Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:30])([F:29])[C:13]2[N:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=3)=[CH:15][CH:14]=2)[CH2:11][O:10]1.[NH:31]1[CH:35]=[N:34][N:33]=[N:32]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][N:31]1[CH:35]=[N:34][N:33]=[N:32]1)[C:12]([C:13]1[N:18]=[CH:17][C:16]([CH2:19][O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=2)=[CH:15][CH:14]=1)([F:29])[F:30]
Reactant: N#Cc1ccc(OCc2ccc(C(F)(F)C3(c4ccc(F)cc4F)CO3)nc2)nc1
Reactant: c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#Cc1ccc(OCc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)nc1
Temperature: 55 °C
Reaction time: 36 h

Procedure:
To a magnetically stirred mixture of 6-((6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-yl)methoxy)nicotinonitrile (BZ; 200 mg, 0.482 mmol) and 1H-tetrazole (67.5 mg, 0.963 mmol) in dry DMF (4.815 mL) was added K2CO3 (133 mg, 0.963 mmol) in a dry 25 mL vial under N2 atmosphere. The reaction mixture was stirred at 55° C. for 36 hours, then cooled to RT, and diluted with ice-water and ether. The layers were separated and the aq. layer was extracted again with ether (2×). The combined ether extracts were dried over sodium sulfate, filtered, and evaporated. The crude residue was purified on silica (40 gram column, gradient over 15 min to 40% EA/Hex, hold 10 min then 10 min at 80% EA/hex, monitor 240 and 254 nm). The respective product fractions were evaporated to afford the title compound contaminated with DMF. The material was diluted with water and extracted 3× with ether, the combined ether extracts were diluted with pet. ether and washed with sat'd NH4Cl (2×) and brine (1×), dried over MgSO4, filtered, and evaporated to afford 98. Yield=62 mg (25.2%) of a white foam. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.63 (d, J=1.3 Hz, 1H), 8.48 (dd, J=2.3, 0.8 Hz, 1H), 7.91 (dd, J=8.2, 2.1 Hz, 1H), 7.85 (dd, J=8.7, 2.4 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.35 (td, J=9.0, 6.5 Hz, 1H), 6.92 (dd, J=8.5, 0.8 Hz, 1H), 6.76 (ddd, J=12.0, 8.5, 2.5 Hz, 1H), 6.71-6.61 (m, 1H), 5.56 (d, J=14.3 Hz, 1H), 5.50 (s, 2H), 5.13 (dd, J=14.2, 1.1 Hz, 1H). 1H-decoupled 19F NMR (376 MHz, CDCl3) δ −103.83 (ddd, J=42.2, 17.0, 10.2 Hz), −104.20 (d, J=16.3 Hz), −104.89 (d, J=16.3 Hz), −107.90-108.07 (m), −110.92 (dd, J=262.9, 42.2 Hz). MS (ESI): m/z 486.1 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:7]#[CH:8].[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].O>CCCCCC.O1CCCC1>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[O:9][CH2:6][C:7]#[C:8][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: C#CCOC1CCCCO1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCC#CCOC1CCCCO1
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
50 ml of a 15% by weight solution of butyllithium in hexane was added dropwise at -50° C. to a solution of 11.48 g of 2-tetrahydropyranyl propargyl ether in 220 ml of tetrahydrofuran followed by 25 g of palmityl bromide, and the mixture was stirred for 30 minutes, during which time the temperature of the mixture was allowed to rise to room temperature. The reaction mixture was heated under reflux for 16 hours, poured into water and then extracted twice with diethyl ether. The combined extracts were washed with water, dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 500 g of silica gel. 14.59 g of the title compound were isolated as an oil from the fractions eluted with a 3:100 by volume mixture of diethyl ether and hexane.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:26])[N:5]([CH2:24][CH3:25])[C:6](=[O:23])[C:7](=NC2C=CC(N(CC)CCO)=CC=2)[C:8]=1[CH3:9])#[N:2].Cl.[OH2:28]>>[C:1]([C:3]1[C:4](=[O:26])[N:5]([CH2:24][CH3:25])[C:6](=[O:23])[C:7](=[O:28])[C:8]=1[CH3:9])#[N:2]
Reactant: CCN1C(=O)C(=Nc2ccc(N(CC)CCO)cc2)C(C)=C(C#N)C1=O
Reactant: O
Agent: Cl
Product: CCN1C(=O)C(=O)C(C)=C(C#N)C1=O

Procedure:
1.02 g of 3-Cyano-1-ethyl-4-methyl-5-[4-(N-ethyl-N-hydroxyethylamino)phenylimino]-pyridine-2,6-dione (prepared as described in German Offenlegungsschrift No. 2808825) is stirred in 7 ml of water, and concentrated hydrochloric acid is slowly added until the blue dye had disappeared. A pale yellow solid precipitates, and is filtered off and recrystallised from ethyl acetate/petrol, yield 0.32 g, m.p. 159°-160° C. This is the compound of formula (4).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:24])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[SH:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][CH:30]=[N:31]2.C1CCN2C(=NCCC2)CC1.O>C(Cl)(Cl)Cl>[C:12]1([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:3]([OH:24])[CH2:2][S:25][C:26]3[CH:35]=[CH:34][CH:33]=[C:32]4[C:27]=3[CH:28]=[CH:29][CH:30]=[N:31]4)[CH2:6][CH2:7]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: Sc1cccc2ncccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: OC(CSc1cccc2ncccc12)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 288 h
Yield: 20.3 %

Procedure:
In 10 ml of chloroform were dissolved 1.2 g of 4-(3-chloro-2-hydroxypropy)-1-diphenylmethylpiperazine prepared in Example 23-(b) and 220 mg of 5-mercaptoquinoline, and 311 mg of DBU was further added thereto. Afterward, the liquid was allowed to stand at room temperature for 12 days. The reaction liquid wa poured into 20 ml of water and was then extracted twice with methylene chloride. The resultant organic layer was separated, then dried with an anhydrous Glauber's salt, and was distilled off under reduced pressure. The resultant residue was purified through a silica gel chromatograph (an AcOEt effluent solvent was used) in order to obtain 130 mg of the desired compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:24]N1C(=O)CCC1=O>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[CH:17]=[C:18]([I:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)ccc1=O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)cc(I)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
A 0.2 M solution of the title compound (264 mg, 0.8 mmol) from Example 98 in DMF stirred at 0° C. was treated with three equal portions of N-iodosuccinimide (187 mg, 84 mmol). After 15 min, the icebath was removed and the mixture was stirred at rt for 2 h. The reaction mixture was treated with 10% sodium thiosulfate (aq) (5 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to afford a crude solid. The resulting solid was purified by silica gel column chromatography using a gradient of EtOAc (0 to 100%) in DCM to afford the title compound (333 mg, 91%) as a white solid. LCMS (M+H)+=460.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][CH2:36][CH:37]([OH:40])[CH2:38][CH3:39].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:40][CH:37]([CH2:38][CH3:39])[CH2:36][CH3:35])=[CH:18][CH:17]=1
Reactant: CCC(O)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 79.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-pentanol (23 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (55 mg, yield 67%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][CH:3]=1.O[CH2:12][C@@H:13]([N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[S:6][C:5]([N:7]([CH2:12][C@@H:13]([N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8](=[O:10])[CH3:9])=[N:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@H](CO)Cc1ccccc1
Reactant: CC(=O)Nc1ncc(Br)s1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N(C[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O)c1ncc(Br)s1
Reaction time: 0.25 h
Yield: 17 %

Procedure:
N-(5-Bromo-thiazol-2-yl)-acetamide) (442.0 mg, 2.0 mmol), (S)-2-(1-hydroxy-3-phenylpropan-2-yl)isoindoline-1,3-dione (281.0 mg, 1.0 mmol), triphenylphosphine (303.0 mg, 1.5 mmol) and THF (15.0 mL) were charged into a 100 mL round bottom flask. The resulting reaction mixture was a suspension. The flask was immersed in an ice-water bath. After stirring for 15 minutes under nitrogen, a solution of DIAD (421.5 mg, 1.5 mmol) in 3.0 mL THF was slowly added to the flask through a syringe. The reaction mixture became a clear solution after the addition was complete. After 10 minutes, the reaction mixture was brought to room temperature by removing the ice water bath and the stirring was continued for 16 hours. THF was evaporated off, and the residue was diluted with 40 mL saturated sodium bicarbonate and extracted with DCM (75 mL×2). The residue was subjected to a silica gel column chromatography purification with hexane-EtOAc (7:3) as the eluant to afford a compound as a white solid (S)—N-(5-bromothiazol-2-yl)-N-(2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropyl)acetamide (20 mg, yield 17%). LCMS (API-ES) m/z (%): 484.0 (100%, M++H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:29])[CH2:16][NH:17][C@H:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([OH:28])=[CH:23][CH:24]=3)[CH2:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([N:33]([CH2:37]C)[CH:34](C)C)(C)[CH3:31].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:42].O>ClCCl.[Cl-].[Na+].O.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]([OH:29])[CH2:16][NH:17][C@H:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:31][C:30]([N:33]([CH3:37])[CH3:34])=[O:42])=[CH:23][CH:24]=3)[CH2:19]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(OCc3ccccc3)cc1)CC2
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(OCc3ccccc3)cc1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of (1R)-1-(4-benzyloxyphenyl)-2-[((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino]-ethanol (350 mg) and N,N-diisopropylethylamine (0.78 ml) in dichloromethane (3.6 ml) was added trifluoroacetic anhydride (0.38 ml) at -15° C. After reaction for 30 minutes, the reaction mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. The resulting residue was dissolved in N,N-dimethylformamide (4.5 ml), and 2-bromo-N,N-dimethylacetamide (0.11 ml), cesium carbonate (880 mg) and molecular sieves 4A powder (350 mg) were added to the solution. After the mixture was stirred at room temperature for 2 hours, diethylamine (0.11 ml) was added to the reaction mixture. After reaction at room temperature for 20 minutes, water (3.5 ml) and methanol (3.5 ml) were added to the reaction mixture under ice-cooling and the mixture was stirred at room temperature for 1.5 hours. Brine was poured into the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: chloroform/methanol=50/1) gave 2-[(2S)-2-[[(2R)-2-(4-benzyloxyphenyl)-2-hydroxy-ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylacetamide (283 mg) as an amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([N+:23]([O-])=O)=[CH:18][C:17]=1[Cl:26])=[CH:8]2)=[O:4].[NH4+].[Cl-]>CCO.C1COCC1.O.[Fe]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:17]([Cl:26])=[CH:18][C:19]([NH2:23])=[CH:20][C:21]=1[Cl:22])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2ncc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(N)cc3Cl)cc2c1
Yield: 110.1 %

Procedure:
To a solution of 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-6-carboxylic acid methyl ester (311) (0.93 mmol) and NH4Cl (283 mg, 5.3 mmol) in EtOH/THF/water (8 ml/16 ml/1 ml)was added Iron powder (296 mg, 5.3 mmol). The reaction mixture was refluxed for 4 hr. Insoluble materials were removed by Celite pad, which was washed by THF, acetone and then EtOH. The filtrate was concentrated, and sat NaHCO3 was added and extracted twice with AcOEt. Organic layer was washed by brine, dried over anhydrous MgSO4, and concentrated to afford compound 312 (372 mg, over weight).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[F:11][C:12]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH3:23])[CH:17]=[CH:16][C:13]=1[CH:14]=O.[Si](C#N)(C)(C)C.[N:30]1([C:35](N2C=CN=C2)=[O:36])C=CN=[CH:31]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:14]([C:13]4[CH:16]=[CH:17][C:18]([O:20][CH2:21][CH2:22][CH3:23])=[CH:19][C:12]=4[F:11])[CH2:31][NH:30][C:35]3=[O:36])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCOc1ccc(C=O)c(F)c1
Agent: C[Si](C)(C)C#N
Product: CCCOc1ccc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)c(F)c1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.09 g, 0.67 mmol), 2-fluoro-4-propoxybenzaldehyde (0.11 g, 0.6 mmol), TMSCN (0.084 mL, 0.67 mmol), PdC (10%, 0.02 g), TEA 0.184 mL, 1.32 mmol), di-(imidazol-1-yl)methanone (0.117 g, 0.72 mmol) as described in method 2.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N+:4]([O-:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.O.[B:11]([F:14])([F:13])[F:12].[F:15]F>C(#N)C>[F:12][B-:11]([F:15])([F:14])[F:13].[F:12][B-:11]([F:15])([F:14])[F:13].[OH:9][N+:4]12[CH2:7][CH2:8][N+:1]([F:12])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: [O-][N+]12CCN(CC1)CC2
Reactant: FF
Reactant: FB(F)F
Solvent: O
Solvent: CC#N
Product: F[B-](F)(F)F
Product: O[N+]12CC[N+](F)(CC1)CC2
Yield: 68 %

Procedure:
A solution of 1,4-diazabicyclo[2.2.2]octane N-oxide (12.8 g, 0.1 mole), water (1.8 mL, 0.1 mole) and boron trifluoride (13.6 g, 0.2 mole) in acetonitrile (250 mL) was cooled to 8° C. and treated with a mixture of fluorine in nitrogen (10% V/V, 0.2 mole). The reaction was evaporated, the remaining solid washed with acetone and dried to afford 22 grams of 1-hydroxyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (68% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[O:13]C)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH2:32])([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH3:23])[CH2:18][CH2:17]1.C(#N)C.O>C(O)(C)C>[NH2:32][C:22]([CH:19]1[CH2:18][CH2:17][CH:16]([O:15][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][C:3]=2[Cl:2])[C:10](=[O:13])[NH:9][CH:8]=[CH:7]3)[CH2:21][CH2:20]1)([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH3:23]
Reactant: COc1ccc(C(C)(N)C2CCC(Oc3cc4ccnc(OC)c4cc3Cl)CC2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(C(C)(N)C2CCC(Oc3cc4cc[nH]c(=O)c4cc3Cl)CC2)cc1
Temperature: 100 °C
Yield: 97 %

Procedure:
Hydrochloric acid (0.4 mL of a 1M aqueous solution) was added to a solution of 1-[4-(7-chloro-1-methoxyisoquinolin-6-yloxy)-cyclohexyl]-1-(4-methoxyphenyl)-ethylamine (109, 30 mg, 0.07 mmol) in isopropanol (0.4 mL). The reaction mixture was heated in a microwave oven at 100° C. for 30 minutes. Isopropanol was removed under reduced pressure and the remaining aqueous solution freeze dried to give crude product as an amorphous powder. This was treated twice with acetonitrile/water and freeze dried to give 29 mg of the desired product Example 117 as a colourless hydrochloride salt. Rt=2.60 min (Method 2). Detected mass: 410.1 (M—NH3+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=O.Cl.[Cl:8][C:9]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][NH2:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[Cl:8][C:9]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][N:18]=[CH:3][C:2]([CH3:6])([CH3:5])[CH3:1]
Reactant: CC(C)(C)C=O
Reactant: NOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CC(C)(C)C=NOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a mixture of 0.07 g of trimethylacetaldehyde and 5 ml of pyridine was added 0.30 g of O-(5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyl)hydroxylamine hydrochloride. After stirring at room temperature for 1 hour, the reaction mixture was poured into 5% aqueous citric acid solution, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.31 g (yield, 96.8%) of trimethylacetaldehyde O-(5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyl)oxime, nD23.0 1.5178.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:10][CH2:11][Cl:12]>C1COCC1.O>[Cl:12][CH2:11][CH2:10][N:5]1[CH:6]=[C:2]([I:1])[N:3]=[CH:4]1
Reactant: ClCCBr
Reactant: Ic1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: ClCCn1cnc(I)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a stirred solution of 4-iodoimidazole (8.8 g, 45.4 mmol) in THF (200 mL) at 0° C. under nitrogen was added portion-wise NaH 60% (1.99 g, 49.9 mmol). After 15 min, 1-bromo-2-chloroethane (4.53 mL, 54.4 mmol) was added at 0° C. The reaction mixture was heated at 60° C. for 20 h. After cooling to RT, the reaction mixture was diluted with water and extracted with AcOEt. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 340 g cartridge; MeOH/AcOEt: 0/100 to 5/95 over 20 CV), to afford crude 1-(2-chloroethyl)-4-iodo-1H-imidazole not shown in the scheme 57 (7 g, 27.26 mmol, 60% yield) as colorless oil. MS (m/z): 256.83 (M+H).
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][C:13]1=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH2:5]([CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH:13]1[NH:28][CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[O:24][CH3:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1CCc2ccccc2C1Cc1ccccc1
Reactant: COc1ccccc1CN
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccccc1CNC1CCc2ccccc2C1Cc1ccccc1
Reaction time: 48 h
Yield: 76.8 %

Procedure:
Sodium cyanoborohydride (0.46 g, 7.28 mmol) was added to a solution of 1-benzyl-2-tetralone (0.86 g, 3.64 mmol), 2-methoxybenzylamine (0.50 g, 3.64 mmol), and acetic acid (0.22 g, 3.64 mmol) in methanol (10 mL) under nitrogen. After 48 h of stirring, the reaction mixture was concentrated in vacuo to provide a brown oil. Saturated aqueous sodium carbonate solution (25 mL) was added to this residue and the resulting mixture was extracted with chloroform. The chloroform extracts were combined, dried (Na2SO4), and concentrated to provide a brown oil which was purified on flash silica gel (1% methanol-chloroform to 5% methanol-chloroform) to provide 1.0 g of 1-benzyl-2-(2-methoxybenzylamino)tetralin as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:2].Cl.[F:27][C:28]1([F:32])[CH2:31][NH:30][CH2:29]1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:30]2[CH2:31][C:28]([F:32])([F:27])[CH2:29]2)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:2]
Reactant: FC1(F)CNC1
Reactant: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(Br)c(OCC2CC2)n1
Agent: Cl
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to the procedure described in Example 69 a, using ethyl 2-(5-bromo-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoate (Example 265) and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) as starting materials. MS (EI): m/e=426.0 [M+H]+.