Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Li+].C([Mg]Cl)(C)C.I[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.[CH:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCCC1.[Cu]I>[CH:20]1([C:25]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: O=C(Cl)C1CCCC1
Agent: [Cu]I
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C2CCCC2)cc1
Temperature: -40 °C
Reaction time: 0.83 h

Procedure:
At −40° C., isopropylmagnesium chloride lithium chloride (13.9 mL, 1.3 M in THF) was added dropwise to a solution of ethyl 4-iodobenzoate (4971 mg, 18.01 mmol) in tetrahydrofuran (30 mL). The solution was stirred at −40° C. for 50 minutes. Copper(I) iodide (1.03 g, 5.4 mmol) was added. The mixture was allowed to warm to −15° C. and stir for 8 minutes. The solution was cooled back to −40° C. and cyclopentanecarbonyl chloride (3580 mg, 27.0 mmol) was added dropwise. The mixture was allowed to gradually warm to 0° C. over 3 hours. The mixture was quenched with 1 N HCl (20 mL) and diluted with ethyl acetate. The mixture was stirred at room temperature for 5 min. A white precipitate formed. The mixture was filtered through celite and the filtrate transferred to a separatory funnel. The layers were separated. The aqueous was extracted twice with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-20% ethyl acetate in heptane) gave ethyl 4-(cyclopentanecarbonyl)benzoate as an oil. 1H NMR (400 MHz, CDCl3, δ): 8.13-8.08 (m, 2H), 8.02-7.97 (m, 2H), 4.39 (q, J=7.22 Hz, 2H), 3.77-3.65 (m, 1H), 1.99-1.79 (m, 4H), 1.77-1.60 (m, 4H), 1.40 (t, J=7.22 Hz, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[O:37][CH:38]=[CH:39][CH:40]=2)[S:34][CH:35]=1.O>CN(C)C=O>[O:37]1[CH:38]=[CH:39][CH:40]=[C:36]1[C:33]1[S:34][CH:35]=[C:31]([CH2:30][O:3][C:4]2[CH:28]=[CH:27][C:7]([CH2:8][N:9]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]3)=[CH:6][CH:5]=2)[N:32]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: ClCc1csc(-c2ccco2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccco4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-(2-furyl)thiazole (299 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-[2-(2-furyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (643 mg, yield: 84%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][N:13]=[C:14]=[S:15].BrBr>C(O)(=O)C>[CH3:12][NH:13][C:14]1[S:15][C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[C:3]([CH3:11])[C:2]=2[N:1]=1
Reactant: Cc1c(N)cccc1C(=O)O
Reactant: CN=C=S
Agent: BrBr
Solvent: CC(=O)O
Product: CNc1nc2c(C)c(C(=O)O)ccc2s1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
99 g of 3-amino-2-methylbenzoic acid (0.655 mol) were initially charged in 500 ml of acetic acid and, at 80° C,. admixed with 51 g of methyl isothiocyanate (7 mol) in 100 ml of acetic acid. After 2 h, 106 g of bromine (0.66 mol) in 20 ml of acetic acid were added dropwise at 50° C. The mixture was subsequently heated at about 100° C. for 2 h and, after the reaction had ended, allowed to cool. The precipitate was filtered off, the filtrate was concentrated to about 50 ml and the remaining filtrate and the precipitate were added to water. The aqueous phase was adjusted to pH 5 and the precipitate was filtered off at 8° C. It was subsequently washed with water and dried. Yield: 66 g (42%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCc1ccncc1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccncc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 78.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.77 g) and 4-(chloromethyl)pyridine (0.49 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(4-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(4-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide dihydrochloride (0.58 g) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1>>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([N:5]2[CH2:6][CH2:7][CH:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN(C)C1CCNC1
Product: CN(C)C1CCN(c2ccc(N)cc2)C1

Procedure:
Dimethylpyrrolidin-3-ylamine was reacted with 4-fluoronitrobenzene by method C, and the product was subsequently hydrogenated by method B. This resulted in the product with the molecular weight of 205.31 (C12H19N3); MS (ESI): 206 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:25]([C:33]2[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][N:34]=2)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]3([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)[CH:7]=1.[N:43]([CH:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)=[C:44]=[O:45].NC(N)=O.[N-]=C=O>C1COCC1.C(OCC)(=O)C.CCN(CC)CC>[Si:18]([O:17][C:13]1([C:11]2[S:12][C:8]([C:6]3[CH:5]=[C:4]([N:25]([C:33]4[N:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][N:34]=4)[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:31])[CH3:29])[CH:3]=[C:2]([NH:1][C:44](=[O:45])[NH:43][CH:46]4[CH2:50][CH2:49][CH2:48][CH2:47]4)[CH:7]=3)=[CH:9][N:10]=2)[CH2:14][CH2:15][CH2:16]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N(c1cc(N)cc(-c2cnc(C3(O[Si](C)(C)C(C)(C)C)CCC3)s2)c1)c1nccc(C(F)(F)F)n1
Reactant: O=C=NC1CCCC1
Agent: NC(N)=O
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(c1cc(NC(=O)NC2CCCC2)cc(-c2cnc(C3(O[Si](C)(C)C(C)(C)C)CCC3)s2)c1)c1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of the product of Step 2 (56 mg; 0.090 mmol) in THF (0.9 mL) was added triethylamine (38 μL; 0.27 mmol) followed by the isocyanatocyclopentane (31 μL; 0.27 mmol), then the mixture was stirred at room temperature overnight, at which point LC-UV analysis indicated ˜70% conversion to the desired urea. Additional Et3N and isocyanate (0.27 mmol each) were added, and the mixture was heated to 50° C. for 3 hours, at which point LC-UV indicated complete conversion. The mixture was diluted with ethyl acetate (30 mL) and washed with water (30 mL) and brine (30 mL). The organic extracts were dried (Na2SO4) and concentrated in vacuo. Purification by chromatography on silica gel (90:10 to 40:60, hexanes:ethyl acetate) provided 57 mg (0.078 mmol, 86%) of tert-butyl {3-[2-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclobutyl)-1,3-thiazol-5-yl]-5-[(cyclopentylcarbamoyl)amino]phenyl}[4-(trifluoromethyl)pyrimidin-2-yl]carbamate as a white foam.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[N:20]1[N:24]=[CH:23][CH:22]=[N:21]1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:28]=[N:27][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=2[N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)=[O:11])=[N:31][CH:30]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CN
Reactant: Clc1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4,5-difluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 448 [M+1]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:15][O:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)[CH2:10][CH2:9]1)C.C([NH2:41])=O.C[O-].[Na+]>>[F:25][C:24]([F:27])([F:26])[C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([C:28]([F:29])([F:31])[F:30])[CH:21]=1)[CH2:17][O:16][CH2:15][CH:14]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][C:4]([NH2:41])=[O:3])[CH2:9][CH2:10]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)CCCN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: NC(=O)CCCN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Temperature: 95 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
In a round-bottomed flask fitted with a reflux condenser are introduced 493 mg (0.9 mmoles) of 4-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-butyric acid ethyl ester (compound 138 prepared at example 1.4.1 above), 15 ml of formamide and 97 mg (1.8 mmoles) of sodium methoxide. The mixture is heated to 95° C. for 4 hours, then 48 mg (0.9 mmole) of sodium methoxide are added and the mixture is kept overnight at 85° C. The mixture is cooled and partitioned between diethyl ether (100 ml) and brine (100 ml). The organic phase is dried and volatile substances are removed under reduced pressure, affording 400 mg of 4-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-butyramide as a yellow oil (yield 86%). The dimaleate salt of compound 288 is prepared in 2-butanone (yield: 4.32 g as a white solid).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7]1>C1COCC1>[CH2:1]([NH:3][C:4]([N:7]1[C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:6]1)=[O:5])[CH3:2]
Reactant: O=c1[nH]oc2ccccc12
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)n1oc2ccccc2c1=O
Yield: 75 %

Procedure:
Ethyl isocyanate (92.4 mg, 1.30 mmol) is added to a stirred solution of benzo[d]isoxazol-3-one (150 mg; 1.10 mmol) in anhydrous THF (4 mL) at ambient temperature under nitrogen. The resultant mixture is heated in an oil bath at 70° C. for 2 hr. After concentration and subsequent flash chromatography on silica (15% hexane in CH2Cl2), 6-1 is obtained as a white solid (170 mg, 75% yield). mp 112.0–113.0° C.; 1H-NMR (CDCl3) δ1.28 (t, J=7.3 Hz, 3H), 3.43–3.51 (m, 2H), 7.21–7.29 (m, 3H), 8.04 (br s, 1H), 8.07 (d, J=6.8 Hz, 1H); ESIMS m/e 207 (M+H)+. Analysis for C10H10N2O3: calcd: C, 58.25; H, 4.89; N, 13.59; found: C, 58.04; H, 4.82; N, 13.41.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[C:13](=O)[C:14]([O:16][CH3:17])=[O:15]>CO>[CH3:2][O:3][N:4]=[C:13]([C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:6]=1[CH3:5])[C:14]([O:16][CH3:17])=[O:15]
Reactant: CON
Reactant: COC(=O)C(=O)c1c(C)cccc1C
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)OC)c1c(C)cccc1C
Reaction time: 32 h

Procedure:
At room temperature (about 25° C.), 83.5 ml (0.15 mol) of a 15% strength solution of O-methylhydroxylamine hydrochloride in methanol were added dropwise to a mixture of 19.2 g (0.1 mol) of methyl 2,6-dimethylphenylglyoxylate and 100 ml of methanol. At the boiling point of the solvent, the resulting reaction mixture was stirred under reflux for 16 hours and then admixed with a further 24 ml of the 15% strength solution of O-methylhydroxylamine hydrochloride in methanol. After a further 32 h at the boiling point of the solvent, the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate. The organic phase was washed with water, dried and freed of the solvent under reduced pressure. The resulting residue (20 g) was purified by distillation. This gave 12 g of the title compound which can be subjected to the isomerization according to Example 3 without further purification.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH2:32][C@H:33]([CH:36]([CH3:38])[CH3:37])[CH2:34][OH:35].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:32][C@@H:33]([CH2:34][OH:35])[CH:36]([CH3:38])[CH3:37])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CC(C)[C@@H](N)CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN[C@@H](CO)C(C)C)c4)cc23)CC1
Yield: 32.5 %

Procedure:
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol), (2R)-2-amino-3-methyl-1-butanol (10.2 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the title compound (14.9 mg, 25%).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Cl.[C:10]([NH:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[N:18][CH:17]=1)([CH3:13])([CH3:12])[CH3:11].CO.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[C:10]([NH:14][C:15](=[O:23])[C:16]1[C:21]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:9])=[CH:20][C:19]([Cl:22])=[N:18][CH:17]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1ccccc1[Mg]Cl
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)nc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1-c1cc(Cl)ncc1C(=O)NC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
92 ml (92 mMol) o-Tolylmagnesium chloride solution (1M in THF) were added over 15 minutes to a solution of 5.0 g (23 mMol) N-tert.-butyl-6-chloro-nicotinamide in 25 ml THF cooled to 0° C. The reaction mixture was stirred 18 hours at 30° C. and cooled again to 0° C. 5.6 ml (138 mMol) Methanol were added over 30 minutes, stirring was pursued for 10 minutes and 6.3 g (27 mMol) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone were added. After 1 hour at room temperature, the reaction mixture was concentrated to 50 g under reduced pressure, heated to 50° C. and 100 ml tert.-butyl-methylether were added. The resulting suspension was refluxed for 30 minutes, cooled to room temperature and, after 1 hour, filtered off. The filtrate was concentrated and dried under high vacuum to yield 6.3 g (90%) of N-tert.-butyl-6-chloro-4-o-tolyl-nicotinamide as an orange foam.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)[N:17]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[N:17]=2)[CH:4]=1
Reactant: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(Cl)c(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c1
Yield: 63.6 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-3-(1-(3-chloro-4-fluorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (0.300 g), KOH (0.300 g), water (5 mL) and THF (10.0 mL) to afford 0.150 g of the desired product.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5][CH2:4][O:3]1.[CH:18]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[O:1]=[C:2]1[N:6]([CH:7]([CH3:18])[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5][CH2:4][O:3]1
Reactant: O=C(CN1CCOC1=O)OCc1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C(=O)OCc1ccccc1)N1CCOC1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a stirred solution of 0.50 g (2.1 mmol) of benzyl (2-oxo-1,3-oxazolidin-3-yl)acetate from step A above in 15 mL of anhydrous THF at −78° C. under an atmosphere of nitrogen was added 1.2 mL (2.4 mmol) of a 2.0 M solution of lithium diisopropylamide in anhydrous THF. The resulting yellow solution was stirred for 15 min at −78° C. and then 0.0360 g (2.55 mmol) of iodomethane was added. The resulting mixture was stirred for 2 h with gradual warming to ambient temperature then quenched with a saturated aqueous ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (3×20 mL) and the combined organics were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was purified by silica gel chromatography eluting with 40% ethyl acetate in hexanes to afford the title compound as a clear gum 0.37 g (70%). LC-MS: m/z (ES) 250 (MH)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[C:10]([CH2:18][C:19](O)=[O:20])=[CH:11][C:12]2[O:16][CH2:15][O:14][C:13]=2[CH:17]=1)[CH3:8].O>O1CCCC1>[CH2:7]([C:9]1[C:10]([CH2:18][CH2:19][OH:20])=[CH:11][C:12]2[O:16][CH2:15][O:14][C:13]=2[CH:17]=1)[CH3:8]
Reactant: CCc1cc2c(cc1CC(=O)O)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc2c(cc1CCO)OCO2
Reaction time: 12 h
Yield: 90.6 %

Procedure:
62 g of lithium aluminum hydride was suspended in 1.5 l of anhydrous tetrahydrofuran. A solution of 200 g of (6-ethyl-1,3-benzodioxol-5-yl)acetic acid in 200 ml of tetrahydrofuran was added dropwise to the suspension and the reaction was conducted at room temperature for 12 h. After the completion of the reaction, water was added thereto and the precipitate was filtered off. The filtrate was concentrated under reduced pressure and water was added to the residue. After extraction with ethyl acetate, the extract was washed with water, dried over magnesium sulfate, concentrated under reduced pressure and purified according to silica gel column chromatography (ethyl acetate/hexane=1:4) to obtain 169 g of the intended compound in the form of a faint yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH3:41][N:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[N:44]=[C:43]1[NH:51][CH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.O>C(C(C)=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@:10]([CH2:13][CH2:14][N:55]2[CH2:56][CH2:57][CH:52]([NH:51][C:43]3[N:42]([CH3:41])[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=3)[CH2:53][CH2:54]2)([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CC[C@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: Cn1c(NC2CCNCC2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(Nc4nc5ccccc5n4C)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
Combine the above solution of (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine, potassium carbonate (4.07 kg, 29.5 mol), (1-methyl-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (12.0 mol), and water (3.3 gal). Heat to about 70° C. When the reaction is complete, dilute the reaction mixture with methyl ethyl ketone (18.1 kg) and after 15 minutes of stirring, separate the layers. Extract the organic layer with water (3.4 gal) and then concentrate in vacuo to give the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH:10]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12][CH2:11]2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>>[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[C:7]([O:8][CH2:9][CH:10]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[O:12][CH2:11]3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:24][CH2:23]1)[CH3:21]
Reactant: CCN1CCNCC1
Reactant: Clc1nccnc1OCC1COc2ccccc2O1
Product: CCN1CCN(c2nccnc2OCC2COc3ccccc3O2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)pyrazine* (150 mg, 0.54 mmol) and N-ethylpiperazine (219 mg, 1.92 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 128 mg (66%) of the title product. HRMS m/z calcd for C19H24N4O3 (M)+ 356.1848, found 356.1848. Anal. (C19H24N4O3) C, H, N.
Reaction SMILES: [I-:1].[N:2]1([C:8]2[CH:17]=[CH:16][C:15]3[N+:14]4[CH:18]=[C:19]5[CH:28]=[CH:27][C:26]6[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=6[N:20]5[C:13]=4[CH:12]=[CH:11][C:10]=3[CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:29]N1CCCC1=O.C(OCC)(=O)C>>[I-:1].[CH3:29][C:24]1[CH:23]=[CH:22][C:21]2[N:20]3[C:13]4[CH:12]=[CH:11][C:10]5[CH:9]=[C:8]([N:2]6[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]6)[CH:17]=[CH:16][C:15]=5[N+:14]=4[CH:18]=[C:19]3[CH:28]=[CH:27][C:26]=2[CH:25]=1
Reactant: c1ccc2c(c1)ccc1c[n+]3c4ccc(N5CCCCC5)cc4ccc3n12
Reactant: CN1CCCC1=O
Agent: [I-]
Solvent: CCOC(C)=O
Product: Cc1ccc2c(ccc3c[n+]4c5ccc(N6CCCCC6)cc5ccc4n32)c1

Procedure:
3-(1-Piperidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium Iodide; dec. at 280° C.-290° C. from N-methyl-2-pyrrolidinone/ethyl acetate.