Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[N+](C1C=CC=CC=1)([O-])=O.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:26]=[C:27]([NH2:39])[C:28]([NH2:38])=[CH:29][C:30]=2[O:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:19]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:39][C:27]2[CH:26]=[C:25]([O:24][C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)[C:30]([O:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:29][C:28]=2[N:38]=1
Reactant: O=Cc1ccccn1
Reactant: Nc1cc(Oc2cccnc2)c(Oc2cccnc2)cc1N
Solvent: O=[N+]([O-])c1ccccc1
Product: c1ccc(-c2nc3cc(Oc4cccnc4)c(Oc4cccnc4)cc3[nH]2)nc1
Reaction time: 2 h

Procedure:
0.01 ml of pyridine-2-carboxaldehyde was added to a nitrobenzene (0.3 ml) solution of 30 mg of 4,5-bis(pyridin-3-yloxy)-benzene-1,2-diamine at 120° C., and the reaction liquid was stirred at the same temperature for 2 hours. The reaction mixture was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The solvent of the resulting fraction was evaporated away under reduced pressure, and this was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=20/1) to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=O)=O)=[CH:5][CH:4]=1.[NH2:25][CH2:26][CH:27]([NH2:29])[CH3:28]>C(O)C>[CH3:28][CH:27]1[CH2:26][N:25]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:4][CH:5]=2)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:29]1
Reactant: CC(N)CN
Reactant: O=C(C(=O)c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: CC1CN=C(c2ccc(C(F)(F)F)cc2)C(c2ccc(C(F)(F)F)cc2)=N1
Yield: 87 %

Procedure:
First, with 150 mL of dehydrated ethanol as a solvent, 5.07 g of 4,4′-bis(trifluoromethyl)benzil and 1.09 g of 1,2-diaminopropane were mixed, and the mixture was refluxed in a nitrogen atmosphere for four hours. After reaction, a reaction solution was condensed under reduced pressure, and an obtained residue was recrystallized by using ethanol to obtain 2-methyl-5,6-bis(4-trifluoromethylphenyl)-2,3-dihydropyrazine (light yellow crystal, yield: 87%). Further, with 100 mL of dehydrated ethanol as a solvent, 5.05 g of 2-methyl-5,6-bis(4-trifluoromethylphenyl)-2,3-dihydropyrazine that is obtained as described above and 4.26 g of iron (III) chloride were mixed, and the mixture was heated in a nitrogen atmosphere for two hours in a gentle manner. After reaction, water was added into a reaction solution for dilution, and extraction was performed with ether. An extraction solution was dried with magnesium sulfate and filtered, and solvent of filtrate was removed. An obtained residue was recrystallized with ethanol to obtain 5-methyl-2,3-bis(4-trifluoromethylphenyl)pyrazine (CF3DPPR-Me) that is a ligand (white powder, yield: 52%). A synthesis scheme (h-1) relating to the synthesis of Step 1 is shown below.
Reaction SMILES: [H-].[Na+].CCCCCC.[C:9]([O:28][CH2:29][C@@H:30]([OH:34])[CH2:31][CH2:32][OH:33])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:35](Cl)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CS(C)=O.O>[CH2:35]([O:33][CH2:32][CH2:31][C@H:30]([OH:34])[CH2:29][O:28][C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OCC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: O
Product: O[C@@H](CCOCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 43.4 %

Procedure:
Sodium hydride (74 mg, 1.85 mmol, 60% in oil) was loaded under argon circumstance in three necked flask and hexane (2 ml) was added thereto. After stirring for a while, it was allowed to stand and the supernatant was removed by syringe. By repeating this procedure three times, the oil of sodium hydride was removed. After drying in vacuo anhydrous dimethyl sulfoxide (DMSO) (2 ml) was added and the solution was cooled to 0° C. (S)-1-Trityloxy-2,4-butandiol (0.62 g, 1.68 mmol) prepared by Example 2-(2) in DMSO (3 ml) was dropped by taking care of the temperature over a one hour period at room temperature to the solution. Then the solution was stirred for 1 hour. To the solution was dropped benzyl chloride (0.213 ml, 1.85 mol) in DMSO (3 ml) over a one hour period at the range of 0° C. to 5° C. and then the solution was stirred for 4 hours. To the reaction mixture was added water (5 ml) and the solution was extracted with ethyl acetate. The extract was washed with water (8 ml) twice and with saturated brine once, dried on sodium sulfate, filtered and condensed in vacuo. The residue was subjected to silica gel chromatography to (S)-4-benzyloxy-1-trityloxy-2-butanol (0.32 g, yield 45%).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][N:9]([C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([OH:16])=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH2:22]([O:24][C:25](=[O:37])[CH:26]([OH:36])[CH:27]([NH3+:35])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:23]>>[OH:36][CH:26]([CH:27]([NH:35][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[N:20][C:12]=1[N:9]1[CH:10]=[CH:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1)[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:25]([O:24][CH2:22][CH3:23])=[O:37]
Reactant: O=C(O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Agent: [Cl-]
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.1 starting from 2-(3-phenyl-1H-pyrazol-1-yl)nicotinic acid and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride; ESI-MS [M+H]+=471.2.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([C:8]1([C:25]#[N:26])[C:17]2[NH+:12]([CH2:13][CH2:14][C:15]3[C:16]=2[N:18]=[C:19]2[C:24]=3[CH:23]=[CH:22][CH:21]=[CH:20]2)[CH2:11][CH2:10][CH2:9]1)[CH3:7].Cl>[Zn].C(O)C>[CH2:6]([C:8]1([C:25]#[N:26])[CH:17]2[N:12]([CH2:13][CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:16]=32)[CH2:11][CH2:10][CH2:9]1)[CH3:7]
Reactant: CCC1(C#N)CCC[NH+]2CCC3=c4ccccc4=NC3=C21
Agent: Cl
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [Zn]
Solvent: CCO
Product: CCC1(C#N)CCCN2CCc3c([nH]c4ccccc34)C21
Reaction time: 10 h
Yield: 42.7 %

Procedure:
In a 1-liter flask there was placed 19 g of the perchlorate of step (c) above, 300 cc of 95% ethanol and 40 g of zinc powder. There was added from a flask 100 ml of concentrated hydrochloric acid. Mild reflux could be observed during the addition of the acid. The mixture was allowed to stand at room temperature for 10 hours. It was then concentrated, washed with water and extracted with methylene chloride. It was made alkaline with sodium hydroxide and filtered through Celite (Trade Mark). After decanting, drying and evaporating the solvents there were obtained 6 g of a product, insoluble in ether, melting at 250° C. The results of analysis are as follows:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](Br)=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[F:19].C(=O)([O-])[O-].[Na+].[Na+].C1(S(O)(=O)=O)C=CC=CC=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]2[C:8]([C:15]3[CH:16]=[CH:17][C:18]([F:19])=[C:13]([Cl:12])[CH:14]=3)=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Nc1nccc2scc(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1ccccc1
Solvent: COCCOC
Product: Nc1nccc2scc(-c3ccc(F)c(Cl)c3)c12
Temperature: 80 °C
Reaction time: 14 h
Yield: 85.4 %

Procedure:
The mixture of 4-amino-3-bromo-thieno[3,2-c]pyridine (12) (300 mg 1.24 mmol), 3-chloro-4-fluoro-benzenboronic acid (432 mg, 2.48 mmol), Pd(PPh3)4 (215 mg, 10 mol %) and sodium carbonate (3.1 ml, 6.0 mmol) in 30 ml of DME was stirred for 14 hours at 80° C. The resultant mixture was directly applied to SCX (benzenesulphonicacid-based strong cation exchange sorbent:Varian, 10 g) and eluted with 1N NH3 in CHCl3 and MeOH. The eluant was collected and concentrated in vacuo. The residue was purified by chromatography on a silica gel column to afford the title compound (295 mg). 1H NMR (400 MHz, DMSO-d6) ppm 7.58 (d, J=5.6 Hz, 1H), 7.71 (dd, J=2.1, 7.2 Hz, 1H), 7.57 (s, 1H), 7.54 (dd, J=9.1 Hz, 1H), 7.47 (ddd, J=2.1, 4.8, 8.5 Hz, 1H), 7.29 (d. J=5.8 Hz, 1H), 5.42 (s, 2H). MS: m/z 279, 281 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:23])=[CH:4][C:5]2[C:9]([C:10]=1[C:11]([OH:13])=[O:12])=[N:8][N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:6]=2.[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36](O)=O)=[CH:34][C:33]([O:39][CH3:40])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1.C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.CS(Cl)(=O)=O>C(#N)C>[Cl:24][C:25]1[C:26]([N:31]2[C:35]([C:36]3[O:12][C:11](=[O:13])[C:10]4[C:9]5=[N:8][N:7]([CH2:14][C:15]6[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=6)[CH:6]=[C:5]5[CH:4]=[C:3]([CH3:23])[C:2]=4[N:1]=3)=[CH:34][C:33]([O:39][CH3:40])=[N:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(Cn2cc3cc(C)c(N)c(C(=O)O)c3n2)cc1
Reactant: COc1cc(C(=O)O)n(-c2ncccc2Cl)n1
Agent: CS(=O)(=O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COc1ccc(Cn2cc3cc(C)c4nc(-c5cc(OC)nn5-c5ncccc5Cl)oc(=O)c4c3n2)cc1
Reaction time: 0.75 h

Procedure:
A suspension of 6-amino-2-(4-methoxy-benzyl)-5-methyl-2H-indazole-7-carboxylic acid (0.288 g, 0.925 mmol) in acetonitrile (4 ml) was stirred at 20° C. for 10 minutes before the acyl chloride prepared from 2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carboxylic acid and oxalyl chloride (0.265 g, 0.971 mmol) was added. After 45 minutes stirring, 2,6-lutidine (0.215 ml) was added, followed 10 minutes later by methanesulfonyl chloride (0.072 ml, 0.925 mmol). After 18 hours of reaction, the mixture was concentrated under vacuum and water (25 ml) was added. The product was extracted with ethyl acetate and purified by flash chromatography on silica gel using a gradient from 50% to 100% ethyl acetate in cyclohexane. The desired product was obtained as light orange crystals.
Reaction SMILES: [CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[S:5][C:6]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:7]2[C:11]([O:13]CC1C=CC([N+]([O-])=O)=CC=1)=[O:12])[CH3:2].C(=O)(O)[O-].[Na+:35]>O1CCOCC1.O.[Pd]>[CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[S:5][C:6]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:7]2[C:11]([O-:13])=[O:12])[CH3:2].[Na+:35]
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Oc3ccccc3)SC12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCC1C(=O)N2C(C(=O)[O-])=C(Oc3ccccc3)SC12
Yield: 96.5 %

Procedure:
A mixture of a solution of 306 mg of 4-nitrobenzyl 6-ethyl-3-phenoxy-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 60 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes. The mixture was then filtered through Celite, and lyophilised to yield 216 mg of the title compound as a pale yellow crystalline solid (96% of the theoretical yield).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=5)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)(C)(C)C>C(O)C.Cl>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][NH:30][C:26]2[N:25]=[C:24]([C:21]3[N:17]4[CH:18]=[CH:19][N:20]=[C:15]([NH:14][CH:11]5[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]5)[C:16]4=[N:23][CH:22]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4cccc(NCc5ccc(Cl)cc5)n4)cnc23)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCC(Nc2nccn3c(-c4cccc(NCc5ccc(Cl)cc5)n4)cnc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (4-{3-[6-(4-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (214 mg, 0.39 mmol) in ethanol (4 mL) and concentrated HCl (4 mL) was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The residue was purified by preparative-HPLC to give N-{3-[6-(4-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 80 mg). 1HNMR (300 MHz, CD3OD): δ 8.22 (d, 1H, J=5.7 Hz), 8.19 (s, 1H), 7.89 (t, 1H, J=8.7 Hz), 7.46-7.39 (m, 4H), 7.23 (d, 1H, J=6.9 Hz), 7.17 (d, 1H, J=5.7 Hz), 7.02 (d, 1H, J=8.7 Hz), 4.70 (s, 2H), 4.04 (brs, 1H), 3.25 (brs, 1H), 2.23 (brs, 4H), 1.81-1.71 (m, 4H). LC-MS: [M+H]+ 448.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[CH:15][CH:16]([CH3:27])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>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>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:37]=[CH:38][C:39]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]=[CH:15][CH:16]([CH3:27])[CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=4)=[CH:6][CH:7]=3)=[CH:40][CH:41]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=CC(C)Cc1ccc(C(C)C)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=CC(C)Cc4ccc(C(C)C)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and the following starting materials: 5-(4-bromo-phenyl)-4-[4-(4-isopropyl-phenyl)-3-methyl-but-1-enyl]-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:34])([F:33])[C:10]1[N:18]2[C:13]([CH:14]=[CH:15][C:16]([N:19]3[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[N:17]2)=[N:12][N:11]=1.C(=O)(O)[O-].[Na+]>ClCCl>[N:19]1([C:16]2[CH:15]=[CH:14][C:13]3=[N:12][N:11]=[C:10]([C:9]([F:8])([F:34])[F:33])[N:18]3[N:17]=2)[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.8 %

Procedure:
Trifluoroacetic acid (8 mL, 103.68 mmol) was added to a mixture of tert-butyl 4-[3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazin-6-yl]-1,4-diazepane-1-carboxylate (5.9 g, 15.3 mmol) and dichloromethane (80 mL) at ambient temperature and the resulting solution was stirred at ambient temperature for 6 hours. The reaction mixture was evaporated to give an involatile residue that was treated with saturated aqueous sodium bicarbonate solution (100 mL) and then extracted with dichloromethane (4×200 mL). The organic phases were combined and dried over Na2SO4, filtered, and evaporated to give 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazine (3.8 g, 86.9%) as a white solid. 1H NMR (300.132 MHz, DMSO) δ 1.68-1.84 (m, 2H), 2.69 (t, 2H), 2.88 (t, 2H), 3.60-3.79 (m, 4H), 7.46 (d, 1H), 8.19 (d, 1H); m/z. 287 (M+H)+.
Reaction SMILES: [F-].[Cs+].[CH3:3]OCCOCCOC.[CH3:12][O:13][C:14](=[O:24])[CH:15]([C:20]([F:23])([F:22])[F:21])[C:16]([O:18][CH3:19])=[O:17].CI>O>[CH3:3][C:15]([C:20]([F:22])([F:23])[F:21])([C:16]([O:18][CH3:19])=[O:17])[C:14]([O:13][CH3:12])=[O:24]
Reactant: COCCOCCOC
Reactant: COC(=O)C(C(=O)OC)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CI
Solvent: O
Product: COC(=O)C(C)(C(=O)OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of dried CsF (9.11 g, 60 mmol), diglyme (41 ml), dimethyl(trifluoromethyl)malonate (4 g, 20 mmol), and methyl iodide (3.12 g, 22 mmol) was stirred overnight at room temperature. The reaction mixture was poured into water and the resultant oily layer and the ether-extract from the aqueous layer were combined and washed with water to remove diglyme. After drying over MgSO4, the ether was evaporated and the residue was subjected to distillation, giving dimethyl methyl(trifluoromethyl)malonate (2.56 g, 60%), b.p. 63°-65° C./10 mmHg. This product showed the following analytical properties: 19F NMR: δ--7.5 (s, CF3); 1H NMR: δ 3.81 (s, 6H, CO2CH3), 1.66 (s, CH3).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH2:18][O:19][C:20]([CH2:22]Br)=[O:21]>CN(C=O)C>[CH2:18]([O:19][C:20](=[O:21])[CH2:22][NH:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Benzo[1,3]dioxol-5-ylamine (1.2 eq.) and potassium carbonate (2.2 eq.) in DMF at 0° C. was added ethyl bromo acetate and stirred at room temperature for overnight. Reaction was then quenched with water and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the (Benzo[1,3]dioxol-5-ylamino)-acetic acid ethyl ester.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[C:9]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)=[O:7])C>CO.O1CCOCC1>[CH3:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([C:19]([F:20])([F:21])[F:22])=[CH:14][CH:15]=2)[N:10]=[C:9]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[C:8]=1[C:6]([OH:7])=[O:5]
Reactant: CCOC(=O)c1c(CC(C)(C)C)nc2cc(C(F)(F)F)ccc2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(C(=O)O)c(CC(C)(C)C)nc2cc(C(F)(F)F)ccc12
Temperature: 80 °C
Yield: 83.3 %

Procedure:
A 2M aq. LiOH sol. (10 ml) was added to a solution of 1.1 g (3.0 mmol) 4-methyl-2-neopentyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in a MeOH/1,4-dioxane mixture (in each case 10 ml) and the mixture was subsequently heated to 80° C. for 72 h. The organic solvents were removed as far as possible in a vacuum and the obtained aqueous solution was washed with ether, adjusted to pH 2 with 2M hydrochloric acid and diluted with EtOAc. The organic phase was separated and washed with brine, dried over MgSO4 and concentrated in a vacuum. 0.8 g (2.5 mmol, 82%) 4-methyl-2-neopentyl-7-(trifluoromethyl)quinoline-3-carboxylic acid was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]([OH:9])[C:6]([OH:8])=O.[NH2:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:9])[C:6]([NH:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=2)=[O:8])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: O=C(O)C(O)c1ccc(Cl)c(Cl)c1
Reactant: COc1cc([C@@H]2CCCC[C@H]2N)ccc1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc([C@@H]2CCCC[C@H]2NC(=O)C(O)c2ccc(Cl)c(Cl)c2)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3.09 g (13.5 mmol) of DL-3,4-dichloromandelic acid, 3.0 g (13.5 mmol) of trans-4-(2-amino-cyclohexyl)-2-methoxy-phenol and 1.89 (13.5 mmol) of N,N-diisopropylethylamine in 30 ml DMF is added 6.0 g (13.5 mmol) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in one portion. The reaction mixture is then stirred at ambient temperature for about 2 hours and thereafter poured into 150 ml of aqueous saturated sodium chloride solution. The two-phase mixture is extracted with two 150 ml portions of ethyl acetate. The organic extract is concentrated under reduced pressure to a residue, which is subjected to column chromatography on silica gel, with 1:1 ethyl acetate/isohexane as the eluant yielding 2-(3,4-dichlorophenyl)-2-hydroxy-N-[trans-2-(4-hydroxy-3-methoxy-phenyl)-cyclohexyl]-acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4](I)[CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](B(O)O)[CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:11][C:12]1[CH:17]=[C:16]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[CH:15]=[CH:14][N:13]=1
Reactant: COc1ccc(Cl)cc1I
Reactant: OB(O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cl)cc1-c1ccnc(Cl)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 4-chloro-2-iodo-1-methoxybenzene (542 mg, 2.02 mmol), (2-chloropyridin-4-yl)boronic acid (400 mg, 2 mmol), and sodium carbonate (860.2 mg, 8.116 mmol) in 1,4-dioxane (8.4 mL, 110 mmol) and water (2.8 mL, 160 mmol) was sparged 5 minutes with argon. Tetrakis(triphenylphosphine)palladium(0) (139.9 mg, 0.1210 mmol) was added and the reaction vial was capped. The reaction mixture was heated at 90° C. After 3 hours, the reaction mixture was cooled to ambient temperature and poured into water. The mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was taken up in methylene chloride, concentrated onto diatomaceous earth, and purified by automated flash chromatography (24 g SiO2, hexanes to 3:1 hexanes-ethyl acetate) to afford the product as a light yellow powder.