[(2S)-1-(N,N-dimethylglycyl)-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (216 mg, 0.315 mmol) in dioxane (5 mL) and a 2M aqueous NaOH solution (10 mL) was heated at 80° C. for 5 h. The resulting mixture was allowed to cool to rt, diluted with EtOAc (50 mL) and a saturated NaCl solution (10 mL). The organic layer was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to afford 2-[(2-{[(2S)-1-(N,N-dimethylglycyl)-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide as a yellow solid (106 mg, 63%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (d, J=5.49 Hz, 3H), 2.27 (s, 6H), 2.60 (d, J=15.57 Hz, 1H), 3.09 (d, J=14.28 Hz, 1H), 3.25-3.50 (m, 2H), 3.80 (s, 3H), 4.71-4.86 (m, 1H), 6.24 (dd, J=3.11, 1.65 Hz, 1H), 6.89 (t, J=9.25 Hz, 1H), 6.98 (s, 2H), 7.25-7.43 (m, 1H), 7.57 (s, 1H), 8.03 (s, 1H), 8.10 (s, 1H), 8.49 (d, J=8.24 Hz, 1H), 8.63 (s, 1H), 10.53 (s, 1H), 11.33 (s, 1H); ESIMS (M+H)+=533.36; Optical rotation −13.1 (1 mg/mL MeOH, rt).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]2)[CH:7]=1.[F:20][C:21]1([F:27])[CH2:23][CH:22]1[C:24](O)=[O:25]>>[F:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24]([CH:22]2[CH2:23][C:21]2([F:27])[F:20])=[O:25])=[CH:7][C:6]=1[C@:8]1([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]1
Reactant: O=C(O)C1CC1(F)F
Reactant: CC1(C)C[C@@](C)(c2cc(N)ccc2F)NC(=S)CO1
Product: CC1(C)C[C@@](C)(c2cc(NC(=O)C3CC3(F)F)ccc2F)NC(=S)CO1
Yield: 61 %

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (S)-5-(5-amino-2-fluoro-phenyl)-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17A) (151 mg, 0.54 mmol) and commercially available 2,2-difluoro-cyclopropanecarboxylic acid [CAS No. 107873-03-0] (82 mg, 0.67 mmol). The compound was obtained as light yellow foam (158 mg, 61%). MS (ISP): m/z=387.1 [(M+H)+].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[O:26][CH3:27]>CC(C)=O.CCCCCCC>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:18]=1[O:17][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH:22]=[O:23]
Reactant: COc1ccc(CCl)cc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCCC
Product: COc1ccc(COc2ccc(C=O)cc2OC)cc1
Temperature: 55 °C
Reaction time: 28 h
Yield: 99 %

Procedure:
5 g (36.1 mmol) of potassium carbonate and then 4.9 ml (36.1 mmol) of 1-chloromethyl-4-methoxy-benzene are added to a solution of 5 g (33 mmol) of 4-hydroxy-3-methoxy-benzaldehyde in 100 ml of acetone. The reaction mixture is then stirred at 55° C. for 28 hours and then filtered. The filtrate is concentrated under vacuum. The residue obtained is taken up in heptane and filtered. 8.9 g (100%) of 3-methoxy-4-(4-methoxy-benzyloxy)-benzaldehyde is obtained in the form of a beige solid.
Reaction SMILES: [CH:1](O)=O.Cl[C:5]1[CH:6]=[C:7]([N:12]2[CH2:16][CH:15](C)[C:14]([NH:18][CH:19]=[O:20])=[N:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11].CCCCCC>ClCCl>[Cl:11][C:10]1[CH:5]=[CH:6][C:7]([N:12]2[CH:16]([CH3:1])[CH2:15][C:14]([NH:18][CH:19]=[O:20])=[N:13]2)=[CH:8][CH:9]=1
Reactant: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Reactant: O=CO
Solvent: ClCCl
Solvent: CCCCCC
Product: CC1CC(NC=O)=NN1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 4.8 g. amount of the above compound is dissolved in 25.0 ml. of a mixture of formic acid and acetic anhydride (Example 15). The reaction mixture is allowed to remain at room temperature for 3 hours, then ice water is added to separate a gum. The aqueous phase is decanted and the gum is dissolved in dichloromethane. The solution is dried over magnesium sulfate and passed through a hydrous magnesium silicate. The effluent is evaporated leaving a gum. The gum is dissolved in dichloromethane. The solution is heated and hexane is added until turbidity results. The mixture is cooled and filtered to yield 3.6 g. of the desired product as off-white crystals, m.p. 112°-113° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:16]=O>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C=O
Reactant: COC1(c2cc(F)cc(F)c2)CCNC1
Solvent: O=CO
Product: COC1(c2cc(F)cc(F)c2)CCN(C)C1

Procedure:
Preparation according to Example 16. (−)-3-(3,5-difluorophenyl)-3-methoxypyrrolidine (0.02 g, 0.094 mmol), formic acid (1 ml) and formaldehyde (40% solution in water, 1 ml) was heated at 85° C. for 5 h, workup according to preparation 16. MS m/z (relative intensity, 70 eV) 227 (M+, 5), 212 (32), 197 (28), 141 (45), 57 (bp).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4]/[CH:5]=[CH:6]/[Cl:7].[OH-].[Na+].C(N(CC)CC)C.[CH3:17][Si:18]([CH3:21])([CH3:20])Cl>C1(C)C=CC=CC=1>[CH3:17][Si:18]([CH3:21])([CH3:20])[N:3]([CH3:2])[CH2:4]/[CH:5]=[CH:6]/[Cl:7]
Reactant: CNC/C=C/Cl
Reactant: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C/C=C/Cl)[Si](C)(C)C
Temperature: 22.5 °C
Reaction time: 0.33 h

Procedure:
Into a reactor under an inert nitrogen atmosphere are introduced 80 g (0.56 mol) trans-1-methylamino-3-chloro-2-propene hydrochloride, 400 ml toluene, 160 ml 25% NaOH and the mixture is stirred for 20 minutes at 20-25° C. The organic phase is separated and the aqueous phase extracted with 100 ml toluene. To the combined organic phases are added 150 ml triethylamine (1.07 mol, 1.9 eq.) and 98 ml trimethylchlorosilane (0.77 mol, 1.4 eq.) are added dropwise at 20/25° C. over a period of 1 hour. Upon complete addition, the suspension thus obtained is stirred for 2 hours at 20°/25° C. The salts are filtered in an inert nitrogen atmosphere, washing them with 160 ml toluene; the organic solution is then concentrated to a small volume under vacuum and used as such in the subsequent step.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:32])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:33][C:34]1[CH:39]=[C:38]([C:40]([OH:43])([CH3:42])[CH3:41])[CH:37]=[C:36]([F:44])[C:35]=1[C:45]1[N:50]=[C:49]([C:51](O)=[O:52])[CH:48]=[CH:47][C:46]=1[F:54].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:32][C:51]([C:49]3[CH:48]=[CH:47][C:46]([F:54])=[C:45]([C:35]4[C:34]([F:33])=[CH:39][C:38]([C:40]([OH:43])([CH3:42])[CH3:41])=[CH:37][C:36]=4[F:44])[N:50]=3)=[O:52])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:22])([F:21])[F:23])[CH2:17][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Reactant: CC(C)(O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(C(C)(C)O)cc3F)n1)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (0.010 g, 0.022 mmol), 6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridine-2-carboxylic acid (0.0082 g, 0.026 mmol), HATU (0.022 g, 0.057 mmol) in DMF (0.06 mL) and DIPEA (0.011 mL, 0.065 mmol) was stirred at room temperature for 1 h. The mixture was quenched with 1N NaOH solution and extracted with EtOAc. The organics were combined, dried over Na2SO4 and concentrated to give the sub-title compound as a brown solid. LCMS calc. for C36H40F6N5O6 (M+H)+ m/z=752.3. found: 752.0.
Reaction SMILES: Cl.[CH:2]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][C:12](C3C=CC=C(OC)C=3)([OH:15])[CH:11](CN(C)C)[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:28][C:29]([O-:32])(C)C.[K+].O1C2(CCC(=O)CC2)OCC1.O>C1(C)C=CC=CC=1>[CH:2]1([CH2:7][CH:8]=[C:9]2[CH2:10][CH2:11][C:12]3([O:15][CH2:28][CH2:29][O:32]3)[CH2:13][CH2:14]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)[O-]
Reactant: COc1cccc(C2(O)CCC(CCC3CCCC3)CC2CN(C)C)c1
Agent: Cl
Agent: O=C1CCC2(CC1)OCCO2
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C(CC1CCCC1)=C1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 1 h
Yield: 245.4 %

Procedure:
The reaction was conducted in a nitrogen atmosphere with the exclusion of moisture. 21.9 g (50 mmole) of compound (52) were added to 5.6 g (50 mmole) potassium tert-butylate in 400 ml toluene. The mixture was stirred for 30 minutes at room temperature and for 1 hour at 80° C., and was subsequently cooled to 60° C. 7.8 g (50 mmole) 1.4-dioxa-spiro[4.5]decan-8-one were added. The mixture was then stirred for 18 hours at 60° C. and cooled. 100 ml water were added drop-wise. The organic phase was separated off, the aqueous phase was extracted twice with toluene and dried over sodium sulphate, and the solvent was removed by distillation. 29 g oil were obtained, which was purified with 1:4 diisopropyl ether/n-hexane on a silica gel column.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[C:8]([C:9]([O:11][CH2:12][CH2:13][CH3:14])=[O:10])[C:7]([OH:16])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:16][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:15][C:8]=1[C:9]([O:11][CH2:12][CH2:13][CH3:14])=[O:10]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCCOC(=O)c1cc(C(C)=O)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCCOC(=O)c1cc(C(C)=O)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
Propyl 5-acetylsalicylate (202 mg), 4-chloro-6,7-dimethoxyquinoline (101 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-hexane to give the title compound (35 mg, yield 9%).
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([F:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:15]([Mg]I)C>C1COCC1>[F:1][C:2]1[C:11]([CH:12]([OH:13])[CH3:15])=[C:10]([F:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC[Mg]I
Reactant: O=Cc1c(F)cc2ncccc2c1F
Solvent: C1CCOC1
Product: CC(O)c1c(F)cc2ncccc2c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of 5,7-difluoroquinoline-6-carbaldehyde (5.0 g, 25.9 mmol) in THF (80 mL) was added ethylmagnesium iodide (3 M, 9.5 mL, 28.5 mmol) at −78° C. After stirring at −78° C. for 1 hour, the reaction was quenched with saturated NH4Cl and concentrated under reduced pressure. The residue was diluted with water, extracted with DCM three times. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography (hexane/EtOAc) to give the title compound as a white solid (3.3 g, 58%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.97 (dd, 1H), 8.47 (d, 1H), 7.66-7.58 (m, 2H), 5.54 (d, 1H), 5.29 (m, 1H), 1.56 (d, 3H). LCMS (method A): [MH]+=210, tR=4.71 min.