Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15].F[C:19]1[C:20]([CH3:39])=[N:21][C:22]2[C:27]([N:28]=1)=[C:26]([C:29]1[NH:37][C:36]3[CH2:35][CH2:34][NH:33][C:32](=[O:38])[C:31]=3[CH:30]=1)[CH:25]=[CH:24][CH:23]=2>CS(C)=O>[CH3:11][O:12][CH2:13][C:14]([NH:17][C:19]1[C:20]([CH3:39])=[N:21][C:22]2[C:27]([N:28]=1)=[C:26]([C:29]1[NH:37][C:36]3[CH2:35][CH2:34][NH:33][C:32](=[O:38])[C:31]=3[CH:30]=1)[CH:25]=[CH:24][CH:23]=2)([CH3:16])[CH3:15]
Reactant: COCC(C)(C)N
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 100 °C
Reaction time: 3 h
Yield: 28.1 %

Procedure:
Prepared according to Example 127, using DIPEA (264 μl, 1.519 mmol), (2-methoxy-1,1-dimethylethyl)amine hydrochloride (78 mg, 0.759 mmol, ChemBridge Corp., San Diego, Calif.), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 75 mg, 0.253 mmol), and DMSO (2.2 mL) and stirring at 100° C. for 3 h. Purification by reverse phase HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 80%) provided 2-(3-((2-methoxy-1,1-dimethylethyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (27 mg, 28.1%). 1H NMR (DMSO-d6) δ: 11.83-11.94 (m, 1H), 7.77-7.83 (m, 1H), 7.56-7.62 (m, 1H), 7.31-7.39 (m, 1H), 6.90-6.98 (m, 1H), 5.87-5.92 (m, 1H), 3.62-3.68 (m, 2H), 3.40-3.46 (m, 1H), 3.16-3.20 (m, 2H), 2.81-2.88 (m, 2H), 2.66-2.69 (m, 2H), 2.31-2.36 (m, 3H), 1.50-1.56 (m, 6H). m/z (ESI, +ve) 380.1 (M+H)+.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:10][C:9]1[C:2]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2c(F)cccc2C#N)cn1
Yield: 28 %

Procedure:
In analogy to example 5a, 2,3-difluoro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. After aqueous workup and crystallization from Ethyl acetate/diisopropylether the title compound was obtained as an off-white solid (yield: 28%). 1H-NMR (300 MHz, DMSO): δ=2.19 (d, J=0.9 Hz, 3H), 7.26 (s with fine splitting, 1H), 7.71-7.89 (m, 1H), 7.86-7.94 (m, 3H)
Reaction SMILES: [C:1]([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].I([O-])(=O)(=O)=[O:16].[Na+]>C(OCC)(=O)C.O.O.[Ru](=O)=O>[C:1]([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C:9]1=[O:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[C@H]1CCCCN1C(=O)OC(C)(C)C
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.6 %

Procedure:
Ruthenium(IV) oxide hydrate (0.8 g, 0.006 mol) then a solution of N-BOC-6(S)-methyl-piperidine (4.00 g, 0.020 mol) in ethyl acetate (240 ml) were added to a solution of sodium periodate (21.36 g, 0.100 mole) in water (200 ml) and strongly stirred for 24 hours at room temperature under argon atmosphere. After separation the aqueous phase was extracted with ethyl acetate (3×100 ml). The combined organic phases were dried with magnesium sulfate and then treated with activated carbon, giving a colorless solution that was evaporated on a rotavapor at 30° C. The residue (3.98 g) was purified by silicagel (125 g) column chromatography with cyclohexane-ethyl acetate (1-1, v/v), furnishing a product (2.50 g, 59% yield) which according to its 1H-NMR spectrum was pure enough for the next reaction step.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.Cl[C:27](OC)=O>ClCCl.C(N(CC)CC)C.O>[CH3:27][O:23][C:22](=[O:24])[C:21](=[O:25])[C:18]1[CH:19]=[CH:20][C:15]([S:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:16][CH:17]=1
Reactant: O=C(O)C(=O)c1ccc(SCCOc2ccc3ccccc3c2)cc1
Reactant: COC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)c1ccc(SCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of crude 4-[[2-(2-naphthalenyloxy)ethyl]thio]-alpha-oxobenzeneacetic acid (1.6 g) in dichloromethane (500 mL) and triethylamine (1 mL) was treated with methyl chloroformate (0.58 mL) and stirred at room temperature for 1 hour. The mixture was diluted with water, extracted with dichloromethane, dried (Na2SO4), filtered and evaporated. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 2:1) and crystallized from dichloromethane-diethyl ether to provide 0.85 g of 4-[[2-(2-naphthalenyloxy)ethyl]thio]-alpha-oxobenzeneacetic acid methyl ester, mp 124°-125° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[CH:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[C:26]([NH:25][C:11]([C:4]5[C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[N:2]([CH3:1])[N:3]=5)=[O:13])[CH:47]=[CH:46][CH:45]=4)=[CH:35][N:34]3[N:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cn1nc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c2ccccc21
Yield: 28.1 %

Procedure:
In the same manner as in Example 18-4 and using 1-methyl-1H-indazole-3-carboxylic acid (300 mg, 1.70 mmol), tetrahydrofuran (10 mL), oxalyl chloride (222 μL, 2.55 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.647 mmol), N,N-dimethylformamide (2 drops) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (85.0 mg, 28%) was obtained as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH3:33])[C:6]([C:8]1[S:20][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11](=[O:30])[C:10]=2[C:9]=1[O:31][CH3:32])=[O:7].C(N(CC)CC)C.[CH3:41][O:42][CH2:43][C:44](Cl)=[O:45]>C1COCC1.C(=O)([O-])O.[Na+]>[CH3:32][O:31][C:9]1[C:10]2[C:11](=[O:30])[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[S:20][C:8]=1[C:6]([N:5]([CH2:4][CH2:3][NH:2][C:44](=[O:45])[CH2:43][O:42][CH3:41])[CH3:33])=[O:7]
Reactant: COc1c(C(=O)N(C)CCN)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: COCC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)NCCN(C)C(=O)c1sc2c(c1OC)c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
To a solution of the compound of Example 103 (100 mg, 0.21 mmol) and triethylamine (46 mg, 0.45 mmol) in THF (10 mL) was added methoxyacetyl chloride (25 mg, 0.23 mmol) under ice-cooling. After stirring at room temperature for 2 hr, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluate; ethyl acetate to ethyl acetate/methanol=50/1) to give a white solid. Recrystallization of the white solid from ethyl acetate-hexane gave the title compound (61 mg, 56%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[CH2:9][CH2:10][C:11](OC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:17][NH2:18]>CCO>[NH:17]([C:11](=[O:12])[CH2:10][CH2:9][N:8]([CH3:15])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[NH2:18]
Reactant: NN
Reactant: COC(=O)CCN(C)C(=O)OC(C)(C)C
Solvent: CCO
Solvent: O
Product: CN(CCC(=O)NN)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a solution of methyl 3-(tert-butoxycarbonyl(methyl)amino)propanoate (6.9 g, 0.0317 mol) in EtOH (15 mL) was added hydrazine monohydrate (7.7 mL, 0.158 mol) at rt. The reaction mixture was heated to 80° C. and stirred at 80° C. overnight. The reaction mixture was concentrated, and then DCM (300 mL) was added. The organic layer was washed with water and saturated sodium chloride, dried over Na2SO4, and concentrated to afford tert-butyl 3-hydrazinyl-3-oxopropyl(methyl)carbamate (6.8 g, 98%) as sticky oil, which was used directly in the next step. ESI-MS (EI+, m/z): 118 [M−100+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][CH:29]=1.CCN=C=NCCCN(C)C>>[F:26][C:27]([F:38])([F:39])[C:28]1[CH:29]=[CH:30][C:31]([CH2:34][C:35]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:36])=[CH:32][CH:33]=1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccc(C(F)(F)F)cc4)c3)c2c1
Yield: 11.4 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 4-(trifluoromethyl)phenylacetic acid (0.15 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 28 mg (11% yield) of the title compound. 1H NMR (DMSOd6) δ 10.4 (s, 1H), 8.6 (s, 1H), 8.22 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.8–7.68 (m, 3H), 7.6 (m, 3H), 7.5 (t, 1H), 7.35 (s, 1H), 7.17 (m, 2H), 3.8 (s, 2H); ES-MS (m/z) 439 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:3]#[N:4].B#B.C(O)C>C1COCC1>[OH:1][CH:2]([CH:5]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[CH2:3][NH2:4]
Reactant: COc1ccccc1OC(c1ccccc1Cl)C(O)C#N
Agent: B#B
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccccc1OC(c1ccccc1Cl)C(O)CN
Reaction time: 16 h
Yield: 78.3 %

Procedure:
Under an atmosphere of nitrogen to 15.7 g of 2-hydroxy-3-(2-chloro-phenyl)-3-(2-methoxy-phenoxy)-propionitrile in 110 ml of anhydrous THF there was added at 15° C. 46.2 ml of a 1.35 M solution of diborane in tetrahydrofuran. Stirring was continued at room temperature for 16 hours. A small quantity of ethanol was added and the whole was evaporated to dryness. The residue was dissolved in ethyl ether, extracted with 3% HCl, made alkaline with 20% NaOH, re-extracted with ethyl ether. After washing with water, drying over Na2SO4, filtration and evaporation to dryness, there was obtained 12.45 g of 2-hydroxy-3-(2-methoxy-phenoxy)-3-(2-chlorophenyl)-propylamine. Yield 78%.
Reaction SMILES: [CH:1]([N:4]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:5]1)([CH3:3])[CH3:2].[C:16]([NH:23][C@H:24]([C:33]([OH:35])=O)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)(OC(C)(C)C)=O.[C:36]([OH:40])(=[O:39])C=O>>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][C@H:24]([NH:23][CH2:16][C:36]([OH:40])=[O:39])[C:33]([NH:9][C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH:7]=2)=[O:35])=[CH:31][CH:30]=1.[ClH:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CC(C)n1nc(-c2ccncc2)cc1N
Reactant: O=CC(=O)O
Product: CC(C)n1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccc(Cl)cc1)NCC(=O)O
Product: Cl
Yield: 14 %

Procedure:
This title compound was prepared starting from 29.B (169 mg, 0.84 mmol) and Boc-4-chloro L-phenylalanine (available from Chem-Impex International, Inc. (305 mg, 1.0 mmol) according the procedure described above for conversion of 17.B to 17.2, except that glyoxylic acid (1.0 equiv.) was used in the last step. After purification by preparative HPLC (5-40% CH3CN/water, 45 min), product fractions were collected, treated with 1.0 N HCl, and concentrated to provided 29 HCl salt as colorless solid (52 mg, 14%). MS ESI (positve.) m/e: 442.1 (M+H); 1H NMR (400 MHz, CD3OD) δ ppm 8.77 (d, J=7.04 Hz, 2H), 8.40 (d, J=7.04 Hz, 2H), 7.39-7.49 (m, 2H), 7.32-7.39 (m, 2H), 7.08 (s, 1H), 4.58 (dd, J=10.17, 5.87 Hz, 1H), 4.06 (s, 2H) 3.99 (quin, J=6.55 Hz, 1H), 3.49 (dd, J=13.30, 5.87 Hz, 1H), 3.23 (dd, J=13.30, 9.78 Hz, 1H), 2.32 (s, 1H), 1.38 (dd, J=10.96, 6.26 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN1CCCCC1

Procedure:
Using general procedure 1 with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.115 g, 0.44 mmol) and piperidine (0.218 mL, 2.20 mmol) give the title compound.
Reaction SMILES: [Cl:1]C1C(F)=CN=C(C)C=1.[Cl:10][C:11]1[C:16]([F:17])=[CH:15][N:14]=[C:13]([CH2:18][CH2:19][CH3:20])[CH:12]=1>>[Cl:1][C:12]1[C:13]([CH2:18][CH2:19][CH3:20])=[N:14][CH:15]=[C:16]([F:17])[C:11]=1[Cl:10]
Reactant: Cc1cc(Cl)c(F)cn1
Reactant: CCCc1cc(Cl)c(F)cn1
Product: CCCc1ncc(F)c(Cl)c1Cl

Procedure:
By following the procedures described in Example 67 and replacing 4-chloro-5-fluoro-2-picoline (the product of Example 66) with 4-chloro-5-fluoro-2-propyl-pyridine (the product of Example 70), the title compound can be prepared.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15](B(O)O)[CH:16]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:20][CH3:21])=[C:13]([C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:12]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: N#Cc1cccnc1Cl
Product: COc1ccc(F)cc1-c1ncccc1C#N
Yield: 89 %

Procedure:
Prepared in 89% yield from 2-chloronicotinonitrile and 5-fluoro-2-methoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 228.9 (M+H)+; 1H NMR (CDCl3) δ 3.86 (s, 3H), 6.98 (dd, J=8.8, 4.0 Hz, 1H), 7.13-7.22 (m, 2H), 7.40 (dd, J=8.0, 4.9 Hz, 1H), 8.04 (dd, J=8.1, 1.7 Hz, 1H), 8.88 (dd, J=5.1, 1.7 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:23])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18](N)[CH:17]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:25]([BH3-])#[N:26].[Na+].C=O.O1CCC[CH:32]1CO.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:23])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:26]([CH3:25])[CH3:32])[CH:17]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)c2cccc(N)c2)cc1
Reactant: OCC1CCCO1
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)c1cccc(C(=O)Nc2ccc(NC(=O)OC(C)(C)C)cc2)c1

Procedure:
A solution of [4-(3-amino-benzoylamino)-phenyl]-carbamic acid t-butyl ester (505 mg), sodium cyanoborohydride (250 mg), acetic acid (3 drops) and 40% aqueous formaldehyde (4 mL) in 1:2 tetrahydrofuran-methanol (15 mL) is stirred for 15 minutes, and then poured into saturated aqueous sodium bicarbonate and extracted into ethyl acetate. The ethyl acetate solution is dried over anhydrous potassium carbonate and concentrated under reduced pressure to give a solid which is recrystallized from acetonitrile to provide a pale pink crystalline solid.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[S:24][C:25]([Cl:30])=[CH:26][C:27]=1[CH2:28]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCOC(C)=O.C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:28][C:27]5[CH:26]=[C:25]([Cl:30])[S:24][C:23]=5[Cl:22])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: OCc1cc(Cl)sc1Cl
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(Cl)sc4Cl)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To a mixture of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (2,5-dichloro-3-thienyl)methanol (130 mg), tributylphosphine (0.264 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO4, and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc), followed by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (39.9 mg) as an off-white solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(OCC)(=O)C.C(OCC)C>CN(C)C(=O)C>[Br-:9].[C:14]([O:13][C:11]([CH2:10][N+:1]12[CH2:8][CH2:7][N:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C1CN2CCN1CC2
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C[N+]12CCN(CC1)CC2
Product: [Br-]
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To an ice-cold solution of 5.61 g of 1,4-diaza-bicyclo[2.2.2]octane in 50 ml of N,N-dimethylacetamide were added 7.33 ml of tert-butyl 2-bromo-acetate. The solution was stirred for 4 h at 20° and then, 0.5 l of ethyl acetate and 0.3 l of diethyl ether were added. The precipitate formed was isolated by filtration, washed thoroughly with 0.5 l of ethyl acetate and dried to give 14.7 g of 1-tert-butoxycarbonylmethyl-4-aza-1-azonia-bicyclo[2.2.2]octane bromide as white crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:13][CH:12]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:7][CH:6]=1.[N:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[N:37]1([C:43]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:22])([Cl:23])[Cl:24])=[O:18])[CH2:13][CH:12]3[O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[CH:9][CH:10]=2)=[O:44])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)N1CCOCC1
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(OCCOc1ccc(C2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2OCc2ccc3ccccc3c2)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 11.3 %

Procedure:
A solution of 250 mg (0.56 mmol) of 2,2,2-trichloroethyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 20 ml of toluene was treated in succession with 250 ml (2.8 mmol, 5.0 eq.) of morpholine-4-carbonyl chloride, 375 mg (3.08 mmol, 5.5 eq.) of 4-dimethylaminopyridine and 20 μl (0.075 mmol, 0.13 eq.) of dibutyltin diacetate. This mixture was boiled under reflux for 64 hours. In the course of the reaction a further 125 ml (1.40 mmol, 5.0 eq.) of morpholine-4-carbonyl chloride and 188 mg (1.56 mmol, 2.3 eq.) of 4-dimethylaminopyridine were added and the mixture was boiled under reflux for a further 24 hours. The reaction mixture, cooled to room temperature, was poured into 100 ml of an ice/water mixture, stirred for 5 minutes and extracted three times with methylene chloride. The organic phases were each washed once with water and saturated sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The crude product (546 mg) was separated on silica gel using a 9:1 mixture of hexane and acetone as the eluent. There were obtained 42 mg (14% of theory) of 2,2,2-trichloro-ethyl (3RS,4RS)-4-[4-[2-(morpholin-4-ylcarbonyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 665.3, 667 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C([NH:17][CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[S:26]([Cl:29])(=[O:28])=[O:27])(=O)C>CO.O1CCCC1>[ClH:29].[F:25][C:23]1[CH:22]=[CH:21][C:20]([S:26]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:28])=[O:27])=[C:19]([CH2:18][NH2:17])[CH:24]=1
Reactant: CC(=O)NCc1cc(F)ccc1S(=O)(=O)Cl
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: Cl
Product: NCc1cc(F)ccc1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(Step 1) To a solution of morpholine (0.36 ml) and triethylamine (0.58 ml) in methanol (15 ml) was added dropwise a suspension of 2-[(acetylamino)methyl]-4-fluorobenzenesulfonyl chloride (1.00 g) in tetrahydrofuran (5 ml) under ice-cooling, and the mixture was allowed to warm to room temperature, and stirred for 1 hr. The reaction mixture was quenched with saturated brine, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate). The obtained oil was dissolved in ethanol (20 ml), hydrochloric acid (10 ml) was added, and the mixture was stirred with heating under reflux for 9 hr. The solvent was evaporated under reduced pressure, and the residue was collected by filtration, and washed with ethyl acetate to give 1-[5-fluoro-2-(morpholin-4-ylsulfonyl)phenyl]methanamine hydrochloride (0.58 g) as a white solid.