Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]#N)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([OH:14])=[N:10][CH:11]=[N:12][CH:13]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1.Cl.[OH-:27].[Na+]>O1CCCC1.C(Cl)Cl.O>[F:1][C:2]1[C:3]([C:15]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[O:27])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([OH:14])=[N:10][CH:11]=[N:12][CH:13]=1
Reactant: N#Cc1nccc(-c2cncnc2O)c1F
Reactant: [OH-]
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1nccc(-c2cncnc2O)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a solution of 3-fluoro-4-(4-hydroxypyrimidin-5-yl)picolinonitrile (0.152 g, 0.703 mmol) in tetrahydrofuran (Volume: 2.344 ml) cooled to 0° C. was added (4-fluorophenyl)magnesium bromide (1.055 ml, 2.109 mmol). The reaction mixture was allowed to stir at room temperature overnight. Water and ice were carefully added, followed by acidification with 6 M HCl. After stirring for 1 hr, CH2Cl2 was added and the pH was adjusted to 8.5 with aqueous 4 M NaOH. The layers were separated. The aqueous phase was extracted with CH2Cl2 (5×). Organics combined, dried over Na2SO4, filtered, and concentrated to afford an orange residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 0-20% MeOH in CH2Cl2 over 25 min, tr=13 min) gave the title compound (162 mg, 0.517 mmol, 73.5% yield) as a yellow residue. ESI MS (M+H)+=314.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].C(NC(C)C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(#N)C>[CH3:15][Si:14]([C:12]#[C:13][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6])([CH3:17])[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccnc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: COC(=O)c1ccnc(C#C[Si](C)(C)C)c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
Methyl 2-bromoisonicotinate (216 g, 1 mol), dry acetonitrile (1.7 L), ethynyl(trimethyl)silane (117 g, 1.2 mol), diisopropylamine (122 g, 1.2 mol), and dichlorobis(triphenylphosphine)palladium (36 g, 0.05 mol) were placed into a well dried three necked flask which was twice purged with a stream of nitrogen. The reaction mixture was stirred for 0.5 hours, cooled to 10° C., and copper iodide (19 g, 0.1 mol) was added under a stream of nitrogen. At 20° C., the reaction mixture became thick and black and an exotherm was observed which was followed by formation of a precipitate. After the addition of copper iodide, the reaction mixture was stirred for further 2 hours at ambient temperature. The precipitated residue was separated by filtration and twice washed with diethyl ether (800 mL). The filtrate was washed with saturated ammonium chloride (2×300 mL) and brine (2×300 mL). After drying over sodium sulfate, the solvent was evaporated. The residue was purified using a silica gel column, eluting with hexane followed by 5% ethyl acetate in petroleum ether to yield 191 g (82%) of methyl 2-((trimethylsilyl)ethynyl)isonicotinate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:65]([O:67][C:68](=[O:77])[C:69]1[CH:74]=[C:73]([NH2:75])[CH:72]=[CH:71][C:70]=1[F:76])[CH3:66]>C(Cl)Cl>[CH2:65]([O:67][C:68](=[O:77])[C:69]1[CH:74]=[C:73]([NH:75][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:30])[CH:72]=[CH:71][C:70]=1[F:76])[CH3:66]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(=O)c1cc(N)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (0.150 mL, 0.855 mmol) and 5-amino-2-fluoro-benzoic acid ethyl ester (Oakwood, 63 mg, 0.34 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (50 g column, eluent EtOAc/Hexanes, 5-20%) to give a white solid. 64 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13].C1(NC2CCCCC2)CCCCC1>C(#N)C>[N:4]1[CH:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:14])[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncnc1
Reactant: C#CCCCCO
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC#N
Product: OCCCCC#Cc1cncnc1
Yield: 86.5 %

Procedure:
A mixture of 5-bromopyrimidine (3.96 g), 5-hexynol (2.44 g), dicyclohexylamine (4 g) and acetonitrile (50 ml) was de-oxygenated by bubbling nitrogen through the solution for 10 min. BTPC (150 mg) and copper (I) iodide (25 mg) were added and the mixture was heated to 60°-70° under nitrogen for 1 h, cooled and evaporated in vacuo. Ether (175 ml) was added, the mixture filtered and evaporated in vacuo and the residue purified by FCC. Elution with ether followed by System C (19:1-92:8) gave the title compound as a pale yellow oil (3.79 g), t.l.c. (System C (17:3) Rf 0.55.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]([CH3:14])[CH:7]2OC.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6]([CH3:14])=[CH:7]2
Reactant: COC1c2cccc(CBr)c2CC1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1=Cc2cccc(CBr)c2C1

Procedure:
To a solution of 17.9 g (70 mmol) of 4-(bromomethyl)-1-methoxy-2-methylindane in 300 ml of toluene 2.0 g of TsOH was added at 110° C. This mixture was refluxed with Dean-Stark trap within 15 minutes and then passed through short column with silica gel 60 (40-63 μm). The silica gel layer was additionally washed by 200 ml of toluene. The combined elute was evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 μm, eluent: hexanes). Yield 15.6 g (96%). Anal. calc. for C11H11Br: C, 59.22; H, 4.97. Found: C, 59.33; H, 5.08. 1H NMR (CDCl3): δ 7.19-7.23 (m, 2H, 4,6-H), 7.10 (m, 1H, 5-H), 6.50 (m, 1H, 3-H), 4.56 (s, 2H, CH2Br), 3.36 (br.s, 2H, 1,1′-H), 2.19 (m, 3H, 2-Me). 13C{1H} NMR (CDCl3): δ 146.6, 146.2, 142.4, 132.0, 127.17, 127.14, 124.4, 120.2, 40.9, 31.7, 16.7.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].N1C=CN=C1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C>[Si:18]([O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: OCC1CCCCN1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CCCCN1
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a DMF (3 ml) solution of 2-piperidinemethanol (1.00 g, 8.7 mmol) and imidazole (1.48 g, 21.7 mmol) was added tert-butyldimethylchlorosilane (1.57 g, 10.4 mmol) at room temperature. After stirring for 30 min., a reaction solution was poured onto water followed by extraction with diethyl ether (about 30 ml). The extract was washed successively with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to afford 1.61 g of the title compound.
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH2:14])=[O:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CCO>[CH:1]1([C:7]2[N:14]=[C:12]([OH:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1ccccc1NC(=O)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1nc(C2CCCCC2)nc2ccccc12

Procedure:
2-(Cyclohexylcarbonylamino)benzamide was stirred for 16 h in a mixture of excess 1M NaOH and EtOH, and the resulting solution was treated with HCl to pH=7 causing the formation of a precipitate. The precipitate was collected by filtration, washed (with water and hexane), and dried under vacuum to give a nearly quantitative yield of 2-cyclohexyl-4-hydroxyquinazoline as a white solid, which was used immediately in the next step.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.FC(F)(F)C(O)=O.[NH:19]1[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[CH2:20]1>>[F:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:19]3[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[NH:32][S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)(=[O:34])=[O:35])[CH2:20]3)[S:3][C:4]=2[CH:10]=1
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: O=S(=O)(Nc1ccccc1OCC1CCNC1)c1ccccn1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccccc1OCC1CCN(c2nc3ccc(F)cc3s2)C1)c1ccccn1

Procedure:
Compound 29 is prepared using synthesis method 3 using intermediates 2a and 6b (yield: 76%).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][C:19]([OH:30])([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C:20](=O)[CH2:21][CH3:22].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]1[O:4][C:21]([CH2:20][C:19]([OH:30])([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:18][C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[Cl:10])([CH3:22])[O:3][CH2:2]1
Reactant: CCC(=O)C(O)(Cc1ccc(Cl)cc1Cl)c1cccnc1
Reactant: OCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(CC(O)(Cc2ccc(Cl)cc2Cl)c2cccnc2)OCCO1
Temperature: 25 °C

Procedure:
27 ml of ethylene glycol and 0.8 ml of concentrated sulphuric acid are added to a solution of 5 g of 5-(2,4-dichlorophenyl)-4-hydroxy-4-(3-pyridyl)-3-pentanone (see Example 1, 3rd end product) in 90 ml of toluene and the reaction mixture is heated at reflux temperature for 24 hours on a water separator. After cooling to room temperature the mixture is neutralized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, the solvent is removed by evaporation under reduced pressure and the residue is recrystallized from methylene chloride/n-hexane. In this manner there are obtained 5.3 g of 5-(2,4-dichlorophenyl)-4-hydroxy-4-(3-pyridyl)-2-pentanone ethylene ketal as colorless crystals, m.p. 136°-137° C.
Reaction SMILES: CC(C)([O-])C.[K+].C([Li])CCC.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20].[C:21](=[O:23])=[O:22]>O.O1CCCC1>[F:12][C:13]1[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][C:18]=1[C:21]([OH:23])=[O:22]
Reactant: COc1ccccc1F
Reactant: O=C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
A mixture of potassium tert-butoxide (30.80 g, 274 mmol) and anhydrous tetrahydrofuran (300 mL) was cooled to -78° C. and treated with a 1.6M solution of n-butyllithium (172 mL, 275 mmol) in hexanes. After stirring for 15 minutes, 2-fluoroanisole (31.35 g, 248 mmol) was added and the reaction was stirred an additional 1.8 hours. The reaction was poured into a 2 L Erlenmeyer flask containing dry ice and warmed to room temperature. Water (250 mL) was added and after extracting with ether (160 mL), the aqueous layer was acidified with concentrated hydrochloric acid, and filtered to give 2-fluoro-3-methoxybenzoic acid (21.43 g, 51%) as a yellow solid: mp 155°-160° C.; 1H NMR (acetone-d6) 300 MHz 7.46 (ddd, J=6.0 Hz J=1.8 Hz J=1.4 Hz, 1H) 7.36 (dt, J=1.6 Hz J=8.1 Hz, 1H) 7.20 (dt, J=1.4 Hz J=8.1 Hz, 1H) 3.92 (s, 3H); 19F NMR (acetone-d6) 300 MHz -134.04 (m). Mass spectrum: M+H=171.
Reaction SMILES: Cl.[NH2:2][C:3](=[NH:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1.O.[NH2:15]N.[CH:17]1([C:22]([NH:24][CH:25]([CH2:33][CH3:34])[C:26](=O)[C:27](OCC)=[O:28])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1>C(O)C>[CH:17]1([C:22]([NH:24][CH:25]([C:26]2[C:27](=[O:28])[NH:13][C:3]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([NH2:10])=[O:9])=[CH:11][CH:12]=3)=[N:2][N:15]=2)[CH2:33][CH3:34])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)C(=O)C(CC)NC(=O)C1CCCC1
Reactant: N=C(N)c1ccc(C(N)=O)cc1
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCC(NC(=O)C1CCCC1)c1nnc(-c2ccc(C(N)=O)cc2)[nH]c1=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2.84 g (14.2 mmol, 1 equiv.) 4-[amino(imino)methyl]benzamide hydrochloride are suspended in 10 ml of ethanol and 1.37 g (26.8 mmol, 1.2 equiv.) hydrazine hydrate are added. After stirring at 60° C. for 1 hour, 6.28 g (24.6 mmol, 1.1 equiv.) ethyl 3-[(cyclopentylcarbonyl)-amino]-2-oxopentanoate (Example 4A), dissolved in 40 ml of ethanol, are added. The reaction mixture is stirred at 70° C. (bath temperature) for 4 hours. The mixture is evaporated to dryness in vacuo and the product is purified by flash chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[N:19]1([CH2:25][CH2:26][O:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Cl-].[Cl-].[Cl-].[Al+3].C(S)C>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[C:32]([C:31]2[CH:35]=[CH:36][C:28]([O:27][CH2:26][CH2:25][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:29][CH:30]=2)=[O:33])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc2cc(-c3ccc(F)cc3)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCCl
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(F)cc2)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product from Example 17, Step 1 (83 mg, 0.32 mmol) and 4-(2-Piperidin-1-yl-ethoxy)-benzoyl chloride (1.39 mL, 0.39 mmol) in 3.3 mL of 1,2-dichloroethane was added, in two portions, aluminum trichloride (322 mg, 2.4 mmol) and the reaction was heated at reflux for 1 hr. At this time the coupling was complete and demethylation was carried out cooling the reaction to room temperature, adding ethanethiol (0.10 mL, 1.41 mmol) dropwise and stirring at room temperature for a further 1.5 hrs. The reaction was quenched with saturated sodium bicarbonate solution and extracted twice with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was chromatographed on silica gel using 1% MeOH:methylene chloride to 3% MeOH:methylene chloride as the gradient eluant to yield the title compound.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[ClH:27]>>[OH:1][C:3]1([CH2:2][Cl:27])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:7][CH2:8]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: Cl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CCl)CC3)c(F)c2)C(=O)O1
Temperature: 55 °C

Procedure:
A mixture of (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (18.0 mmol) and aqueous hydrochloric acid was heated at a temperature 50-60° C. for 12 hours to provide crude (S)-N-{3-[4-(4-hydroxy-4-chloromethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide which was purified by silica gel column chromatography and used further.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][NH:5]2.C=O.O.[C:16](O)(=O)C.[BH3-]C#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][N:5]2[CH3:16]
Reactant: CC(=O)O
Reactant: O=C1CNc2cc(Br)ccc2N1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC(=O)Nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of 6-bromo-3,4-dihydroquinoxalin-2(1H)-one (370 mg, 1.63 mmol) in 10 ml methanol was added a solution of 37% formaldehyde in water (59 mg, 1.95 mmol) and acetic acid (196 mg, 3.26 mmol). The mixture was stirred at room temperature for 2 h, then refluxed for 1 h. After addition of NaBH3CN (307 mg, 4.89 mmol) stirring was continued for 2.5 h at room temperature. Then methanol was removed under vacuum. To the remaining mixture water was added. Then the solution was basified to pH 8-9 with an aqueous solution of sodium hydrogen carbonate and extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and evaporated, affording 6-bromo-4-methyl-3,4-dihydroquinoxalin-2(1H)-one (369 mg, 1.53 mmol, 94%) as off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[C:5]2[CH2:18][OH:19].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=O)C.CC1(C)N([O])C(C)(C)CCC1>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[C:5]2[CH:18]=[O:19]
Reactant: O=c1[nH]c2ccc(Br)cc2c(CO)c1-c1cccs1
Agent: CC(=O)Oc1cccc(I)c1OC(C)=O
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1c(-c2cccs2)c(=O)[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-bromo-4-(hydroxymethyl)-3-(thiophen-2-yl)quinolin-2(1H)-one (0.155 g, 0.461 mmol) in acetonitrile (4.60 ml) were added bisacetoxy iodobenzene (0.134 g, 0.415 mmol) and 2,2,6,6-tetramethyl piperidin-1-oxyl (7.30 mg, 0.046 mmol). The reaction was allowed to stir at room temperature for 16 h. The reaction was diluted with ethyl acetate (30 ml) and extracted with saturated sodium thiosulfate (1×25 ml), sodium bicarbonate (1×25 ml) and sodium chloride (1×25 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated. Purification of the crude oil by silica chromatography gave 6-bromo-2-oxo-3-(thiophen-2-yl)-1,2-dihydroquinoline-4-carbaldehyde as a white solid. LCMS (M+H)=335.76.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>CCOCC>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)nc2)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 51.2 %

Procedure:
n-Butyl lithium (1.6M in hexanes, 6.50 mL, 10.39 mmol) was added dropwise to 5-bromo-2-chloropyridine (2.0 g, 10.39 mmol) in ether (30 mL) cooled to −78° C. over a period of 15 minutes. The resulting solution was stirred at −78° C. for 45 minutes then a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (1.66 g, 8.31 mmol) in ether (10 mL) was added dropwise. The reaction was allowed to warm slowly to room temperature then quenched with ammonium chloride solution (50 mL) and extracted with EtOAc. The extract was washed sequentially with water and saturated brine, dried over MgSO4 and concentrated by evaporation, then purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(6-chloropyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (1.33 g, 41%) as a cream solid.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[N:6]#[O+].[F:8][C:9]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:10]=1[NH2:11]>C(#N)C.C(OCC)C>[F:1][B-:2]([F:5])([F:4])[F:3].[F:8][C:9]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:10]=1[N+:11]#[N:6]
Reactant: N#[O+]
Reactant: Nc1cc(F)ccc1F
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CC#N
Product: N#[N+]c1cc(F)ccc1F
Reaction time: 1 h

Procedure:
Nitrosonium tetrafluoroborate (905 mg, 7.75 mmol, 1.00 equiv) was added to a solution of 2,5-difluoroaniline (0.780 mL, 7.75 mmol, 1 equiv) in acetonitrile (50 mL) at 0° C. The resulting mixture was stirred for 1 hour, then diluted with ethyl ether (150 mL). The precipitate was filtered and air-dried to give 2,5-difluorobenzenediazonium tetrafluoroborate (1-1) as a tan solid. 1H NMR (300 MHz, CD3OD) δ 8.54 (m, 1H), 8.24 (m, 1H), 7.95 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[OH:48][CH:49]([CH2:59][NH:60][C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][C:68]([N+:71]([O-:73])=[O:72])=[CH:67][CH:66]=1)=[O:62])[CH2:50][C:51]([NH:53][C@H:54]1[CH2:58][CH2:57][NH:56][CH2:55]1)=[O:52]>O1CCCC1>[OH:48][CH:49]([CH2:59][NH:60][C:61]([O:63][CH2:64][C:65]1[CH:66]=[CH:67][C:68]([N+:71]([O-:73])=[O:72])=[CH:69][CH:70]=1)=[O:62])[CH2:50][C:51]([NH:53][C@H:54]1[CH2:58][CH2:57][N:56]([C:27]([C@@H:11]2[CH2:10][C@H:9]([S:8][CH2:7][C:6]3[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])=[O:29])[CH2:55]1)=[O:52]
Reactant: O=C(CC(O)CNC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](NC(=O)CC(O)CNC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (2.87 g) in anhydrous tetrahydrofuran (30 ml), N,N'-carbonyldiimidazole (1.25 g) was added, followed by stirring at 30° C. for one hour. To the reaction mixture, N,N-diisopropylethylamine (1.68 ml) and a solution of (3S)-3-[3-hydroxy-4-(4-nitrobenzyloxycarbonyl)aminobutanoylamino]pyrrolidine trifluoroacetate (3.19 g) in anhydrous tetrahydrofuran (30 ml) was added. The resulting mixture was allowed to stand overnight at room temperature. The reaction mixture was concentrated by evaporation under reduced pressure and ethyl acetate was added to the residue. The resulting mixture was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography (dichloromethane-ethyl acetate-methanol) through a silica gel column, whereby 3.81 g of the title compound were obtained as an amorphous substance.