Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[C:25]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:26]=[CH:27][CH:28]=2)O1>>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:27]3[CH:26]=[C:25]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:24]=[CH:23][CH:28]=3)=[CH:3][N:4]=[C:5]2[N:10]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Product: N#Cc1ccccc1-c1cccc(-c2cnc3nc(C(F)(F)F)ccn23)c1
Yield: 44 %

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-a]pyrimidine (0.28 g, 1.04 mmol) was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-(7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (165 mg, 44%) as a yellow powder: δH (400 MHz, CDCl3) 7.29 (1H, d, J 7), 7.53 (1H, td, J 8 and 1), 7.59-7.68 (3H, m), 7.70-7.75 (2H, m), 7.80-7.85 (2H, m), 8.14 (1H, s), 9.20 (1H, d, J 7); m/z (ES+) 365 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(N)c2)CC1
Reaction time: 16 h
Yield: 99.8 %

Procedure:
A suspension of 4-(3-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.390 g) and 10% Pd/C (0.100 g) in ethanol was stirred under an hydrogen atmosphere (1 atm at balloon pressure) for 16 hr. The reaction mixture was filtered through a bed of Celite using ethyl acetate as solvent. Concentration afforded 4-(3-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as a clear oil (0.353 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ 6.85 (t, 1H), 6.15-6.05 (m, 3H), 4.99 (br s, 2H), 4.43-4.30 (m, 1H), 3.67-3.53 (m, 2H), 3.20-3.06 (m, 2H), 1.89-1.80 (m, 2H), 1.53-1.4 (m, 2H), 1.38 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Cl:14][C:15]1[CH:16]=[C:17]([NH2:29])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26].C(N(C(C)C)C(C)C)C>S(Cl)(Cl)=O.ClCCl>[Cl:14][C:15]1[CH:16]=[C:17]([NH:29][C:11](=[O:13])[CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: O=C(O)CCc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CCN(CC)CCOc1ccc(NC(=O)CCc2ccc(Cl)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.271 g (1.236 mmol) of (3-(2,4-dichloro-phenyl)-propionic acid in 3.00 mL thionyl chloride was stirred for 2 hours at RT, evaporated down i. vac. and dissolved in 10 mL dichloromethane. This solution of the acid chloride was slowly added dropwise, while cooling with ice, to a solution of 0.300 (1.236 mmol) of 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (intermediate product Z1b) and 0.32 mL (1.854 mmol) of ethyl-diisopropylamine in 10 mL dichloromethane and the mixture was stirred for 16 hours at RT. The reaction mixture was washed with sat. aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated down i. vac. The residue was dissolved in EtOAc and purified by column chromatography (silica gel, EtOAc/MeOH/conc. aqueous ammonia 90:10:1).
Reaction SMILES: IC.[Cl:3][C:4]1[C:5]([C:18]([OH:20])=[O:19])=[N:6][CH:7]=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1.[C:21]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:21][O:19][C:18]([C:5]1[C:4]([Cl:3])=[CH:9][C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][N:6]=1)=[O:20]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ncc(COc2ccccc2)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ncc(COc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
Iodomethane (0.4 mL, 6.39 mmol) was added to a suspension of 3-chloro-5-phenoxymethyl-pyridine-2-carboxylic acid (265 mg, 1.92 mmol) and K2CO3 (265 mg, 1.92 mmol) in DMF (15 mL) in a sealed tube. The mixture was stirred at RT for 16 h. The solvent was evaporated in vacuo and the mixture was diluted with H2O and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in DCM 0/100 to 70/30). The desired fractions were collected and the solvents evaporated in vacuo to yield 3-chloro-5-phenoxymethyl-pyridine-2-carboxylic acid methyl ester (258 mg, 73%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:3]=1[Cl:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B2OCCCO2)=[C:20]([F:30])[C:19]=1[O:31][CH3:32].[F-].[Cs+].C(#N)C>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.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([O:31][CH3:32])[C:20]=2[F:30])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:3]=1[Cl:16]
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Reactant: CC(C)OC(=O)c1nc(Cl)c(F)c(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)c(Cl)c(N)c2F)c1F
Temperature: 70 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A 50 mL Schlenk flask was charged with propan-2-yl 4-amino-3,6-dichloro-5-fluoropicolinate (2.162 g, 8.09 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (2.775 g, 11.35 mmol) and CsF (2.601 g, 17.12 mmol). Acetonitrile (20 mL) and water (7 mL) were added. The solution was evacuated/backfilled with nitrogen (5×). Solid bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2; 281 mg, 4.9 mol %) was added. The solution was evacuated/backfilled with nitrogen (5×) and then heated at 70° C. under nitrogen for 3 h. After 3 h, the reaction mixture was allowed to cool to room temperature. The aqueous layer was separated. Water (20 mL) was added to the organic layer. The resulting dark brown precipitate was filtered and washed with water. The solid was dissolved in EtOAc (60 mL) and filtered to remove a small amount of black solid. The EtOAc solution was treated with activated carbon (175 mg) and filtered to give a wine-colored solution. Evaporation under reduced pressure gave a dark red solid. Purification (120 g silica column; 0-50% EtOAc-hexane gradient) gave a white solid (2.59 g, 82%): mp 110.6-112.1° C.; 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 2H), 5.32 (septet, J=6.3 Hz, 1H, CHMe2), 5.07 (br s, 2H), 3.97 (d, JF-H=1.0 Hz, 3H, OMe), 1.40 (d, J=6.3 Hz, 6H, CHMe2); 13C{1H} NMR (101 MHz, CDCl3) δ 164.2 (CO2R), 153.8 (d, JF-C=254 Hz, C5/C2′), 145.5 (d, JF-C=258 Hz, C5/C2′), 145.0 (d, JF-C=5 Hz), 144.4 (d, JF-C=14 Hz), 140.0 (d, JF-C=13 Hz), 137.5 (d, JF-C=14 Hz), 129.7 (d, JF-C=3 Hz), 125.4 (d, JF-C=2 Hz, C5′/C6′), 125.2 (d, JF-C=3 Hz, C5′C6′), 122.7 (dd, JF-C=14, 4 Hz, C1′), 114.6 (C3), 70.2 (CHMe2), 61.5 (d, JF-C=4 Hz, OMe), 21.6 (CHMe2); 19F NMR (376 MHz, CDCl3) δ −128.16 (dd, JF-F=33.3 Hz, JF-H=2.5 Hz, phenyl F), −138.35 (d, JF-F=33.4 Hz, pyridine F5). Anal. Calcd for C16H14Cl2F2N2O3: C, 49.12; H, 3.61; N, 7.16. Found: C, 49.30; H, 3.69; N, 7.08. The product was found to be 97.5% pure by HPLC.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[N:17]1([C:23]2[S:24][CH:25]=[C:26]([C:28]3[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=3)[C:31]#[N:32])[N:27]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:31]([C:30]1[CH:29]=[C:28]([C:26]2[N:27]=[C:23]([N:17]3[CH2:22][CH2:21][N:20]([C:9]([NH:8][C:5]4[O:4][N:3]=[C:2]([CH3:1])[C:6]=4[CH3:7])=[O:16])[CH2:19][CH2:18]3)[S:24][CH:25]=2)[CH:35]=[CH:34][CH:33]=1)#[N:32]
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: N#Cc1cccc(-c2csc(N3CCNCC3)n2)c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4cccc(C#N)c4)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 15 h
Yield: 39.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (277 mg, 0.964 mmol), 3-(2-piperazin-1-yl-1,3-thiazol-4-yl)benzonitrile (237 mg, 0.877 mmol) and diisopropylethylamine (0.305 ml, 1.75 mmol) in dimethyl sulfoxide (2.9 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and recrystallized from a mixed solvent of hexane and ethyl acetate to give 142 mg (39.6%) of the desired product as a solid.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:7]1[CH:2]([CH3:1])[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5][CH:6]1[CH3:8])[CH3:22]
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1C(C)CN(C(=O)OC(C)(C)C)CC1C

Procedure:
2.0 g (9.33 mmol) of tert-butyl (3RS,5SR)-3,5-dimethylpiperazine-1-carboxylate (preparation: Helvetica Chimica Acta 1990, 73 (4), 839-855), 2.3 g (18.67 mmol) of ethyl chloroacetate, 3.9 g (28.00 mmol) of potassium carbonate and 0.5 g (2.80 mmol) of potassium iodide are stirred under reflux overnight in 80 ml of acetonitrile. For the work-up, some of the acetonitrile is removed on a rotary evaporator, and the residue is diluted with ethyl acetate, subsequently washed twice with water and once with a saturated sodium chloride solution. The combined aqueous phases are extracted once with ethyl acetate, the combined organic phases are dried over sodium sulfate, and the solvent is removed completely on a rotary evaporator. The residue is taken up in cyclohexane and after subsequent elution over silica gel 60 using subatmospheric pressure (cyclohexane/ethyl acetate 100/10→80/10→40/10) 2.5 g (88% of theory) of product are obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=2)[C:12]=1[F:29])[CH2:9][CH3:10])(C)(C)C.Cl.O1CCOCC1.[OH-].[Na+]>C(Cl)Cl.O>[NH2:7][C@@H:8]([C:11]1[C:12]([F:29])=[C:13]([C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[C:19]([C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[C:26]#[N:27])=[O:28])[CH2:9][CH3:10]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(OC)c(C(=O)c2cccc(C#N)c2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC[C@@H](N)c1ccc(OC)c(C(=O)c2cccc(C#N)c2)c1F
Reaction time: 5 h

Procedure:
Step 5 {(R)-1-[3-(3-Cyano-benzoyl)-2-fluoro-4-methoxy-phenyl]-propyl}-carbamic acid tert-butyl ester (200 mg) was dissolved in DCM (5 mL), 4M HCl in dioxane (485 uL, 1.94 mmol, 4 eq) was added and the reaction mixture was stirred for 5 hours. Water was then added and the mixture was made basic with 1M NaOH. The organic phase was isolated by phase separator and combined and concentrated to give 3-[3-((R)-1-amino-propyl)-2-fluoro-6-methoxy-benzoyl]-benzonitrile.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2([CH3:21])[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([CH3:20])[C:11]([CH3:19])=[C:12]([OH:18])[C:13]=3[CH3:17])[O:8]2)=[O:6])[CH2:3][CH2:2]1.[O:22]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]([OH:22])([CH3:21])[CH2:16][CH2:15][C:14]2[C:9](=[O:8])[C:10]([CH3:20])=[C:11]([CH3:19])[C:12](=[O:18])[C:13]=2[CH3:17])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NC1CC1)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NC2CC2)=C(C)C1=O
Yield: 37.9 %

Procedure:
Oxidation as described in protocol B, using 100 mg (0.346 mmol) of N-cyclopropyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide and 417 mg CAN (0.762 mmol) yielded 40 mg of N-cyclopropyl-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[CH:11][C:10]=2[CH3:17])=[CH:4][C:3]=1[N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].[O:27]=[C:28]1[NH:32][C:31](=[O:33])[CH:30]([CH2:34][C:35]2[CH:45]=[CH:44][C:38]([O:39][CH2:40][C:41](O)=[O:42])=[CH:37][CH:36]=2)[S:29]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:27]=[C:28]1[NH:32][C:31](=[O:33])[CH:30]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:39][CH2:40][C:41]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[CH:11][C:10]=4[CH3:17])=[CH:4][C:3]=3[N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:42])=[CH:44][CH:45]=2)[S:29]1
Reactant: Cc1cc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)c(C)cc1O
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)c(C)cc1O
Yield: 75.8 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-hydroxy-2,5-dimethylphenoxy)phenyl]-N-methylcarbamate (0.54 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.51 g), diethyl cyanophosphonate (0.29 g), triethylamine (0.18 g) and anhydrous tetrahydrofuran (10 ml) and the reaction mixture was purified to give the desired product (0.71 g).
Reaction SMILES: C[Mg]Cl.O1CCC[CH2:5]1.[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:28][CH3:29])=[C:14]([C:16]([CH3:27])([CH3:26])[CH2:17][C:18]([OH:25])([C:21]([F:24])([F:23])[F:22])[CH:19]=[O:20])[CH:15]=1.[Cl-].[NH4+]>C(OCC)C>[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:28][CH3:29])=[C:14]([C:16]([CH3:27])([CH3:26])[CH2:17][C:18]([C:21]([F:24])([F:23])[F:22])([OH:25])[CH:19]([OH:20])[CH3:5])[CH:15]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: C1CCOC1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C(C)O)C(F)(F)F
Reaction time: 2 h

Procedure:
8 ml of 3 M methylmagnesium chloride-tetrahydrofuran solution is added in drops to the solution of 3.6 mg (11.7 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal in 150 ml of diethyl ether at +2° C. Stirring is continued for 1 hour at +2° C. and for 2 hours at room temperature. Then, it is hydrolyzed with saturated ammonium chloride solution while being cooled with ice, the organic phase is separated, dried on sodium sulfate and concentrated by evaporation. Column chromatography on silica gel with hexane-ethyl acetate yields 2.23 g of the product.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10]([N:13]3[CH2:20][CH:19]4[NH:21][CH:15]([CH2:16][CH2:17][CH2:18]4)[CH2:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH3:24].C(N(CC)C(C)C)(C)C.[OH-].[Na+]>CN(C)C=O>[CH2:23]([N:21]1[CH:15]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:20][N:13]([C:10]1[N:11]=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=1)[CH2:14]2)[CH3:24]
Reactant: c1ccc(-c2ccc(N3CC4CCCC(C3)N4)nn2)cc1
Reactant: CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1C2CCCC1CN(c1ccc(-c3ccccc3)nn1)C2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(6-phenyl-pyridazin-3-yl)-3,9-diaza-bicyclo[3.3.1]nonane free base (0.20 g, 0.71 mmol), bromoethane (0.059 ml, 0.78 mmol), N,N-diisopropylethylamine (0.18 g, 1.42 mmol) and dimethylformamide (5 ml) was stirred at 80° C. for 2 hours. Aqueous sodium hydroxide (20 ml, 1 M) was added and the mixture was extracted twice with diethylether (2×20 ml). Chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave the title compound as a crystalline solid. LC-ESI-HRMS of [M+H]+ shows 281.1761 Da. Calc. 281.176621 Da, dev. −1.9 ppm.
Reaction SMILES: Br[C:2]1([CH3:32])[C:25]2([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[O:24][C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH:9]=[C:4]2[C:3]1=[O:31].CC(O)=O>CCOC(C)=O.[Zn]>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:7]1[N:6]=[C:5]2[O:24][C:25]3([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[CH:2]([CH3:32])[C:3](=[O:31])[C:4]2=[CH:9][C:8]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: CC1(Br)C(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2OC12CCCCC2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1C(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2OC12CCCCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The product of Step B (20 mg, 0.037 mmol) was dissolved in EtOAc (1 mL) and AcOH (1 mL) and zinc (5 mg) were added. The reaction was stirred at rt for 10 min and concentrated. The residue was redissolved in CH2Cl2 and purified directly by silica gel flash chromatography gradient eluted with 0-15% EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 452.4 (M+1), 545.4 (M+3); Rt=4.30 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH2:25][CH3:26].CCOCC>CO.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:24](=[O:27])[CH2:25][CH3:26])[CH2:11]2)[CH:5]=1
Reactant: CCC(=O)Cl
Reactant: COC(=O)c1cccc(-c2cccnc2)c1
Agent: O=[Pt]=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOCC
Product: CCC(=O)N1CCCC(c2cccc(C(=O)OC)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
A solution of the HCl-salt of methyl-3-(3-pyridyl)benzoate (5.54 g, 0.022 mol) in methanol was hydrogenated (atm. pressure) at r.t. using PtO2 as catalyst. After filtration and evaporation the residue was partitioned between a saturated potassium-carbonate solution and ether. The ether layer was dried (K2CO3), cooled and treated with triethylamine (2.23 g. 0.022 mol) and propionylchloride (2.05 g), 0.033 mol). Stirring at r.t. for one hour followed by filtration and evaporation gave an oil which was eluated twice through an Al2O3 -column with ether. Evaporation of the ether gave 4.8 g of pure methyl-3-(1-propionylpiperdin-3-yl)benzoate as an oil, which could not be crystallized.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].S(Cl)(Cl)=O.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]2[N:32]([CH3:33])[C:31]3[CH:34]=[CH:35][C:36]([NH:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[CH:37][C:30]=3[N:29]=2)=[CH:22][CH:21]=1)#[N:19].CN1CCOCC1>C(Cl)(Cl)Cl.ClCCl.O>[C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]2[N:32]([CH3:33])[C:31]3[CH:34]=[CH:35][C:36]([N:38]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:11](=[O:13])[CH2:10][CH2:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[CH:37][C:30]=3[N:29]=2)=[CH:22][CH:21]=1)#[N:19]
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Reactant: CC(C)CNc1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(C(=O)CCc1ccc(C#N)cc1)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C

Procedure:
3-(p-cyanophenyl)-propionic acid (0.69 g, 3.9 mmol) in 15 mL chloroform is combined with 1.3 mL of thionyl chloride and refluxed for 3 h. The solvent and the excess thionyl chloride are distilled off, the residue is dissolved in 10 mL of dichloromethane and added dropwise to a solution of 2-[2-(4-cyanophenyl)-ethyl]-1-methyl-5-isobutylamino-benzimidazole (1.25 g, 3.8 mmol) and 1.3 mL N-methylmorpholine in 50 mL dichloromethane. This is refluxed for 0.5 h, cooled, mixed with water and extracted into the organic phase. It is washed with dilute, aqueous NaOH and with water, dried and evaporated down. The product is further reacted without being purified.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:24][C:25](=[N:27]O)[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([O:16][N:27]=[C:25]([CH3:26])[CH3:24])=[O:15])=[CH:10][CH:9]=2)=[CH:20][CH:21]=1
Reactant: CC(C)=NO
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)=NOC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
After 15 g of 2-[p-(p-trifluoromethylphenoxy)phenoxy]-propionic acid are suspended in 20 ml of methylene chloride, 3.5 g of acetone oxime are added at room temperature. 9.8 g of dicyclohexylcarbodiimide, in 10 ml of methylene chloride, are then added dropwise over a period of 10 minutes as the temperature increases to about 40° C. The reaction mixture is then stirred at room temperature for 2 hours and filtered. The filtrate is evaporated to dryness on a rotary evaporator to yield acetone O-[2-[p-(p-trifluoromethylphenoxy)phenoxy]propionyl]-oxime, nD20 : 1.5212.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[Cl:20][C:21]1[C:22]([O:29][CH:30]([F:32])[F:31])=[N:23][CH:24]=[C:25]([CH:28]=1)[CH:26]=O>>[Cl:20][C:21]1[CH:28]=[C:25]([CH2:26][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:24]=[N:23][C:22]=1[O:29][CH:30]([F:32])[F:31]
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cnc(OC(F)F)c(Cl)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cnc(OC(F)F)c(Cl)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 5-chloro-6-(difluoromethoxy)-nicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.88 min.; [M+H]+: 427.28 g/mol.
Reaction SMILES: N([O-])=O.[Na+].[C:5]1([NH:11][C:12]([C:14]2[C:18](N)=[CH:17][NH:16][N:15]=2)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[I-:20].[K+]>O.Cl.CC(C)=O.[Cl-].[Na+].O.C(OCC)(=O)C.[Cu]I>[C:5]1([NH:11][C:12]([C:14]2[C:18]([I:20])=[CH:17][NH:16][N:15]=2)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1c[nH]nc1C(=O)Nc1ccccc1
Reactant: [I-]
Agent: [Cu]I
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)c1n[nH]cc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
An aqueous solution of sodium nitrite (760 mg) in 2 ml of water was added drop wise to a stirred suspension of 4-amino-1H-pyrazole-3-carboxylic acid phenylamide (2 g; 10 mmol) in concentrated hydrochloric acid (20 ml) at 0° C., then stirred at 0° C. for a further 60 minutes. The reaction mixture was diluted with acetone (10 ml) then treated with potassium iodide (1.8 g) and copper (I) iodide (2.1 g) and stirred at room temperature for 90 minutes. The reaction mixture was diluted with brine and ethyl acetate then washed with saturated sodium thiosulphate solution. The ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated to give 680 mg of 4-iodo-1H-pyrazole-3-carboxylic acid phenylamide.