Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14][CH2:15][C:16](=[O:22])[CH2:17][C:18](=[O:21])[CH2:19][CH3:20].S(Cl)(Cl)=O.CCOCC>CC(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:17]([C:16](=[O:22])[CH2:15][CH3:14])[C:18](=[O:21])[CH2:19][CH3:20])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CCC(=O)CC(=O)CC
Solvent: CC(C)O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCC(=O)C(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)C(=O)CC
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a solution of 3,4-dihydroxy-5-nitrobenzaldehyde (7.6 g) and 3,5-heptanedione (8.0 g) in 50 ml of 2-propanol was added thionyl cloride (3.5 ml) with stirring at 20° C. Ether (60 ml) was added and the solution was filtered and allowed to stand overnight. The resulting crystal were filtered. Yield 1.2 g, mp 133°-135° C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH3:16].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:17][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH3:16]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCOc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: CCOc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(Br)cnn1C
Yield: 61.5 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-ethoxy-phenylamine (0.039 g, 0.13 mmol) was treated with 4-fluorophenyl isocyanate (0.020 g, 16.6 μL, 0.14 mmol, 1.1 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 68 (0.034 g, 0.08 mmol, 59%) as a white solid. LCMS m/z (%)=433 (M+H79Br, 100), 435 (M+H81Br, 99). 1H NMR (400 MHz, acetone-d6) δ: 8.13 (s, 1H), 8.11 (s, 1H), 7.66 (dd, J=2.7, 8.9 Hz, 1H), 7.50-7.57 (m, 2H), 7.49 (s, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.11 (d, J=8.9 Hz, 1H), 7.04 (t, J=8.8 Hz, 2H), 3.96-4.18 (m, 2H), 3.71 (s, 3H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=O)[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[C:11]([CH2:12][CH2:13]1)=[CH:10][C:9]([OH:20])=[C:8]([O:21][CH3:22])[CH:7]=3)[CH2:4][CH2:3]2.O.NN.[OH-].[K+].Cl>C(O)CO.C(O)CCC>[CH3:22][O:21][C:8]1[C:9]([OH:20])=[CH:10][C:11]2[CH2:12][CH2:13][C@@H:14]3[C@@H:5]([C:6]=2[CH:7]=1)[CH2:4][CH2:3][C@@:2]1([CH3:1])[C@H:15]3[CH2:16][CH2:17][CH2:18]1
Reactant: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: OCCO
Solvent: CCCCO
Solvent: O
Product: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)CCC[C@@H]12
Temperature: 130 °C
Yield: 72 %

Procedure:
2-Methoxyestrone (Scheme 1, Compound 4) (450 mg, 1.5 mmol) was suspended in ethylene glycol (10 mL) and n-butanol (2 mL). Hydrazine hydrate (0.145 mL, 3 mmol) was added and the mixture was heated to 130° C. for 1 h. The reaction was cooled to 70° C., KOH (253 mg, 4.5 mmol) was added, then the reaction was heated at 200° C. for 1 h. The mixture was cooled to room temperature, poured into ice and HCl (6N, 6 mL) was added. The resulting solid was filtered off. The solid was dissolved in acetone, which was then evaporated to give a product (Scheme 1, Compound 7) (310 mg, 72% yield). 1H NMR (300 MHz, CDCl3) δ 6.93 (1H, s, aromatic), 6.75 (1H, s, aromatic), 5.35 (1H, s, phenol), 3.95 (3H, s, methoxy), 2.95 (2H, dd, J=5.0, 3.0 Hz), 2.25 (2H, m,), 1.95 (2H, m), 1.95-1.05 (11H, m), 0.8 (3H, s)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[NH:5][C:4](=[O:11])[CH:3]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[C:4](=[O:11])[CH:3]=1
Reactant: CCCc1nc(C)cc(=O)[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 46.8 %

Procedure:
To a solution of 6-methyl-2-propylpyrimidin-4(3H)-one (8 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (15.7 g) in acetonitrile (200 mL) was added potassium carbonate (14.5 g), and the mixture was stirred at 50° C. for 12 hr. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (8.44 g, 47%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH2:12])[N:8]=[CH:9]2)=[CH:4][N:3]=1.[F:13][C@H:14]1[CH2:16][C@H:15]1[C:17](O)=[O:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:17]([C@@H:15]3[CH2:16][C@@H:14]3[F:13])=[O:18])[N:8]=[CH:9]2)=[CH:4][N:3]=1
Reactant: Nc1cc2cnc(Cl)cc2cn1
Reactant: O=C(O)[C@@H]1C[C@@H]1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc2cnc(Cl)cc2cn1)[C@@H]1C[C@@H]1F
Temperature: 70 °C
Yield: 43.4 %

Procedure:
A mixture of 7-chloro-2,6-naphthyridin-3-amine (230 mg, 1.3 mmol), (1S,2S)-2-fluorocyclopropanecarboxylic acid (266 mg, 2.6 mmol), HATU (1.1 g, 2.8 mmol), and N,N-diisopropylethylamine (0.45 mL, 2.6 mmol) in N,N-dimethylformamide (3 mL) was heated at 70° C. for 16 hours. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-60% ethyl acetate in heptane) to afford the title compound as a white solid (150 mg, 44%). 1H NMR (400 MHz, DMSO) δ 11.22 (s, 1H), 9.29 (s, 1H), 9.28 (s, 1H), 8.66 (s, 1H), 8.16 (s, 1H), 5.08-4.85 (m, 1H), 2.29 (m, 1H), 1.71 (m, 1H), 1.22 (m, 1H).
Reaction SMILES: [ClH:1].C([O-])(O)=O.[Na+].O[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[N:15][CH:16]=2)[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]=1>C(O)(=O)C>[Cl:1][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[N:15][CH:16]=2)[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]=1
Reactant: Cl
Reactant: Oc1nc(-c2ccccc2)cc2ccncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1nc(-c2ccccc2)cc2ccncc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
HCl gas was bubbled through a warmed solution of Intermediate 1 (3.49 g, 14.0 mmol) in glacial acetic acid (35 ml) for about 2 min. The reaction flask was stoppered and the reaction mixture was stirred at 40° for 6 h and at room temperature for 18 h. The volatiles were removed in vacuo to afford a yellow solid which was treated with saturated aqueous NaHCO3 (50 ml). The obtained light yellow powder was collected by filtration, washed with water and dried to afford a mixture of 1-hydroxy-3-phenyl-2,7-naphthyridine and the title compound (2.58 g, 2:1 ratio). This mixture was treated with phosphorus oxychloride (30 ml) at 130° for 7 h. The volatiles were removed in vacuo and the obtained yellow solid partitioned (with CARE) between EtOAC (150 ml) and ice-cold saturated aqueous NaHCO3 (50 ml+5 g solid NaHCO3). The phases were separated and the aqueous layer re-extracted with EtOAc (2×50 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a dull yellow solid (2.5 g). Chromatography (silica: 1:1:2-2:1:1 EtOAc/DCM/Hexane) afforded the title compound as a pale yellow solid (2.21 g, 51% over two steps). δH (CDCl3) 9.74 (1H, s), 8.81 (1H, d, J 5.7 Hz), 8.17 (1H, d, J 8.0 Hz), 7.99 (1H, s), 7.70 (1H, d, J 5.7 Hz), 7.60-7.49 (3H, m); m/z (ES+, 70V) 241 and 243 (MH+).
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[C@:9]2([CH2:25][CH2:24][C@H:23]3[C@@H:14]([CH2:15][CH2:16][C:17]4[CH:18]=[C:19]([O:26]C)[CH:20]=[CH:21][C:22]=43)[C@@H:11]2[CH2:12][CH:13]=1)[CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([NH:5][C:6]([C:8]1[C@:9]2([CH2:25][CH2:24][C@H:23]3[C@@H:14]([CH2:15][CH2:16][C:17]4[CH:18]=[C:19]([OH:26])[CH:20]=[CH:21][C:22]=43)[C@@H:11]2[CH2:12][CH:13]=1)[CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 77.8 %

Procedure:
To a solution comprising 119 mg of compound 9a in 2 ml of anhydrous CH2Cl2 was added 0.64 ml of BBr3 (1M solution in CH2Cl2) at −15° C. under nitrogen atmosphere. The reaction solution was stirred at room temperature for 1.3 hours and quenched by adding methanol and water at 0° C. The organic layer was separated and the aqueous layer was extracted with chloroform (CHCl3). The combined organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was triturated with 2.5 ml of EtOAc and 2.5 ml of hexane, yielding compound 10a (89 mg, 78%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:10]([C:22]2[O:23][C:24]([C:37](C)(C)[O:38][SiH2]C(C)(C)C)=[CH:25][C:26](=[O:36])[C:27]=2[O:28][Si](C(C)(C)C)(C)C)=[CH:9]1)=O)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:28][C:27]1[C:26](=[O:36])[CH:25]=[C:24]([CH2:37][OH:38])[O:23][C:22]=1[C:10]1[C:11]2[C:16](=[C:15]([CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH:13][CH:12]=2)[NH:8][CH:9]=1
Reactant: CC(C)=CCc1cccc2c(-c3oc(C(C)(C)O[SiH2]C(C)(C)C)cc(=O)c3O[Si](C)(C)C(C)(C)C)cn(C(=O)OC(C)(C)C)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)=CCc1cccc2c(-c3oc(CO)cc(=O)c3O)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate 204 (200 mg, 0.306 mmol) was dissolved in anhydrous THF (2 mL). TBAF (1M, 4.6 mL) was added dropwise. After stirring for 2 h at room temperature, the solution was brought to reflux for 12 h, then cooled to room temperature and quenched with dilute HCl. The mixture was extracted with EtOAc. The organic phase was combined and washed with water and brine. The organic layer was dried over Na2SO4 then solvent removed under vacuum. After flash column chromatography, the desired product was obtained as a yellow solid (54 mg, 54%). Mp: 201° C. (dec). 1H NMR (CDCl3): δ 1.69 (3H, s), 1.72 (3H, s), 3.75 (2H, d, J=6.6 Hz), 4.61 (2H, s), 5.25 (1H, m), 6.45 (1H, s), 7.2-7.3 (2H, m), 7.85 (1H, m), 8.24 (1H, m). 13C NMR (CDCl3): δ 28.5, 31.4, 33.1, 61.8, 111.3, 119.4, 123.1, 123.9, 126.1, 127.5, 129.1, 129.7, 130.6, 133.7, 134.6, 137.5, 141.1, 149.3, 165.6, 175.9. IR (KBr): 3376, 3148, 2975, 2870, 1611, 1569, 1205, 976 cm−1. HRMS (FAB): m/z Calcd. for C19H19NO4 [M+] 325.1314, found 325.1332.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:15]=O.Cl.[NH2:18]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:15]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:13][C:14]=2[CH:1]=1)#[N:18]
Reactant: O=Cc1ccc2c(c1)Sc1ccccc1O2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)Sc1ccccc1O2
Reaction time: 1 h

Procedure:
The crude phenoxathiin-2-aldehyde was dissolved in acetic acid (150 ml) and boiled with hydroxylamine hydrochloride (2.76 g) and sodium acetate (3.24 g) for 1.5 hr. Acetic anhydride (150 ml) was added, and the mixture boiled under reflux for 3 hr., cooled and filtered. The filtrate was poured into water and stirred for 1 hour to decompose the acetic anhydride, then extracted with chloroform, washed with water and sodium bicarbonate solution, dried, and evaporated to give crude 2-cyanophenoxathiin as an oil which solidified.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10](=O)(OC)OC.C(=O)([O-])[O-].C([O-])([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+]>>[C:1]1([CH:7]([CH3:10])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: COC(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Product: CC(C#N)c1ccccc1

Procedure:
The procedure of example (1) is followed, using phenylacetonitrile, dimethyl carbonate and a catalytic amount of alkali carbonate in a 1:18:0.05 molar ratio. Li2CO3, Na2CO3, K2CO3 and Cs2CO3 were used respectively, to obtain the following results:
Reaction SMILES: C([O:5][C:6](=[O:19])[C:7]#[C:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])(C)(C)C>FC(F)(F)C(O)=O.ClCCl.ClCCCl>[CH3:15][O:14][C:12]([C:11]1[CH:10]=[C:9]([C:8]#[C:7][C:6]([OH:19])=[O:5])[CH:18]=[CH:17][CH:16]=1)=[O:13]
Reactant: COC(=O)c1cccc(C#CC(=O)OC(C)(C)C)c1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(C#CC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
The mixture of methyl 3-(3-(tert-butoxy)-3-oxoprop-1-yn-1-yl)benzoate (9-1) (139 mg, 0.53 mmol) in a mixture of trifluoroacetic acid and dichloromethane (v:v=95:5, 1.5 mL) was stirred at room temperature for 2 h. The mixture was diluted with 1,2-dichloroethane and the whole was evaporated to dryness. The residue was triturated with hexane and the solid was collected by decantation and dried under vacuum to give the title compound 9-2 (102 mg, 94% yield) as a light brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH2:15][N:14](C(=O)C)[CH:13]([CH3:24])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH2:15][NH:14][CH:13]([CH3:24])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)CC(C)N(C(C)=O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c(cc1OCc1ccccc1)CC(C)NC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.6 %

Procedure:
A solution of 212 (2.1 g, 6.5 mmol) in EtOH (60 ml) with 10% NaOH (15 ml) was heated under reflux for 20 h. A further 15 ml of 10% NaOH was added and heating continued for another 24 h. The reaction mixture was cooled to rt and concentrated to remove the EtOH. Chloroform (30 ml) was added, the layers separated and the aqueous layers extracted with chloroform (3×). The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford an orange oil. Purification by flash column chromatography eluting with EtOAc to 20% MeOH/80% EtOAc/0.5% TEA afforded the title compound (858 mg, 47%) as an orange powder. 1H NMR (270 MHz; CDCl3) 1.20 (3H, d, J=6.4 Hz, CH3CH), 1.46 (1H, brs, NH), 2.35 (1H, dd, J=15.8, 10.6 Hz, CHH), 2.61 (1H, dd, J=15.8, 3.7 Hz, CHH), 2.88-3.0 (1H, m, CH3CH), 3.83 (3H, s, OCH3), 3.93 (1H, d, J=15.6 Hz, one of ArCH2N), 4.04 (1H, d, J=15.6 Hz, one of ArCH2N), 5.09 (2H, s, CH2Ph), 6.54 (1H, s, CH), 6.57 (1H, s, CH), 7.25-7.43 (5H, m, 5×CH, phenyl). 13C NMR (67.5 MHz; CDCl3) 22.60 (CH3), 36.76 (CH2), 48.43 (CH2), 49.37 (CH), 56.16 (OCH3), 71.23 (CH2), 109.51 (CH), 114.75 (CH), 126.82 (C), 127.37 (CH), 127.82 (CH), 128.09 (C), 128.59 (CH), 137.41 (C), 146.62 (C), 148.0 (C). LC/MS (ES+) tr=1.21 min, m/z 284.13 (M++H). HPLC tr=2.49 min (>99%).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[N:9]=[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23]C)[N:7]=1.C(=O)=O>ClCCl.C([O-])(O)=O.[Na+]>[Cl:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[N:9]=[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[N:7]=1
Reactant: COc1ccccc1-c1nc(Cl)c2ccc(C)cc2n1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: O=C=O
Solvent: ClCCl
Product: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C

Procedure:
Boron tribromide in dichloromethane (1 M, 900 mL, 900 mmol) was added drop wise to a cooled (−30-−40° C.) solution of 4-chloro-2-(2-methoxyphenyl)-7-methylquinazoline (93.2 g, 328 mmol) in dichloromethane (2 L) under nitrogen atmosphere. The resulting mixture was left warming to room temperature in about four hours and was slowly poured in 4 L sat. aq. NaHCO3. Stirring was continued until no more CO2 was produced. The layers were separated and the organic layer was dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure, yield: 90 g. The residue was filtered over a short plug of silica with dichloromethane as the eluent. Yield: 57.9 g (65%) of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (1H-NMR, LC-MS: >90% purity). It was found that the only impurity still present was the corresponding bromo quinazoline (LC-MS, M+found=271 [M+1]; 315, 317 [M-Cl+Br], Br-isotope patterns present).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.Cl[C:34]([O:36][CH3:37])=[O:35].ClC([O-])=O>CN(C=O)C.N1C=CC=CC=1.O>[C:34](=[O:35])([O:36][CH3:37])[O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: COC(=O)Cl
Agent: O=C([O-])Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 54.7 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.2 g, 0.46 mmol) was dissolved in DMF (4 ml) and pyridine (1 ml), then cooled to 0° C. Methyl chloroformate (0.2 ml, 2.57 mmol) was added and the mixture was stirred for 45 minutes at 0° C. A further portion of methyl chloroformate was added (0.2 ml), and the mixture was stirred for a further 2 hours 15 minutes before addition of a third portion of methyl chloroformate (0.2 ml). The mixture was stirred for a further hour at 0° C. after the third chloroformate addition, then diluted with water, extracted twice with ethyl acetate and dried over sodium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0 to 10% acetonitrile in ethyl acetate). Evaporation of the fractions containing product and trituration of the resulting solid with diethyl ether yielded the title compound as a white solid (0.125 g), melting point: 205° C.
Reaction SMILES: CC([N:5]([CH2:9][C:10]1([F:30])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[N:25]=3)[N:20]=[CH:19][C:18]=2[F:29])[CH2:11]1)C(=O)[O-])(C)C.Cl.[O:32]=[C:33]1[NH:38][C:37]2[N:39]=[C:40]([CH:43]=O)[CH:41]=[CH:42][C:36]=2[S:35][CH2:34]1.CCN(CC)CC.[BH4-].[Na+]>O1CCOCC1.C(Cl)Cl.CCO>[F:30][C:10]1([CH2:9][NH:5][CH2:43][C:40]2[CH:41]=[CH:42][C:36]3[S:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=3[N:39]=2)[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[N:25]=3)[N:20]=[CH:19][C:18]=2[F:29])[CH2:11]1
Reactant: COc1ccc2ncc(F)c(CCN3CCC(F)(CN(C(=O)[O-])C(C)(C)C)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(CCN3CCC(F)(CNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 4 h
Yield: 66.9 %

Procedure:
To a stirred solution of 1,1-dimethylethyl[(3-fluoro-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (0.85 g, 2.0 mmole) in dioxane (50 mL) was added 4M HCl in dioxane (20 mL). After 4 h at RT, the reaction solution was concentrated to dryness under vacuum. To the amine hydrochloride salt in dry CH2Cl2 (25 mL) and dry EtOH (20 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.39 g, 2.0 mmole) and Et3N (0.84 mL, 6.0 mmole). After 24 h at RT, NaBH4 (0.01 g, 0.23 mmole) was added. After 2 h, silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.67 g, 67%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.67 (s, 1H), 8.19 (d, J=9.0 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.15 (m, 2H), 4.31 (s, 2H), 4.13 (s, 3H), 3.75 (m, 2H), 3.64 (m, 2H), 3.60 (m, 4H), 3.57 (m, 4H), 2.54 (m, 2H). LC-MS (ES) m/e 501 (M+H)+.
Reaction SMILES: [CH:1]([N:4]([CH:22]([CH3:24])[CH3:23])[C:5](=[O:21])[CH2:6][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19]C)[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)([CH3:3])[CH3:2].B(Br)(Br)Br>ClCCl>[CH:22]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[CH2:6][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)([CH3:24])[CH3:23]
Reactant: COc1ccccc1C(CC(=O)N(C(C)C)C(C)C)c1cccs1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)N(C(=O)CC(c1cccs1)c1ccccc1O)C(C)C
Temperature: 25 °C

Procedure:
A solution of N,N-diisopropyl-3-(2-methoxyphenyl)-3-(2-thienyl)propanamide (2.37 g, 6.9 mmol) in dichloromethane(35 mL) was cooled down to −78° C. and boron tribromide (5.9 g 23.57 mmol) was added. The reaction mixture was allowed to slowly warm to room temperature. The reaction was quenched by slow addition of water (20 mL). The pH was adjusted to around 6 with NaHCO3(s) and the mixture was extracted three times with CH2Cl2. The combined organic phases were washed once with brine, dried (MgSO4) and the solvent was evaporated. This crude product (2.46 g, 107%) was used without further purification. 1H NMR (CDCl3) δ1.05 (d, 3H), 1.20 (m, 6H), 1.35 (d, 3H), 3.16 (m, 2H), 3.4 (br, 1H), 4.0 (m, 1H), 5.24 (dd. 1H), 6.7-7.2 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[S:18](Cl)(=[O:20])=[O:19]>>[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[S:18]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:19])=[O:20]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Cc1noc(N)c1Br
Product: Cc1cc(C)c(S(=O)(=O)Nc2onc(C)c2Br)c(C)c1
Yield: 64 %

Procedure:
2,4,6-Trimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,4,6-trimethylbenzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a pink solid, m.p. 92-95° C., yield 64%