Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]1[CH:33]=[CH:32][C:14]2[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:43])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccn1
Reactant: CCCCCCCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)c(OC)c1
Yield: 55 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxyphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-heptyl chloroformate. Yield: 55% of theory, C36H45N7O6 (671.8); Rf value: 0.54 (silica gel; dichloromethane/ethanol=9:1); EKA mass spectrum: (M+H)+=672; (M+H+Na)++=347.9.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][S:13]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([NH:22][CH2:23][C:24](O)=[O:25])=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:5].C(OC([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=O)(C)(C)C>>[ClH:1].[Cl:1][C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][S:13]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([NH:22][CH2:23][C:24](=[O:25])[N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:5]
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccc(Cl)cc2Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cl
Product: O=C(NCC(=O)N1CCNCC1)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccc(Cl)cc2Cl)cc1

Procedure:
The title compound was prepared from {4-[2-(2,4-dichloro-benzoyl)-phenylsulfamoyl]-benzoylamino}-acetic acid (Example 6.1/c)) and piperazine-1-carboxylic acid tert-butyl ester (Aldrich) according to the method described in Example 11.1. MS (EI) 575.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH3:24])(=[O:14])=[O:13])[C:3]1=[O:25].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13])[C:3](=[O:25])[C:2]2([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[NH:1][S:34]([CH3:33])(=[O:36])=[O:35]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(NS(C)(=O)=O)(c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Reaction time: 18 h

Procedure:
A solution of 0.4 g of the compound obtained in EXAMPLE 3 in 5 ml of pyridine is cooled to 0° C. and 0.1 g of methanesulfonyl chloride is added. The mixture is stirred for 18 hours, the temperature being allowed to rise to RT, and evaporated under vacuum. The residue is extracted with AcOEt, washed with a 5% solution of potassium hydrogensulfate, dried over sodium sulfate and evaporated under vacuum. The residue due is chromatographed on silica using a DCM/AcOEt mixture (98/2; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether mixture. m=0.22 g. M.p.=252° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH2:10][CH:9]1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[F:54][C:55]([F:69])([F:68])[C:56]1[CH:57]=[C:58]([N:62]2[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]2)[CH:59]=[CH:60][CH:61]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]([C:25]([F:28])([F:26])[F:27])[CH:18]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:20]=2)[CH2:10][C@H:9]1[C:29]([N:65]1[CH2:64][CH2:63][N:62]([C:58]2[CH:59]=[CH:60][CH:61]=[C:56]([C:55]([F:68])([F:69])[F:54])[CH:57]=2)[CH2:67][CH2:66]1)=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C([C@@H]1C[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 8 h
Yield: 10.6 %

Procedure:
The mixture of 1-benzyl-4-(3,5-bis-trifluoromethyl-benzylamino)-pyrrolidine-2-carboxylic acid (65 mg, 0.146 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (54.5.0 mg, 0.292 mmol), N-hydroxybenzotriazole (20.7 mg, 0.146 mmol), and 1-(3-trifluoromethyl-phenyl)-piperazine (29.67 mg, 0.219 mmol), triethylamine (0.08 ml) in dry dichloromethane (2 mL) was stirred overnight, and then concentrated. The residue was purified by preparative HPLC on reversed phase eluting with an acetonitrile/water [0.1% aq NH3 (25%)] gradient to afford the title compound (10.2 mg, 10.6%) as a light yellow oil. MS m/e=659.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.ClC1C=CC(O)=CC=1.C1(O)C=CC=CC=1.O(CCC(O)=O)C1C=CC=CC=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:53][CH2:54][CH2:55][CH2:56][N:57]1[CH:61]=[CH:60][N:59]=[CH:58]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][C:9]([NH:53][CH2:54][CH2:55][CH2:56][N:57]2[CH:61]=[CH:60][N:59]=[CH:58]2)=[O:11])=[CH:12][CH:13]=1
Reactant: O=C(O)CCOc1ccc(Cl)cc1
Reactant: NCCCn1ccnc1
Agent: O=C(O)CCOc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: Oc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: O=C(CCOc1ccc(Cl)cc1)NCCCn1ccnc1

Procedure:
A solution of 3-(4-chlorophenoxy)propionic acid (5.0 g, prepared from 4-chlorophenol by the process described in J.A.C.S. 1923, 2708 for the conversion of phenol into 3-phenoxypropionic acid) in THF (90 ml) was treated with 1,1'-carbonyldiimidazole (4.05 g) at room temperature with stirring. The mixture was stirred at ambient temperature for two hours. 1-(3-Aminopropyl)imidazole (3.12 g) was added and the mixture was stirred at ambient temperature for 18 hours. The solvent was distilled off and the residue was dissolved in dichloromethane, washed with water, dried and then evaporated to give a solid which was recrystallised from ethyl acetate to give 3-(4-chlorophenoxy)-N-[3-(imidazol-1-yl)propyl]propionamide, m.p. 114-115.5° C.
Reaction SMILES: [Cl:1][CH:2]([Cl:17])[S:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([F:15])=[CH:10][CH:11]=2)[N:6]([CH3:16])[CH:5]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl>[Cl:17][CH:2]([Cl:1])[S:3]([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([F:15])=[CH:10][CH:11]=2)[N:6]([CH3:16])[CH:5]=1)=[O:26]
Reactant: Cn1cc(SC(Cl)Cl)c(=O)c2ccc(F)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1cc(S(=O)C(Cl)Cl)c(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
665 mg (2.276 mmol) of the 3-dichloromethylthio-7-fluoro-1-methyl-4-quinolone (Compound 2, FIG. 21), as prepared in Step A, was dissolved in 20 ml of DCM at 0° C. to form a solution. To this solution was added 505.7 mg (2.345 mmol) of 80% MCPBA to form a mixture. This stirred mixture was then allowed to warm to room temperature and was stirred for 1 hour. An additional 25 mg of MCPBA was added and the mixture and stirred for 1 hour. The mixture was washed with 5% aqueous Na2CO3. The aqueous layer was extracted with DCM, and the combined DCM extracts were dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed on silica gel with hexane-ethyl acetate (gradient 4:1,2:1,1:1) to give 352 mg (50%) of the product (Compound 3, FIG. 21) as a white solid, that was approximately 98% pure according to 1H NMR, CDCl3; d=3.96 s, 3H, N—CH3; 7.09 s, 1H, CHCl2; 7.22 dd, 1H, J=10.2 & 2.4 Hz, H at C8, 7.27 ddd, 1H, J=9.0, 7.6 & 2.2 Hz, H at C6; 8.03 s, 1H, H at C2; 8.43 dd, 1H, J=8.8 & 6.1 Hz, H at C5. This white solid product was further purified by recrystallization from methanol to give 252 mg of white crystals.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:5](=[O:7])[CH3:6])=[CH:12][CH:11]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C)cc1
Temperature: 0 °C
Yield: 76.1 %

Procedure:
Anhydrous aluminum chloride (88 g, 0.66 mol) was suspended in methylene chloride (1500 mL), and then acetyl chloride (51.5 g, 0.66 mol) was added while stirring and cooling on ice. The mixture was stirred for 20 minutes while cooling on ice and 4-methylphenol (50 g, 0.46 mol) was added. The reaction mixture was stirred at room temperature for 1 h, and then poured into ice water slowly to quench the reaction. After extraction with ethyl acetate, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to yield acetic acid 4-methyl-phenyl ester (52.6 g, 76%). 1H-NMR (CDCl3): 2.25 (s, 3H), 2.36 (s, 3H), 6.96 (d, 2H), 7.18 (d, 2H).
Reaction SMILES: [H-].[Na+].[CH:3]([N:16]1[CH2:19][CH:18]([OH:20])[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H].[F:23][C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:4]1([CH:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:16]2[CH2:19][CH:18]([O:20][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH2:17]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Fc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.80 g, 20 mmol) in anhydrous DMF (10 ml) under nitrogen was added dropwise a solution of 1-benzhydryl-azetidin-3-ol (3.5 g, 15 mmol) in DMF (10 ml)—Care: hydrogen gas evolution! The mixture was stirred 30 min after gas evolution had ceased then 1,4-difluorobenzene (1.8 mL, 18 mmol) was added dropwise. The mixture was heated to 100 C and stirred for 12 h, then cooled to room temperature and poured into aq sodium hydrogencarbonate solution (50 ml) and extracted twice with EtOAc (2×50 ml). The combined organic layers were washed with water, concentrated under vacuum and purified by flash column chromatography (25 g silica gel; heptane-EtOAc: 1:0-9:1). The product-containing fractions were combined, concentrated under vacuum, washed with heptane and dried under vacuum to give the title compound (3.256 g, 67%). Method B HPLC-MS: MH+ requires m/z=334 Found: m/z=334, Rt=1.69 min (89%). 1H NMR (250 MHz, CDCl3) δ ppm 7.48-7.39 (4H, m), 7.39-7.12 (6H, m), 6.94 (2H, t), 6.71 (2H, dd), 4.75 (1H, m), 4.46 (1H, s), 3.78-3.65 (2H, m), and 3.20-3.07 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:3]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:21][CH2:20]1.C(N(CC)CC)C>CN(C)C=O>[ClH:1].[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([N:19]3[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:21][CH2:20]3)=[N:3][N:4]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cl
Product: O=C(NC1CCN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CC1)c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Combine 1-chloro-4-(4-fluorophenyl)phthalazine (150 mg, 0.58 mmol), N-(piperidin-4-yl)benzamide (178 mg, 0.87 mmol), triethylamine (0.404 mL, 2.9 mmol) and dimethylformamide (1 mL) at room temperature. Heat to 100° C. and stir overnight. Pour the crude reaction mixture onto a strong cation exchange Phenomenex Strata® SCX (55 μm, 70 Å) 10 g/60 mL column (with a benzene sulfonic acid functional group). Elute the desired product with 2 N methanolic ammonia (40 mL) and concentrate. Purify the residue by flash chromatography (20-30% [10% 2 N methanolic ammonia in ethyl acetate] in hexane). Add 1 N hydrochloric acid in diethyl ether to a solution of the isolated product in dichloromethane/methanol and remove the solvents under a stream of nitrogen gas to yield the title compound as a solid (137 mg, 51%). ES/MS m/z 427.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][OH:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([O:12][CH3:11])[CH:3]=1
Reactant: CO
Reactant: N#Cc1ccc(Cl)cc1F
Product: COc1cc(Cl)ccc1CN

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and methanol analogously to the preparation of Intermediate 98.1 as a colorless oil; HPLC: AtRet=2.24 min; 1HNMR (CDCl3) δ 7.20-7.10 (m, 1H), 7.00-6.80 (m 2H), 3.90-3.80 (m, 5H), 1.80 (bs, 2H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27](Cl)(=O)C.[C:31]1([CH2:41][NH2:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>>[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([NH:42][CH2:41][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)=[O:26])(=[O:7])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Reactant: NCc1cccc2ccccc12
Product: CC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)NCc1cccc2ccccc12

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, acetyl chloride, and 1-naphthylmethylamine the title compound was obtained in 60% purity by LC/MS. MS(ESI+): m/z=484.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:30]=[N:31][N:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[CH:33]=1.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[CH:30]=[N:31][N:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])[CH:33]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: Clc1ccccc1-n1cc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: O=c1n(Cc2cnn(-c3ccccc3Cl)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h

Procedure:
27 mg (0.09 mmol) of the compound from Example 5A were dissolved in 2 ml of acetonitrile, and 58 mg (0.18 mmol) of cesium carbonate and 24 mg (0.09 mmol) of the compound from Example 43A were added. The mixture was stirred at 65° C. for 2 h and then at RT for 20 h. For work-up, 5 ml of water were added and the mixture was extracted twice with in each case 10 ml of ethyl acetate. The organic phase was washed once with 5 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 25 mg (56% of theory) of the target compound.
Reaction SMILES: C([Li])CCC.C([Sn]([O:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)(CCCC)CCCC)CCC.[CH3:29][Si:30]([CH3:39])([CH3:38])[C:31]1[O:35][CH:34]=[C:33](C=O)[CH:32]=1.[C:40]([O:43][C:44](=[O:46])[CH3:45])(=O)[CH3:41]>CCCCCC.O1CCCC1>[C:44]([O:43][CH:40]([C:33]1[CH:32]=[C:31]([Si:30]([CH3:39])([CH3:38])[CH3:29])[O:35][CH:34]=1)[CH2:41][O:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)OCCCc1ccccn1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)OC(COCCCc1ccccn1)c1coc([Si](C)(C)C)c1
Reaction time: 0.08 h

Procedure:
n-Butyl lithium (a 1.6M solution in hexane; 0.46 ml, 0.74 mmol) was added dropwise to a solution of (2-pyridyl)propyl tributylstannyl ether (309.2 mg, 0.70 mmol) in tetrahydrofuran (5 ml) at -78° under argon. After 5 minutes, a solution of 5-trimethylsilyl-3-furaldehyde (118 mg, 0.70 mmol) in tetrahydrofuran (1.5 ml) was added, followed by acetic anhydride (0.1 ml, 1.05 mmol) after 1 hour. Stirring was continued at -78° for 4 hours and the mixture was quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was flash chromatographed on silica using 40% ethyl acetate/hexane. Fractions with Rf of about 0.12 on evaporation afforded the title ester as a yellow oil.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.[NH:10]1[CH2:16][CH2:15][CH2:14][C@H:11]1[CH2:12][OH:13].C(N(CC)CC)C>C(Cl)Cl>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:10]1[CH2:16][CH2:15][CH2:14][C@H:11]1[CH2:12][OH:13])=[O:9]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: OC[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC[C@@H](C(=O)N2CCC[C@H]2CO)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
L-pyroglutamic acid (100 g, 0.775 mol), L-prolinol (78.3 g, 0.775 mol) and triethylamine (322 ml) are dissolved in methylene chloride (2.5 l), and a solution of DMC (196.5 g, 1.163 mol) in methylene chloride (600 ml) is added dropwise over a period of forty minutes under water-cooling. The mixture is stirred for a further 3 hours at room temperature, and the reaction liquid is filtered to remove insolubles. The filtrate is concentrated to dryness under reduced pressure, and the residue is crystallized from dioxane-ether to give L-pyroglutamyl-L-prolinol (38.4 g, 23.3%).
Reaction SMILES: [CH:1](/[C:9]1[N:10]=[CH:11][S:12][C:13]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19][O:20][CH:21](OC)N(C)C>>[CH3:19][O:20]/[CH:21]=[C:14](\[C:13]1[S:12][CH:11]=[N:10][C:9]=1[CH:1]=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)/[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)Cc1scnc1/C=C/c1ccccc1
Reactant: COC(OC)N(C)C
Agent: CO/C=C(/C(=O)OC)c1scnc1/C=C/c1ccccc1
Product: CO/C=C(/C(=O)OC)c1scnc1C=Cc1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 2.5 g of the product of Step A and 25 ml of dimethylformamide dimethyl acetal was heated to 50° C. and after 4 hours at this temperature, the mixture was allowed to return to 25° C. The reaction mixture was evaporated to dryness and the residue was dissolved in 30 ml of tetrahydrofuran and 5 ml of an aqueous solution of 2N hydrochloric acid. After standing for 2 hours at 25° C., the mixture was decanted followed by extraction with methylene chloride. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was dissolved in 30 ml of acetone and 4 g of potassium carbonate and 6 ml of methyl iodide were added. The mixture was stirred for 16 hours at 20° to 25° C. and after filtering and evaporating to dryness, the residue was chromatographed on silica, eluting with a hexane-ethyl acetate mixture (7-3) to obtain 1.1 g of the desired product. Thin layer chromatography; Rf=0.17 [eluant: hexane-acetate of ethyl (7-3)].
Reaction SMILES: O.[Li+].[OH-].[Cl:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]2[CH2:20][CH2:19][CH2:18][CH:12]([C:13]([O:15]CC)=[O:14])[CH2:11]2)=[CH:7][CH:6]=1>C1COCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH2:20][CH2:19][CH2:18][CH:12]([C:13]([OH:15])=[O:14])[CH2:11]2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)C1CCCN(Cc2ccc(Cl)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
An H2O (25 mL) solution of LiOH (1.66 g) was added to a THF (60 mL) solution of ethyl 1-(4-chlorobenzyl)nipecotate. The resulting reaction mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure to provide an amorphous solid. The obtained crude product was purified by column chromatography (SiO2, 50% methanol-dichloromethane) to afford 1-(4-chlorobenzyl)nipecotic acid (9.75 g, 98.2%) as an off-while amorphous solid. The purity was determined by RPLC/MS (>95%). ESI/MS m/e 254.0 (M++H, C13H17ClNO2).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=O)C.O.[NH2:19][NH2:20]>CO>[N:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:11][CH:6]([C:4]([NH:19][NH2:20])=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCN(c2ccccn2)CC1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)C1CCN(c2ccccn2)CC1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester (1 g, 4.3 mmol)(see reference Farmaco, 1993, 48(10), 1439) was dissolved in methanol (20 ml) containing hydrazine hydrate (620 μl, 20 mmol) and was heated under reflux for 18 hours. The mixture was cooled to room temperature and evaporated under reduced pressure. The solid formed was triturated with propan-2-ol to give the title compound as a white solid (493 mg).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].C(O)C>[Pd].ClCCl>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: OC1(c2cccc(F)c2F)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Product: OC1(c2cccc(F)c2F)CCNC1
Yield: 118.9 %

Procedure:
Preparation according to preparation 4: (−)-1-benzyl-3-(2,3-difluorophenyl)pyrrolidin-3-ol (5.5 g, 19 mmol), ammonium formiate (3 g, 48 mmol), ethanol (100 mL) and palladium on carbon (300 mg). Refluxed for 35 min. Dichloromethane/tert-butylmethyleter (1:1, 100 mL) was added and the mixture was filtrated through celite, the filtrate was evaporated to give the title compound (4.5 g). MS m/z (relative intensity, 70 eV) 199 (M+100) 141 (82), 113 (61), 124 (59), 63 (45).