Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([NH:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(C)(=O)=O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of dimethyl 5-aminoisophthalate (2.09 g, 10 mmol) in dichloromethane (30 mL), pyridine (2.43 mL, 30 mmol) was added at room temperature. At 0° C., methanesulfonyl chloride (0.86 mL, 11 mmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was then concentrated under reduced pressure and ethyl acetate (50 mL) was added. The resulting white precipitate was filtered and washed with hexanes to give dimethyl 5-(methylsulfonamido)isophthalate in 95% (2.715 g) yield as a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C:8]([OH:10])=[O:9])[C@@H:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[N+](=[CH2:18])=[N-]>CCOCC>[OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C:8]([O:10][CH3:18])=[O:9])[C@@H:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C=[N+]=[N-]
Reactant: CCCCC[C@H]1[C@@H](CC(=O)O)CC[C@H]1O
Solvent: CCOCC
Product: CCCCC[C@H]1[C@@H](CC(=O)OC)CC[C@H]1O

Procedure:
It is to be noted that (+)-(1R,2S,3R)-3-hydroxy-2-pentyl-1-cyclopentaneacetic acid, used as starting product in this variant of the process of the invention, can also be directly methylated, for example by reacting it with an excess of diazomethane in ether solution, to provide pratically pure methyl (+)-(1R,2S,3R)-3-hydroxy-2-pentyl-1-cyclopentaneacetate, which can then be converted into (+)-cis-Hedione® via oxidation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH2:17][OH:18])[N:14]=[CH:13]1)[N:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6](=[O:24])[NH:5]2.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH2:17][O:18][C:32](=[O:33])[NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:14]=[CH:13]1)[N:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6](=[O:24])[NH:5]2
Reactant: CCOC(=O)c1nc2cc(-n3cnc(CO)c3)c(Cl)cc2[nH]c1=O
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2cc(-n3cnc(COC(=O)Nc4ccccc4)c3)c(Cl)cc2[nH]c1=O
Yield: 56.6 %

Procedure:
To a suspension of the compound (100 mg, 287 μmol) of Example 41 in ethyl acetate (3 ml) were added phenyl isocyanate (68.4 mg, 574 μmol) and triethylamine (58.1 mg, 574 μmol), and the mixture was refluxed for 24 hours. After cooling, the insolubles were filtered off and solvent was distilled off. The residue obtained was purified by means of silica gel column chromatography [ethyl acetate], thereby obtaining 76.0 mg of title compound as light brown powder. Yield 57%.
Reaction SMILES: [C:1]1([C:11]2[C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][C:15]=3[C:14]([C:24]#[N:25])=[C:13]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1C[O:37]CC1>>[C:1]1([C:11]2[C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16](=[O:37])[C:15]=3[C:14]([C:24]#[N:25])=[C:13]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2cccc3ccccc23)c2c1Cc1ccccc1-2
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2cccc3ccccc23)c2c1C(=O)c1ccccc1-2
Temperature: 2.5 °C

Procedure:
A solution of 4-(naphthalen-1-yl)-2-(piperidin-1-yl)-9H-fluorene-1-carbonitrile (400 mg) in THF was added sodium hydride (37 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCL. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Light red solid; mp 202-204° C.; ESIMS 0.415 (M++1); IR (KBr) 2221 (CN), 1719 cm−1 (CO), HRMS calcd. for C29H22N2O 414.1732. Found 414.1714.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@@H:29]([CH3:34])[C:30](OC)=[O:31])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH3:35][NH2:36]>>[CH3:35][NH:36][C:30](=[O:31])[C@@H:29]([O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2)[CH3:34]
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: CN
Product: CNC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Yield: 46 %

Procedure:
Using the same procedure as in Example 5, methyl (2S)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.55 mmol) was reacted with methylamine to give the title compound as a beige solid (110 mg, 46%); NMR Spectrum 1.65 (d, 3H), 2.67 (d, 3H), 5.16 (q, 1H), 5.77 (s, 2H), 6.96 (d, 1H), 7.00 (d, 1H), 7.29 (m, 1H), 7.36 (d, 1H), 7.72 (m, 4H), 8.17 (s, 1H), 8.38 (m, 1H), 8.53 (m, 3H), 10.68 (br s, 1H); Mass spectrum MH+ 454.
Reaction SMILES: O=[O+][O-].[Si:4]([O:21][CH:22]=[C:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])(C(C)(C)C)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[BH4-].[Na+]>CO>[C:23]([C:22](=[C:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])[O:21][SiH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:27])([CH3:24])[CH3:22]
Reactant: CC(C)(C)[Si](OC=C(CCO)CCO)(c1ccccc1)c1ccccc1
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(O[SiH](c1ccccc1)c1ccccc1)=C(CCO)CCO

Procedure:
Ozone was bubbled through a -78° C. dry methanol (500 mL) solution of 3-(tert-butyldiphenylsilyloxymethylene)-1,5-pentanediol (17 g, 47 mmol) until a blue tint persisted (30 minutes). The reaction was purged with nitrogen (20 min.) and NaBH4 (17.6 g, 47 mmol) was added. The cold bath was removed and the reaction brought to room temperature. The reaction was concentrated in vacuo and the residue partitioned between ether and brine. The ether layer was concentrated and the residue eluted over a silica plug with 0-50% ethyl acetate/hexanes. The minor component was pooled and concentrated to yield the diol , 3-(tertbutyldiphenylsilyloxymethylene)-pentane-1,5-diol, 3.8 g (22%) of the desired diol as a colorless oil. Overall the yield for the three steps is 17%. MS.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:18].[Na+]>CC(C)=O.C(OCC)C>[CH2:1]([O:8][C@H:9]1[CH2:12][C@H:11]([I:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@H]1C[C@@H](OCc2ccccc2)C1
Reactant: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: I[C@H]1C[C@H](OCc2ccccc2)C1
Yield: 86 %

Procedure:
A solution of cis-3-benzyloxy-1-methanesulfonyloxycyclobutane (1.25 g, 4.8 mmol) and sodium iodide (2.16 g, 14.4 mmol) in dry acetone (20 ml) was refluxed under nitrogen for 3.5 days. The mixture was cooled and diluted with diethyl ether (150 ml). The suspension was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and filtered through a plug of silica gel, eluting with ethyl acetate to give trans-3-benzyloxy-1-iodocyclobutane (1.19 g, 86%) as an orange oil; 1H NMR (250 MHz, CDCl3) δ 2.54-2.65 (2H, m), 2.94-3.04 (2H, m), 3.85-4.06 (2H, m), 4.40 (2H, s), 7.26-7.38 (5H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][S:8][C:4]1[N:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)[CH:7]=[CH:6][N:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CSc1nccc(Cl)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSc1nccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-chloro-2-methylthiopyrimidine (2.17 mL, 18.7 mmol) in dimethoxyethane (140 mL) and water (70 mL) was added sodium carbonate (5.15 g, 48.5 mmol), 4-trifluoromethylphenylboronic acid and tetrakis(triphenylphosphine) palladium (0) (0.43 g). The resulting mixture was heated at reflux under nitrogen for 18 h, then allowed to cool to room temperature and the dimethoxyethane removed in vacuo. The residue was diluted with water (30 mL) and extracted CH2Cl2 (2×100 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) eluting 19:1 cyclohexane:EtOAc yielded the title compound as a pale yellow solid (4.47 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:12]([OH:14])=O)([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][C@@H:22]([OH:40])[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[C:32]=2[CH3:39])[CH2:26][CH2:25]1>>[C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:12]([NH:20][CH2:21][C@@H:22]([OH:40])[CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[C:32]=3[CH3:39])[CH2:26][CH2:25]2)=[O:14])[CH:15]=[CH:16][C:17]=1[Cl:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(OC2CCN(C[C@H](O)CN)CC2)ccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)COc1cc(C(=O)O)ccc1Cl
Product: Cc1c(OC2CCN(C[C@H](O)CNC(=O)c3ccc(Cl)c(OCC(=O)OC(C)(C)C)c3)CC2)ccc(Cl)c1Cl

Procedure:
Prepared as for Example 15, Step 2 using 3-(2-tert-butoxy-2-oxoethoxy)-4-chlorobenzoic acid and (2R)-1-amino-3-[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]propan-2-ol to yield the subtitle compound as a colourless oil (0.14 g).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[N:12].[BH4-].[Na+].[Cl-].[NH4+]>C(O)C.C(OC(=O)C)C>[OH:2][CH2:3][CH2:4][C:5]1[C:6]([C:11]#[N:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccncc1C#N
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1cnccc1CCO
Reaction time: 2 h
Yield: 76.8 %

Procedure:
1.58 g of (3-cyano-pyridine-4-yl)-acetic acid methyl ester was dissolved in 18 mL of ethanol and slowly added with 682 mg of sodium borohydride at −0° C. and stirred for about 2 hours. The above mixture was added with 3 mL of saturated solution of ammonium chloride, diluted with 200 mL ethylacetate. Then, the organic solvent layer was washed with water, and saturated solution of sodium chloride, dried with anhydrous sodium sulfate and filtered. The filtrate was concentreated under reduced pressure and a silica gel column chromatography was performed on the resulting residue by using a mixed eluant of methylene chloride and methanol, wherein methylene chloride and methanol are mixed in 50:1 volume ratio, and 1.02 g (74%) of 4-(2-hydroxy-ethyl)-nicotinonitrile was obtained in colorless oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1Br.[Li]CCCC.S(C)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.CCCCCC>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(OC)c1cc(OCc2ccccc2)ccc1Br
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CSC
Solvent: CCCCCC
Product: COC(OC)c1cc(OCc2ccccc2)ccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-5-benzyloxy benzaldehyde dimethyl acetal (Tet. Lett., 22, 5027 (1981)) (52.2 g) in THF (600 mL), cooled to -78° C., was added dropwise a solution of n-BuLi (78 ml, 2.1M) in hexane. After 15 min. CuBr.SMe2 (32 g) was added in 3 portions. The reaction mixture was stirred at -78° C. until CuBr.SMe2 was dissolved (approx. 1 hr.), then benzoyl chloride (20 mL) was added dropwise. The cooling bath was removed and the reaction mixture was stirred at room temperature over night and was quenched with a saturated NH4Cl solution. The organic phase was diluted with Et2O, washed with H2O (3×), brine, dried (MgSO4) and evaporated to afford the title compound which was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:38]2[CH:42]=[N:41][N:40]=[N:39]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@H:13]2[C:22]([NH:24][C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=2)=[O:23])=[O:11])[CH:7]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:38]2[CH:42]=[N:41][N:40]=[N:39]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@H:13]2[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][CH:37]=2)=[O:23])=[O:11])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2c3ccccc3CCN2C(=O)/C=C/c2cc(Cl)ccc2-n2cnnn2)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(NC(=O)[C@@H]2c3ccccc3CCN2C(=O)/C=C/c2cc(Cl)ccc2-n2cnnn2)cc1
Reaction time: 1 h

Procedure:
(S,E)-tert-Butyl 4-(2-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoate: To Intermediate 2 (0.213 g, 0.851 mmol) and 3B (0.3 g, 0.851 mmol) in EtOAc (5 mL), cooled in ice bath, was added DIEA (0.446 mL, 2.55 mmol) and 50% T3P in EtOAc (0.481 mL, 1.702 mmol). After 1 h, the reaction was concentrated and the crude was taken on to next step. MS (ESI) m/z: 585.3 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[CH2:14][C:15](O)=[O:16].C(Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1.O>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[CH2:14][CH2:15][OH:16]
Reactant: O=C(O)Cc1c([N+](=O)[O-])ccc(F)c1F
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(F)c1CCO
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a mixture of NaBH4 (3.60 g, 95.4 mmol) in THF (12 mL) cooled below 10° C. was added a solution of 2-(2,3-difluoro-6-nitrophenyl)acetic acid (10.9 g, 50.2 mmol), as prepared in the preceding step, in THF (4 mL) over a period of 1 hour. To this mixture was added a solution of boron trifluoride diethyl etherate complex (16.5 mL, 131 mmol) in THF (24 mL) over a period of 1 hour, keeping the reaction temperature below 10° C. After the addition the reaction was continued to stir on ice for 15 minutes, and then at ambient temperature for 20 minutes. To a mixture of DCM (180 mL) and H2O (140 mL) was added NaHCO3 (15 g, 179 mmol). The reaction mixture was slowly added to the above NaHCO3 solution and stirred overnight. The organic layer was separated, dried over Na2SO4, and concentrated to give the title compound (10.1 g, 99% yield) as light brown oil. 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J=9.1, 4.4 Hz, 1H), 7.27-7.18 (m, 1H), 3.95 (t, J=6.3 Hz, 2H), 3.30-3.27 (m, 2H), 1.82 (s, 1H).
Reaction SMILES: [H-].[K+].[C:3]1([CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[C:15]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[CH3:17][C:16]([CH3:19])([CH3:18])[C:15]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:13][C:11](=[O:12])[CH2:10][CH2:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:26])=[CH:23][CH:22]=1)=[O:20]
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)Cl)cc1
Reactant: NC(=O)CCc1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1ccc(C(=O)NC(=O)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A slurry of potassium hydride (from 46 grams of 35% potassium hydride in oil washed three times with hexane)in 50 ml of THF is added with stirring under nitrogen to 20 grams of 3-phenylpropionamide in 350ml of THF. After addition of the hydride is complete, the reaction is allowed to warm to room temperature and is stirred for 30 minutes. The thickened reaction mixture is cooled to 0° to 5° C. and is then added dropwise over 30 minutes to a solution of 30 grams of p-pivaloylbenzoyl chloride in 50 ml of dry THF. The resulting solution is stirred for 15 minutes at 0° to 5° C. and is then quenched with 150 ml of saturated ammonium chloride solution. The THF phase is decanted off, and the aqueous phase is extracted with ethyl acetate. The ethyl acetate extract is combined with the THF phase, dried with magnesium sulfate, filtered, and then evaporated almost to dryness. The resulting solids are triturated with ether, and the white crystals obtained are filtered, washed with ether and dried to yield the title product (m.p. 137°-138° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[O:14])([O-:3])=[O:2].[CH3:15][C:16]([CH3:21])([CH2:19]O)[CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1>[CH3:15][C:16]1([CH3:21])[CH2:17][O:18][C:7]2([C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][C:8]2=[O:13])[O:14][CH2:19]1
Reactant: CC(C)(CO)CO
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CC1(C)COC2(OC1)C(=O)Nc1ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Yield: 108.9 %

Procedure:
A mixture of 5-nitroindoline-2,3-dione (305 mg, 1.587 mmol), 2,2-dimethylpropane-1,3-diol (165 mg, 1.587 mmol) and p-toluenesulfonic acid monohydrate (catalytic amount) in cyclohexane (9 ml) was stirred at reflux temperature (removing water by a Dean-Stark apparatus) for 6 hours. The reaction was cooled to room temperature and the solid was recovered by filtration and washed with petroleum ether, affording 5,5-dimethyl-5′-nitrospiro[[1,3]dioxane-2,3′-indolin]-2′-one (481 mg). that was used as such in the following step. MS/ESI+ 279.0 [MH]+.
Reaction SMILES: Cl[C:2]1[N:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[C:4]([NH:6][C:7](=[NH:22])[CH2:8][O:9][CH2:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:27][C:24]1[CH:25]=[N:26][C:2]2[N:22]=[C:7]([CH2:8][O:9][CH2:10][CH2:11][C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=3)[NH:6][C:4](=[O:5])[C:3]=2[CH:23]=1
Reactant: N=C(COCCc1ccc2ccccc2c1)NC(=O)c1cc(Cl)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(COCCc2ccc3ccccc3c2)nc2ncc(Cl)cc12

Procedure:
In analogy to the procedure described in example 78.4, 2,5-dichloro-N-[1-imino-2-(2-naphthalen-2-yl-ethoxy)-ethyl]-nicotinamide was treated with potassium carbonate in DMF for 3 h at 100° C. to obtain 6-chloro-2-(2-naphthalen-2-yl-ethoxymethyl)-3H-pyrido[2,3-d]pyrimidin-4-one as brown crystals. MS: m/e=366.0 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:15])=[C:6]([C:8](=[O:14])[CH2:9]N(OC)C)[CH:7]=1.Br[Mg]C1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:15])=[C:6]([C:8]([C:9]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:14])[CH:7]=1
Reactant: CON(C)CC(=O)c1cc(Br)ccc1Cl
Reactant: FC(F)(F)Oc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 41.1 %

Procedure:
To the solution of 1-(5-bromo-2-chlorophenyl)-2-[methoxy(methyl)amino]ethanone 15b (0.74 g, 2.65 mmol) in dry tetrahydrofuran (10 mL) was added bromo-[4-(trifluoromethoxy)phenyl]magnesium 15d afforded from the last step at 0° C. under N2. The resulting mixture was stirred at 0° C. for 4 hours. The reaction mixture was quenched with 20 mL of saturated brine, and then 20 mL of water and 40 mL of ethyl acetate were added in turn. The mixture was partitioned. The aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=50/1 to give the title compound 15e as a white solid (415 mg, 41.1%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ (ppm): 7.88 (d, 2H), 7.60 (dd, 1H), 7.53 (d, 1H), 7.37 (d, 1H), 7.33 (d, 2H).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:10][CH:9]2[N:11](C(OC(C)(C)C)=O)[CH:6]1[CH2:7][CH2:8]2)=[N+:2]=[N-:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]([CH2:4][CH:5]1[CH2:10][CH:9]2[NH:11][CH:6]1[CH2:7][CH2:8]2)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(CN=[N+]=[N-])C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NCC1CC2CCC1N2
Reaction time: 3 h

Procedure:
To the title compound of step B in DCM was added TFA. After 3 h at rt, the reaction mixture was concentrated to give the title compound (1.7 g) as the TFA salt.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[OH-].[Na+].I[CH2:33][CH:34]([OH:37])[CH2:35][OH:36].CN(C)P(N(C)C)(N(C)C)=O>O.CCOCC>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH2:33][CH:34]([OH:37])[CH2:35][OH:36])=[O:24])=[CH:21][CH:20]=1
Reactant: OCC(O)CI
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A solution of 7.34 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield the product as a white solid.
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:11][C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:17][Si:14]([CH3:15])([CH3:16])[C:13]#[C:12][CH2:11][C:8]1([CH2:6][OH:5])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)C1(CC#C[Si](C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C[Si](C)(C)C#CCC1(CO)CC1

Procedure:
In analogy to the procedure described in example 24D], reduction of the crude 1-(3-trimethylsilanyl-prop-2-ynyl)-cyclopropane carboxylic acid tert-butyl ester with LAH (1 M in THF) gave after naturally warming up to ambient temperature (during 2.75 h) the title compound as yellow oil.