Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[C@H:3]([OH:5])[CH3:4].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Na+]>[CH2:7]([O:5][C@H:3]([CH3:4])[C@H:2]([OH:6])[CH3:1])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H](O)[C@@H](C)O
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](C)OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
5.00 g (44.6 mmol) of potassium tert.-butylate was added to a solution of 4.00 g (44.4 mmol) (2R,3R)-butane-2,3-diol in 300 ml THF at room temperature and the mixture was refluxed for 15 minutes. The mixture was cooled to approx. 50° C. and 5.3 ml (44.6 mmol) benzyl bromide was added. It was refluxed for 3 hours, and was then stirred overnight at room temperature. The mixture was diluted with ethyl acetate and sodium chloride solution and then washed with 1N hydrogen chloride solution (1×) and sodium chloride solution (2×). The organic phase was dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was purified chromatographically (hexane/ethyl acetate 1:1). 3.41 g (18.9 mmol; yield: 43%) of the product was obtained.
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.[CH3:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[CH:9]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.[Zn+2].[I-].[I-]>[NH2:6][CH2:5][C:14]([C:10]1[CH:9]=[C:8]([CH3:7])[CH:13]=[CH:12][N:11]=1)([OH:18])[CH2:15][CH2:16][CH3:17]
Reactant: CCCC(=O)c1cc(C)ccn1
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCCC(O)(CN)c1cc(C)ccn1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
TMSCN (0.3 mL, 2.28 mmol) followed by ZnI2 (51 mg, 0.16 mmol) were sequentially added to neat 1-(4-methylpyridin-2-yl)butan-1-one (372 mg, 2.28 mmol) with stirring under Ar. Reaction stirred at rt for 4 hours. THF (6 mL) was added to cyanohydrin, then this was slowly added dropwise over 10 min via cannula to LAH (140 mg, 3.6 mmol) in THF (10 mL) with stirring under Ar. Reaction warmed as addition progressed. Once addition was ended, reaction heated to reflux for 1 hour, then cooled to rt then in ice. To the cool reaction with stirring was added Na2SO4.10H2O, the reaction stirred overnight and was allowed to warm to RT as the bath warmed. The reaction was filtered, the solid washed with EtOAc; the organic phase extracted with 10% HCl (2×). The aqueous extracts were combined and washed with Et2O. Aqueous phase was basified to pH ˜12 with 5M NaOH, saturated with NaCl, then extracted with Et2O (3×). The combined extracts were dried (MgSO4), filtered and concentrated to afford 330 mg of 1-amino-2-(4-methylpyridin-2-yl)pentan-2-ol as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.36 (d, J=5.05 Hz, 1H), 7.18 (s, 1H), 7.00 (d, J=5.81 Hz, 1H), 3.04 (d, J=12.88 Hz, 1H), 2.90 (d, J=12.88 Hz, 1H), 2.37 (s, 3H), 1.71 (m, 2H), 1.40 (m, 1H), 0.77-0.95 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C([Li])CCC.CON(C)[C:23](=[O:27])[CH2:24][CH2:25][CH3:26].Cl.C(=O)([O-])O.[Na+]>C(OCC)C>[C:23]([C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1)(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC(=O)N(C)OC
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC(=O)c1ccc(NC(=O)C(C)(C)C)nc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 71.6 %

Procedure:
A solution of N-(5-bromopyridin-2-yl)-2,2-dimethyl-propionamide (3.582 g, 13.9 mmol) in diethyl ether (36 mL) was cooled to −78° C. under argon and n-butyllithium (1.6 M, 19 mL, 30.4 mmol) was added dropwise within 20 min. 5 min after complete addition the mixture was allowed to warm up to 0° C. N-Methoxy-N-methyl butyramide (3.65 g, 27.8 mmol) was added within less than 5 min and stirring was continued for 45 min. The clear solution was acidified with 2 N hydrochloric acid to pH 2. After vigorous stirring for 15 min the mixture was neutralised with sodium hydrogen carbonate and the layers were separated. The aqueous layer was extracted three times with diethyl ether. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The resulting oil was dried in oil pump vacuum to remove the excess reagent. After flash chromatography (dichloromethane/methanol 60:1) crude N-(5-butyryl-pyridin-2-yl)-2,2-dimethyl-propionamide (2.47 g, 71%) was obtained as a light orange oil which was not purified further.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.O=[C:24]1[C@@:29]([O:35][C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[C:38]([F:44])[CH:37]=2)([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27][CH2:26][NH:25]1>C1(C)C=CC=CC=1>[S:10]=[C:24]1[C@@:29]([O:35][C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[C:38]([F:44])[CH:37]=2)([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27][CH2:26][NH:25]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCNC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@]1(Oc2cc(F)c(F)c(F)c2)CCCNC1=S
Temperature: 100 °C
Yield: 142.8 %

Procedure:
Lawesson's reagent (4.46 g) was added to a mixture of ethyl (3R)-2-oxo-3-(3,4,5-trifluorophenoxy)piperidine-3-carboxylate (5.00 g) in toluene (50 mL) at room temperature, and the mixture was stirred with heating at 100° C. for 1 hr. After cooling to room temperature, the reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give ethyl (3S)-2-thioxo-3-(3,4,5-trifluorophenoxy)piperidine-3-carboxylate (5.25 g). To a mixture of ethyl (3S)-2-thioxo-3-(3,4,5-trifluorophenoxy)piperidine-3-carboxylate (5.25 g) in acetonitrile (25 mL) was added methyl iodide (2.94 mL) at room temperature, and the mixture was stirred under a nitrogen atmosphere at 50° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, to the residue was added 10% aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (5.65 g).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:39]([NH:46][CH2:47][CH2:48][CH:49]=O)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C(OC(=O)NCCCNC(C1N(CC2C=CC=CC=2)C(=O)C2C(=CC(Cl)=CC=2)N=1)C(C)C)(C)(C)C>C(Cl)Cl>[C:42]([O:41][C:39](=[O:40])[N:46]([NH:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4])[CH2:47][CH2:48][CH3:49])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)NCCC=O
Reactant: CC(C)C(N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)C(NCCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Product: CCCN(NC(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C)C(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 109.6 %

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, nitrogen inlet and cold bath was charged with 10.0 g of 2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-quinazolin-4-one (a compound of Formula 301 prepared, e.g., as described in Example 1.6 or 3.1), 50 mL of DCM and 6.20 g (1.2 eq) of sodium triacetoxyborohydride and cooled to 10° C., followed by the portionwise addition of N-Boc-3-aminopropanal 7.1 g (1.4 eq). Upon indication of completion by TLC, the reaction was quenched with 2.0 mL of methanol and stirred for an additional 30 minutes, during which a slight exotherm was observed. The mixture was washed with 1 N hydrochloric acid (until the aqueous layer was clear and acidic)(also exothermic) and then washed with 2N sodium hydroxide (until basic), followed by drying over sodium sulfate, and filtration. The resulting off-white foam solid was filtered and solvents partially stripped under vacuum to give 16.0 g (110% yield) of the title compound of Formula 302, {3-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][OH:13].CCN(CC)CC.[Cl:21][C:22](OC(Cl)(Cl)Cl)=[O:23]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][O:13][C:22]([Cl:21])=[O:23]
Reactant: O=[N+]([O-])c1cccc(F)c1CCO
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cl)OCCc1c(F)cccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of 2-(2-fluoro-6-nitrophenyl)ethanol (500 mg, 2.7 mmol) and Et3N (273 mg, 2.7 mmol, dist. over KOH) in THF (6.75 ml, dist. over CaH2) was dropped into a solution, cooled to 0° C., of trichloromethyl chloroformate (641 mg, 3.24 mmol) in THF (6.75 ml, see above) for 5 min. It was stirred for 1 h while cooling in an ice bath and then stirred for 1 h at room temperature. The mixture was filtered over Celite. Rewashing the filter cake with THF and removing the solvent and excess reagent from the pooled filtrates by distillation at 30° C. in a high vacuum yielded 2-(2-fluoro-6-nitrophenyl)ethoxycarbonyl chloride (620 mg, 93%) as a light-brown oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]OC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: COC(OC)OC
Reactant: O=C(O)c1cccc(Br)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1cccc(Br)c1F
Reaction time: 16 h
Yield: 84 %

Procedure:
A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in dry methanol (5 ml) under nitrogen was treated with trimethylorthoformate (0.22 ml, 2 mmol) and p-toluenesulfonic acid (catalytic amount), and then heated under reflux. After 16 h, the mixture was evaporated and the residue partitioned between water and Et2O. The organic layer was washed with sat. sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 84%): 1H NMR (CDCl3) δ 7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H), 7.10 (dt, 1H, J=8.0, 1.0 Hz) and 3.94 (s, 3H): MS (EI) 232 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][NH2:25].[OH:26][CH2:27][CH:28]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][N:25]=[CH:28][CH2:27][OH:26]
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Reactant: O=CCO
Product: CC1=C(CCON=CCO)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylsulfinylphenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with hydroxyacetaldehyde by the method of Example 1.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O>>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2cccnc2n1Cc1ccccc1
Solvent: Cc1ccccc1
Product: Clc1nc2cccnc2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
Grams 21 3-benzyl-2-hydroxy-3H-imidazo[4,5-b]pyridine in 330 ml phosphoryl chloride are refluxed until complete dissolution then gaseous hydrogen chloride is bubbled therein for 3 and a half hours. It is then cooled to room temperature and the undissolved product filtered and washed with toluene; the solution is evaporated in vacuo to a small volume and cautiously poured into ice. The solution is then filtered on charcoal and the filtrate adjusted to pH 7.5 by adding 30% ammonium hydroxyde. The undissolved product is separated by filtration, washed with water ed evaporated in vacuo to dryness, the product thus obtained suspended in 150 ml boiling toluene and the undissolved product filtered off. From the toluene solution are obtained by crystallization 5 g 3-benzyl-2-chloro-3H-imidazo[4,5-b]pyridine melting at 74°-76° C.
Reaction SMILES: F[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CS(C)=O.CCN(C(C)C)C(C)C.[Cl-].[CH3:24][N:25]([CH3:32])[S:26]([CH2:29][CH2:30][NH3+:31])(=[O:28])=[O:27]>CCOC(C)=O>[C:8]([C:3]1[C:2]([NH:31][CH2:30][CH2:29][S:26]([N:25]([CH3:32])[CH3:24])(=[O:28])=[O:27])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:9]
Reactant: CN(C)S(=O)(=O)CC[NH3+]
Reactant: N#Cc1ncccc1F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)CCNc1cccnc1C#N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-fluoro-2-cyanopyridine (Sakamoto et. al., Chem. Pharm. Bull. 1985, 33: 565-571) (1 g, 8.2 mmol) was placed in a high pressure tube equipped with a stir bar. DMSO (7 mL), Hunig's base (1.57 mL, 9.0 mmol) and 2-[(dimethylamino)sulfonyl]-ethanaminium chloride (1.7 g, 9.0 mmol) were added and the vessel was sealed and heated to 80° C. for 5.5 hours, then stirred at room temperature overnight. The reaction was treated with an additional 0.3 equivalent of Hunig's base and 0.2 equivlanet of the amine salt and heated for 3 hours, but the reaction progressed no further. The mixture was cooled, added to the top of a silica gel column (60 mm by 7 inches) packed in EtOAc and the column eluted with EtOAc. Careful cutting of fractions allowed isolation of the product after evaporation as a clear, colorless oil that solidified upon standing.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]([CH3:37])([O:6][C:7]([N:9](C(OC(C)(C)C)=O)[C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([CH:22]=[C:23]([C:25]([O:27]CC)=[O:26])[N:24]=3)[CH:21]=2)[CH:13]=[CH:12][CH:11]=1)=[O:8])[CH3:5].O1CCCC1.Cl.Cl>CO>[CH3:5][C:4]([CH3:37])([O:6][C:7]([NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([CH:22]=[C:23]([C:25]([OH:27])=[O:26])[N:24]=3)[CH:21]=2)[CH:13]=[CH:12][CH:11]=1)=[O:8])[CH3:3]
Reactant: CCOC(=O)c1cn2cc(-c3cccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n3)ccc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3nc(C(=O)O)cn3c2)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 90.9 %

Procedure:
0.9 mL of aqueous 2 M lithium hydroxide solution is added to a solution of 292 mg of ethyl 6-(6-{bis[(1,1-dimethylethoxy)carbonyl]amino}pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate in 4.73 mL of a 50/1 mixture of tetrahydrofuran and methanol. The reaction mixture is stirred for 7 hours at 25° C. and then treated dropwise at 0° C. with 2 N hydrochloric acid HCl until a pH of 3 is obtained. The precipitate formed after 20 minutes is filtered off by suction and washed with water (20 mL) and diethyl ether (20 ml) and then dried under reduced pressure to give 195 mg of 6-(6-{[(1,1-dimethylethoxy)carbonyl]amino}pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylic acid in the form of a beige-coloured solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:36])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34]O)[CH:28]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:70]=[N+:71]=[N-:72])(C2C=CC=CC=2)=O)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:36])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:70]=[N+:71]=[N-:72])[CH:28]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(CCO)c3)c2)Cc2ccccc2C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(CCN=[N+]=[N-])c3)c2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
300 mg (0.613 mmol) of 2-(3-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-indane-2-carboxylic acid methyl ester (methyl ester intermediate of example 27) and triphenylphosphine (0.241 g, 0.920 mmol) were dissolved in THF (5 ml) and cooled in an ice bath. Diphenylphosphoryl azide (0.258 g, 0.920 mmol) and DIAD (0.198 g, 0.920 mmol) were added sequentially, the ice bath was removed and the mixture was stirred for 2 h at room temperature. The mixture was evaporated to dryness and purified by silica gel chromatography (HEP/EA gradient) to yield 0.188 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1c(F)cccc1Cl
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4c(F)cccc4Cl)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(2-chloro-6-fluoro-phenyl)-1-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7]O)[CH2:3][CH2:2]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][CH:15]=[N:16]2)=[C:12]([Cl:19])[N:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[C:12]([Cl:19])[N:11]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: OCC1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2ncn(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tetrahydro-2H-pyran-4-ylmethanol (2.44 g) and 2,6-dichloropurine (1.97 g) was dissolved in dry THF (25 mL). To this solution was added triphenylphosphine (5.51 g), followed by diisopropyl azodicarboxylate (4.14 mL) added drop wise. The temperature of the reaction was kept below 43° C. (some cooling with a water bath was required). The reaction was stirred overnight at ambient temperature before being quenched with water (100 mL) and extracted into ethyl acetate (50 mL, twice). The separated and combined organic layer was then washed with water (100 mL). The organic layer was separated and then dried by passing through a hydrophobic frit before evaporation under reduced pressure to give pale yellow viscous oil. The material was partially purified by silica chromatography (ISCO) using 0-100% ethyl acetate: cyclohexane.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:23]([OH:25])=[O:24])=[C:7]([CH3:22])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[N:9]2)=[CH:4][C:3]=1[S:26]([CH3:29])(=[O:28])=[O:27].[C:30](Cl)(=O)C(Cl)=O.CO>CN(C=O)C.ClCCl>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:23]([O:25][CH3:30])=[O:24])=[C:7]([CH3:22])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)=[N:9]2)=[CH:4][C:3]=1[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(S(C)(=O)=O)cc2c1C(=O)O
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(S(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
DMF (5 drops) was added to a suspension of 7-hydroxy-3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (6.92 g, 16.27 mmol) in dichloromethane (120 mL) at 0° C. Oxalyl chloride (2.14 mL, 24.40 mmol) was added slowly. After 1 h at 0° C., the mixture was warmed to room temperature, and additional oxalyl chloride (2.14 mL, 24.40 mmol) was added. The mixture was warmed to room temperature and stirred overnight. Methanol (30 mL) was added and the mixture was stirred overnight. The solvent was removed under reduced pressure, the residue was diluted with water, and the aqueous mixture was treated with saturated aqueous NaHCO3. The mixture was extracted with methylene chloride (three times). The combined organic extracts were washed with brine (2 times), dried over Na2SO4, filtered, and concentrated to afford methyl 7-hydroxy-3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (6.0 g, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ11.85 (br. s., 1H), 8.18 (s, 1H), 7.95-8.02 (m, 2H), 7.91 (d, J=7.78 Hz, 1H), 7.78 (t, J=7.78 Hz, 1H), 7.55 (s, 1H), 4.07 (s, 3H), 3.41 (s, 3H), 2.32 (s, 3H); MS (m/z) 440.0 (M+H+).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[OH:28])([CH3:21])[CH3:20])[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:34][CH2:35][Cl:36]>>[Cl:36][CH2:35][CH2:34][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]([NH:18][C:14]1[C:13](=[O:29])[N:12]([C:10]2[CH:11]=[C:6]([CH:7]=[C:8]([F:31])[C:9]=2[CH3:30])[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:32])[CH:17]=[CH:16][N:15]=1)([CH3:20])[CH3:21]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Reactant: ClCCBr
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O

Procedure:
The title product was prepared from N-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (Example 169g, 0.33 g) and 1-bromo-2-chloroethane using a similar method to that described for example 167e.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH2:10]([CH:12]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:13][NH:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]1)[CH3:11].[OH-].[Na+]>CC(C)=O.O>[Cl:3][C:2]1[N:1]=[C:8]([N:14]([CH2:13][CH:12]([CH2:10][CH3:11])[CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]2[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:21])([CH3:22])[CH2:20]2)[N:7]=[C:5]([N:14]([CH:15]2[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:21])([CH3:22])[CH2:20]2)[CH2:13][CH:12]([CH2:10][CH3:11])[CH2:25][CH2:26][CH2:27][CH3:28])[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCC(CC)CNC1CC(C)(C)NC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCC(CC)CN(c1nc(Cl)nc(N(CC(CC)CCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 4 h

Procedure:
A suspension of 9.2 g of cyanuric chloride in 60 ml of acetone and 20 ml of water was added dropwise, with stirring, at 20°-25° C. to a solution of 29.5 g of 4-(2-ethylhexylamino)-2,2,6,6-tetramethylpiperidine in 50 ml of acetone, after which a solution of 4.2 g of sodium hydroxide in 20 ml of water was added to the mixture. The resulting reaction mixture was then stirred for 4 hours at 45°-50° C. At the end of this time, the acetone was distilled off and the oily residue was extracted with ethyl acetate. The extract was dried over anhydrous potassium carbonate, and the ethyl acetate was distilled off. The resulting oil was purified by column chromatography through silica gel, eluted with a 4:1 by volume mixture of hexane and ethyl acetate, to give the title compound as a colourless oil. The Rf value of this compound on thin layer chromatography was 0.62, using silica gel and using, as developing solvent, a 4:1:0.4 by volume mixture of ethyl acetate, methanol and triethylamine.