Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[N:3]1.C([Li])CCC.CON(C)[C:15](=[O:27])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=1.Cl>C1COCC1>[CH3:1][N:2]1[C:6]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:25])[F:26])[CH:17]=2)=[O:27])=[N:5][N:4]=[N:3]1
Reactant: CON(C)C(=O)c1cccc(OC(F)(F)F)c1
Reactant: Cn1cnnn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nnnc1C(=O)c1cccc(OC(F)(F)F)c1
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 21 %

Procedure:
To a stirred solution of 1-methyl-1H-tetrazole (7.68 g, 91.3 mmol) in anhydrous THF (360 mL), cooled to −70° C. with an acetone/dry ice bath, was added dropwise a solution of n-butyllithium (1.6 M in hexanes, 57.1 mL, 91.3 mmol). After the addition was over, the resulting cloudy suspension was stirred for 45 min at −70° C. A solution of N-methoxy-N-methyl-3-(trifluoromethoxy)benzamide (22.3 g, 76.1 mmol) in THF (60 mL) was then added dropwise while keeping the internal temperature below −60° C. The reaction mixture was then allowed to warm up and stirred at room temperature for 18 h. The reaction mixture was poured into a mixture of ice-cold water (100 mL) and aq. HCl (1 M, 100 mL), the layers were separated, the water phase was extracted with ethyl acetate (2×150 mL), the combined organic layers were washed with water (2×200 mL) and dried (MgSO4). Purification on silica gel afforded (1-methyl-1H-tetrazol-5-yl)[3-(trifluoromethoxy)phenyl]methanone as a light yellow oil [5.12 g, yield 21%; HPLC/MS:m/z=273 (M+H); log P(HCOOH)=2.96].
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:30])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[NH:27][CH:28]=[CH:29][C:22]=34)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.C(OC([NH:39][CH2:40][C:41](O)=[O:42])=O)(C)(C)C>>[NH2:39][CH2:40][C:41]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12](=[O:30])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]4[NH:27][CH:28]=[CH:29][C:22]=34)[CH:6]=2)[C:2]([CH3:31])([CH3:1])[CH2:3]1)=[O:42]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC1(C)CNc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21
Product: CC1(C)CN(C(=O)CN)c2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21

Procedure:
The titled compound was prepared from N-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)amino]nicotinamide (Example 16) and tert-butoxycarbonylamino-acetic acid by the method described in Example 13. MS (ES+): 470 (M+H). Calc'd. for C26H27N7O2—469.55.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9](/[CH:10]=[CH:11]/[C:12](=[O:22])[CH2:13][C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])[O:8][C@@H:7]([N:23]2[CH:30]=[C:29]([CH2:31][CH3:32])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:6]1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][C:12](=[O:22])[CH2:13][C:14]2[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:20])[O:8][C@@H:7]([N:23]2[CH:30]=[C:29]([CH2:31][CH3:32])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](/C=C/C(=O)Cc3c(Cl)cccc3Cl)O2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CO
Product: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](CCC(=O)Cc3c(Cl)cccc3Cl)O2)c(=O)[nH]c1=O
Yield: 73.9 %

Procedure:
A solution of 3.30 g of (E)-3'-O-acetyl-5'-[3-(2,6-dichlorophenyl)-2-oxopropylidene]-2',5'-dideoxy-5-ethyluridine in 1.50 l of methanol was hydrogenated over 1.10 g of 10% Pd/C catalyst at room temperature and under atmospheric pressure for 3 hours. The mixture was filtered and the filtrate was evaporated. The residue was triturated with diethyl ether to give 2.45 g of 3'-O-acetyl-5'-[3-(2,6-dichlorophenyl)-2-oxopropyl]-2',5'-dideoxy-5-ethyluridine, mp 186°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(OCC)(=O)C>[CH3:25][S:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1)(=[O:28])=[O:27]
Reactant: COC(=O)c1ccc(OCCCCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCCCCCOS(C)(=O)=O)cc1
Reaction time: 2 h

Procedure:
To a solution of the compound 24 (3.58 g) and triethylamine (2.76 mL) in ethyl acetate (50 mL), methanesulfonyl chloride (0.78 mL) was slowly added under ice cooling. The reaction mixture was stirred under ice cooling for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL). The diluted solution was washed in turn with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (ethyl acetate:methanol=1:0→10:1) to obtain the title compound (3.70 g) having the following physical properties.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH:12]([CH3:14])[CH3:13])(=[O:3])[CH3:2].[I:15]Cl>C(Cl)Cl.CCOCC>[C:1]([O:4][C:5]1[CH:10]=[C:9]([I:15])[CH:8]=[CH:7][C:6]=1[O:11][CH:12]([CH3:14])[CH3:13])(=[O:3])[CH3:2]
Reactant: ClI
Reactant: CC(=O)Oc1ccccc1OC(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)Oc1cc(I)ccc1OC(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-isopropoxyphenyl acetate (10 mmol) in CH2Cl2 at 0° C., iodine monochloride (1.0 M in CH2Cl2, 11.0 mL) was added dropwise in 20 min. The mixture was stirred at 0° C. for 2.0 h, diluted with ether, washed with saturated Na2S2O3 and brine. The organic extract was dried over MgSO4 and evaporated to give 5-iodo-2-isopropoxyphenyl acetate as an oil.
Reaction SMILES: CS(O[CH:6]([CH3:20])[CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH:12]=1)(=O)=O.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].O.Cl>CN(C)C=O.C(OCC)(=O)C>[S:15]1[CH:16]=[CH:17][C:13]2[CH:12]=[C:11]([CH2:10][CH2:9][O:8][CH2:7][CH:6]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])[CH3:20])[CH:19]=[CH:18][C:14]1=2
Reactant: CC(COCCc1ccc2sccc2c1)OS(C)(=O)=O
Reactant: CCNCC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)C(C)COCCc1ccc2sccc2c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
In 10 mL of N,N-dimethylformamide is dissolved 1.00 g of 2-(2-benzo[b]thiophen-5-ylethoxy)-1-methylethyl methanesulfonate, to which is added 3.3 mL of diethylamine. The mixture thus obtained is stirred in an ampoule at 100° C. for 15 hours. After cooling, the reaction mixture is introduced into a mixture of water and ethyl acetate, pH is adjusted to 2.0 with 6 mol/L hydrochloric acid, and the aqueous layer is separated. Ethyl acetate is added to the aqueous layer, pH is adjusted to 9.5 with 5 mol/AL aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=20:1 to 10:1). Thus, 0.63 g of N-[2-(2-benzo[b]thiophen-5-ylethoxy)-1-methylethyl]-N,N-diethylamine is obtained as an oily product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[F:19])=[O:4].[OH-].[Na+]>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10]2[N:9]3[CH:20]=[N:21][CH:22]=[C:8]3[CH:7]=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])=[C:13]([F:19])[CH:14]=1
Reactant: COC(=O)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc2cncn2c1Nc1ccc(Br)cc1F
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 85.3 %

Procedure:
To a solution of 5-(4-Bromo-2-fluorophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (5.4 g, 15 mmol) in IMS (110 mL) was added aqueous sodium hydroxide (30 mL, 1M, 30 mmol) and the reaction mixture stirred at 65° C. for 1.5 hours. The reaction mixture was concentrated in vacuo to ˜50 mL volume and the resultant solution was acidified to pH ˜2 by addition of aqueous hydrochloric acid (1M) causing a precipitate to form. The precipitate was collected by filtration and dried under vacuum at 35° C. to yield the title compound as a dark tan solid (4.48 g, 85%). LCMS (Method B): RT=2.81 min, M+H+=350/352.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccc3ccccc3n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 2-(chloromethyl)quinolinehydrochloride (0.73 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.49 g, 26%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH2:18][CH2:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3.[OH-].[Na+].[CH2:23](O)[CH3:24]>O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:20])[C:18]([CH2:13][C:12]5[CH:4]=[N:5][CH:6]=[C:23]([CH3:24])[CH:11]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3
Reactant: CCO
Reactant: COc1cc2c3c(c1)c1ccc(Br)cc1n3CCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(=O)c(Cc3cncc(C)c3)cn3c4cc(Br)ccc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
9-bromo-5,6-dihydro-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (300 mg) obtained in Example 101, step 6 was suspended in ethanol (18 ml), and 5-methylnicotinic aldehyde (176 mg) prepared in accordance with the procedure described in J.O.C., 53, 3513 (1988) and sodium hydroxide (291 mg) dissolved in water (1.5 ml) were added to the suspension at room temperature. The mixture was stirred at room temperature for 12 hours, and approximately half of the solvent was evaporated under reduced pressure. The crystals precipitated were recovered by filtration, and washed with water, ethanol and ether in succession to obtain the title compound (312 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]([O-])=[O:14].N12CCCN=C1CCCCC2>C(OCC)(=O)C.O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:13](=[O:14])[C:12]([O:17][CH2:18][CH3:19])=[O:16])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(=O)Cc1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 84.1 %

Procedure:
1 g (5.79 mmol) of 2-chloro-4-methyl-5-nitropyridine and 4.23 g (28.94 mmol) of ethyl oxalate are placed, under a stream of nitrogen, in a 100 ml three-necked flask equipped with a magnetic stirrer. 0.96 ml (6.4 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene is then added to the reaction medium stirred at room temperature. The reaction mixture is then stirred at room temperature for 1 hour, and then diluted with a mixture of ethyl acetate (40 ml), water (30 ml) and acetic acid (1 ml). The mixture is extracted twice with ethyl acetate. The combined organic phases are washed with 100 ml of water, with 100 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and then concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of heptane and ethyl acetate. 1.33 g (4.87 mmol) of the expected product are thus isolated in the form of a pink powder.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[CH:13]=[N:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:20].[F:21][C:22]([F:34])([F:33])[C:23]1[CH:24]=[C:25]([N:30]=[C:31]=[O:32])[CH:26]=[CH:27][C:28]=1[Cl:29]>>[Cl:29][C:28]1[CH:27]=[CH:26][C:25]([NH:30][C:31]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:16]4[NH:15][C:14](=[O:17])[CH:13]=[N:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:20])=[O:32])=[CH:24][C:23]=1[C:22]([F:21])([F:33])[F:34]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc3ncc(=O)[nH]c23)cc1F
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Oc2ccnc3ncc(=O)[nH]c23)cc1F

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[2,3-b]pyrazin-2(1H)-one and 3-trifluoromethyl-4-chloro-phenylisocyanate to afford the title compound as a beige powder. Yield: 60 mg (79%).
Reaction SMILES: [C:1]12([CH2:11][C:12]3[NH:13][C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][C:16]=3[C:17](O)=[O:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)(Cl)=O.[CH2:30]([O:37][C:38](=[O:56])[C:39]1[CH:54]=[C:53]([NH2:55])[CH:52]=[C:41]([C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[CH:40]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[CH2:45]([O:44][C:42](=[O:43])[C:41]1[CH:52]=[C:53]([NH:55][C:17]([C:16]2[CH:15]=[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:13][C:12]=2[CH2:11][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:18])[CH:54]=[C:39]([C:38]([O:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:56])[CH:40]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: Nc1cc(C(=O)OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Reactant: O=C(O)c1cc(-c2ccccc2)[nH]c1CC12CC3CC(CC(C3)C1)C2
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1cc(NC(=O)c2cc(-c3ccccc3)[nH]c2CC23CC4CC(CC(C4)C2)C3)cc(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a suspension of the product of step c above (290 mg, 0.91 mmol) in DCM (5 ml) was added thionyl chloride (200 μl, 2.74 mmol) and one drop of DMF. The mixture was stirred at room temperature for 30 min, the solvent was evaporated and the residue was coevaporated with DCM (2×5 ml). 5-Amino-isophthalic acid dibenzyl ester (361 mg, 1.00 mmol) was added to the residue followed by anhydrous pyridine (2 ml). The solution was kept at room temperature for 16 h and diluted with DCM (30 ml). The organic phase was washed with 2M hydrochloric acid (2×20 ml), brine (20 ml), dried (MgSO4) and the solvent was evaporated. The residue was purified by flash column chromatography (silica, DCM/hexane/ethyl acetate 9:9:2) to afford the product as pale yellow solid (300 mg, 45%). 1H NMR (300 MHz, CDCl3) 8.48 (3H, s), 8.30 (1H, br s), 7.69 (1H, s), 7.49-7.27 (15H, m), 6.66 (1H, d), 5.40 (4H, s), 2.91 (2H, s), 1.95 (3H, br s), 1.63 (12H, m).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl[CH:22]([C:28]([O:30]CC)=[O:29])[C:23]([O:25]CC)=[O:24]>C(O)C>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][CH:22]([C:28]([OH:30])=[O:29])[C:23]([OH:25])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(CCNCc2ccccc2)c1
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(Oc1cccc(CCNCc2ccccc2)c1)C(=O)O
Reaction time: 4 h

Procedure:
To a solution of 8.0 g. (35.2 mMol) 3-(2-benzylaminoethyl)-phenol and 100 ml. ethanol there are added 35.2 mMol sodium methylate in the form of a methanolic solution and thereafter 6.8 g. (35.2 mMol) diethyl chloromalonate. After stirring for 4 hours, the reaction mixture is evaporated. 50 ml. Diethyl ether are added to the residue, as well as ice-cold 1N aqueous sodium hydroxide solution, shaken up and the ethereal phase is separated off. After drying over anhydrous sodium sulphate, the sulphate is precipitated from it by the dropwise addition of concentrated sulphuric acid, which is filtered off with suction and washed with diethyl ether. The product is very hygroscopic and is obtained in the form of a somewhat greasy mass. Yield 11.7 g. (74% of theory).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[CH:41]1([C:44]2([OH:55])[CH2:47][N:46]([CH2:48][C@H:49]([CH:52]3[CH2:54][CH2:53]3)[NH:50][CH3:51])[CH2:45]2)[CH2:43][CH2:42]1.[OH-].[K+]>C(Cl)Cl>[CH:52]1([C@H:49]([N:50]([CH3:51])[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=2)[CH2:48][N:46]2[CH2:45][C:44]([CH:41]3[CH2:42][CH2:43]3)([OH:55])[CH2:47]2)[CH2:53][CH2:54]1
Reactant: CN[C@H](CN1CC(O)(C2CC2)C1)C1CC1
Reactant: Cc1cc(C(=O)O)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N(C)[C@H](CN2CC(O)(C3CC3)C2)C2CC2)ccc1F
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
4-Fluoro-3-methylbenzoic acid (0.102 g, 0.66 mmol), TBTU (0.248 g, 0.77 mmol) and NMM (0.063 mL, 0.58 mmol) was mixed in DCM (10 mL). After 10 min at rt was (S)-3-cyclopropyl-1-(2-cyclopropyl-2-(methylamino)ethyl)azetidin-3-ol (Compound L2) (0.116 g, 0.55 mmol) added. The resultant mixture was stirred at rt for 48 h. To the mixture was 1.4 N KOH (5 mL) added. The organic phase was isolated, filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (96 mg, 50%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.09-0.14, 0.22-0.70, 1.01, 1.18, 2.30, 2.52-2.55, 2.72-3.10, 3.20, 3.72, 5.12, 7.15-7.44. Total no of protons: 27. HRMS (M+H)+: calculated 347.2135. found 347.2124.
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:31]=[C:32](O)[CH:33]=[CH:34][C:35]=1[Cl:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[Cl:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][C:35]=1[Cl:36])[O:1][C@@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3ccc(Cl)c(Cl)c3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.6 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 3,4-dichlorophenol (8.20 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (5.20 mg, 39.7% yield) as a thick oil: 1H NMR (CDCl3) δ 7.70–7.63 (m, 2H), 7.55 (m, 1H), 7.47–7.43 (m, 3H), 7.40–7.19 (m, 3H), 7.00–6.50 (m, 2H), 6.69 (dd, 1H, J=2.2, 8.8 Hz), 5.25 (m, 1H), 3.20 (m, 2H), 2.70 (m, 2H), 2.53 (m, 2H), 2.40–2.20 (m, 4H), 2.10–1.80 (m, 4H), 1.25 (d, 6H, J=7, 1 Hz); ESMS m/e: 525.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16][NH:17][O:18][CH3:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:19][O:18][N:17]([CH3:16])[C:11](=[O:13])[CH2:10][CH2:9][N:8]([CH3:14])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)CCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
To a stirred solution of 3-[(tert-butoxycarbonyl)(methyl)amino]-propanoic acid (5.0 g, 24.6 mmol), N,O-dimethylhydroxylamine hydrochloride (3.1 g, 32.0 mmol) and HBTU (11.2 g, 29.5 mmol) in DMF (50 mL) at 0° C. was added triethylamine (10.2 mL, 73.8 mmol). The mixture was stirred at room temperature over night and the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (300 mL), washed with water (100 mL) and 0.6 N NaOH solution (100 mL). The aqueous phases were back extracted with ethyl acetate (100 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (120 g column, 0% ethyl acetate in hexanes to 100% ethyl acetate in hexanes) to give product (6.0 g, 99%). 1H NMR (CDCl3) 3.69 (s, 3H), 3.52 (t, J=6.2 Hz, 2H), 3.18 (s, 3H), 2.88 (s, 3H), 2.66 (brs, 2H), 1.45 (s, 9H); MS EI m/z 269 (M+Na)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:11]([C:12]2[S:13][C:14]3[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][C:19]=3[N:20]=2)[N:10]=[C:9]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[S:8]1)=[N+:2]=[N-:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:11]([C:12]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[N:20]=2)[N:10]=[C:9]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])[S:8]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN=[N+]=[N-])c3ccccc3)sc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nc2c(s1)CNCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of tert-butyl 2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (0.313 g, 0.524 mmol) in 10.0 mL of DCM at 0° C. was added TFA (1 mL). The mixture was stirred for 1 hour at 0° C. then at room temperature for 1 hour. The reaction was then concentrated to dryness and partitioned between EtOAc (30 mL) and saturated NaHCO3 solution (30 mL). The aqueous layer was extracted with EtOAc (2×20 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo to afford the desired product as a yellow gum (0.251 g, 96%).