Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:49])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]([N:41]3[CH2:46][C@@H:45]([CH3:47])[NH:44][CH2:43][C@@H:42]3[CH3:48])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=3)[CH:28]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16].[CH:50](=O)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(O)(=O)C>CN(C)C=O>[CH2:15]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:49])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C@@H:33]([N:41]3[CH2:46][C@@H:45]([CH3:47])[N:44]([CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH2:43][C@@H:42]3[CH3:48])[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=3)[CH:28]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4ccccc4)C[C@@H]3C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (1.083 g) was added to a mixture of 1-{3-[(R)-((2S,5R)-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester (981 mg, Example 121), benzaldehyde (434.1 mg) and acetic acid (245.6 mg) in dimethylformamide (15 mL). The reaction was stirred under nitrogen at room temperature for 2 hours. The reaction was quenched by the addition of saturated NH4Cl solution (2 mL), followed by the addition of H2O (10 mL). The resulting solution was diluted with 120 mL of H2O which caused precipitation of product. The solution was neutralized with saturated NaHCO3 solution to pH=7 to precipitate additional product. The mixture was filtered thru a celite pad. The collected solid was rinsed with water (35 mL×2). The solid was dissolved with EtOAc (50 mL) and then eluted through the celite pad. The filtrate (EtOAc solution) was washed with H2O (15 mL×2) and brine (15 mL×1), dried over Na2SO4 and concentrated to give crude product, which was purified by silica gel chromatography conducted on CombiFlash™ Sq 16×(gradient: 100% CH2Cl2 to 10% MeOH in CH2Cl2) to give 1-{3-[(R)-((2S,5R)-4-benzyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester as pink solid (570 mg; 49%). 1H NMR (300 MHz, CDCl3) δ 7.47 (m, 3H), 7.26 (m, 6H), 7.07 (dd, J=8.0, 8.0 Hz, 1H), 6.60 (m, 2H), 6.54 (s, 1H), 5.04 (s, 1H), 4.50 (m, 1H), 4.16 (q, J=7.0 Hz, 2H), 3.98 (d, J=13.0 Hz, 1H), 3.69 (m, 1H), 3.18 (d, J=13.0 Hz, 1H), 3.02 (m, 2H), 2.70-2.52 (m, 5H), 2.00 (m, 3H), 1.73 (m, 31H), 1.26 (t, J=7.0 Hz, 3H), 1.10 (d, J=6.0 Hz, 3H), 1.02 (d, J=6.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[CH:20]=[CH:19][C:11]([O:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>CC(C)=O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[CH:20]=[CH:19][C:11]([O:12][C:13]([CH3:18])([CH3:17])[C:14]([N:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: OCCNCCO
Reactant: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)Cl
Solvent: CC(C)=O
Product: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)N(CCO)CCO

Procedure:
A solution of 3.36 g (10 millimoles) of 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionoyl chloride in 15 ml of acetone were added, slowly under stirring at room temperature, to a solution of 2.1 g (20 millimoles) of diethanolamine in 30 ml of acetone.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11](O)(=O)[CH2:12][OH:13]>C1(C)C=CC=CC=1>[OH:13][CH2:12][C:11]1[NH:1][C:2]2[C:7]([N:8]=1)=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2
Reactant: O=C(O)CO
Reactant: Cc1cc(C)c(N)c(N)n1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2nc(CO)[nH]c2n1
Yield: 15.2 %

Procedure:
A mixture of 13.72 g of 2,3-diamino-4,6-dimethylpyridine and 25 g of glycolic acid in 200 ml of toluene was heated under reflux for 3.5 hours, whilst distilling off azeotropically the water formed in the course of the reaction. At the end of this time, the reaction mixture was freed from the toluene by decantation and the oily residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethanol and ethyl acetate in ratios ranging from 2:3 to 1:1 by volume as a eluent, to give 2.7 g of the title compound, melting at 244-246° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][C:13]([O-:16])(C)[CH3:14].[K+].Cl>C(O)(C)C.O>[Cl:1][C:2]1[C:3]([O:16][CH:13]([CH3:14])[CH3:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ncc(C(=O)O)cc1Cl
Temperature: 80 °C

Procedure:
5,6-Dichloronicotinic acid (1.95 g, 10 mmol) is added to a solution of KOtBu (2.28 g, 20 mmol) in isopropanol (20 mL). The mixture is heated at 80° C. for 15 h. The mixture is diluted with water (60 mL) and acidified with 1M aq. HCl. The aq. solution is extracted with ether (5×50 mL) and the combined org. extracts are dried (Na2SO4), filtered and evaporated to provide 5-chloro-6-isopropoxy-nicotinic acid; 1H NMR (d6-DMSO) δ 1.38 (d, J=6.2 Hz, 7H), 5.44 (hept, J=6.2 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.65 (d, J=2.1 Hz, 1H)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8][CH:7]=1.[Cl:15][CH2:16][C:17]([CH2:19]Cl)=O>C(#N)CC>[Cl:15][CH2:16][C:17]1[N:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:7][CH:8]=2)[S:14][CH:19]=1
Reactant: NC(=S)c1ccc(OCCCCl)cc1
Reactant: O=C(CCl)CCl
Solvent: CCC#N
Product: ClCCCOc1ccc(-c2nc(CCl)cs2)cc1
Temperature: 100 °C
Yield: 91 %

Procedure:
4-(3-chloropropoxy)benzenecarbothioamide ax71 (0.9 g, 4 mmole, 1 eq) is dissolved in propionitrile (20 ml) and 1,3-dichloroacetone (0.6 g, 4.7 mmole, 1.17 eq) is added. The mixture is refluxed 1 h at 100° C. then concentrated to dryness. The crude material is taken up in dichloromethane, washed with water and dried over magnesium sulfate. The residue is triturated in diisopropylether and filtered off to give 1.1 g of 4-(chloromethyl)-2-[4-(3-chloropropoxy)phenyl]-1,3-thiazole ax72 as a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:20][CH2:21][C@@H:22]1[C@@H:27]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26][CH:25]=[CH:24][CH2:23]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S([O-])(O)=O.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.CCCCCC>[C:30]([O:29][CH2:28][C@@H:27]1[C@@H:22]([CH2:21][O:20][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:23][CH:24]2[CH:25]([O:9]2)[CH2:26]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(OC[C@H]1CC=CC[C@@H]1COC(=O)c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(OC[C@H]1CC2OC2C[C@@H]1COC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
m-Chloroperbenzoic acid (777 mg, 4.5 mmoles) was added to a solution of (4S,5S)-4,5-bis(benzoyloxymethyl)-1-cyclohexene (1.05 g, 3.0 mmoles) in methylene chloride (6 ml) under cooling with ice. After stirring the mixture at room temperature for 2 hours, a saturated aqueous solution of sodium hydrogen sulfite was added to the reaction mixture and the excessive peracid was decomposed, after which a saturated aqueous solution of sodium hydrogen carbonate was added and the whole mixture was subjected to extraction with ethyl ether. The ether extract solution was washed with water and then with saturated aqueous solution of sodium hydrogen carbonate, and dried on anhydrous sodium sulfate. After distilling off the solvent therefrom under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3, v/v) to obtain (3S,4S)-3,4-bis(benzoyloxymethyl)-7-oxabicyclo[4.1.0]heptane (1.025 g, Yield 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[O:24][CH2:25][C:26]([O:28]C)=[O:27])[CH:5]=[CH:6][C:7]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].C1COCC1.CO>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[O:24][CH2:25][C:26]([OH:28])=[O:27])[CH:5]=[CH:6][C:7]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9]
Reactant: COC(=O)COc1ccc(C(F)(F)F)cc1-c1ccc(S(=O)(=O)C(C)C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(-c2cc(C(F)(F)F)ccc2OCC(=O)O)cc1F

Procedure:
A solution of the product from step e) (140 mg) in NaOH (0.35 ml, 1 M), THF (2 ml) and MeOH (1 ml) was stirred for 2 h. The solvent was removed in vacuo and the residue was washed with ether, acidified (2M HCl) and extracted with DCM (thrice). The organic extracts were dried (MgSO4), evaporated and crystallised from isohexane-DCM to give the title compound (105 mg). M.p. 170-1° C.
Reaction SMILES: [CH3:1][C:2]([N:9]([CH3:11])[CH3:10])([CH2:5][CH2:6][CH2:7][CH3:8])[C:3]#[N:4].O>CCOCC>[CH3:1][C:2]([N:9]([CH3:10])[CH3:11])([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][NH2:4]
Reactant: CCCCC(C)(C#N)N(C)C
Solvent: CCOCC
Solvent: O
Product: CCCCC(C)(CN)N(C)C
Temperature: 0 °C

Procedure:
A solution of 2-methyl-2-dimethylamino-hexanenitrile (7.70 g.,) in dry ether (100 ml.) was added dropwise to a stirred solution of sodium dihydro-bis(2-methoxyethoxy)aluminate (45.3 g., 70% solution in benzene, 25% excess) in dry ether (100 ml.) under nitrogen with ice water cooling. The solution was refluxed overnight under nitrogen and allowed to cool. Ether (200 ml.) was added, followed by dropwise addition of excess water with ice-water cooling to destroy excess reducing reagent. The mixture was filtered on hyflo and the filtrates extracted with ether (4 × 100 ml.). The combined ether extracts were washed with water (4 × 200 ml.), dried (Na2SO4) and evaporated leaving a colourless oil. Distillation of the oil afforded 2-methyl-2-dimethylamino-hexylamine as a colourless liquid (4.808 g., 61%) b.p. 86-88/12 mm.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][N:10]([CH:13]([CH3:15])[CH3:14])[CH2:9][C@H:8]2[C:16]([O:18][CH3:19])=[O:17])[C:3]1=[O:20].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C(N(CC)CC)C>C(O)C>[CH:13]([N:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[C:3]2=[O:20])[C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9]1)([CH3:14])[CH3:15]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: COC(=O)[C@@H]1CN(C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CN(C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O

Procedure:
(3R,4S)-Methyl 4-((3S)-3-amino-2-oxopyrrolidin-1-yl)-1-isopropylpiperidine-3-carboxylate (50 mg, 0.176 mmol, 1 eq.), 4-chloro-6-(trifluoromethyl)-quinazoline (45 mg, 0.194 mmol, 1.1 eq.) and triethylamine (98 uL, 0.706 mmol, 4 eq.) were dissolved in ethanol (3 mL) at room temperature then microwaved at 100° C. for 1 hour. Purified by HPLC. Obtained (3R,4S)-methyl 1-isopropyl-4-(2-oxo-(3S)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)piperidine-3-carboxylate, bis TFA salt (88 mg) as a white solid. LCMS detects (M+H)+=480.39. 1H NMR (400 MHz) (CD3OD) δ 8.82 (s, 1H, J=7 Hz); 8.20 (s, 1H, J=7 Hz); 8.78 (s, 1H, J=7 Hz); 7.91 (d, 1H, J=7 Hz); 7.30-7.10 (m, 1H); 5.37 (m, 1H); 4.3-4.05 (m, 1H); 3.80-3.00 (m, 9H); 2.60-2.45 (m, 1H); 2.45-2.10 (m, 2H); 2.10-1.80 (m, 2H); 1.27 (m, 6H).
Reaction SMILES: C([O:8][C:9]([CH:11]([CH2:24][CH2:25][C:26]([O:28]CC1C=CC=CC=1)=[O:27])[CH2:12][P:13]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[OH:14])=[O:10])C1C=CC=CC=1>O.[Pd]>[CH2:16]([P:13]([CH2:12][CH:11]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:9]([OH:10])=[O:8])([OH:15])=[O:14])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(CCC(CP(=O)(O)CCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: O
Product: O=C(O)CCC(CP(=O)(O)CCc1ccccc1)C(=O)O
Yield: 115.7 %

Procedure:
2,4-Di(benzyloxycarbonyl)butyl(phenethyl)phosphinic acid (1.1 g, 2.2 mmol) in 20 mL of water containing 120 mg of 10% Pd/C was hydrogenated on a Parr hydrogenator at 40 psi overnight. Filtration through a Celite pad followed by evaporation on high vacuum gave 0.8 g (114%) of 2-[(phenethylhydroxyphosphinyl)methyl]pentanedioic acid (4, R=CH2CH2Ph) as a white solid.
Reaction SMILES: [C:1]([N:4](C)[NH:5][C:6](=[O:24])[CH:7](OCC1C=CC=CC=1)[C:8]([NH:10][N:11](C(O)=O)[CH3:12])=[O:9])(O)=O>[Pd].CO>[CH3:12][NH:11][NH:10][C:8](=[O:9])[CH2:7][C:6]([NH:5][NH:4][CH3:1])=[O:24]
Reactant: CN(NC(=O)C(OCc1ccccc1)C(=O)NN(C)C(=O)O)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CNNC(=O)CC(=O)NNC
Reaction time: 8 h

Procedure:
A flask was charged with crude N′1,N′3-dicarboxybenzyloxy-N′1,N′3-dimethylmalono-hydrazide from the step below, methanol, 10% palladium on carbon, put under an atmosphere of hydrogen, and stirred overnight. The suspension was filtered through celite and evaporated to dryness to give N′1,N′3-dimethylmalonohythazide (2.4 g; 15 mmol)
Reaction SMILES: Cl.[F:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:10]([C:11]2[CH:15]=[CH:14][O:13][N:12]=2)=[CH:9][C:8]([C:16]2[N:21]=[C:20]([NH2:22])[C:19]([NH2:23])=[CH:18][N:17]=2)=[N:7]1.ClCCl.[CH2:31]([O:33]CC)[CH3:32]>C(O)(=O)C>[NH2:22][C:20]1[C:19]([NH:23][C:31](=[O:33])[CH3:32])=[CH:18][N:17]=[C:16]([C:8]2[CH:9]=[C:10]([C:11]3[CH:15]=[CH:14][O:13][N:12]=3)[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=3[F:2])[N:7]=2)[N:21]=1
Reactant: Nc1cnc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)nc1N
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)Nc1cnc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)nc1N
Temperature: 25 °C
Yield: 79 %

Procedure:
A solution of 2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidine-4,5-diamine hydrochloride (I-107) (30 mg, 0.077 mmol) in acetic acid (2 mL) was heated to 110° C. for 18 h. After cooling to room temperature, the solution was partitioned between ethyl actetate (50 mL) and saturated aqueous sodium carbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organics were dried over MgSO4, filtered, and the solvent was removed in vacuo to give the crude product as a tan residue. Dichloromethane (3 mL) and diethyl ether (5 mL) were added, and the resulting white solid was filtered and washed with additional diethyl ether ether to give N-(4-amino-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-5-yl)acetamide (24 mg, 0.061 mmol, 79% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, 1H), 8.26 (s, 1H), 7.66 (br s, 1H), 7.34 (s, 1H), 7.18-7.13 (m, 1H), 7.01-6.96 (s, 1H), 6.92 (t, 1H), 6.77 (t, 1H), 6.56 (d, 1H), 5.96 (s, 2H), 5.57 (br s, 2H), 2.12 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[H-].[Na+].Br[C:22]([CH3:28])([CH3:27])[C:23](C#N)=[O:24]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:18][C:22]([CH3:28])([CH3:27])[C:23](=[O:24])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CSc1ccc(C(=O)Cc2ccccc2)cc1Cl
Reactant: CC(C)(Br)C(=O)C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.6 g of 1-{3-chloro-4-(methylthio)phenyl}-2-phenyl-ethanone in 100 ml dry THF was stirred at 0° C. for 20 minutes in the presence of 60% oil dispersion of sodium hydride (1.5 g), which was followed by dropwise addition of α-bromoisobutyryl cyanide (3.0 ml) diluted in 50 ml THF. The reaction solution was allowed to warm slowly to room temperature and was stirred overnight. Then the solvent was removed in vacuo, which was followed by extraction with 30 ml water and diethylether (50 ml×3). The organic layer was concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=8:1) to yield 3.2 g of 5-{3-chloro-4-(methylthio)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone. NMR: δ1.52 (s, 6H), 2.45 (s, 3H), 7.17 (d, J=8.4 Hz, 1H), 7.25 (m, 3H), 7.32 (m, 2H), 7.87 (dd, J=8.4, 1.8 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H). IR (cm−1): 1694, 1613, 1592, 1389, 1252, 1145, 1128.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[O:11]([CH2:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>[OH-].[Na+]>[O:11]([CH2:18][C:19]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(COc1ccccc1)Nc1ccccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a solution of anthranilic acid (5 g, 0.036 mol) in NaOH (3 g, 30 mL) was added phenoxyacetyl chloride (6.2 g, 5.2 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 min, acidified with dilute hydrochloric acid and filtered. The filtered solid was dissolved in EtOAc and filtered. The filtrate was dried, filtered, concentrated and dried for 4 h under vacuum, affording 8 g (81%) of the title compound, mp 201-203° C. A small amount (100 mg) of the title compound was recrystallized from EtOH, affording 75 mg of the title compound, mp 202-203° C.; 1H NMR (DMSO-d6) δ 13.70 (s, 1H, COOH), 12.20 (s, 1H, NH), 8.71 (d, 1H, J=8.4), 8.02 (dd, 1H, J=7.6), 7.65-7.60 (m, 1H), 7.35-6.89 (m, 6H), 4.73 (s, 2H); 13C NMR (DMSO-d6) δ 169.44, 167.23, 157.11, 140.22, 134.34, 131.32, 129.65, 129.45, 123.06, 121.65, 120.96, 119.45, 116.14, 114.81, 114.38, 67.22; MS (EI, m/z) 271 (M+).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.Cl.[CH3:46][O:47][C:48](=[O:51])[CH2:49][NH2:50]>C(N(CC)CC)C>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:10]=[C:11]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:26][CH:27]=3)[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:50][CH2:49][C:48]([O:47][CH3:46])=[O:51])[CH2:19][CH2:20]3)[N:14]=1)[CH2:2]2
Reactant: COC(=O)CN
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.TFA (50 mg) and glycine methyl ester hydrochloride (20 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118 the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 574.8 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[S:12][C:8]=2[C:7]=1[C:21]#[N:22].[N:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)=[C:27]=[O:28]>CN(C)C=O.C(OCC)(=O)C>[C:21]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])=[N:10][C:9]=2[CH:19]=[CH:20][C:6]=1[O:5][C:4]1[CH:23]=[CH:24][CH:25]=[C:2]([NH:1][C:27](=[O:28])[NH:26][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=2)[CH:3]=1)#[N:22]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(Oc2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (120 mg, 0.342 mmol) produced in Example 3(vi) was dissolved in N,N-dimethylformamide (2 mL), 1-isocyanato-4-(trifluoromethyl)benzene (63 mg, 0.445 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (5 ml) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→5/95). The obtained solution was concentrated under reduced pressure to give the title compound (173 mg, 94%) as a white powder.
Reaction SMILES: O[CH:2]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10].CCN(S(F)(F)[F:23])CC.C(O)C>O1CCOCC1>[F:23][CH:2]([CH2:12][O:13][C:14](=[O:16])[CH3:15])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)OCC(O)Cn1ccnc1[N+](=O)[O-]
Reactant: CCN(CC)S(F)(F)F
Solvent: C1COCCO1
Solvent: CCO
Product: CC(=O)OCC(F)Cn1ccnc1[N+](=O)[O-]
Yield: 29.1 %

Procedure:
To a solution of 3.93 g (17.1 mmol) of 1-(2'-hydroxy-3'-acetoxypropyl)-2-nitroimidazole in 30 ml of dry dioxane, 4.00 g of DAST was dropwise added with stirring and cooling by ice. After addition, the mixture was reacted for 5 hours at room temperature with stirring. Thereafter, to the solution, 10 ml of ethanol was added to decompose excess DAST. The solution was then concentrated and partitioned between chloroform and an aqueous solution of sodium hydrogen carbonate. The chloroform phase was dried on magnesium sulfate and filtered. The filtrate was concentrated and subjected to isolation and purification by silica gel column chromatography to give 1.15 g of 1-(2'-fluoro-3'-acetoxypropyl)-2-nitroimidazole.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C([O:8][CH2:9][CH2:10][CH:11](Cl)[C:12](=O)[CH3:13])(=O)C>C1(C)C=CC=CC=1>[NH2:1][C:2]1[S:3][C:11]([CH2:10][CH2:9][OH:8])=[C:12]([CH3:13])[N:4]=1
Reactant: CC(=O)OCCC(Cl)C(C)=O
Reactant: NC(N)=S
Solvent: Cc1ccccc1
Product: Cc1nc(N)sc1CCO
Temperature: 80 °C

Procedure:
2-(2-Amino-4-methyl-thiazol-5-yl)-ethanol was prepared according to general procedures presented hereinabove, by adding 20 grams (0.263 moles) of thiourea to 200 ml of dry toluene, followed by addition of 47 grams (0.263 moles) of 5-acetoxy-3-chloro-2-pentanone over a time period of 20 minutes. The reaction mixture was heated at 80° C. for 24 hours and thereafter approximately 180 ml of toluene were removed by evaporation. 180 ml of water and 20 ml of HCL solution (32%) were then added and the reaction mixture was refluxed for 1 hour at 90° C. The organic phase was then removed by washing with chloroform, and the aqueous phase was turned basic (pH 8-9) using a 5 N solution of sodium hydroxide. The product was extracted once with 70 ml chloroform and once with 70 ml ethyl acetate. The combined organic extracts were dried over sodium sulfate and the solvents were removed by evaporation to give 30 grams (72% yield) of violet-brown crystals.