Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:40]([N:43]=[C:44]=[O:45])([CH3:42])[CH3:41].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH3:39])[CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:44]([NH:43][CH:40]([CH3:42])[CH3:41])=[O:45])[CH:3]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:38])[C:30]=2[CH:31]=1
Reactant: CC(C)N=C=O
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2cccc(N)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NC(=O)Nc1cccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)c1
Reaction time: 0.2 h
Yield: 12.2 %

Procedure:
To a solution of N-[1-(3′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (52 mg, 0.6 mmol) in dichloromethane (1 mL) was added isopropylisocyanate (36.5 mg, 0.51 mmol). Triethylamine (60 mg, 0.60 mmol) was added and the resultant mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure and the residue was purified by Gilson preparative HPLC (Sunfire Prep C18, 30×150 mm, 50 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 30 to 60% over 12 min, UV detection at 214 nm) to give 40.8 mg (52%) of the title compound as off white solid. MS (ES) m/e 654.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([F:23])([CH:16](OS(C)(=O)=O)[CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([CH:16]([N:24]=[N+:25]=[N-:26])[CH3:17])([F:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OS(C)(=O)=O)C1(F)CCN(C(=O)OCc2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])C1(F)CCN(C(=O)OCc2ccccc2)C1
Temperature: 120 °C
Yield: 76 %

Procedure:
To a solution of 3-fluoro-3-(1-methanesulfonyloxyethyl)pyrrolidine-1-carboxylic acid benzyl ester (Example A15, 0.25 g, 0.72 mmol) in N,N-dimethylformamide (5 mL) is added sodium azide (0.13 g, 2 mmol). The reaction mixture is heated at 120° C. overnight. The mixture is diluted with water and extracted with ethyl acetate. The extracts are washed with brine, dried over Na2SO4 and concentrated to afford the title compound (0.160 g). 1H NMR (200 MHz, CDCl3): δ 7.28 (s, 5H), 5.08 (s, 2H), 3.80-3.25 (m, 5H), 2.13-1.75 (m, 2H), 1.40 (d, 3H).
Reaction SMILES: [CH2:1]([N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[P:24]([OH:27])([OH:26])[OH:25].P(Cl)(Cl)Cl>O>[CH2:1]([N:11]([CH:12]([P:24]([OH:27])(=[O:25])[OH:26])[P:24]([OH:27])(=[O:26])[OH:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: OP(O)O
Reactant: CCCCCCCCCCN(C=O)CCCCCCCCCC
Solvent: O
Solvent: ClP(Cl)Cl
Product: CCCCCCCCCCN(CCCCCCCCCC)C(P(=O)(O)O)P(=O)(O)O
Temperature: 70 °C
Yield: 130 %

Procedure:
81.4 parts of didecylformamide and 20.5 parts of phosphorous acid were slowly reacted with 34.3 parts of phosphorus trichloride at 70°C, and the mixture was maintained at 70°C for a further 3 hours. The product was hydrolyzed by the addition of 500 parts of water, the diphosphonic acid thereby being precipitated. This was dissolved in ethanol, precipitated with acetone and dried in vacuo at 50°C. N,N-didecylaminomethane-diphosphonic acid was obtained in a yield of 130% based on PCl3 or 65% based on total phosphorus.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:42])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:32]=1)[C:20](=[O:29])[CH2:21][C:22]([O:24][C:25](C)(C)C)=[O:23].Cl>CO.O1CCOCC1>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:42])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:32]=1)[C:20](=[O:29])[CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)CC(=O)OC(C)(C)C)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)CC(=O)OC)c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product from step (i) (100 mg) was dissolved in methanol (3 ml) and 4N—HCl in dioxane added. The mixture was stirred at rt for 5 h and purified by RPHPLC, which afforded the title compound. Yield 80 mg
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:16][CH:17]([O:19][CH2:20][CH3:21])[CH3:18])[C:9]1[S:10][CH:11]=[CH:12][C:13]=1[CH:14]=[O:15].[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([Mg]Cl)[CH2:25][CH2:24]1.CN1CCC(Cl)CC1.[Cl-].[NH4+]>CCOCC.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:16][CH:17]([O:19][CH2:20][CH3:21])[CH3:18])[C:9]1[S:10][CH:11]=[CH:12][C:13]=1[CH:14]([CH:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)[OH:15]
Reactant: CN1CCC([Mg]Cl)CC1
Reactant: CCOC(C)OC(c1ccccc1F)c1sccc1C=O
Agent: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(C)OC(c1ccccc1F)c1sccc1C(O)C1CCN(C)CC1
Temperature: -20 °C
Yield: 20 %

Procedure:
To a stirred solution of the 2-[(2-fluorophenyl)(1-(ethoxy)ethoxy)methyl]-3-thiophenecarboxaldehyde and tetrahydrofuran (400 ml), cooled to -78° C. under nitrogen, was added, via syringe, N-methyl-4-piperidinylmagnesium chloride over 1.5 hrs. (the Grignard reagent was prepared from N-methyl-4-chloropiperidine (29.4 g) according to the procedure of J. T. Strupczewski, et al., et al., J. Med. Chem., 28, 761 (1985), followed by dilution with tetrahydrofuran (45 ml)). The solution was allowed to warm slowly to -20° C. over 2.5 hrs, and dilute aqueous ammonium chloride solution and ether were added. The layers were separated and the organic layer washed with water. The combined aqueous layers were back-extracted with ether, and the combined organic layers washed with brine, dried over anhydrous potassium carbonate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-45% methanol/dichloromethane) to afford 6.4 g (20% overall) of α-[2-[2-fluorophenyl(1-(ethoxy)ethoxy)methyl]-3-thienyl]-1-methyl-4-piperidinemethanol.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]([OH:12])=O)[N:5]=[CH:4][C:3]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[C:10]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:12])[N:5]=[CH:4][C:3]=1[O:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)C(CC1CCCCC1)n1ncc(Oc2ccccc2)c(Cl)c1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCCC2)n2ncc(Oc3ccccc3)c(Cl)c2=O)n1

Procedure:
Using the method described in Example 49, 2-(5-chloro-6-oxo-4-phenoxy-6H-pyridazin-1-yl)-3-cyclohexyl-propionic acid (Intermediate 102) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-(5-chloro-6-oxo-4-phenoxy-6H-pyridazin-1-yl)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (136 mg); ES+-HRMS m/e calcd for C26H32N5O5Cl [M+H+] 514.2216 found 514.2214. 1H NMR (300 MHz, CDCl3) δ ppm 0.72-0.98 (m, 2H), 1.09 (br. s., 10H), 1.47-1.80 (m, 5H), 1.88-2.16 (m, 2H), 3.87 (s, 2H), 5.68 (dd, J=8.6, 6.2 Hz, 1H), 6.62 (s, 1H), 7.08 (d, J=7.8 Hz, 2H), 7.20-7.29 (m, 2H), 7.30-7.47 (m, 2H), 7.52 (s, 1H), 8.51 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH2:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:8]=1.Cl.[N:29]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:13][N:29]=[C:14]2[S:15]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16]
Reactant: O=N[O-]
Reactant: Nc1ccc(OCCCCCl)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OCCCCCl)cc12
Temperature: 3 °C

Procedure:
A mixture of 4-(4-chloro-butoxy)-2-(naphthalene-1-sulfonylmethyl)-phenyl amine (1.54 g, 3.8 mmoles) in THF (7 mL), and 4M HCl (15 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.34 g, 4.0 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.55 g, 3.75 mmoles).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH:49]([CH:54]([CH3:56])[CH3:55])[C:50]([O:52][CH3:53])=[O:51]>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH:49]([C:50]([O:52][CH3:53])=[O:51])[CH:54]([CH3:56])[CH3:55])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)C(Br)C(C)C
Product: CCCCc1nn(C(C(=O)OC)C(C)C)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 56 %

Procedure:
The alkylation of 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) with methyl 2-bromo-3-methylbutyrate was carried out as described in Example 3, Step A, except that only 5 equivalents of the alkylating agent was used. After work-up, the residue was flash chromatographed over silica gel (50 mL for 0.324 mmole, eluted using 0.5% MeOH/CH2Cl2) to give the desired material as a white foam in 56% yield, homogeneous by TLC in 5% MeOH/CH2Cl2.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19](=[O:35])/[CH:20]=C/C1C=CC(CC2C=CC=CC=2)=CC=1)[CH3:17]>>[C:1]1([S:7][C:8]2[CH:15]=[CH:14][C:11](/[CH:12]=[CH:20]/[C:19]([O:18][CH2:16][CH3:17])=[O:35])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(Sc2ccccc2)cc1
Reactant: CCOC(=O)/C=C/c1ccc(Cc2ccccc2)cc1
Product: CCOC(=O)/C=C/c1ccc(Sc2ccccc2)cc1

Procedure:
The title compound was prepared from 4-(phenylthio)benzaldehyde (S41) and triethylphosphonoacetate using the procedure described for ethyl-(E)-3-(4-benzylphenyl)acrylate (S38). Column chromatography (SiO2, 4×8 cm, 10% EtOAc-hexanes) afforded S42 (1.55 g, 5.5 mmol, 84%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) 9.91 (s, 1H), 7.62 (d, 1H, J=15.8 Hz), 7.46-7.21 (m, 9H), 6.38 (d, 1H, J=15.8 Hz); 13C NMR (CDCl3, 100 MHz) 166.8, 143.6, 140.0, 133.4, 132.7, 132.3, 129.4, 129.1, 128.5, 128.0, 117.8, 60.4, 14.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[CH:4][CH:3]=1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[CH:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:18]=2[N:19]=1.FC(F)(F)C(O)=O>C(O)C(F)(F)F>[Cl:13][C:14]1[N:15]=[C:16]([NH:1][C:2]2[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[CH:4][CH:3]=2)[C:17]2[CH:22]=[CH:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:24])=[O:25])[C:18]=2[N:19]=1
Reactant: NC(=O)c1c(N)ccc(F)c1F
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: OCC(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc(F)c(F)c4C(N)=O)nc(Cl)nc32)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
To a pressure flask is added 6-amino-2,3-difluorobenzamide (0.700 g, 4.07 mmol), 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (1.4 g, 4.07 mmol), trifluoroethanol (30 mL) and trifluoracetic acid (1.6 mL, 20.4 mmol). The resulting clear solution was stirred overnight. The next morning all precipitates were collected to afford analytically pure 6-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluorobenzamide as a white solid (1.07 g, 55% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 6.74 (s, 1 H), 7.41-7.48 (m, 3 H), 7.49-7.60 (m, 1 H), 7.64 (d, J=3.67 Hz, 1 H), 7.82 (s, 1 H), 7.96 (d, J=8.43 Hz, 3 H), 10.13 (s, 1 H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3(O)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:20][C:21]([C:23]2[NH:24][C:25]([C:28]#[N:29])=[CH:26][N:27]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:30][S:31]([O-:33])=[O:32].[Na+].C(O)(C(F)(F)F)=O>CO>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:20][C:21]([C:23]2[NH:24][C:25]([C:28]#[N:29])=[CH:26][N:27]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CS(=O)[O-]
Reactant: N#Cc1cnc(C(=O)Nc2ccc(C3(O)CCOCC3)cc2C2=CCCCC2)[nH]1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CS(=O)(=O)C1(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCCCC3)c2)CCOCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
To a mixture of 5-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide (as prepared in Example 27, 75 mg, 0.19 mmol) and sodium methylsulfinate (195 mg, 1.90 mmol) in 4 mL of methanol was added 0.28 mL (3.80 mmol) of TFA. The mixture was stirred overnight at 70° C. and then concentrated in vacuo. The crude residue was partitioned in EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was dried (Na2SO4) and then concentrated in vacuo. The residue was purified by preparative TLC on silica gel (20% ethyl acetate-hexane) to afford the title compound as a light brown oil (18 mg, 21%). 1H-NMR (CDCl3; 400 MHz): δ 9.64 (s, 1H), 8.32 (d, 1H, J=8.0), 7.71 (s, 1H), 7.33 (m, 1H), 7.23 (d, 1H, J=1.8 Hz), 5.87 (s, 1H), 3.90-3.81 (m, 4H), 3.01 (s, 3H), 2.30-2.25 (m, 4H), 2.07-1.79 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][OH:6].CO[C:18](OC)([CH3:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][O:6][C:18]([CH3:20])([CH3:19])[N:7]1[C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])=[O:15]
Reactant: COC(C)(C)OC
Reactant: COC(=O)C(CO)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (34) in CH2Cl2 stirring under nitrogen at 0° C., was added 2,2-dimethoxypropane (29,5 mL, 237.9 mmol) and p-toluene sulfonic acid monohydrate (9.050 g, 47.58 mmol). The mixture was removed from the ice bath after 15 minutes and stirred at room temperature for 1.5 hours. The reaction mixture was poured into 50 mL of saturated NaHCO3 (aq) and extracted with diethyl ether (3×50). The organic layer was extracted with NaHCO3 and brine, then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on SiO2 (1:1 EtOAc/Hexanes) to yield 7.659 g (62%, 3 steps) of a clear liquid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCCCCO
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: OCCCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 4-aminobutan-1-ol according to general procedure 1 providing the intermediate (150 mg, 82%) as a yellow solid: Rf=0.45 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.53 (d, J=9.7 Hz, 1H), 7.38 (s, 1H), 6.68 (d, J=9.7 Hz, 1H), 3.62 (t, J=6.6 Hz, 2H), 3.40 (t, J=6.9 Hz, 2H), 1.77-1.72 (m, 2H), 1.69-1.64 (m, 2H).
Reaction SMILES: [C:1](O)(=[O:4])[CH2:2][OH:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:37][CH2:38][CH:39]([OH:64])[CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][C:50]([C:52]2[S:53][C:54]([CH3:63])=[C:55]3[CH2:60][C:59]([CH3:62])([CH3:61])[CH2:58][CH2:57][C:56]=23)=[O:51])=[CH:44][CH:43]=1>C(Cl)Cl>[OH:4][CH2:1][C:2]([NH:37][CH2:38][CH:39]([OH:64])[CH2:40][O:41][C:42]1[CH:43]=[CH:44][C:45]([CH2:48][CH2:49][C:50](=[O:51])[C:52]2[S:53][C:54]([CH3:63])=[C:55]3[CH2:60][C:59]([CH3:61])([CH3:62])[CH2:58][CH2:57][C:56]=23)=[CH:46][CH:47]=1)=[O:3]
Reactant: O=C(O)CO
Reactant: Cc1sc(C(=O)CCc2ccc(OCC(O)CN)cc2)c2c1CC(C)(C)CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)CCc2ccc(OCC(O)CNC(=O)CO)cc2)c2c1CC(C)(C)CC2

Procedure:
To a solution of glycolic acid (1.5 eq.) in DCM (10 mL), TBTU (1.3 eq.) and DIPEA (4.0 eq.) is added. The mixture is stirred at rt for 10 min before the appropriate 3-[4-(3-amino-2-hydroxy-propoxy)-phenyl]-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (0.5-1.0 mmol, 1. eq.) is added. Stirring is continued at rt for 1 h before another portion of glycolic acid (0.7 eq.) and TBTU (0.6 eq.) is added. The mixture is stirred for another hour, is diluted with DCM and washed with sat. aq. NaHCO3 solution. The wash solutions are extracted back with DCM. The combined organic extracts are dried over MgSO4, filtered and the solvent is evaporated. The crude product is purified by chromatography on prep. TLC plates using DCM containing 5% of methanol to give the desired 2-hydroxy-N-(2-hydroxy-3-{4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propyl]-phenoxy}-propyl)-acetamide as an almost colourless foam.
Reaction SMILES: [CH3:1][O:2][O:3][P:4](OCCOC(N1C2C(=CC=CC=2)/C(=C/C2NC(C)=CC=2C)/C1=O)=O)([O:6][O:7][CH3:8])=[O:5].[OH:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)/[C:42](=[CH:49]/[C:50]2[NH:51][C:52]([CH3:56])=[CH:53][C:54]=2[CH3:55])/[C:41]1=[O:57])=[O:39]>>[CH3:1][O:2][O:3][P:4]([O:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)/[C:42](=[CH:49]/[C:50]2[NH:51][C:52]([CH3:56])=[CH:53][C:54]=2[CH3:55])/[C:41]1=[O:57])=[O:39])([O:6][O:7][CH3:8])=[O:5]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCCCO)c3ccccc32)[nH]1
Reactant: COOP(=O)(OCCOC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21)OOC
Product: COOP(=O)(OCCCOC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21)OOC

Procedure:
3-[1-(3,5-Dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-(dimethoxy-phosphonooxy)-propyl ester was prepared using the same protocol for synthesizing 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-(dimethoxy-phosphonooxy)-ethyl ester by replacing 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-ethyl ester with 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-hydroxy-propyl ester with a yield of (31%). 1H NMR (400 MHz, CDCl3) δ 12.63 (s, br, 1H, NH-1′), 7.82–7.84 (m, 1H, H-4), 7.48–7.52 (m, 1H, H-7), 7.41 (s, 1H, H-vinyl), 7.17–7.24 (m, 2H, H-5, 6), 6.04 (s, br, 1H, H-4′), 4.61 (t, J=6.25 Hz, 2H, NCOOCH2CH2CH2OPO(OCH3)2-1), 4.31 (q, J=6.38, 10.94 Hz, 2H, NCOOCH2CH2CH2OPO(OCH3)2-1), 3.80 (s, 3H, NCOOCH2CH2CH2OPO(OCH3)2-1), 3.77 (s, 3H, NCOOCH2CH2CH2OPO(OCH3)2-1), 2.40 (s, 3H, CH3), 2.35 (s, 3H, CH3), and 2.23–2.29 (m, 2H, NCOOCH2CH2CH2OPO(OCH3)2-1). 13P NMR (162 MHz, CDCl3) δ 2.40.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]O)=[CH:18][CH:17]=1)([O-:15])=[O:14].Cl.C(N=C=NCCCN(C)C)C.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:11][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of N-(t-butoxycarbonyl)glycine (1.51 g, 8.62 mmol) in anhydrous methylene chloride (75 ml) were added p-nitrobenzyl alcohol (2.63 ml, 17.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafter referred to as WSC) (3.3 g, 17.2 mmol) and 4-dimethylaminopyridine (106 mg, 0.87 mmol) in an ice bath. The mixture was stirred at room temperature under an atmosphere of nitrogen overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (2:1) as the eluant to afford N-(t-butoxycarbonyl)glycine p-nitrobenzyl ester (2.67 g, yield 100%) as white crystals.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8](=[O:17])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[C:18]1([Mg])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:18]1[CH:19]=[CH:20][C:21]([C:8]([OH:17])([CH:2]2[CH:1]3[CH:6]=[CH:5][CH:4]([CH2:7]3)[CH2:3]2)[CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: [Mg]c1ccccc1
Reactant: O=C(CCN1CCCCC1)C1CC2C=CC1C2
Product: OC(CCN1CCCCC1)(c1ccccc1)C1CC2C=CC1C2

Procedure:
It has been possible to achieve this object by a method for producing biperiden by reacting 1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) with an exo/endo ratio of at least 2.5:1 with a phenylmagnesium compound to give a biperiden (Ia)-containing mixture of isomers of 1-(bicyclo-[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol (I), characterized in that the isolation of biperiden (Ia) from the mixture of isomers comprises the following steps: