Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[F:39][C:40]([F:56])([F:55])[C:41]1[CH:42]=[C:43]([S:51](Cl)(=[O:53])=[O:52])[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:51]([C:43]3[CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=[C:41]([C:40]([F:39])([F:55])[F:56])[CH:42]=3)(=[O:53])=[O:52])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
Diisopropylethylamine (0.6 mL, 3.4 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. 3,5-Bis(trifluoromethyl)benzenesulfonyl chloride (available from Sigma-Aldrich; 169 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 10% ethyl acetate/hexanes, to give {4-[1-(3,5-bis-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (87 mg, 42%) as an off-white solid. MS cald. for C26H23F7NO4S [(M+H)+]: 578, obsd. 578.4.
Reaction SMILES: C([N-][CH:5]([CH3:7])[CH3:6])(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:17])CC(C)C)[CH3:10].CI.[CH2:20]1[CH2:24]OC[CH2:21]1>>[CH2:9]([O:11][C:12](=[O:17])[C:5]([CH3:6])([CH3:7])[CH:20]([CH3:24])[CH3:21])[CH3:10]
Reactant: CCOC(=O)CC(C)C
Reactant: CC(C)[N-]C(C)C
Reactant: C1CCOC1
Agent: [Li+]
Solvent: CI
Product: CCOC(=O)C(C)(C)C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Lithium diisopropylamide (1.5 M solution in cyclohexane/THF/ethylbenzene) (113 mL, 169 mmol, 1.1 equiv) was syringed into a 1000 mL round-bottom flask under a blanket of Ar. Dry THF (150 mL) was added and the mixture was cooled to −78° C. with a dry-ice/acetone bath. 3-Methyl-butanoic acid ethyl ester (20 g, 23 mL, 154 mmol, 1.0 equiv) was added dropwise from a syringe over a 10 min period followed by stirring at −78° C. for 1 h. Methyl iodide (10.5 mL, 169 mmol, 1.1 equiv) was added dropwise from a syringe over a 10 min period and the creamy mixture was stirred for 1 h at −78° C., resulting in a very thick mixture. The dry-ice bath was removed and replaced with an ice bath at 0° C. Another 150 mL of dry THF was added followed by another addition of LDA (113 mL, 169 mmol, 1.1 equiv). The resulting mixture was stirred for 10 min and then the flask was re-immersed in a dry-ice/acetone bath. Stirring was continued for another 50 min and then methyl iodide was added dropwise (10.5 mL, 169 mmol, 1.1 equiv) and the dry-ice/acetone bath was removed and the resulting mixture was stirred at ambient temperature for 14 h. The reaction mixture was quenched with 3 mL of conc. HCl and 2 N HCl was added until the pH was adjusted to <1. The mixture was further diluted with 150 mL water and 500 mL Et2O. The layers were separated and the organic layer was washed with 2 N HCl (1×100 mL), saturated NaHCO3 (1×100 mL), and brine (1×200 nL). The organic layer was dried over Na2SO4 and then concentrated in vacuo to provide 2,2,3-trimethylbutanoic acid ethyl ester as an orange oil mixed with ethyl benzene (36.4 g of which 22.1 g was product by NMR). The mixture was used without further purification.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)(Cl)=O.Cl[CH:19](Cl)C>>[Cl:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:19])=[O:10])=[CH:12][CH:13]=1)(=[O:4])=[O:3]
Reactant: CC(Cl)Cl
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
4-Chlorosulfonyl benzoic acid (5 g, 23 mmol) and thionyl chloride (20 mL) in dichloroethane (10 mL) was heated to 80° C. for 2 hr. The reaction mixture was concentrated via rotary evaporation to give a brownish solid. The solid was chilled on ice for 5 minutes and ice-cold methanol (40 mL) was added with stirring at 0° C. for 5 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred an additional 10 min. The addition of ice-cold water (40 mL), produced a white solid that was collected by filtration and dried under vacuum to afford pure methyl 4-(chlorosulfonyl)benzoate (4.5 g, 84%). 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.84 (s, 3H), 7.70 (d, 2H, J=8.4 Hz), 7.93 (d, 2H, J=8.4 Hz).
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[C:18](F)=[C:19]([F:35])[CH:20]=[C:21]2[C:26]=1[N:25]([C@H:27]1[CH2:29][C@H:28]1[F:30])[CH:24]=[C:23]([C:31]([OH:33])=[O:32])[C:22]2=[O:34]>>[Cl:16][C:17]1[C:18]([N:4]2[CH2:3][CH2:2][N:1]([CH2:7][C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[O:9])[CH2:6][CH2:5]2)=[C:19]([F:35])[CH:20]=[C:21]2[C:26]=1[N:25]([C@H:27]1[CH2:29][C@H:28]1[F:30])[CH:24]=[C:23]([C:31]([OH:33])=[O:32])[C:22]2=[O:34]
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: O=C(O)c1cn([C@H]2C[C@H]2F)c2c(Cl)c(F)c(F)cc2c1=O
Product: O=C(O)c1cn([C@H]2C[C@H]2F)c2c(Cl)c(N3CCN(CC(=O)N4CCOCC4)CC3)c(F)cc2c1=O

Procedure:
The preparation takes place in analogy to Example 1A from 4-[2-(piperazin-1-yl)acetyl]morpholine and 8-chloro-6,7-difluoro-1-[(1S,2R)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (for preparation see Journal of Medicinal Chemistry (1994) 37:3344-3352). The compound is used as a crude product in the subsequent reaction stages.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH3:11])[S:7][C:6]=2[C:12]=1[Cl:13].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:14][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH3:11])[S:7][C:6]=2[C:12]=1[Cl:13]
Reactant: CCc1cc2cc(O)c(Cl)c(Cl)c2s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2cc(CC)sc2c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 83.8 %

Procedure:
A mixture of 1.15 g of 6,7-dichloro-2-ethyl-5-hydroxybenzo[b]thiophene, 0.87 g of ethyl bromoacetate, 0.4 g of potassium carbonate and 12 ml of dimethylformamide is stirred at 90° for 20 min. The cooled mixture is diluted with 100 g of ice water and the solid collected by filtration. Recrystallization of the crude product from pentane gives 1.3 g of ethyl [(6,7-dichloro-2-ethylbenzo[b]thien-5-yl)oxy]acetate as colorless prisms, mp 67°-68°.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[C:10]([CH2:11][CH3:12])=[N:9][C:8]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:7]=2[C:6]=1[NH:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)C(C)C)(C)C.[CH2:34]([O:36][C:37]1[C:38](=O)[C:39](=[O:44])[C:40]=1[O:41]CC)[CH3:35]>C(O)C>[CH2:16]([N:13]1[C:8]2=[N:9][C:10]([CH2:11][CH3:12])=[C:5]([CH2:4][NH:3][C:38]3[C:39](=[O:44])[C:40](=[O:41])[C:37]=3[O:36][CH2:34][CH3:35])[C:6]([NH:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[C:7]2[CH:15]=[N:14]1)[CH3:17]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CCOc1c(OCC)c(=O)c1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOc1c(NCc2c(CC)nc3c(cnn3CC)c2NC2CCOCC2)c(=O)c1=O
Reaction time: 8 h

Procedure:
A suspension of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine dihydrochloride (0.60 g, 1.6 mmol) in ethanol (8 mL) was treated with N,N-diisopropylethylamine (DIEA, 0.57 mL, 3.3 mmol), giving a clear, homogeneous mixture, which was then cooled in an ice-water bath. 3,4-Diethoxycyclobut-3-ene-1,2-dione (TCI America, 0.41 g, 0.36 mmol) was then added dropwise via syringe. Following completion of the addition, the mixture was allowed to regain room temperature and stir overnight. The precipitated solid was collected by Büchner filtration, washed with ethanol, and dried under house vacuum to provide the title compound as a white solid. ES/MS calcd. for C22H30N5O4+ 428.2, found m/z=428.3 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][CH:27]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:28]([OH:30])=[O:29].C[O-].[Na+].CO.Cl>O>[C:35]([O:34][C:32]([NH:31][C@@H:27]([CH2:26][NH:25][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4])[C:28]([OH:30])=[O:29])=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)NC(CN)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 95 °C
Yield: 71 %

Procedure:
A 20-mL scintillation vial was charged with 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol), 3-amino-2-tert-butoxycarbonylamino-propionic acid (319 mg, 1.56 mmol) (Bachem) and 0.5 M NaOMe/MeOH solution (2.5 mL, 1.25 mmol). The vial was close capped and heated in a 90-100° C. oil bath for 2 days. Reaction mixture was diluted with water (70 mL), acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 108 mg (0.22 mmol) in 71% yield. LC-MS ESI−: 491.16 (M−1)−.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][O:13][Si](C(C)(C)C)(C)C)=[C:8]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][OH:13])=[C:8]([S:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][CH:28]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2CO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2CO)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 15 ml round bottom flask charged with 2-tert-butyl-4-tert-butyldimethylsilyloxymethyl-5-(4-tert-butylbenzyl)thio-3(2H)-pyridazinone (2 g, 4.2 mmol) is added tetrabutylammonium fluoride solution (1M in THF, 21 ml, 21 mmol). The mixture is first stirred at room temperature for 5 hours and to it is added dichloromethane followed by water. The layers are separated and the organic layer is washed with water and dried. The organic layer is then concentrated and subjected to purification using silica gel flash chromatography (ethyl acetate/hexanes) to obtain the above compound.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33](=O)[CH3:34])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2].N1C=CC=C[CH:42]=1.CC(OC(C)=O)=O>C1(C)C=CC=CC=1.C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]([CH3:42])=[CH2:34])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2]
Reactant: c1ccncc1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C(C)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: C=C(C)c1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Reaction time: 0.67 h

Procedure:
To a solution of Ph3PMeI (378 mg, 0.935 mmol) in toluene (3 mL) was added KN(TMS)2 (0.5 M, 1.8 mL) dropwise. After stirring for 40 min, (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-acetylbenzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (intermediate AV) (360 mg, 0.626 mmol) in toluene (5 mL) was added. After stirring overnight, the reaction was quenched with a saturated solution of NaHCO3. The mixture was extracted 3× with AcOEt. The combined organic extracts were washed 1× with brine prior to drying over Na2SO4. Concentration of the solution gave an oily residue, which was redissolved in 3 of CH2Cl2, and then 0.2 mL of pyridine (2.47 mmol), 0.23 mL of Ac2O (2.44 mmol) and DMAP (catalytic quantity) were added. The mixture was stirred for 2 h at room temperature. Additional CH2Cl2 (20 mL) was added, the mixture was washed 2× with 1N HCl and 1× with brine prior to drying over Na2SO4. Concentration of the solution and purification of the crude product by silical gel column gave intermediate AZ (286 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH:17]=O)=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.CN(C)CC[O:31][NH2:32]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH:17]=[N:32][OH:31])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(C)CCON
Reactant: N#Cc1ccccc1-c1cc(-c2cnc3nc(C=O)ccn23)ccc1F
Solvent: CCO
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(C=NO)ccn23)ccc1F
Temperature: 55 °C
Yield: 28.7 %

Procedure:
A mixture of 2′-fluoro-5′-(7-formylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile (100 mg) and O-(2-dimethylaminoethyl)hydroxylamine (150 mg) in ethanol (5 ml) was heated at 55° C. for 16 h then cooled to ambient temperature. The resulting solid was collected by filtration and washed with ice-cold ethanol to give 2′-fluoro-5′-[7-(hydroxyiminomethyl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as a white solid (30 mg): δH (360 MHz, DMSO) 7.44 (1H, d, J 7), 7.62-7.73 (2H, m), 7.80 (1H, s), 7.89 (1H, dd, J 8 and 1), 7.90-7.93 (2H, m), 8.06 (1H, dd, J 8 and 1), 8.08 (1H, s), 8.13 (1H, s), 9.05 (1H, d, J 7), 12.25 (1H, s); m/z (ES+) 358 (M++H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:26])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:8]C(OCC1C=CC=CC=1)=O.[H][H]>C(O)C.[Pd].C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:26])[C@H:7]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH2:8]
Reactant: COCCOC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCCOC(=O)[C@@H](N)Cc1ccccc1
Yield: 91 %

Procedure:
A solution of N-(carbobenzyloxy)-L-phenylalanine 2-methoxy-ethyl ester (4.4 g, 12.3 mmol) in ethanol (75 mL) was treated with palladium on charcoal catalyst (440 mg, 10% Pd on charcoal) as a slurry in ethyl acetate (10 mL). Hydrogen gas was passed through the suspension for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide L-phenylalanine 2-methoxy-ethyl ester as a colorless oil (2.5 g, 92%). 1H-NMR; d (methanol-d4), 7.35-7.20 (5H, m), 4.27 (2H, m), 3.79 (1H, m), 3.57 (2H, m), 3.38 (3H, s), 3.10 (1H, dd), 2.90 (1H, dd) and 1.64 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C@@H:10]([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.I[CH:14]([CH3:16])[CH3:15].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH:14]([CH3:16])[CH3:15])[C@@H:10]([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)N1c2cc(Cl)nc(=O)n2C[C@@H]1C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a mixture of (S)-7-chloro-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50 mg, 0.27 mmol) and 2-iodopropane (68.7 mg, 0.404 mmol) in acetonitrile (1 mL) was added Cs2CO3 (176 mg, 0.539 mmol). The reaction mixture was stirred at 90° C. for 1 h, then cooled to room temperature, filtered and concentrated to give the residue as a brown solid. The crude was used into next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](=[O:27])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[CH:3]=2)=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: Nc1cccc(-c2ccncc2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccncc2)c1

Procedure:
Using the same method as in Example 1-(ii), 4-(3-aminophenyl)pyridine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-oxo-2-([3-(pyridin-4-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13](F)=[C:14]([N+:16]([O-])=O)[CH:15]=3)=[N:7][C:6]=2[CH:20]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.O.[H][H]>C(#N)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:14]([CH:15]=3)[NH2:16])=[N:7][C:6]=2[CH:20]=1
Reactant: NC1CCOCC1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(-c2nc3cc(Cl)ccc3o2)ccc1F
Agent: [Pd]
Solvent: O
Solvent: CC#N
Product: Nc1cc(-c2nc3cc(Cl)ccc3o2)ccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
To a suspension of 5-chloro-2-(2-fluoronitrobenzen-5-yl)benzoxazole (see Working Example 100-1) (5.00 g, 17.1 mmol) in acetonitrile (20 mL) was added 4-aminotetrahydropyran (3.81 g, 38.0 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered, washed with water and then dried. To a solution of the crystals obtained in a solvent mixture of methanol/tetrahydrofuran (1:1, 100 mL) was added 10% palladium-carbon (500 mg). A hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature overnight. After the reaction was complete, this was filtered through Celite, the filtrate was concentrated, and the residue obtained was purified by silica gel column chromatography to yield the title compound (2.86 g, 49% yield) as yellowish-brown crystals.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Cl[CH2:7][C:8]([N:10]([CH3:12])[CH3:11])=[O:9]>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:7][C:8]([N:10]([CH3:12])[CH3:11])=[O:9])(=[O:3])[CH3:2]
Reactant: CN(C)C(=O)CCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)OCC(=O)N(C)C
Temperature: 25 °C

Procedure:
A suspension of anhydrous sodium acetate (16.4 g, 0.2 mole) and 2-chloro-N,N-dimethylacetamide (24.3 g, 0.2 mole) in toluene (70 ml) was refluxed for 4 h. After cooling to room temperature the mixture was filtered and the filtrate washed with water (2×10 ml), dried and evaporated in vacuo. The solid residue obtained was recrystallized from ether yielding 22.0 g (76%). Mp 52°-53° C.
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH3:10])C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:22]1([NH:27][C:28]2[C:33]([CH:34]=O)=[CH:32][N:31]=[C:30]([S:36][CH3:37])[N:29]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH:22]1([N:27]2[C:28]3[N:29]=[C:30]([S:36][CH3:37])[N:31]=[CH:32][C:33]=3[CH:34]=[C:5]([CH2:6][CH2:7][O:8][CH2:9][CH3:10])[C:4]2=[O:11])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Reactant: CCOCCCC(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOCCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of 4-ethoxy-butyric acid ethyl ester (9.85 g, 61.47 mmol) in THF (25 ml) was added lithium bis(trimethylsilyl)amide (77.0 ml, 76.85 mmol, 1 M solution in THF). The reaction mixture was stirred for 10 minutes to form the anion. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde was then added and the reaction allowed to warm to RT and stirred overnight. The reaction mixture was quenched with 10% aqueous HCl (100 ml). The aqueous layer was extracted with ethylacetate (150 ml total) and the organic layers were combined and concentrated to give a yellow oil. Chromatographic purification on silica gel (chloroform/ethyl acetate gradient) gave 8-cyclopentyl-6-(2-ethoxy-ethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (3.22 g, 9.65 mmol). MS (APCI+) 334 (M+1, 100); 1H NMR δ (400 MHz, DMSO-d6) 8.54 (s, 1H), 7.47–7.46 (m, 1H), 5.99–5.90 (m, 1H), 3.69 (t, J=6.25 Hz, 2H), 3.49 (q, J=7.03 Hz, 2H), 2.84 (t, J=6.25 Hz, 2H), 2.59 (s, 3H), 2.34–2.29 (m, 2H), 2.08–2.02 (m, 2H), 1.88–1.83 (m, 2H), 1.69–1.65 (m, 3H), 1.17 (t, J=7.04 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])OC(C)(C)C)[C:3]=1[CH:16]=O.[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].CC(O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[CH:16]3[N:22]([C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])[CH2:21][CH2:20][CH2:19][N:18]3[C:9](=[O:15])[NH:8][C:4]=2[N:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C=O
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCN2C(=O)Nc3nccc(Cl)c3C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (4-chloro-3-formylpyridin-2-yl)carbamate (1.2 g, 4.67 mmol), tert-butyl (3-amino-propyl)carbamate (855 mg, 4.91 mmol), and AcOH (0.28 g, 4.67 mmol) were suspended in toluene (50 mL), and stirred overnight at room temperature. The reaction mixture was concentrated. The crude intermediate was dissolved in NMP (8 mL) in a 40 mL sealed tube, and stirred for 30 min. at 160 ° C. The reaction mixture was cooled, and the resulting precipitate was filtered, washed with MeOH, and dried under vacuum. LC-MS (M+H=339, obsd.=339).
Reaction SMILES: [BH4-].[Na+].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[O:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH:16]([CH2:24][CH2:25][N+:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH3:35])=[O:33])[CH:27]=2)[CH2:15]1.O.[Cl:37]CCl>CO>[ClH:37].[CH3:35][O:34][C:32]([C:28]1[CH2:27][N:26]([CH2:25][CH2:24][CH:16]2[CH2:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][CH2:15]2)[CH2:31][CH2:30][CH:29]=1)=[O:33]
Reactant: COC(=O)c1ccc[n+](CCC2COc3ccccc3C2)c1
Reactant: ClCCl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C1=CCCN(CCC2COc3ccccc3C2)C1
Product: Cl
Reaction time: 2 h

Procedure:
At -10° and while stirring, 1.41 g of sodium borohydride are introduced within a period of 90 minutes into a suspension of 8.45 g (18 mmol) of 1-[2-(chroman-3-yl)ethyl]-3-methoxycarbonylpyridinium p-toluenesulphonate in 43 ml of methanol. Stirring is continued for 1 hour at 0° and for 2 hours at room temperature and then 50 ml of water are added to the reaction mixture and extraction by shaking is carried out twice with 100 ml of dichloromethane each time. The dichloromethane phases are combined, dried over magnesium sulphate and concentrated to dryness by evaporation. The crude product is purified by chromatography on 150 g of silica gel (0.063-0.2 mm) using ethyl acetate as the eluant. The main eluate, which is concentrated by evaporation, is treated with ethereal hydrochloric acid to yield 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride having a melting point of 175°-177°.