Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOCC.Cl[C:7]1[N:12]=[C:11]([Cl:13])[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=1.[CH3:18][N:19]1[CH:23]=[C:22]([NH2:24])[CH:21]=[N:20]1.CCN(C(C)C)C(C)C>ClCCCl.CC(O)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:13][C:11]1[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=[C:7]([NH:24][C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)[N:12]=1
Reactant: Cn1cc(N)cn1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Nc2ncc(C(F)(F)F)c(Cl)n2)cn1
Temperature: 50 °C

Procedure:
ZnCl2 in Et2O (1M, 23.2 mL, 23.2 mmol) was added to 2,4-dichloro-5-trifluoromethylpyrimidine (5.2 mL, 39 mmol) in DCE:t-BuOH (1:1, 150 mL) under a nitrogen atmosphere. The mixture was stirred for 45 minutes before addition of 1-methyl-1H-pyrazol-4-amine (1.880 g, 19.36 mmol) in DCE/t-BuOH (1:1, 150 mL) and DIPEA (3.2 mL, 18 mmol). The mixture was heated to 50° C. for 16 hours, cooled and filtered using vacuum filtration. The solid was washed with MeOH and the filtrate concentrated under reduced pressure before being poured into water. The resulting precipitate was collected under vacuum filtration and washed with water then petroleum benzine 40-60° C. and finally dissolved in Et2O and filtered. The Et2O filtrate was concentrated under reduced pressure to give the crude product which was further purified in batches by a combination of trituration with Et2O and cyclohexane or silica gel column chromatography (0-30% EtOAc in petroleum benzine 40-60° C.) then combined to give the title compound A74 (1.6 g, 30%). 1H NMR (400 MHz, d-DMSO) δ ppm 10.66-10.58 (m, 1H), 8.77-8.68 (m, 1H), 7.93-7.86 (m, 1H), 7.53 (s, 1H), 3.88-3.78 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].[OH-].[Na+].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl>CO.O1CCCC1.O>[CH2:25]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CCCCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCOc1ccc(C(=O)O)cc1Cl

Procedure:
In a mixed solvent of methanol and tetrahydrofuran was dissolved 5.17 g of 4-hydroxy-3-chlorobenzoic acid, and a solution of 2.4 g of sodium hydroxide in 5 ml of water was added to the solution. Then, 10 ml of n-dodecyl bromide was added dropwise to the mixture and the resulting mixture was refluxed for 2 hours. Then, 1.2 g of sodium hydroxide was further added and the mixture was refluxed for 1 hour. The thus-obtained solution was put in a 1N aqueous solution of hydrochloric acid, and the precipitate was recovered and filtration, washed with water and then with n-hexane and recrystallized from ethyl acetate to obtain 4.1 g of 4-n-dodecyloxy-3-chlorobenzoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:13]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([Br:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: COc1cccc(C(=O)O)c1N
Solvent: ClC(Cl)Cl
Product: COc1cc(Br)cc(C(=O)O)c1N
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-amino-3-methoxybenzoic acid (20.0 g, 119.64 mmol) is suspended in chloroform, cooled to 0° C. and combined with bromine (6.48 mL, 126.56 mmol), which is dissolved in 100 mL chloroform. After the addition the reaction mixture is heated to 20° C. and stirred for 16 h at this temperature. The precipitate is filtered off, dried and 2-amino-5-bromo-3-methoxybenzoic acid (HPLC-MS: tRet.=1.76 min, MS(M+H)+=246/248; method FECS) is obtained.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:19][C:20]([C:22]1([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:2]([C@@H:3]([NH:19][C:20]([C:22]1([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)=[CH:7][CH:6]=1)#[N:1]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(F)c(F)c3)cc2)C(N)=O)CCOCC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc(F)c(F)c3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(3′,4′-difluorobiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 13, step (i), 305 mg) in dichloromethane (10 mL) was treated with Burgess' reagent (289 mg) and the mixture was stirred at room temperature for 18 h. The solvent was partially evaporated and the residue was purified by chromatography on silica eluting with ethyl acetate/isohexane (1:1) to yield the sub-titled compound (239 mg).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[CH3:15][N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.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>[CH3:15][N:16]1[CH:20]=[C:19]([C:2]2[C:7]([NH2:8])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=2)[CH:18]=[N:17]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
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: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ncc(C(F)(F)F)cc2N)cn1
Temperature: 90 °C
Yield: 4.8 %

Procedure:
2-Chloro-3-nitro-5-(trifluoromethyl)pyridine (406 mg, 1.79 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (559 mg, 2.69 mmol), cesium carbonate (1752 mg, 5.38 mmol) and palladium tetrakis (207 mg, 0.179 mmol) were combined in DMF (3 mL) and water (1 mL). The headspace was evacuated and back-filled with nitrogen (4×). The mixture was heated to 90° C. overnight. The mixture was poured into EtOAc (40 mL) and washed with water (3×20 mL) and satd brine (3×20 mL). The organics were concentrated in vacuo and purified by silica gel chromatography to provide 2-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyridin-3-amine (21 mg, 5% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1 H), 8.13 (br s, 1 H), 7.98 (s, 1 H), 7.40 (d, J=2.0 Hz, 1 H) 5.55 (s, 2 H), 3.91 (s, 3 H); MS (ESI): m/z 473.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][N:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([NH2:12])[CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][N:3]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])cn2c(C)nnc12
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)cn2c(C)nnc12

Procedure:
A suspension of 3,8-dimethyl-6-nitro-[1,2,4]triazolo[4,3-a]pyridine (Step 67.3) (14.1 g, 71.9 mmol) and 10% Pd/C (2.75 g, 25.9 mmol) in MeOH (300 mL) was shaken for 5 h under 4 bar hydrogen atmosphere at RT. Further 10% Pd/C was added and the reaction mixture was shaken another 1 hh under hydrogen atmosphere. The mixture was filtered through Celite. The pad of Celite was washed with MeOH and the resulting filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/(CH2Cl2-MeOH 19:1) 50-100% (CH2Cl2-MeOH 19:1)) to afford the title product as yellow solid. tR: 0.29 min (LC-MS 2); ESI-MS: 163 [M+H]+ (LC-MS 2); TLC (CH2Cl2-MeOH 9:1) Rf=0.26; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.43 (s, 3H) 2.54 (s, 3H) 5.05 (br. s, 2H) 6.75 (br. s, 1H) 7.18 (br. s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][N:4]=1.[NH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[NH2:12]>CCO>[CH3:1][S:2][C:3]1[N:8]=[C:7](/[CH:9]=[N:12]/[NH:11][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:6]=[CH:5][N:4]=1
Reactant: NNc1ccccn1
Reactant: CSc1nccc(C=O)n1
Solvent: CCO
Product: CSc1nccc(/C=N/Nc2ccccn2)n1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A mixture of 2-methylsulfanyl-pyrimidine-4-carbaldehyde (1.00 g) (U.S. Pat. No. 6,218,537) and 2-hydrazinopyridine (0.71 g) in EtOH (20 mL) was heated to reflux for 24 h, then cooled to RT and the resulting solid collected by filtration to give N-[1-(2-methylsulfanyl-pyrimidin-4-yl)-meth-(E)-ylidene]-N′-pyridin-2-yl-hydrazine (1.26 g). A mixture of this material and DCM (20 mL) was gently heated, and a second aliquot of DCM (10 mL) and chloroform (5 mL) added to facilitate solubilization. Iodobenzene diacetate (1.65 g) was added, and the resulting mixture stirred at RT under N2 for 17 h. The reaction mixture was then evaporated under reduced pressure and the crude residue was triturated with hot Et2O. Once the mixture cooled to RT, the solid was collected by filtration to afford 3-(2-methylsulfanyl-pyrimidin-4-yl)-[1,2,4]triazolo-[4,3-a]pyridine (1.12 g).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.[O-]CC.[Na+].[N+:14]([CH3:17])([O-:16])=[O:15].Cl.C(O)(C)C>C1(C)C=CC=CC=1.C(O)C>[N+:14]([CH2:17][C:3]1([OH:9])[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)([O-:16])=[O:15]
Reactant: O=C1CN2CCC1CC2
Reactant: C[N+](=O)[O-]
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])CC1(O)CN2CCC1CC2

Procedure:
Quinuclidin-3-one (125 g., 1 mole) was dried by azeotropic distillation (40% w/w in toluene) and placed in a 3 l. flask equipped with a mechanical stirrer, 1 l. methanolic sodium ethoxide was added and the clear solution was stirred at 15°-20° C. Nitromethane, 61 g. (1.0 mole), dissolved in 500 ml. absolute ethanol was then added over 0.5 hour while keeping the temperature below 20° C. The solution was acidified to pH=1 using HCl-isopropanol, filtered and dried to yield 160 g. crude product which was used as such for the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH2:25]Cl.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:25][C:24]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:23]=2[Cl:22])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 57.5 %

Procedure:
To a 25 mL vial which contained a solution of the product from step 1 (150 mg, 0.5 mmol) and 2,4-dichloro-benzyl chloride (180 mg, 0.8 mmol) in anhydrous DMF (15 mL) was added dry Cs2CO3 (150 mg, 0.75 mmol) at rt. The reaction mixture which resulted was allowed to stir at rt for 7 d. The mixture was poured onto 50 mL ice-water solution and extracted with EtOAc (3×30 mL) allowed). The combined organic layers were washed with water (30 mL) and brine (30 mL) and dried over anhy. Na2SO4. The solvent was removed under vacuo to obtain the crude product which was purified by silica gel flash chromatography to afford the title product (130 mg, 55%); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.10 (m, 4H), 3.26-3.45 (m, 2H), 3.69-3.91 (m, 1H), 4.01-4.18 (m, 2H), 5.07 (s, 2H), 6.84-6.90 (m, 4H), 7.25-7.28 (m, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H),
Reaction SMILES: [CH:1]1([CH2:6][C:7]([N:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1)([CH3:18])[CH3:17].CO>C1COCC1>[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:12]2[CH2:13][CH2:14][CH2:15][N:9]([C:7](=[O:8])[CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:10][CH2:11]2)=[S:27])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1ccc(N=C=S)cc1
Reactant: O=C(CC1CCCC1)N1CCCNCC1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1ccc(NC(=S)N2CCCN(C(=O)CC3CCCC3)CC2)cc1
Reaction time: 8 h
Yield: 71 %

Procedure:
The 1-(2-cyclopentyl-acetyl)-1,4-diazepane (100 mg; 0.475 mmol) and 4-isopropylphenyl isothiocyanate (80 mg; 0.45 mmol) were mixed together at room temperature in 5 mL anhydrous THF. The reaction mixture was left stirring overnight, then 1 mL methanol was added and the solvents were evaporated in vacuo. The crude mixture was purified by flash column chromatography on SiO2 using 0-50% EtOAc in hexanes mixtures as eluent, followed by 1-4% methanol in DCM mixtures. The desired product was isolated as a colorless foam, 180 mg (71% yield). ES+MS: 388 amu (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][CH:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:13](=O)[CH2:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH2:4][O:3]1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:18])[O:6][CH:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH2:4][O:3]1
Reactant: CC1(C)OCC(c2ccc3c(n2)CCCC3=O)O1
Reactant: C1COCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)OCC(c2ccc3c(n2)CCC=C3N2CCOCC2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a mixture of 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-7,8-dihydroquinolin-5(6H)-one (0.182 g, 0.736 mmol) and morpholine (0.321 mL, 3.68 mmol) in toluene (3 mL) at 0° C. was added titanium(IV) chloride (1.0 M in toluene) (0.405 mL, 0.405 mmol) dropwise. The ice-bath was removed, and the orange, heterogeneous reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a pad of CELITE®, which was then rinsed with toluene (3×10 mL). The pale yellow filtrate was concentrated under reduced pressure to give 4-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)-7,8-dihydroquinolin-5-yl)morpholine (0.194 g, 0.613 mmol, 83% yield) as a yellow oil.
Reaction SMILES: [CH3:1][S:2][C:3](=[S:15])[S:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=O.[CH2:16]([N+:20]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].[NH2:33][CH:34]1[CH2:37][N:36]([S:38]([O-:41])(=[O:40])=[O:39])[C:35]1=[O:42].C1(N=C=NC2CCCCC2)CCCCC1.C1(NC(=O)NC2CCCCC2)CCCCC1>C(#N)C>[CH2:29]([N+:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31][CH3:32].[CH3:1][S:2][C:3](=[S:15])[S:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([NH:33][C@H:34]1[CH2:37][N:36]([S:38]([O-:41])(=[O:40])=[O:39])[C:35]1=[O:42])=[O:8]
Reactant: NC1CN(S(=O)(=O)[O-])C1=O
Reactant: CSC(=S)SC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: CC#N
Product: CSC(=S)SC(C(=O)N[C@H]1CN(S(=O)(=O)[O-])C1=O)c1ccccc1
Yield: 50.3 %

Procedure:
A solution of 1.03 g of (±)-α-[[(methylthio)thioxomethyl]thio]benzeneacetic acid and 1.63 g of 3-amino-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (see Example 6A) in 30 ml of acetonitrile is treated with 0.8 g of dicyclohexylcarbodiimide dissolved in 10 ml of acetonitrile at -5° C. After stirring for about 16 hours the formed dicyclohexyl urea is filtered off and the mother liquor is evaporated. The remaining oily residue is chromatographed on a column of 400 g of silica (ethyl/acetate/methanol/water (8.5:1:0.5) is the eluent), yielding 1.3 g of the title compound.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:14](=[O:16])[CH3:15])[N:4]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[S:6][C:5]=12.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O>>[F:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:15][C:14]([C:3]2[N:4]3[C:5]([S:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=43)=[N:1][CH:2]=2)=[O:16])[CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CC(=O)c1cnc2sc3c(n12)CCCCC3
Product: O=C(C=Cc1cccc(F)c1)c1cnc2sc3c(n12)CCCCC3

Procedure:
[1-(6,7,8,9-Tetrahydro-5H-cyclohept[d]-imidazo[2,1-b]thiazol-3-yl)-ethanone (Formula N-4), 2.34 g and 3-fluorobenzaldehyde were reacted using non-critical variations of the teachings Example 15 to give 3-(3-fluorophenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept [d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one (Formula N-5, X=3-fluoro), 3.08 g, m.p. 176-177°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](F)[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([N:31]([CH:39]2[CH2:43][CH2:42][O:41][CH2:40]2)C(=O)OC(C)(C)C)[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CCOC(C)=O.CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:24][C@H:25]3[CH2:26][CH2:27][C@H:28]([NH:31][CH:39]4[CH2:43][CH2:42][O:41][CH2:40]4)[CH2:29][CH2:30]3)[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(C1CCOC1)[C@H]1CC[C@H](N)CC1
Reactant: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Cl)c(Cl)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Clc1cnc(N[C@H]2CC[C@H](NC3CCOC3)CC2)cc1-c1nc(NCC2CCOCC2)ccc1Cl
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
To a scintillation vial was added 3,5′-dichloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (25 mg, 0.070 mmol), racemic tert-butyl trans-4-aminocyclohexyl(tetrahydrofuran-3-yl)carbamate (21.95 mg, 0.077 mmol), DIPEA (24.51 μl, 0.140 mmol) and NMP (0.2 ml). This was heated at 110° C. for 48 h. The mixture was diluted with EtOAc and washed with water (×2), saturated brine (×2), then dried (Na2SO4), filtered and evaporated under reduced pressure. The resulting residue was dissolved in CH2Cl2 (0.4 mL) and treated with TFA (100 μl, 1.298 mmol). After 30 minutes, the mixture was concentrated in vacuo and the resulting residue was purified by reverse phase preparative HPLC and then lyophallized to yield racemic 3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(tetrahydrofuran-3-yl-amino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine (10.8 mg), LCMS (m/z): 520.1/522.0 (bis-chloro isotopic signature for MH+), retention time=0.59 min as a TFA salt.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH3:41])=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][O:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)=[CH:35][CH:34]=1
Reactant: CCCc1ccc(OC)cc1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Na+]
Product: COc1ccc(CCCOCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of 3-(4-methoxyphenyl)propane chloride are treated as described in Example 5.
Reaction SMILES: BrBr.[Br-].[Na+].Br.[C:6]1([C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-:18].[Na+]>O>[O:18]1[C:12]2([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:13]1[CH2:14][NH:15][CH2:16][CH2:17]2
Reactant: [OH-]
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Br
Agent: BrBr
Agent: [Br-]
Solvent: O
Product: c1ccc(C23CCNCC2O3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 33.6 g of bromine and 60 g of sodium bromide in 450 ml of water was added dropwise with stirring to solution comprising 50 g of 4-phenyl-1,2,5,6-tetrahydropyridine hydrobromide in 600 ml of water and the reaction mixture was then stirred at room temperature for 30 minutes. The solution was stirred on an ice bath while 252 ml of 10% sodium hydroxide was added dropwise thereto. The resulting mixture then being stirred at room temperature for a further 30 minutes. The aqueous solution was extracted with methylene chloride and the organic phase solution dried over sodium sulfate and then concentrated in vacuo to give 25.2 g of the desired 3,4-epoxy-4-phenyl piperidine as an oil.
Reaction SMILES: F[C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[F:13].[C:21]([NH:28][C:29]1[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:24]([O:23][C:21](=[O:22])[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:2]2[CH:16]=[C:15]([F:17])[CH:14]=[C:4]([NH:5][C:6]3[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=3[F:13])[C:3]=2[N+:18]([O-:20])=[O:19])[CH:30]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
3.0 g of 3,5-difluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline (Intermediate 1A; 70% pure, 5.3 mmol, 1 eq.), 1.1 g N-Boc-3-amino-phenol (5.3 mmol, 1 eq.) and 3.4 g caesium carbonate (10.7 mmol, 1.5 eq.) were suspended in 30 mL DMF and stirred at rt for 16 h. LCMS analysis showed complete turnover. The reaction mixture was partitioned between water and ethyl acetate, the layers were separated and the aqueous layer was reextracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (n-hexane/ethyl acetate gradient) providing 1.35 of the desired product (44% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[C:20]([CH3:21])=[C:19]2[C:15]([C:16]([CH3:25])([CH3:24])[C:17](=[O:23])[N:18]2[CH3:22])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:11][C:12]1[C:20]([CH3:21])=[C:19]2[C:15]([C:16]([CH3:25])([CH3:24])[C:17](=[O:23])[N:18]2[CH3:22])=[CH:14][CH:13]=1)=[O:7]
Reactant: Cc1c(N)ccc2c1N(C)C(=O)C2(C)C
Reactant: O=C(O)c1ccnc(Cl)c1
Product: Cc1c(NC(=O)c2ccnc(Cl)c2)ccc2c1N(C)C(=O)C2(C)C

Procedure:
Prepared in analogy to example 26 from 2-chloroisonicotinic acid and 6-amino-1,3,3,7-tetramethyl-1,3-dihydro-indol-2-one. The title compound was obtained as light yellow crystals.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.C(N(CC)CC)C.[NH2:21][C@H:22]1[C:31]2[C:26](=[CH:27][C:28]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=2)[O:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1.O.ClCCl>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:21]([C@H:22]1[C:31]3[C:26](=[CH:27][C:28]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=3)[O:25][CH2:24][CH2:23]1)[CH2:11]2
Reactant: COC(=O)c1ccc2c(c1)OCC[C@H]2N
Reactant: COC(=O)c1c(Cl)cccc1CBr
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)OCC[C@H]2N1Cc2cccc(Cl)c2C1=O

Procedure:
2-Bromomethyl-6-chlorobenzoic acid methyl ester (1.689 mmol, 1.0 eq) was dissolved in toluene (5.2 ml) and triethylamine (2.534 mmol, 1.5 eq), and (R)-methyl 4-aminochromane-7-carboxylate (A-04) (1.689 mmol, 1 eq) was added. The reaction mixture was refluxed for 16 h and then diluted with water and dichloromethane. The phases were separated and the aqueous phase was extracted with dichloromethane (2×). The organic phases were washed with sat. NaCl solution, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, cyclohexane:EA 3:1), and the desired product (R)-methyl 4-(7-chloro-1-oxoisoindolin-2-yl)chromane-7-carboxylate (D-03) was thus obtained. Yield: 60%