Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12]Br>CN(C)C=O>[Br-:8].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][N+:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCCC1
Reactant: BrCCCCBr
Solvent: CN(C)C=O
Product: C[N+]1(CCCCBr)CCCCC1
Product: [Br-]
Reaction time: 48 h

Procedure:
A solution of 1-methylpiperidine (˜24.80 g) in anhydrous dimethylformamide (˜500 mL) was added slowly to a solution of 1,4-dibromobutane (˜269.9 g) in anhydrous dimethylformamide (˜250 mL) over the course of about 24 hours under a nitrogen atmosphere with rapid stirring. Stirring of the solution was continued for a further ˜48 hours. The reaction mixture was then passed through a D-frit (˜10-20 microns) to separate any solid 1,1′-(butane-1,4-diyl)bis(1-methylpiperidin-1-ium) bromide impurity. Anhydrous diethyl ether (˜2000 mL) was then added to the filtrate to precipitate the product which was then filtered using a D-frit and rinsed with anhydrous diethyl ether (3×˜400 mL). After drying the product (˜63.7 g, ˜80%) was confirmed to be 1-(4-bromobutyl)-1-methylpiperidin-1-ium bromide by 1H NMR.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:6])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(Cl)(Cl)Cl>[CH3:3][C:2]([CH3:15])([O:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:12][CH:13]=1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 102.8 %

Procedure:
To a 500 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(1,1-dimethylethoxycarbonylamino)phenol (8.20 g, 39.19 mmol), Cs2CO3 (25.54 g, 78.38 mmol), DMF (75 mL), and ethyl bromoacetate (4.78 mL, 43.11 mmol). This heterogeneous mixture was stirred at ambient temperature for 3.5 h. The mixture was diluted with a little CHCl3 and filtered through a frit to remove the salts. The DMF was removed under high vacuum and the residue was suspended in 500 mL of EtOAc. This mixture was washed with H2O (3×), and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo, gave an oil. This material was chromatographed on 400 g of silica gel using 20% EtOAc-hexane as eluant. There was obtained 11.9 g (100%) of ethyl (4-(1,1-dimethylethoxycarbonylamino)phenoxy)acetate as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C@H:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[CH2:11]2)=[CH:2]1.[CH3:20][NH2:21].C(O[Si](OCC)(OCC)OCC)C.[H][H]>CO.O=[Pt]=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C@H:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@@H:12]([NH:21][CH3:20])[CH2:11]2)=[CH:2]1
Reactant: O=C1C[C@@H](c2c[nH]c3ccccc23)c2ccccc21
Reactant: [H][H]
Reactant: CN
Agent: O=[Pt]=O
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: CO
Product: CN[C@H]1C[C@@H](c2c[nH]c3ccccc23)c2ccccc21
Yield: 66 %

Procedure:
(R)-3-(1H-indol-3-yl)-indan-1-one, methyl amine (5 mL 2M in THF) and 1 mL tetraethoxy silane in 10 mL methanol were stirred 11 minutes at 150° C. under microwave irradiation using the Emry Optimizer™ instrument. PtO2 (10 mg) was added and the reaction mixture was stirred under 1 atm. hydrogen over night at room temperature, filtered and concentrated in vacuo. [(1S,3R)-3-(1H-Indol-3-yl)-indan-1-yl]-methyl-amine was isolated in 66% yield after flash chromatography (ethyl acetate, methanol, triethylamine, silica gel).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-])=O.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>C(OC)(C)(C)C.[Pd]>[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=[O:21])[NH:1][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1
Reactant: Cc1ccccc1N=C=O
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: [Pd]
Solvent: COC(C)(C)C
Product: Cc1ccccc1NC(=O)Nc1ccc(CO)cc1
Reaction time: 0.5 h

Procedure:
30.6 g (200 mmol) of 4-nitrobenzyl alcohol were hydrogenated with ice cooling over 1.0 g of palladium/carbon (10% strength; 50% water) in 500 ml of methyl tert-butyl ether. After the absorption of hydrogen was complete, the catalyst was filtered off and 24.8 ml (200 mmol) of 2-methylphenyl isocyanate were added to the filtrate at 15° C. with stirring in the course of 30 minutes. The precipitated solid was filtered off with suction and washed with methyl tert-butyl ether. Yield: 46.9 g (92%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.Br[C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1.C(N(CC)CC)C>CN(C)C=O>[N:1]1([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: C1CSCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(N2CCSCC2)n1

Procedure:
The reaction described in Preparation 26 was repeated, but using 1.53 g of thiomorpholine, 2.36 g of ethyl 2-bromothiazole-4-carboxylate, 2.02 g of triethylamine and 40 ml of dimethylformamide, giving the title compound as a pale yellow powder.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>>[CH3:15][O:16][C:17]1[CH:26]=[C:25]([NH:27][C:12]([C:6]2[O:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:14])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Reactant: COC(=O)c1ccc(N)cc1OC
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1OC
Yield: 44.3 %

Procedure:
In the same manner as that of Example 24, 4,5-diisopropylfuran-2-carboxylic acid (80 mg, 0.408 mmol) and methyl 2-methoxy-4-aminobenzoate (133 mg, 0.734 mmol) were condensed, the reaction mixture was treated in a conventional manner, and then the residue was purified by silica gel chromatography [hexane-ethyl acetate (5:1)] to obtain methyl 2-methoxy-4-[(4,5-diisopropylfuran-2-carbonyl)amino]benzoate (65 mg, 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[CH3:11][N:12]=[C:13]=[O:14].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:11][NH:12][C:13]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)=[O:14]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CNC(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 3-amino-5-t-butylisoxazole (16.82 g) in anhydrous benzene (140 ml), methyl isocyanate (8.90 g) and triethylamine (0.5 ml) are added. The resulting mixture is stirred at room temperature for about 8 hours, allowed to stand overnight and refluxed for 1 hour. After ice cooling, the reaction mixture is filtered to give a precipitate, which is recrystallized from ethyl acetate to give 1-methyl-3-(5-t-butyl-3-isoxazolyl)urea (21.61 g) as colorless needles melting at 187.0° to 187.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][N:3]=1.[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[K+].CI.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1ccnc(Cl)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccnc(Cl)c1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
To a stirred solution of ethyl 2-(2-chloropyridin-4-yl)acetate (44) (2.5 g, 12.52 mmol) in THF (25 mL), under nitrogen at −78° C. was added a solution of KHMDS (0.5M in toluene, 26.3 mL, 13.2 mmol). The mixture was warmed to RT for 10 min, then re-cooled to −78° C. and methyl iodide (0.820 mL, 13.15 mmol) added in a single portion and the mixture allowed to warm to RT. Saturated aqueous NH4Cl solution was added and the mixture was diluted with ether. The organic layer was washed with water and brine and then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 100 g, 5-10% EtOAc in isohexane, gradient elution) to afford the title compound (51) (1.57 g, 56%): m/z 214 (M+H)+ (ES+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]\[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:40][CH2:41][C:42]([NH:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:43]>C1COCC1.CCOCC>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]\[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:15])([F:17])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([NH:40][CH2:41][C:42](=[O:43])[NH:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:6]
Reactant: NCC(=O)NCC(F)(F)F
Reactant: O=C(O)c1ccc(/C=C\C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1ccc(/C=C\C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br)NCC(F)(F)F
Temperature: 50 °C

Procedure:
To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added carbonyldiimidazole (82 mg, 0.51 mmol). The mixture was heated in a 50° C. oil bath for 1.5 h, treated with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (109 mg, 0.057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et2O and washed twice with aq. 5% NaHSO4 (2×) and once with sat. NaCl (1×). After dying over MgSO4, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61° C.: 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=7.9 Hz, 1H), 7.44-7.29 (m, 3H), 7.14 (dd, J=7.9, 1.6 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 6.59 (br s, 1H), 6.21-6.04 (m, 1H), 4.23 (d, J=5.5 Hz, 1H), 3.98 (qd, J=9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −69.31, −72.3; EIMS m/z 626.9 ([M+1]+).
Reaction SMILES: Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.FC(F)(F)S([O-])(=O)=O.[N:25]1([S:30](N2C=C[N+](C)=C2)(=[O:32])=[O:31])[CH:29]=[CH:28][N:27]=[CH:26]1>CC#N>[F:2][C:3]1([F:7])[CH2:6][N:5]([S:30]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)(=[O:32])=[O:31])[CH2:4]1
Reactant: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Reactant: FC1(F)CNC1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=S(=O)(N1CC(F)(F)C1)n1ccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
A solution of 3,3-difluoroazetidine hydrochloride (1.00 g, 7.72 mmol) and DIEA (1.5 mL, 8.6 mmol) in MeCN (5 mL) was stirred for about 5 min and then was added to a solution of 1-(1H-imidazol-1-ylsulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (4.20 g, 11.6 mmol) in MeCN (10 mL) at about 0° C. The reaction mixture was stirred at about 0° C. for about 1 h, and then warmed to ambient temperature and stirred for about 16 h. The reaction mixture was then concd under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a gradient of 5-100% EtOAc in DCM to give 1-(3,3-difluoroazetidin-1-ylsulfonyl)-1H-imidazole (0.95 g, 55%) as a yellow solid: LC/MS (Table 1, Method c) Rt=1.16 min; MS m/z 224 (M+H)+.
Reaction SMILES: [Mg].Cl[CH:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:4].[CH3:11][CH:12]([Mg]Cl)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21]([Sn:25](Cl)(Cl)Cl)[CH2:22][CH2:23][CH3:24]>C1(C)C(C)=CC=CC=1.O1CCCC1>[CH2:21]([Sn:25]([CH:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:4])([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:11])[CH:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:4])[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(Cl)Cl
Reactant: CCCCCCC(C)[Mg]Cl
Reactant: CCCCCCC(C)Cl
Agent: [Mg]
Solvent: Cc1ccccc1C
Solvent: C1CCOC1
Product: CCCCCCC(C)[Sn](CCCC)(C(C)CCCCCC)C(C)CCCCCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1-liter four-necked flask equipped with a thermometer, a condenser, a stirrer and a dropping funnel was charged with 19.4 g (0.8 mole) of magnesium, 118.9 g (0.8 mole) of 2-chlorooctane and 200 g of tetrahydrofuran, and they were reacted in a stream of nitrogen. To the resulting 2-octyl magnesium chloride solution was added dropwise a solution of 67.7 g (0.24 mole) of mono-n-butyltin trichloride in 200 ml of xylene with stirring at room temperature over the course of 30 minutes. The reaction mixture was reacted for 3 hours at the refluxing temperature, and then subjected to hydrolysis to obtain 120 g of n-butyl tri-2-octyltin having a purity of 98.7%.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C(OCC)(=O)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:23][C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]3)=[CH:25][CH:24]=2)[N:10]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(Nc3nc(Cl)ccc3C(N)=O)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A solution of 2,6-dichloronicotinamide (100 mg, 0.524 mmol) and 4-(4-methylpiperazin-1-yl)aniline (300 mg, 1.571 mmol) in THF (5 mL) was cooled to −78° C. and treated with 1 M solution of lithium bis(trimethylsilyl)amide (3.14 mL, 3.14 mmol) in THF. The reaction mixture was stirred at −78° C. for 1 h and then at rt for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water, and concentrated. The residue was purified by MPLC chromatography (ISCO, 5% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to give 131 mg of 6-chloro-2-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide as a yellow solid. LCMS: (M+H)+=346.09, 348.05 (Cl pattern). 1H NMR (400 MHz, CDCl3-MIX) δ ppm 10.56 (1H, s), 7.59 (1H, d, J=7.91 Hz), 7.56 (2H, d, J=8.79 Hz), 6.93 (2H, d, J=9.23 Hz), 6.61 (1H, d, J=7.91 Hz), 5.76 (2H, br. s.), 3.16-3.21 (4H, m), 2.57-2.62 (4H, m), 2.36 (3 H, s).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:19]=[CH:18][C:7]2[C:8]([C:11]3[CH:12]=[C:13](O)[CH:14]=[CH:15][CH:16]=3)=[N:9][O:10][C:6]=2[CH:5]=1.CC1C=CC(S([O:30][CH2:31][C@@H:32]2[O:34][CH2:33]2)(=O)=O)=CC=1.O>CN(C)C=O>[F:3][C:4]1[CH:19]=[CH:18][C:7]2[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:30][CH2:31][C@H:32]4[CH2:33][O:34]4)=[CH:15][CH:16]=3)=[N:9][O:10][C:6]=2[CH:5]=1
Reactant: Oc1cccc(-c2noc3cc(F)ccc23)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a cold (0° C.) solution of sodium hydride (1.80 g, 45.0 mmol) in dimethylformamide (anhydrous,40 mL) and under a nitrogen atmosphere, add dropwise a solution of 3-(6-fluoro-benzo[d]isoxazol-3-yl)-phenol (10 g, 43.63 mmol) in dimethylformamide (anhydrous, 50 mL). Precipitate forms. Cool (0° C.) reaction mixture for 20 minutes and the material solidifies. Add dimethylformamide (anhydrous, 120 mL) and (2R)-(−)-glycidyl tosylate (10.47 g, 45.87 mmol) dissolved in dimethylformamide (40 mL), dropwise, over a period of time of 0.5 hours, while cooling with an ice bath. After this addition, the reaction mixture becomes homogeneous. Warm reaction mixture to room temperature and stir overnight. Pour reaction mixture into cold water (600 mL), stir for 1 hour under an ice bath, filter and wash the filter cake with water to obtain an off-white solid. Add dichloromethane (200 mL) to the off-white solid, wash with saturated sodium chloride and dry (MgSO4). Directly purify by column (silica) chromatography (dichloromethane) and triturate with pentane to give the title compound as an off-white solid (9.70 g, 78% Yield). MS shows [M+H]+=286. NMR and microanalysis (C, H, N) are consistent with the final, desired compound. mp=132-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@H:6]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:7][C@H:8]2[N:11]2[CH2:20][C:15]3([CH2:19]C[CH2:17][CH2:16]3)[N:14]([CH3:21])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C([O-])(=O)/C=C/C([O-])=O>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@H:6]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:7][C@H:8]2[N:11]2[CH2:20][C:15]3([CH2:19][CH2:17][CH2:16]3)[N:14]([CH3:21])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CN1CCN([C@@H]2C[C@@H](c3ccc(F)cc3)c3ccc(Cl)cc32)CC12CCCC2
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: CN1CCN([C@@H]2C[C@@H](c3ccc(F)cc3)c3ccc(Cl)cc32)CC12CCC2
Product: Cl

Procedure:
(±)-Trans-9-[6-chloro-3-(4-fluorophenyl)-2,3-dihydro- 1H-inden- 1-yl]-6-methyl-6,9-diazaspiro[4.5]decane, fumarate; mp 144°-147° C. Compd. 29.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:49][C@@H:50]([CH2:64][C:65]1[CH:70]=[C:69]([F:71])[CH:68]=[C:67]([F:72])[CH:66]=1)[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1>CN(C=O)C.C(Cl)(Cl)Cl>[F:71][C:69]1[CH:70]=[C:65]([CH:66]=[C:67]([F:72])[CH:68]=1)[CH2:64][C@H:50]([NH:49][C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[C:1]([O:12][CH3:13])=[O:11])=[O:7])[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)OC)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To methyl hydrogen isophthalate (1.0 g, 5.6 mmol) in DMF/chloroform (1:2, 15 mL) is added diisopropylethylamine (3.9 mL, 22 mmol), HATU (2.5 g, 6.7 mmol), then (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method of EXAMPLE SP-272 (2.5 g, 6.1 mmol). The reaction is stirred 1 h at room temperature. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) gives the title compound. ESI MS m/z 497.3 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[C:11](OC(=O)C)(=[O:13])[CH3:12]>O>[C:11]([NH:1][CH:2]([CH:6]1[CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NC(C(=O)O)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NC(C(=O)O)C1CC1
Reaction time: 0.75 h
Yield: 8.9 %

Procedure:
DL-α-aminocyclopropyl acetic acid (29.4 g.) was added with stirring to a solution of sodium hydroxide (20.9 g.) in distilled water (140 ml.). The solution became homogeneous, was cooled to ca. 5° and acetic anhydride (53 g.) was added dropwise over a period of 1.5. hr. whilst maintaining the temperature below 20°. The pH of the solution was adjusted to 3.0 after stirring for a further 0.75 hr., and was then extracted with chloroform: n-propanol, 3:1 (7×100 ml.) and the combined extracts evaporated down to give a white solid which was dried in vacuo over fresh phosphorus pentoxide. Freeze-drying of the aqueous layer and similar work-up to the above gave further product (total yield 26.0 g., 65%). A sample of the solid was recrystallised from chloroform:n-propanol:ether to give crystals of DL-α-acetamidocyclopropyl acetic acid [m.p 150°-154°, found C, 53.2; H. 7.0; N,8.7; C7H11NO3 requires C, 53.5; H, 7.0; N, 8.9 %. νmax (KBr) 3340 (NH), 1720 (CO2H) 1600 and 1550 (amide I and II) cm-1, τ](CD3)2SO]-0.46 (H, broad, CO2H), 1.87 (H,d, 6.9 Hz., NH), 6.32 (H,t, 8.0 Hz., side-chain CH), 8.18 (3H,s,methyl), 8.95 (H, broad, ring methine), 9.65 (4H, broad, complex, ring methylenes)].
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[C:6]([C:17]#[C:18][CH2:19][N:20]3C(=O)C4=CC=CC=C4C3=O)=[CH:7][CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CN>C(O)C>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[C:6]([C:17]#[C:18][CH2:19][NH2:20])=[CH:7][CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CC#CC1=CCN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: CN
Solvent: CCO
Product: Cl
Product: NCC#CC1=CCN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5 g (11.4 mmole) of 8-chloro-5-(1-phthalimido-2-propyn-3-yl)-1-phenyl-3H-2-benzazepine, 100 ml of ethanol and 20 ml of 40% aqueous methylamine was stirred at room temperature for 1 hr, poured into ice water and extracted with ether. The ether solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was dissolved in an excess of methanolic hydrogen chloride and concentrated at reduced pressure to dryness. The residue crystallized from a mixture of ethanol and isopropanol to give a tan solid, mp 247°-248° C. Recrystallization from a mixture of ethanol and ether gave tan prisms, mp 247°-248° C.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][N:17]2[C:19]([CH:22]=[O:23])=[CH:20][N:21]=[C:16]2[C@H:15]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:14][CH2:13]1>O1CCCC1>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][N:17]2[C:19]([CH:22]([OH:23])[CH3:1])=[CH:20][N:21]=[C:16]2[C@H:15]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C=O)cnc21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
Methylmagnesium bromide (3.0 M in ether; 0.33 mL, 1.0 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-formyl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (130 mg, 0.33 mmol) in tetrahydrofuran (3 mL) at 0° C. After 10 min, the reaction was quenched with water and the mixture was extracted with dichloromethane (3×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 408.1 (M+1).