Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6](OC)=[CH:7][CH:8]=2)[N:3]=1.N1CC[O:18][CH2:17]C1.CCN(C(C)C)C(C)C>O1CCOCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:18][CH3:17])[N:3]=1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1
Reactant: C1COCCN1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cccc2nc(Cl)cc(Cl)c12
Temperature: 140 °C
Yield: 60.1 %

Procedure:
To a solution of 2,4-dichloro-7-methoxyquinoline (1 g, 4.38 mmol) in 1,4-dioxane (15 ml) was added morpholine (1.9 g, 4.38 mmol) followed by DIPEA (1.7 g, 13.15 mmol) at room temperature. The reaction mass was heated at 140° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.6 g, 49.1%) as white solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.89-7.86 (d, J=12 Hz, 1H), 7.07 (s, 1H), 6.97-6.94 (d, J=12 Hz, 1H), 6.89 (s, 1H), 3.91 (s, 3H), 3.85-3.82 (m, 4H), 3.69-3.66 (m, 4H); MS: MS m/z 279.1 (M++1).
Reaction SMILES: [OH-].[Na+].[O:3]1[C:8]([C:9](=[N:15][O:16][CH2:17][CH:18]=[CH2:19])[C:10]([O:12]CC)=[O:11])=[CH:7][S:6][CH2:5][CH2:4]1>CO>[O:3]1[C:8]([C:9](=[N:15][O:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=[O:11])=[CH:7][S:6][CH2:5][CH2:4]1
Reactant: C=CCON=C(C(=O)OCC)C1=CSCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCON=C(C(=O)O)C1=CSCCO1
Temperature: 25 °C
Reaction time: 22 h
Yield: 62.4 %

Procedure:
1N Aqueous solution of sodium hydroxide (1.22 ml.) was added to a solution of ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-allyloxyiminoacetate (0.90 g.) in methanol (9 ml.) and stirred at room temperature for 22 hours. After removing methanol from the solution, the residue was dissolved in water (20 ml.). The solution was adjusted to pH 7.0 with conc.hydrochloric acid, washed with ethyl acetate (20 ml.), adjusted to pH 1.5 with conc.hydrochloric acid and extracted with ethyl acetate (50 ml.). The extract was washed with water (50 ml.), dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from a mixture of diisopropyl ether, diethyl ether and n-hexane (1:1:1) to give 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-allyloxyiminoacetic acid (syn isomer, 0.50 g.), colorless crystals, mp 119° to 121° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH2:21][CH2:22][N:23]=3)[C:8]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)=[N:9][C:10]=2[CH:11]=1.Br[CH2:25][CH2:26][N:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:27]1([CH2:26][CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:7]([CH2:21][CH2:22][N:23]=4)[C:8]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)=[N:9][C:10]=3[CH:11]=2)[CH:31]=[CH:30][CH:29]=[CH:28]1
Reactant: O=C(NC1=Nc2cc(O)ccc2C2=NCCN12)c1cccnc1
Reactant: BrCCn1cccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1=Nc2cc(OCCn3cccc3)ccc2C2=NCCN12)c1cccnc1
Temperature: 120 °C
Yield: 53.2 %

Procedure:
The suspension of N-(8-Hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (example 2-1) 70.0 mg (0.23 mmol), N-(2-bromoethyl)pyrrole 47.6 mg (0.27 mmol) and potassium carbonate 126 mg (0.91 mmol) in N,N-dimethylformamide 5 mL was heated in a sealed tube to 120° C. for 3 hours. The reaction mixture was concentrated and partitioned between dichloromethane and water. The organic layer was washed with 0.1N NaOH solution and brine, dried over Na2SO4 and the solvent was evaporated to give the title compound 49.0 mg as off-white solid. Yield 54%.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[C@H:23]3[C@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)[C:17](=[O:24])[NH:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]>>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[C@H:23]3[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)[C:17](=[O:24])[NH:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: NN
Solvent: O
Product: COc1ccc(C2=NNC(=O)[C@@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound B (see starting compounds) and hydrazine hydrate as described for compound 1. M.p. 143-146° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][N:9]2[C:10](=[O:13])[C:11]=1[Br:12])(=O)C.Cl.O1CCOCC1.[OH-].[NH4+]>O>[Br:12][C:11]1[C:10](=[O:13])[N:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]2=[N:7][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1nc2ccccn2c(=O)c1Br
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=c1c(Br)c(CO)nc2ccccn12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A heterogeneous mixture of the (3-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate (4.24 g, 1.0 equiv.), conc. HCl (8.0 equiv.) and 1,4-dioxane (39 mL) was heated with stirring at 70° C. for 3 h. LCMS showed the completion of reaction. The residue was diluted with water (100 mL) and treated with 28% ammonium hydroxide (10 mL) to pH 10. The precipitate was filtered, washed with water (200 mL) and dried under high vacuum to give 3-bromo-2-(hydroxylmethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as tan solid. Used without further purification: 1HNMR (400 MHz, DMSO-d6): δ 8.96-8.98 (dd, 1H), 8.03-8.08 (m,1H), 7.74-7.76 (dd, 1H), 7.43-7.48 (m,1H), 5.3 (t,1H), 4.6 (d,2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:10][NH2:11])[C:6]([F:9])=[N:7][CH:8]=1)C.Cl.FC1C=CC(C)=CN=1>>[F:9][C:6]1[C:5]([CH2:10][NH2:11])=[CH:4][C:3]([CH3:1])=[CH:8][N:7]=1
Reactant: CCc1cnc(F)c(CN)c1
Agent: Cc1ccc(F)nc1
Agent: Cl
Product: Cc1cnc(F)c(CN)c1

Procedure:
(2-fluoro-5-methylpyridin-3-yl)methanamine (2-e) was prepared by the same synthetic route as that of (2-g) but utilizing the commercially available 2-fluoro-5-methylpyridine (2-c) as a starting material; 1H NMR (500 MHz, DMSO-d6) δ 8.65 (bs, 3H), 8.07 (d, 1H, J=1.0 Hz), 8.01 (dd, 1H, J=15.5, 3.0 Hz), 4.02 (s, 2H), 2.30 (s, 3H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].Cl[Al](C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]CC)=O)=[CH:13][CH:12]=1>C(Cl)Cl>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([N:3]([O:4][CH3:5])[CH3:2])=[O:20])=[CH:15][CH:16]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: CNOC
Agent: C[Al](C)Cl
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To a round bottom flask containing N-methyl-N-methoxy amine hydrochloride (878 mg, 9 mmol) in CH2Cl2 (6 mL), a solution of ClAlMe2 (9 mL, 1M, 9 mmol) was added at 0° C. dropwise. The solution was stirred at rt for 30 min. A solution of ethyl 4-bromophenylacetate (1.09 g, 4.05 mmol) was added dropwise at 0° C. The solution was stirred at rt for 1 h, quenched with sat. NH4Cl, and extracted with EtOAc (3×20 mL). The organic layer washed with brine, dried (Na2SO4) and concentrated. Purification via flash chromatography (0-50% EtOAc/hexanes) afforded 70A (1.03 g, 80%). MS (ESI) m/z 258.1 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:23][CH3:24])=[N:8][N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[C:12]([CH3:22])[O:11][C:10]=12)=[O:5])C.O.[OH-].[Li+].CO.O>O.C(O)(=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:13]1[N:9]2[N:8]=[C:7]([CH2:23][CH3:24])[C:6]([C:4]([OH:5])=[O:3])=[C:10]2[O:11][C:12]=1[CH3:22]
Reactant: CCOC(=O)c1c(CC)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1C(=O)O
Temperature: 25 °C

Procedure:
A suspension containing 3-(2,4-dichloro-phenyl)-6-ethyl-2-methyl-pyrazolo[5,1-b]oxazole-7-carboxylic acid ethyl ester (1.80 g, 4.90 mmol) and lithium hydroxide monohydrate (1.0 g, 24.51 mmol) is heated at 70° C. in a 3/1 mixture of methanol/water (32 ml) for 2 hrs. The resulting solution is cooled to RT, diluted with water (60 ml) and glacial acetic acid added (approx. 3 ml) to adjust the pH to 4-5. The resultant suspension is stirred for 1 h and filtered and washed with water. The product is dried in vacuo at 50° C.; MS: m/z 339.03 [M+H]+
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[I-].[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:18][C:17]=1[N+:42]([O-:44])=[O:43])([CH3:15])([CH3:14])[CH3:13].[Si]([O:52][C@@H:53]([CH2:56][CH:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1)CO)(C(C)(C)C)(C)C>O1CCCC1>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:53](=[O:52])[CH2:56][CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]2)=[CH:18][C:17]=1[N+:42]([O-:44])=[O:43])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CO)CC1CCCCC1
Reactant: CC(C)(C)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CC(=O)CC2CCCCC2)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 72 %

Procedure:
8.6 ml (8.6 mmol) of a 1.0M tetrahydrofuran solution of sodium hexamethyldisilazide were added dropwise over a period of 20 minutes to a suspension of 5.04 g (8.67 mmol) of (4-t-butyl-3-nitrophenyl)methyltriphenylphosphonium iodide (prepared as described in Preparation 52) in 80 ml of tetrahydrofuran at -78° C., and the mixture was allowed to stand for 1 hour. A solution of 2.33 g (8.61 mmol) of (S)-2-t-butyldimethylsilyloxy-3-cyclohexylpropanol [prepared as described in step (iv) above] in 7 ml of tetrahydrofuran was then added all at once, and the resulting mixture was stirred for 1 hour at the same temperature. The cooling bath was then removed, and the mixture was stirred for a further 4 hours. The reaction was then stopped by adding a saturated aqueous solution of ammonium chloride, after which the reaction mixture was extracted with a 1:3 by volume mixture of ethyl acetate and hexane. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 150 g of silica gel, using a 1:19 by volume mixture of diethyl ether and hexane as the eluent, to give fractions containing small amounts of impurities. These fractions were again purified by column chromatography through 150 g of silica gel, using a 1:4 by volume mixture of methylene chloride and hexane as the eluent, to give 2.78 9 (yield 72%) of the title olefin derivative as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[H-].[Na+].[CH2:13]([N:20]([CH2:22][CH2:23]Cl)[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CN(C=O)C.C1(C)C=CC=CC=1.[OH-].[Na+].CCOCC>[CH2:13]([N:20]([CH2:22][CH2:23][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(CCCl)Cc1ccccc1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN(CCOc1ccc(Cl)cc1C=O)Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 5-chloro-2-hydroxybenzaldehyde (25.68 g) in dry DMF (100 ml) was added dropwise to a stirred suspension of sodium hydride (6.84 g of a 60% dispersion in mineral oil) in dry DMF (100 ml) at ambient temperature under nitrogen with stirring. The mixture was heated on a steam bath for 1.5 hours, then cooled to ambient temperature and a solution of N-benzyl-2-chloro-N-methylethylamine in toluene (60 ml) [prepared by dissolving the hydrochloride (48.5 g) in 2M sodium hydroxide solution (50 ml) and extracting with toluene (2×30 ml) with drying] and the resulting mixture was heated on a steam bath for 4 hours. The mixture was cooled to ambient temperature and then poured into ice/water (100 ml). The mixture was extracted with ether and the combined ether extracts were washed with 2M sodium hydroxide solution until the washes were colourless. The ether extracts were then washed with 2M hydrochloric acid. The acidic extracts were basified with concentrated sodium hydroxide solution and extracted with dichloromethane to give an oil. A portion of the oil was dissolved in ether and treated with ethereal hydrogen chloride. The solid which precipitated was collected by filtration and recrystallised from propan-2-ol to give 2-[2-(N-benzyl-N-methylamino)ethoxy]-5-chlorobenzaldehyde, m.p. 154°-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3([C:16]=2[CH:17]=1)[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]3.[OH-].[Na+].Cl.[O-:21]C#N.[K+].[O-]C#N>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9]([NH:10][C:11]([NH2:12])=[O:15])([C:13]([OH:21])=[O:14])[C:16]=2[CH:17]=1
Reactant: N#C[O-]
Reactant: O=C1NC(=O)C2(CCCc3ncc(Cl)cc32)N1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: NC(=O)NC1(C(=O)O)CCCc2ncc(Cl)cc21
Temperature: 20 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
3-Chlorospiro-[5,6,7,8-tetrahydroquinolin-5,4'-imidazolidine]-2',5'-dione (133.2 grams, 0.53 mol) and sodium hydroxide (70 grams, 1.75 mol) in water (500 ml) was refluxed for 48 hours. The reaction was cooled to 20° C. and the pH adjusted to about 7 by the addition of HCl (first conc. HCl, then 3N as neutrality is reached). Potassium cyanate (8.59 grams, 1.06 mol) was added carefully in portions over 30 minutes and the reaction stirred at room temperature for 4 hours, then at 60° C. overnight. Additional potassium cyanate (40 grams, 0.53 mol) was added in the morning and the reaction stirred for 48 hour at 60° C. During the reaction with cyanate, the pH of the reaction became basic and was periodically adjusted to ca. pH 7.5. The reaction mixture was stirred with a small amount of activated carbon and filtered. The filtrate was cooled to 5° to 10° C. and acidified to pH 3.5 with 6N HCl. The precipitate was collected, washed with water and slurried in acetone (500 ml). The product was filtered and dried in vacuo. 96 grams; 67.3% yield. mp 188°-89.5° C. NMR (DMSO-d6, 300 MHz) δ8.43 (d, 1), 7.94 (d, 1), 6.92 (s, 1), 5.72 (s, 1), 2.83 (t, 2), 2.26 (m, 1), 2.12 (m, 1), 1.90 (m, 2).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][CH2:10][C:11]([F:14])([CH3:13])[CH3:12])C1C=CC=CC=1.[C:22]([OH:25])(=[O:24])[CH3:23]>CO.[Pd]>[C:22]([OH:25])(=[O:24])[CH3:23].[F:14][C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][NH2:8]
Reactant: CC(C)(F)CCN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(F)CCN

Procedure:
Treat a solution of N,N-dibenzyl-3-fluoro-3-methylbutan-1-amine (18.03 g, 63.2 mmol) in MeOH (150 mL) and acetic acid (7.23 mL, 126 mmol) with 10% Pd/C (3.36 g, 3.16 mmol) and hydrogenate (345 kPa) for 2.5 days. Add additional palladium on carbon (1 g) and hydrogenate the mixture (345 kPa) overnight. Filter the mixture through diatomaceous earth, rinse well with MeOH and concentrate the filtrate to dryness to afford the title compound MS (m/z): 106.1 (M-AcOH+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](O)=[O:44])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23>>[Br:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](=[O:44])[NH:14][C:13]3[CH:15]=[CH:16][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:11][C:12]=3[O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23
Reactant: CC(C)(C)OC(=O)COc1cc(CNC(=O)OC(C)(C)C)ccc1N
Reactant: O=C(O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: CC(C)(C)OC(=O)COc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 80.8 %

Procedure:
A procedure similar to that described in Example 18-6) was performed with 4-tert-butoxycarbonylaminomethyl-2-tert-butoxycarbonylmethoxyaniline (990 mg, 2.61 mmol) and (S)-9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (1.06 g, 3.12 mmol) to give a total amount of 1.42 g of the title compound (81%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24](=S)[CH2:25][C:26](=O)[CH3:27])=[O:4].Cl.[CH:31]1([NH:35][NH2:36])[CH2:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:11])=[O:12])[CH2:7][N:6]1[C:24]1[N:35]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:36]=[C:26]([CH3:27])[CH:25]=1)=[O:4]
Reactant: NNC1CCC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=S)CC(C)=O
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1c1cc(C)nn1C1CCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give the title compound as yellow oil. MS (ESI): m/z=490.1 [M+H]+.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:17]([N+:27]([O-:29])=[O:28])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:17]([N+:27]([O-:29])=[O:28])[CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1cc(Br)ccc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(-c2cccc3ccccc23)ccc1-c1ccccc1

Procedure:
1.62 g (1.40 mmol) of Pd(PPh3)4 are added to a well-stirred, degassed suspension of 46 g (268 mmol) of 1-naphthylboronic acid, 71 g (255.3 mmol) of 4-bromo-2-nitrobiphenyl and 93 g (433.9 mmol) of potassium carbonate in a mixture of 700 ml of water and 700 ml of THF, and the mixture is heated under reflux for 17 h. After cooling, the organic phase is separated off, washed three times with 400 ml of water and once with 400 ml of saturated, aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo in a rotary evaporator. The grey residue is recrystallised from hexane. The deposited crystals are filtered off with suction, washed with a little MeOH and dried in vacuo; yield: 83.1 g, 97.9% of theory; purity: 99.0% according to HPLC.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[N:19]=[CH:18][C:17]3[C:16]4[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][O:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]2[N:35]=[C:36]([NH:38][C:39]3[C:40](=[O:55])[N:41]([CH3:54])[CH:42]=[C:43](B4OC(C)(C)C(C)(C)O4)[CH:44]=3)[CH:37]=[C:31]2[CH2:30]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:20][C:14]1([CH3:21])[CH2:13][C:12]2[S:11][C:10]3[C:9](=[O:22])[N:8]([C:4]4[C:3]([CH:23]=[O:24])=[C:2]([C:43]5[CH:44]=[C:39]([NH:38][C:36]6[CH:37]=[C:31]7[CH2:30][N:29]([CH2:28][CH2:27][O:26][CH3:25])[CH2:34][CH2:33][N:32]7[N:35]=6)[C:40](=[O:55])[N:41]([CH3:54])[CH:42]=5)[CH:7]=[CH:6][N:5]=4)[N:19]=[CH:18][C:17]=3[C:16]=2[CH2:15]1
Reactant: CC1(C)Cc2sc3c(=O)n(-c4nccc(Cl)c4C=O)ncc3c2C1
Reactant: COCCN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: COCCN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6c7c(sc6c5=O)CC(C)(C)C7)c4C=O)cn(C)c3=O)cc2C1
Temperature: 100 °C

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-{4,4-dimethyl-9-oxo-7-thia-10,11-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),11-trien-10-yl}pyridine-3-carbaldehyde 282i (60 mg, 0.167 mmol), 304d (143.4 mg, 0.334 mmol), Pd(dppf)Cl2 (6.8 mg, 0.0084 mol), K3PO4 (70.8 mg, 0.334 mmol), sodium acetate (27.4 mg, 0.334 mmol), acetonitrile (10 mL), and water (3 drops). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. for 1 h under N2 protection. Analysis of reaction mixture by LCMS showed complete conversion to the desired product. It was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 304e (80 mg, 77%) as white solid. MS-ESI: [M+H]+ 626.8
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:14][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(O)c1cccc(CO)n1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(O)c1cccc(CBr)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of 2-hydroxymethyl-6-(1-hydroxy-1-methylethyl)pyridine (5.1 g, 30.5 mmol) in dichloromethane (300 mL) was added carbon tetrabromide (8.81 g, 33.6 mmol) and triphenylphosphine (11.14 g, 33.6 mmol). The reaction was stirred at ambient temperature overnight then poured into a saturated solution of sodium bicarbonate. The organic layer was separated, concentrated to dryness and purified by column chromatography, eluting with a gradient of hexane to 3:1 hexane:ethyl acetate. The title compound (5.21 g, 74%) was obtained as a colourless oil; LC-MS Retention time 2.08 min, (M+H)+ 230, 232
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([C:14]([CH2:17][O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[N:15][N:16]=2)[CH:5]=[C:6]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[CH:9]=2)[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:49][O:50][CH2:51][CH2:52]O.C(Cl)Cl.CCOC(/N=N/C(OCC)=O)=O>>[F:1][C:2]1[C:3]2[N:4]([C:14]([CH2:17][O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH2:52][CH2:51][O:50][CH3:49])=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[N:15][N:16]=2)[CH:5]=[C:6]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[CH:9]=2)[CH:7]=1
Reactant: Cc1cc(-c2cc(F)c3nnc(COc4ccnc5cc(O)ccc45)n3c2)on1
Reactant: COCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCOc1ccc2c(OCc3nnc4c(F)cc(-c5cc(C)no5)cn34)ccnc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
4-((8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinolin-7-ol (0.110 g, 0.28 mmol), PPh3 (polymer supported: 2.3 mmol/g) (1.2 g, 2.8 mmol) and 2-methoxyethanol (0.11 ml, 1.3 mmol) were combined in DCM (11 ml, 0.28 mmol). The mixture was cooled to 0° C., and DEAD (0.089 ml, 0.56 mmol) was added dropwise. The reaction was removed from the ice bath, and stirred at RT for 1 h. The material was diluted with DCM, and the PS-PPh3 was filtered off and washed thoroughly with DCM. The filtrate was concentrated in vacuo. The crude material was dissolved in minimal DCM and purified via MPLC (eluting with 0-100% 90:10:1 DCM:MeOH:NH4OH in DCM) to yield 4-((8-fluoro-6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-(2-methoxyethoxy)quinoline (0.070 g, 55% yield) as a white solid. MS (ESI pos. ion) m/z: 450.0 (M+H). Calc'd Exact Mass for C23H20FN5O4: 449.44