Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:34]=[CH:33][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:32])[C:15]([CH2:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:35](Cl)([CH3:38])(=[O:37])=[O:36].N1C=CC=CC=1>CC(C)=O>[CH:26]1([CH2:25][C:15]2([CH3:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]([OH:23])=[C:13]([C:8]3[NH:7][C:6]4[CH:33]=[CH:34][C:3]([NH:2][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:4][C:5]=4[S:10](=[O:12])(=[O:11])[N:9]=3)[C:14]2=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC1(CC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 76.4 %

Procedure:
A solution of Example 41H (1.17 g, 2.33 mmol), mesyl chloride (0.720 mL, 9.31 mmol), and pyridine (1.51 mL, 18.61 mmol) in acetone (30 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.968 g, 42%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.84 m, 7 H) 1.34 m, 4 H) 1.53 (m, 3 H) 2.20 m, 2 H) 3.07 m, 3 H) 7.57 m, 3 H) 7.76 m, 3 H) 8.17 m, 1 H) 10.28 m, 1 H) 13.83 m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12](O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][CH:12]([CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:13])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(CC(C)O)cc1OC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(CC(C)NCc2ccccc2)cc1OC

Procedure:
The 1-(3,4-dimethoxyphenyl)-2-propanol obtained above was subjected to sulfonylation by p-toluenesulfonyl chloride and reacted with benzylamine to give N-benzyl-3,4-dimethoxyamphetamine. The resultant compound was converted into 3,4-dimethoxyamphetamine by hydrogenation decomposition under hydrogen atmosphere with 5% Pd-C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([CH2:12][NH2:13])[O:8][C:7]=2[CH:14]=1.C(N(CC)CC)C.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1.Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([CH2:12][NH:13][C:25]([CH:22]3[CH2:24][CH2:23]3)=[O:26])[O:8][C:7]=2[CH:14]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc2c(c1)OC(CN)=CO2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)OC(CNC(=O)C1CC1)=CO2
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
The amine obtained in Step C of Example 24 is dissolved in 16 ml of anhydrous dichloromethane and the mixture is cooled to 0° C. 2.5 ml (18 mmol) of triethylamine and 0.467 g (4.48 mmol) of cyclopropanecarboxylic acid chloride are slowly added to the medium. After 25 minutes of stirring under an argon atmosphere, the solution is acidified with a hydrochloric acid solution (1N); the aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrated in vacuo. The title amide is obtained pure after passage over a silica column (eluant: MeOH/CH2Cl2: 2/98) in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=3[F:24])=[C:12]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:11]=2)[CH:3]=1.C1COCC1.[Br-].[CH2:35]([O:37][C:38](=[O:42])[CH2:39][CH2:40][Zn+])C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.C1C=CC([C]2[C](C3C=CC=CC=3)[C](C3C=CC=CC=3)[C](C3C=CC=CC=3)[C]2C2C=CC=CC=2)=CC=1.[Fe]>[CH3:26][C:25]([C:12]1[CH:11]=[C:10]([CH2:9][O:8][C:4]2[CH:3]=[C:2]([CH2:40][CH2:39][C:38]([O:37][CH3:35])=[O:42])[CH:7]=[CH:6][N:5]=2)[CH:15]=[CH:14][C:13]=1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[F:24])([CH3:28])[CH3:27]
Reactant: COc1ccc(F)c(-c2ccc(COc3cc(Br)ccn3)cc2C(C)(C)C)c1
Reactant: CCOC(=O)CC[Zn+]
Agent: [Fe]
Agent: [Pd]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)CCc1ccnc(OCc2ccc(-c3cc(OC)ccc3F)c(C(C)(C)C)c2)c1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
To a sealed tube containing 72.2 (0.0980 g, 0.22 mmol), bis(dibenzylideneacetone)palladium (0.0068 g, 0.012 mmol), and CTC-Q-Phos (commercially available from Strem Chemicals.) (0.0083 g, 0.0116 mmol) was added dry THF (3.000 mL, 0.22 mmol). After about 5 minutes, 3-ethoxy-3-oxopropylzinc bromide, 0.5M solution in THF (1.000 mL, 0.50 mmol) was added dropwise. After 1 hour, the mixture was heated to 80° C. and monitored with TLC and LC-MS. After 16.5 hours, the reaction was cooled to room temperature and the organic solvent was then removed under reduced pressure. The residue was purified by flash chromatography (SiO2 gel 60, eluted with 0 to 40% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to a light brown oil (0.0646 g, 63%). 1H NMR (400 MHz) (CDCl3) δ ppm 8.11 (1H, d, J=5.3 Hz), 7.65 (1H, d, J=1.6 Hz), 7.32 (1H, dd, J=7.7, 1.7 Hz), 7.07 (2H, m), 6.85 (1H, dt, J=8.9, 3.6 Hz), 6.80 (2H, m), 6.70 (1H, s), 5.41 (2H, s), 4.15 (2H, q, J=7.2 Hz), 3.79 (3H, s), 2.93 (2H, t, J=7.6 Hz), 2.64 (2H, t, J=7.7 Hz), 1.29 (12H, m).
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]=[C:9]1[N:15]2[CH2:16][C@@H:11]([CH2:12][CH2:13][C@H:14]2[C:17]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[O:18])[N:10]1[O:34][S:35]([OH:38])(=[O:37])=[O:36]>>[O:8]=[C:9]1[N:15]2[CH2:16][C@@H:11]([CH2:12][CH2:13][C@H:14]2[C:17]([O:19][CH2:20][CH:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)=[O:18])[N:10]1[O:34][S:35]([OH:38])(=[O:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCC1CCNCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
TFA was added to the product of Step 3 at 0° C. under nitrogen. The reaction mixture was stirred for 1 hour then concentrated under vacuum. The residue was triturated with ether to remove excess trifluoroacetic acid and organic-soluble impurities. The resulting solid was dried, dissolved in water, and purified by preparative HPLC on a Phenomenex Synergy Polar-RP 80A column eluted with methanol/water and lyophilized to afford the title compound. LC-MS (negative ionization mode) m/e 362 (M−H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[O:23]1[CH2:28][CH2:27][O:26][C:25]2[C:29]([C:33](O)=[O:34])=[CH:30][CH:31]=[CH:32][C:24]1=2>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:33]([C:29]2[C:25]3[O:26][CH2:27][CH2:28][O:23][C:24]=3[CH:32]=[CH:31][CH:30]=2)=[O:34])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3cccc4c3OCCO4)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate (Example 26b) and 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid as brown solid. MS 466 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.[Li+].[CH3:15]C([N-]C(C)C)C.IC.O>C1COCC1.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([CH:8]([CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1ncc(Br)cn1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CCOC(=O)C(C)c1ncc(Br)cn1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
Ethyl 2-(5-bromopyrimidin-2-yl)acetate (500 mg, 2.04 mmol) was dissolved in THF (8 mL) and the mixture was cooled to −78° C. under nitrogen. LDA in THF/heptane/ethylbenzene (2M, 1.25 mL) was added dropwise, then the mixture was stirred for 15 minutes. Iodomethane (0.22 mL, 3.53 mmol) was added, then the reaction mixture was warmed to room temperature and stirred for a further 2 h. Water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL). The aqueous layer was acidified to pH ˜5 with 1M HCl, then extracted with additional ethyl acetate (2×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with a gradient of 0-50% ethyl acetate in heptane, to afford the title compound (417 mg, 79%) as a yellow oil. δH (500 MHz, CDCl3) 8.75 (s, 2H), 4.18 (m, 2H), 4.08 (q, J 7.2 Hz, 1H), 1.60 (d, J 7.3 Hz, 3H), 1.22 (t, J 7.1 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([CH3:14])[CH2:11][CH:12]=[O:13])=[CH:2]1.CC(=CC)C.[O-:20]Cl=O.[Na+]>C(O)(C)(C)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([CH3:14])[CH2:11][C:12]([OH:20])=[O:13])=[CH:2]1
Reactant: CC(CC=O)c1c[nH]c2ccccc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(CC(=O)O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-(1H-Indol-3-yl)-butanal (130 mg, 0.690 mmol) was dissolved in tert-butyl alcohol (27 mL) and 2-methyl-2-butene (4.7 mL) and subsequently was stirred for 10 min. To this solution was added an aqueous solution (4.7 mL) of NaClO2 (75 mg, 0.83 mmol) and NaH2PO4 (115 mg, 0.830 mmol) in one portion. The reaction mixture was stirred at room temperature for 12 h. The organics were removed by concentrating in vacuo. The residue was diluted with 10 mL of H2O, and adjusted to a neutral pH with 1M HCl. Extraction with EtOAc (3×10 mL), drying over Na2SO4, and concentration in vacuo provided 3-(1H-indol-3-yl)-butanoic acid. TMS-diazomethane was added dropwise to a solution of the crude 3-(1H-indol-3-yl)-butanoic acid in methanol (7 mL) until a yellow color persisted. The residual TMS-diazomethane was quenched by the dropwise addition of acetic acid until the yellow color disappeared. The reaction was then treated with an excess of saturated aqueous sodium bicarbonate, extracted with Et2O (3×20 ml), dried over Na2SO4 and purified by silica gel chromatography (20:80 EtOAc/hexanes to provide (R)-3-(1H-indol-3-yl)-butyric acid methyl ester. [α]D=−7.6 (c=1.0 benzene); reported rotation for (S)-3-(1H-indol-3-yl)-butyric acid methyl ester [α]D=+10.9 (c=2.12, benzene).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[OH:14])([CH3:6])([CH3:5])[CH3:4].[CH2:15]([O:17][P:18](Cl)(=[O:22])[O:19][CH2:20][CH3:21])[CH3:16]>C1COCC1>[P:18]([O:19][CH2:20][CH3:21])([O:17][CH2:15][CH3:16])([O:14][C:8]1[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=1[C:3]([CH3:6])([CH3:5])[CH3:4])=[O:22]
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Reactant: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)Oc1ccc(C)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
To a suspension of NaH (60% in mineral oil, 8.4 g, 0.21 mol) in THF (200 mL) was added dropwise a solution of 2-tert-butyl-4-methylphenol (33 g, 0.20 mol) in THF (100 mL) at 0° C. The mixture was stirred at 0° C. for 15 min and then phosphorochloridic acid diethyl ester (37 g, 0.21 mol) was added dropwise at 0° C. After addition, the mixture was stirred at ambient temperature for 30 min. The reaction was quenched with sat. NH4Cl (300 mL) and then extracted with Et2O (350 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and then evaporated under vacuum to give 2-tert-butyl-4-methylphenyl diethyl phosphate (contaminated with mineral oil) as a colorless oil (60 g, ˜100%), which was used directly in the next step.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.O.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=2[S:18](=[O:28])(=[O:27])[N:17]=1>O>[Cl:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:16]([NH:15][CH2:14][CH2:13][NH:12][CH:1]=[O:3])=[N:17][S:18](=[O:28])(=[O:27])[C:19]=2[CH:25]=1
Reactant: NCCNC1=NS(=O)(=O)c2cc(Cl)ccc2N1
Reactant: O=CO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=CNCCNC1=NS(=O)(=O)c2cc(Cl)ccc2N1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of formic acid (1 mL) and acetic anhydride (2 mL) was heated at 50° C. for 20 min. After cooling at room temperature, 3-(2-aminoethyl)amino-7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxide monohydrate (0.5 g) was added, and the reaction mixture was stirred for 2 h, then supplemented with water (20 mL) and stirred for 20 min. The precipitate was collected by filtration, washed with water and dried (yield: 0.3 g); m.p. 245-247° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH3:29])[C:25]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:24]=2[C:23]2[CH:35]=[CH:36][CH:37]=[CH:38][C:22]1=2)=[O:19])[CH3:17]>CO.C(Cl)(Cl)Cl>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH3:29])[C:25]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:24]=2[C:23]2[CH:35]=[CH:36][CH:37]=[CH:38][C:22]1=2)=[O:19])[CH3:17])=[O:8]
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Reactant: CC1C(=O)N(NC(=O)[C@H](C)N)c2ccccc2-c2ccc(F)cc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1C(=O)N(NC(=O)[C@H](C)NC(=O)[C@@H](O)c2cc(F)cc(F)c2)c2ccccc2-c2ccc(F)cc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-O), the title compound was prepared. The reaction was monitored by tlc (Rf=0.4, 10% MeOH/CHCl3) and product was purified by chromatography (silica, 2.5% MeOH/CHCl3).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:10](OCC)(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[O-]CC.[Na+]>[O:4]=[C:3]1[CH2:5][C:10](=[O:19])[CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]1[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C=Cc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C1C(=O)CC(=O)CC1c1ccccc1

Procedure:
To a cooled solution of sodium ethoxide (from 2.3 g. sodium and absolute ethanol, 30 ml.) was added with shaking ethyl acetoacetate (13 g.). When homogeneous the mixture was treated with ethyl cinnamate (17.8 g.) and then heated under reflux for 18 hrs. After cooling the solution, the precipitated enolate salt (formula III) was collected by filtration and washed with acetone. Dissolution in cold water, followed by acidification with 2N-sulphuric acid (to convert the enolate salt to the corresponding dione II) afforded crystalline ethyl 2,4-dioxo-6-phenylcyclohexanecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]([OH:20])[CH2:16][N+:17]([O-])=O)[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH2:10][O:11][CH3:12]>C(O)C.[Pd]>[NH2:17][CH2:16][CH:15]([C:5]1[CH:6]=[C:7]([O:13][CH3:14])[C:8]([O:9][CH2:10][O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[OH:20]
Reactant: COCOc1c(OC)cc(C(O)C[N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CCO
Product: COCOc1c(OC)cc(C(O)CN)cc1OC
Reaction time: 6 h
Yield: 81.2 %

Procedure:
To a solution of 1-[3,5-dimethoxy-4-(methoxymethoxy)-phenyl]-2-nitro-1-ethanol (11.78 g, 41.0 mmol) in ethanol (100 ml) was added 10% palladium on charcoal (3.5 g), followed by hydrogenation at room temperature for 6 hours. After completion of the reaction, the catalyst was filtered off. The filtrate was concentrated, whereby the title compound (8.57 g, yield: 81.6%) was obtained as colorless crystals.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])[CH2:4]1)#[N:2].C(O)(=[O:21])C>Cl.O>[C:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[O:11])[CH2:4]1)(=[O:21])[NH2:2]
Reactant: CC(=O)O
Reactant: N#CN1CCCC(CC(=O)c2ccc(F)cc2)C1
Agent: Cl
Solvent: O
Product: NC(=O)N1CCCC(CC(=O)c2ccc(F)cc2)C1

Procedure:
1-Cyano-3-(4-fluorophenacyl)piperidine (Example 19), 21.5 g, was dissolved in a mixture of 150 ml of glacial acetic acid, 30 ml of concentrated aqueous hydrochloric acid, and 70 ml of water. The resulting solution, under a nitrogen atmosphere, was heated on a steam-bath for 16 hours. The reaction solution was distilled under reduced pressure, the residue was diluted with water, and the resulting solution was made alkaline with 3 N sodium hydroxide. Upon extracting the alkaline aqueous solution with ethyl ether, solid precipitated and was isolated by filtration and washed with ether. The solid, 6.7 g, was recrystallized once from aqueous acetone and then four times from acetone/diethyl ether, to give 1-carbamoyl-3-(4-fluorophenacyl)piperidine, mp 136°-137.5°. The following elemental analysis was obtained:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][C:10]=1[CH:25]=[CH:26][C:27]1[S:31][C:30]([CH:32]=O)=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:36]1[C:37](=[C:44]([C:47]#[N:48])[C:45]#[N:46])[O:38][C:39]([CH3:43])([CH3:42])[C:40]=1[CH3:41])#[N:35].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][C:10]=1[CH:25]=[CH:26][C:27]1[S:31][C:30]([CH:32]=[CH:41][C:40]2[C:39]([CH3:42])([CH3:43])[O:38][C:37](=[C:44]([C:45]#[N:46])[C:47]#[N:48])[C:36]=2[C:34]#[N:35])=[CH:29][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCCO)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCCO)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.4 %

Procedure:
In 7 ml of ethanol and 2 ml of tetrahydrofuran were dissolved 218 mg (0.47 mmol) of 5-[2-[2-benzyloxy-4-[butyl(4-hydroxybutyl)amino]phenyl]vinyl]thiophene-2-carboaldehyde and 103 mg (0.52 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 40 mg (0.52 mmol) of ammonium acetate, and the mixture was stirred at room temperature for 90 minutes. The precipitate was separated by filtration, purified by silica gel column chromatography and washed with methanol to give 171 mg of a dark brown crystal having a mp of 216-217° C. (yield: 56.4%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][CH3:11])[CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCOC(=O)C1CCNC1
Product: CCOC(=O)C1CCN(C(=O)c2ccccc2OC)C1
Yield: 68 %

Procedure:
The title compound was prepared according to the method described for Preparation 2 using pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 1) and 2-methoxy-benzoyl chloride to afford the title compound as a colourless oil (4.17 g, 68%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[N+]=[N-])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[CH:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH3:1][O:2][C:3](=[O:15])[CH:4]([O:22][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(Cl)c(Cl)c1
Reactant: OC1CCCCC1
Agent: [Rh]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
In a dry 25 mL round bottom flask under argon was placed diazo-(3,4-dichloro-phenyl)-acetic acid methyl ester (from Example 1, 550 mg 2.24 mmol) and cyclohexanol (0.47 mL, 4.49 mmol) in dichloromethane (10 mL). The solution was stirred at 25° C. and as rhodium (II) acetate dimer (20 mg, 0.045 mmol) was added, the immediate evolution of gas was observed and the color changed from bright yellow to an aquagreen color. After the solution was stirred at 25° C. for 1 h, it was poured into water and the layers were separated. The aqueous layer was washed with dichloromethane (3×15 mL) and the combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The residual oil was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 hexanes/ethyl acetate) to furnish rac-cyclohexyloxy-(3,4-dichloro-phenyl)-acetic acid methyl ester (527 mg, 74% yield) as a clear colorless oil: EI-HRMS m/e calcd for C15H18Cl2O3 (M+) 316.0633, found 316.0646.
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:38]=[CH:37][C:27]([CH2:28][N:29]2[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]2)=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[O:36]=[S:32]1(=[O:35])[CH2:33][CH2:34][N:29]([CH2:28][C:27]2[CH:37]=[CH:38][C:24]([NH:1][C:2]3[N:22]=[C:5]4[C:6]([C:10]5[CH:11]=[CH:12][C:13]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:15]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:25][CH:26]=2)[CH2:30][CH2:31]1
Reactant: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Reactant: CN(c1ccc(-c2cccn3nc(N)nc23)cc1)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ccc(-c2cccn3nc(Nc4ccc(CN5CCS(=O)(=O)CC5)cc4)nc23)cc1)S(C)(=O)=O

Procedure:
N-{4-[2-({4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}amino)[1,2,4]triazolo[1,5-a]pyridin-8-yl]phenyl}-N-methylmethanesulfonamide was prepared from N-[4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 4-(4-bromo-benzyl)-thiomorpholine 1,1-dioxide (80.0 mg, 0.263 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as an orange solid (0.083 g, 65%). MP=177-180° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.45 (dd, J=6.7, 1.1 Hz, 1H), 8.04 (d, J=8.6 Hz, 2H), 7.60-7.52 (m, 5H), 7.28 (d, J=8.5 Hz, 2H), 7.00 (t, J=6.9 Hz, 1H), 6.89 (s, 1H), 3.62 (s, 2H), 3.39 (s, 3H), 3.08-2.96 (m, 8H), 2.90 (s, 3H). MS=541 (MH)+.