Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:10]=1[Cl:11].ClC1C=C(Br)C=CC=1Cl.C(OCC)C.[CH3:27][N:28]1[CH2:33][CH:32]=[C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1>C(OCC)C.[Cu]I.O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:32]2[CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: CCOC(=O)C1=CCN(C)CC1
Reactant: Clc1ccc(Br)cc1Cl
Agent: [Cu]I
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1CCN(C)CC1c1ccc(Cl)c(Cl)c1
Temperature: 37.5 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a suspension of magnesium (10.76 g) in diethyl ether (110 mL) was added a trace amount of iodine. About one-tenth of a solution of 3,4-dichlorobromobenzene (100 g) in diethyl ether (110 mL) was added slowly at 35-40° C., and the mixture was vigorously stirred until the reaction started. When the reaction started, the rest of the 3,4-dichlorobromobenzene/diethyl ether solution was added slowly while cooling the reaction mixture to 35-40° C. When all was added, the mixture was stirred at 40° C. for 1 hr, and then cooled to 0° C. To the reaction mixture was added copper(I) iodide (12.6 g), and the compound (56.2 g) obtained in step 1 was slowly added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, and at room temperature for 1 hr. The reaction mixture was poured into water (40 mL), diethyl ether (500 mL) was added, and the precipitate was removed by decantation. The reaction mixture was washed with aqueous ammonium chloride solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20% ethyl acetate/hexane→2.5% aqueous ammonia/17.5% methanol/ethyl acetate) to give crude ethyl 3-(3,4-dichlorophenyl)-1-methylpiperidine-4-carboxylate (cis/trans mixture) (75.5 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[F:11].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[F:11]
Reactant: CC(O)c1ccc(Cl)c(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of the above alcohol (1 eq) in CH2Cl2 (0.3M) at rt was added Dess-Martin periodinane (1.5 eq). The reaction mixture was stirred for 45 minutes at rt and H2O (10 eq) was added. The mixture was stirred for 30 minutes and filtered through silica gel pad eluted with 30% EtOAc/hexane and concentrated. The residue was purified by flash chromatography on silica gel eluted with 20% EtOAc/hexane to give the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)[CH3:18]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCNCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCN(CCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)C(=O)C(c1ccccc1)c1ccccc1

Procedure:
Example 126 was prepared from diphenylacetyl chloride and N-(3-{1-[3-(ethylamino)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.33–7.21 (m, 13H), 6.94 (m, 2H), 4.88 (s, 1 H), 3.39 (m, 4H), 2.93 (d, 2H, J=10.9 Hz), 2.52–2.36 (m, 7H), 1.97 (t, 2H, J=10.9 Hz), 1.83–1.58 (m, 6H), 1.24 (d, 6H, J=7.6 Hz); ESMS m/e: 526.4 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C:15]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:16]([O:18]CC)=[O:17])=[O:13])[CH:9]=[CH:8][C:7]=2[C:25]([F:28])([F:27])[F:26])[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C:15]([CH2:21][CH3:22])([CH2:23][CH3:24])[C:16]([OH:18])=[O:17])=[O:13])[CH:9]=[CH:8][C:7]=2[C:25]([F:28])([F:26])[F:27])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)C(=O)O
Temperature: 60 °C
Reaction time: 72 h
Yield: 100.6 %

Procedure:
Ethyl 2-(6-(cyclopropylmethoxy)-5-(trifluoromethyl)picolinamido)-2-ethylbutanoate (62 mg, 154 μmol) was dissolved in a mixture of 1 M aqueous sodium hydroxide solution (616 μL, 616 μmol), THF (600 μL) and MeOH (600 μL). The mixture was stirred at 60° C. for 3 d, poured onto ice water/brine/1N HCl (20 mL) and extracted with EtOAc (2×30 mL). The combined extracts were washed with ice water/brine (20 mL) and dried over Na2SO4. The solvent was removed in vacuo to give the title compound (58 mg, quant.) as a light yellow solid. MS: 373.1 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=[NH:5])[NH2:4].[CH:8]1(/[C:12](/O)=[CH:13]/[C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10][CH2:9]1.Cl>C(O)C>[CH:8]1([C:12]2[N:4]=[C:3]([C:2]([F:7])([F:6])[F:1])[N:5]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)C(=O)/C=C(\O)C1CCC1
Reactant: N=C(N)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(C2CCC2)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
To a solution of 2,2,2-trifluoroethanimidamide (1.80 g, 13.6 mmol, Matrix) in ethanol (22 mL, 370 mmol) was added a solution of ethyl (3Z)-4-cyclobutyl-4-hydroxy-2-oxobut-3-enoate (2.7 g, 14 mmol, from Step A) in a small volume of ethanol. The solution was cooled in an ice bath and a solution of hydrogen chloride in ethanol (21 mL, 360 mmol, prepared by bubbling HCl gas through the ethanol for 10 minutes) was added. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was added slowly to a saturated solution of sodium bicarbonate. Additional solid potassium carbonate was added. After neutralization was complete, ethanol was removed in vacuo. The product was extracted with three portions of DCM. The combined extracts were dried over sodium sulfate, filtered and evaporated. The product was purified by flash chromatography on silica gel, eluting with a gradient from 0-25% EtOAc/hexanes to afford a yellow oil (1.8 g, 48%). 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 4.51 (q, J=7.1 Hz, 2H), 3.81 (p, J=8.6 Hz, 1H), 2.48-2.33 (m, 4H), 2.21-2.08 (m, 1H), 2.03-1.93 (m, 1H), 1.45 (t, J=7.1 Hz, 3H); LCMS (M+H)+: 275.1
Reaction SMILES: [CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(NCc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc(C#Cc2ccc(C3(NCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-benzylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 111, 75.0 mg, 0.19 mmol) in ethanol (4 mL) and tetrahydrofuran (4 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 35.0 mg (50%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[NH:13][C:12]2=[O:21])[N:4]=1.CN1C=CN=C1.[F:28][CH:29]([F:34])[S:30](Cl)(=[O:32])=[O:31].O>ClCCl>[F:28][CH:29]([F:34])[S:30]([N:13]1[C:14]2[C:19](=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:11]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)[C:12]1=[O:21])(=[O:32])=[O:31]
Reactant: COc1nc(OC)nc(C2C(=O)Nc3ccc(F)cc32)n1
Reactant: O=S(=O)(Cl)C(F)F
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Product: COc1nc(OC)nc(C2C(=O)N(S(=O)(=O)C(F)F)c3ccc(F)cc32)n1
Temperature: -10 °C

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-5-fluoro-1,3-dihydro-2H-indol-2-one (50 g) and 1-methyl-1H-imidazole (30.5 g) are introduced as initial charge in 430 ml of dichloromethane and cooled to −10° C. under nitrogen. With stirring, a solution of difluoromethanesulfonyl chloride (41.8 g) in 70 ml of dichloromethane is added dropwise at −15° C. to −5° C. over the course of 30 minutes, and the mixture is after-stirred for 4 hours at −15° C. to 0° C. 1-Methyl-1H-imidazole (2.7 g) and difluoromethanesulfonyl chloride (4.9 g) are added to the reaction mixture and stirred for 2 hours at 0° C. With ice cooling, 300 ml of water are added to the reaction mixture, the mixture is after-stirred for 30 minutes and the organic solvent is largely distilled off in vacuo. The residue is filtered, the solid product is washed twice with 150 ml of water and twice with 40 ml of acetonitrile and dried. This gives the title compound as a solid in an HPLC purity of 96% (63.9 g, 95% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH:9](OCC)=[O:10]>>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][CH:9]=[O:10]
Reactant: CCOC=O
Reactant: NCCCCCCO
Product: O=CNCCCCCCO
Yield: 72 %

Procedure:
The reaction was carried out in similar procedure to Example 71a using 1.50 g (12.8 mmol) of 6-amino-1-hexanol and 3 mL of ethyl formate to obtain 1.34 g (yield: 72%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].O[CH2:11][CH:12]([CH2:14]O)O.[N+](C1C=CC=CC=1)([O-])=O.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[CH3:9])[N:6]=[CH:14][CH:12]=[CH:11]2
Reactant: Cc1cc(N)ccc1Br
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cc2ncccc2cc1Br
Reaction time: 3 h
Yield: 31.4 %

Procedure:
A mixture of 4-bromo-3-methylaniline (20 g, 107.5 mmol), ferric sulfate (6.6 g, 43.4 mmol), glycerol (40.8 g, 440 mmol), nitrobenzene (8.12 g, 66 mmol), and concentrated sulfuric acid (23 ml) was heated gently. After the first vigorous reaction, the mixture was boiled for 3 h and then evaporated to remove the excess nitrobenzene. The solution was added a saturated aqueous solution of sodium bicarbonate until pH=7-8, then the solution was filtered and extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The solid was purified by flash column chromatography to give a yellow solid, which was further washed with petroleum ether to give 7.5 g of 6-bromo-7-methyl-quinoline (31% yield): 1H NMR (CDCl3): 2.60 (s, 3H), 7.36 (m, 1H), 7.96 (s, 1H), 8.04 (m, 2H), 8.89 (m, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].[CH2:8](O)[CH2:9][CH2:10][OH:11]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:7]1[CH2:8][CH2:9][CH2:10][O:11][CH:6]1[C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1nccs1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1csc(C2OCCCO2)n1
Yield: 73 %

Procedure:
2-Thiazolecarboxaldehyde (1 g) was dissolved in toluene (50 ml), followed by the addition of trimethylene glycol (3.36 g) and p-toluenesulfonic acid (17 mg). The resulting mixture was heated under reflux with a Dean-Stark apparatus for 4 hr. After cooling as it was, the reaction mixture was washed sequentially with an aqueous solution of saturated sodium bicarbonate and brine, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a brown solid (1.104 g, yield; 73%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:20][CH:19]=[CH:18][CH2:17][O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[C:21]1([C:15]2([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C1=CCC(c2ccccc2)(c2ccc(OCc3ccccc3)cc2)OC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc(C2(c3ccccc3)CCCCO2)cc1
Reaction time: 6 h
Yield: 101.9 %

Procedure:
2-(4-Benzyloxy-phenyl)-2-phenyl-3,6-dihydro-2H-pyran (4.1 g) was dissolved in methanol (25 mL) and ethyl acetate (5 mL). 5% Palladium on carbon (10 mg) was added. Nitrogen was bubbled through the solution. Ammonium acetate (4 g) was added. The mixture was stirred for 6 h, filtered through a block of celite and concentrated to a solid. NMR indicated full conversion to the title product (3.1 g, 12.2 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH2:10][C@@H:11]([NH:22][C:23](OC(C)(C)C)=O)[C:12]([NH:14][C@@H:15]([CH2:20][OH:21])[C:16]([OH:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[C:38]1([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:43]=[CH:42][C:41]([CH:44]2[CH2:48]C(OC)O[CH:45]2OC)=[CH:40][CH:39]=1>ClCCCl>[CH2:1]([O:8][C:9](=[O:30])[CH2:10][C@@H:11]([N:22]1[CH:23]=[CH:45][C:44]([C:41]2[CH:42]=[CH:43][C:38]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:39][CH:40]=2)=[CH:48]1)[C:12]([NH:14][C@@H:15]([CH2:20][OH:21])[C:16]([OH:19])([CH3:17])[CH3:18])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)C(C)(C)O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)[C@H](CO)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Yield: 11 %

Procedure:
According to the procedure described in Example 1(c) for N-(8-oxo-4-oxa-1,7-diazatricyclo-[9.6.1.012,17 ]-octa-deca-11(18),12,14,16-tetraen-9S-yl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-t-butoxycarbonylamino-N-(2-hydroxy-1(S)-hydroxymethyl-2-methyl-propyl)succinamic acid benzyl ester was deprotected with trifluoroacetic acid. The crude amine salt and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) were condensed in anhydrous 1,2-dichloroethane with trifluoroacetic acid to give in 11% yield 3(R)-[3-(biphenyl4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-(hydroxymethyl)-2-methylpropyl]succinamic acid benzyl ester as an amorphous solid. 1H NMR (acetone-d6): δ 7.67-7.61 (m, 6H), 7.48 (t, 2H, J=7.7 Hz), 7.39 (t, 1H, J=1.8 Hz), 7.37-7.27 (m, 6H), 7.09 (bd, 1H, J=9.2 Hz), 6.96 (t, 1H, J=2.6 Hz), 6.53 (dd, 1H, J=1.7, 2.8 Hz), 5.35 (t, 1H, J=7.4 Hz), 5.11 (s, 2H), 3.81-3.62 (m, 3H), 3.39 (dd, 1H, J=6.8, 16.4 Hz), 3.12 (dd, 1H, J=7.7, 16.6 Hz), 1.24 (s, 3H), 1.21 (s, 3H). Anal. Calculated for C32H34N2O5 : C, 72.98; H, 6.51; N, 5.32. Found: C, 72.83; H, 6.60; N, 5.24.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:10]F>C(#N)C>[NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][C:5]([F:10])=[CH:6][N:7]=1
Reactant: FF
Reactant: N#Cc1nccnc1N
Solvent: CC#N
Product: N#Cc1nc(F)cnc1N
Temperature: 25 °C

Procedure:
In 15 mL of acetonitrile was dissolved 0.3 g of 3-amino-2-pyrazinecarbonitrile. While cooling the solution with ice, 10% fluorine gas (a fluorine gas diluted with nitrogen gas) was introduced into the solution at a rate of 45 mL per minute for a period of 20 minutes. Then, while elevating the temperature from the ice-cooled temperature to room temperature, nitrogen gas was introduced for one hour. The reaction mixture was concentrated under reduced pressure, and the oily product thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=3:1] to obtain 0.01 g of 3-amino-6-fluoro-2-pyrazinecarbonitrile as a yellow-colored solid product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([O:15][CH3:16])[CH:10]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:24]=[O:25]>[OH-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: COc1cc(-c2c(F)cccc2F)n(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1nn(C)c(-c2c(F)cccc2F)c1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-(2,6-difluorophenyl)-3-methoxy-1-methyl-1H-pyrazole (0.5 g, 2.2 mmol) (i.e. the product of Step C) in dimethylformamide (5 mL) at 80° C. was added phosphorus oxychloride (0.31 ml, 3.3 mmol). After 2 h the reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with sodium hydroxide (1 N, about 5 mL) and water. The resulting mixture was extracted with diethyl ether (2×) and the combined organic layers were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (0 to 100% gradient of ethyl acetate in dichloromethane as eluant) to provide the title compound (0.5 g).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1.C(=O)(O)[O-].[Na+]>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1 mL, 13.5 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (110 mg, 0.57 mmol) in dichloromethane (2 mL). After 2 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 346.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.[CH3:17][O:18][CH2:19][CH2:20][CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:21][CH2:20][CH2:19][O:18][CH3:17])[CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: COCCC=O
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COCCCN1CCC(C(=O)OC)=Cc2cc(Br)ccc21
Reaction time: 24 h
Yield: 93.1 %

Procedure:
To a solution of methyl 7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.80 g) and 3-methoxypropionaldehyde (1.25 g) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (1.81 g) at room temperature, and the mixture was stirred for 24 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the resulting residue was separated and purified with column chromatography (ethyl acetate hexane=1:3→1:2) to give methyl 7-bromo-1-(3-methoxypropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (935 mg) as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][CH2:12][CH2:13]Cl)[CH:7]=[C:6]([CH3:15])[N:5]=2.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN1C(=O)CCC1>[CH3:1][C:2]1[N:3]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][CH2:12][CH2:13][NH:31][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH:7]=[C:6]([CH3:15])[N:5]=2
Reactant: NC1CCCCC1
Reactant: Cc1cc(C)c(-n2c(C)nc3c(NCCCl)cc(C)nc32)c(C)c1
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-n2c(C)nc3c(NCCNC4CCCCC4)cc(C)nc32)c(C)c1

Procedure:
Heat a solution of [2,5-dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl](2-chloroethyl)amine (0.04 g, 0.12 mmol), and cyclohexyl amine (0.13 mL g, 1.16 mmol) in dry NMP (2 mL) at 80° C. for 20 h. Pour the cooled mixture onto water (20 mL) and extract twice with ethyl acetate (20 mL). Wash the combined extracts with brine (20 mL), dry, and evaporate in vacuo. Purify by flash column chromatography (10% methanol in CH2Cl2 with 0.1% ammonium hydroxide) to obtain the title compound as a white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C@H:7]([CH:12]=[CH2:13])[CH2:8][CH2:9][C:10]#[CH:11])([CH3:4])([CH3:3])[CH3:2].[Li][CH2:17]CCC.CI>C1COCC1>[C:1]([Si:5]([CH3:14])([CH3:15])[O:6][C@H:7]([CH:12]=[CH2:13])[CH2:8][CH2:9][C:10]#[C:11][CH3:17])([CH3:3])([CH3:4])[CH3:2]
Reactant: [Li]CCCC
Reactant: C#CCC[C@@H](C=C)O[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Solvent: CI
Product: C=C[C@H](CCC#CC)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
Compound (4a) (481.6 mg, 2.146 mmol) was dissolved in THF (21.5 mL) and cooled to −78° C. before treated with 1.6 M n-BuLi (2.7 mL, 4.32 mmol) dropwise. The resulting solution was stirred 15 minutes at the same temperature and then methyl iodide (0.67 mL, 1.528 g, 10.765 mmol) was added. During the night the mixture was slowly warmed to room temperature. After 13 hours the reaction was quenched with water. The solution was extracted with ether (3×), the combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by chromatography (pentane/ether 200/1) provided 395.5 mg of compound (5a) as clear colourless oil with 77% yield.
Reaction SMILES: [F:1][C:2](=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3](OCC)=[O:4].CC(C[AlH]CC(C)C)C.O.Cl>C1COCC1>[F:1][C:2](=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][OH:4]
Reactant: CCCCCCCCCCCCCC=C(F)C(=O)OCC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCC=C(F)CO
Temperature: 25 °C

Procedure:
Ethyl 2-fluorohexadec-2-enoate mixture 50 (6.83 g, 16.6 mmol, purity: 73% (GC)) was dissolved in dry THF (23 mL). At 0° C. DIBAL-H (1 M solution in heptane, 56.8 mL, 56.8 mmol, 3.4 eq.) was added dropwise. The reaction mixture was allowed to warm up to r.t. overnight and was poured into water (50 mL). 2 M hydrochloric acid (50 mL) was added and the phases were separated. The aqueous layer was extracted with diethyl ether (3×50 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 27×4 cm, cyclohexane/ethyl acetate, 10:1→5.1). The diastereomeric mixture was isolated as a waxy, white solid. Yield: 2.67 g (61%), purity: 98% (GC).