Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[C:19]3[C:20](=[N:24][O:25][C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[CH:21]=[N:22][N:23]=2)[N:9]=[N:8]1.C(#N)C>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo].O>[NH2:24][C:20]1[C:19]([C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])=[O:25])=[C:18]([C:10]2[N:9]=[N:8][N:7]([CH2:6][C:5]3[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=[C:3]([C:2]([F:41])([F:1])[F:42])[CH:4]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:23]=[N:22][CH:21]=1
Reactant: FC(F)(F)c1cc(Cn2nnc(-c3nncc4noc(-c5ccccc5Cl)c34)c2-c2ccccc2)cc(C(F)(F)F)c1
Agent: [Mo]
Agent: [C-]#[O+]
Solvent: O
Solvent: CC#N
Product: Nc1cnnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
Combine 4-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-isoxazolo[3,4-d]pyridazine (79 mg, 0.1314 mmol), acetonitrile (2.5 mL), water (131 μL), and molybdenum hexacarbonyl (17.4 mg, 0.066 mmol), and heat to 73° C. After 4 hours, cool to RT. Pour the mixture through a plug of Celite® (1 cm) and silica gel (2 cm). Concentrate the dark liquid to 1.5 mL and apply to a 2 mm chromatotron plate with CH2Cl2 and EtOAc and elute with a EtOAc/hexanes gradient to provide 70 mg of a pink solid. Exact Mass 602.1: mass spectrum (IS): m/z=603.0 (M+1), 601.0 (M−1). 1H NMR (250 MHz, CDCl3) 8.62 (s, 1H), 7.75 (s, 1H), 7.45-7.32 (m, 3H), 7.28-7.10 (m, 3H), 7.00-6.80 (m, 3H), 6.10 (s, 2H).
Reaction SMILES: FC1C=C(CC(N[C@H](C(O)=O)CO)=O)C=C(F)C=1.N[C@H]1C(=O)NC2C=CC=CC=2S[C@H]1C1C=C(F)C=CC=1F.CN1CCOCC1.[F:47][C:48]1[CH:49]=[C:50]([CH2:55][C:56]([NH:58][C@@H:59]([CH2:83][OH:84])[C:60]([NH:62][C@H:63]2[C:69](=[O:70])[NH:68][C:67]3[CH:71]=[CH:72][CH:73]=[CH:74][C:66]=3[S:65][C@H:64]2[C:75]2[CH:80]=[C:79]([F:81])[CH:78]=[CH:77][C:76]=2[F:82])=[O:61])=[O:57])[CH:51]=[C:52]([F:54])[CH:53]=1>ClCCl>[F:47][C:48]1[CH:49]=[C:50]([CH2:55][C:56]([NH:58][C@@H:59]([CH2:83][OH:84])[C:60]([NH:62][C@@H:63]2[C:69](=[O:70])[NH:68][C:67]3[CH:71]=[CH:72][CH:73]=[CH:74][C:66]=3[S:65][C@@H:64]2[C:75]2[CH:80]=[C:79]([F:81])[CH:78]=[CH:77][C:76]=2[F:82])=[O:61])=[O:57])[CH:51]=[C:52]([F:54])[CH:53]=1
Reactant: O=C(Cc1cc(F)cc(F)c1)N[C@@H](CO)C(=O)N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1cc(F)ccc1F
Agent: N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1cc(F)ccc1F
Agent: O=C(Cc1cc(F)cc(F)c1)N[C@@H](CO)C(=O)O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(Cc1cc(F)cc(F)c1)N[C@@H](CO)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1cc(F)ccc1F
Reaction time: 0.08 h

Procedure:
To a solution N-[(3,5-difluorophenyl)acetyl]-L-serine (4b (75 mg) in dichloromethane (15 mL) at 0° C. under N2, was added racemic 2,3-cis-3-amino-2-(2,5-difluorophenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one-HCl (1d) (100 mg) followed by the HOBt-hydrate (97 mg) and NMM (32 μL). Reaction stirred for 5 min. and then added EDAC-HC1 (84 mg) and NMM (50 μL). The reaction mixture was stirred 2 H at 0° C. under N2, concentrated in vacuo and partitioned between water (100 mL) and ethyl acetate (125 mL). The organic phase was collected and consecutively washed with water, saturated aqueous sodium bicarbonate, brine, dried, filtered and evaporated to yield a mixture of the title compound and (2S)-2-{[(3,5-difluorophenyl)acetyl]amino}-N-[(2S,3S)-2-(2,5-difluorophenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]-3-hydroxypropanamide. The crude product (165 mg) was purified by flash chromatography (80% ethyl acetate/hexanes) to afford the title compound (60 mg, 73%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ(d, 3H), 3.48 (s, 2H), 4.21 (q, 1H), 4.74, (t, 1H), 4.85 (bs, 1H), 5.50 (d, 1H), 6.93 (d, 2H), 7.09 (m, 1H), 7.18-7.35 (m, 4H), 7.45-7.55 (m, 2H), 7.71 (t, 2H), 8.17(d, 1H), 10.68 (s, 1H). MS APCI, m/z=548 (M+1). LC/MS: 2.34 min.
Reaction SMILES: B.[CH3:2][C:3]1([CH3:11])[C@H:9]2[CH2:10][C@@H:4]1[CH2:5][CH2:6][C:7]2=[CH2:8].[OH-:12].[Na+].OO>ClCCl>[CH3:2][C:3]1([CH3:11])[C@H:9]2[CH2:10][C@@H:4]1[CH2:5][CH2:6][C@H:7]2[CH2:8][OH:12]
Reactant: [OH-]
Reactant: C=C1CC[C@H]2C[C@@H]1C2(C)C
Agent: B
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)[C@H]2CC[C@@H](CO)[C@@H]1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 192.6 %

Procedure:
A 6.0M borane adduct (9i) was dissolved in dichloromethane (12 ml) and (-)-β-pinene (5.0 g, 26 mmol), 91% ee was added at 0° C. The reaction was completed in 0.5 h, as indicated in 11B NMR. The mixture was maintained at room temperature for 1 h and oxidized by the addition of 3M sodium hydroxide (5.6 ml, 17 mmol) and 30% hydrogen peroxide (4.0 ml, 40 mmol), keeping the temperature during the addition below 30° C. and then stirring at room temperature overnight. The dichloromethane layer was separated and stirred with water (20 ml) for 0.5 h. The organic layer was separated, dried over anhydrous magnesium sulfate and distilled to give 5.05 g (91%) of pure product, bp 116°-118° C./15 mm Hg. α!20D=-19.4°.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[CH:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1)#[N:2]>N.C(O)C.[Co]>[NH2:2][CH2:1][CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[CH:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1
Reactant: CCOC(=O)c1cnn2ccc3c(c12)C(CC#N)CC3
Agent: [Co]
Agent: N
Solvent: CCO
Product: CCOC(=O)c1cnn2ccc3c(c12)C(CCN)CC3
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.5 %

Procedure:
Ethyl 9-(cyanomethyl)-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (150 mg, 0.557 mmol) and Raney cobalt (1.5 g) were suspended in 2M ammonia/ethanol solution (28 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 12 hr. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (150 mg, yield 99%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][P:9](=O)([O:18]CC2C=CC=CC=2)[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[C:33]1([CH2:39][O:40][C:41]([NH:43][CH2:44][CH2:45][CH2:46][CH2:47][C@H:48]([OH:66])[C:49]([N:51]2[CH2:65][CH2:64][CH2:63][C@H:52]2[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[O:54])=[O:50])=[O:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][P:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([O:66][C@@H:48]([CH2:47][CH2:46][CH2:45][CH2:44][NH:43][C:41]([O:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:42])[C:49]([N:51]2[CH2:65][CH2:64][CH2:63][C@H:52]2[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[O:54])=[O:50])=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=P(CCc1ccccc1)(OCc1ccccc1)OCc1ccccc1
Reactant: O=C(NCCCC[C@H](O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: CN(C)c1ccccn1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(NCCCC[C@H](OP(=O)(CCc1ccccc1)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A mixture of (2-phenylethyl)phosphonic acid, dibenzyl ester (1.48 g., 4.04 mmole, 1.5 eq.) in dry benzene (15 ml.) is treated with phosphorus pentachloride (952 mg., 4.57 mmole, 1.7 eq.) and the solution is heated at 75° (oil bath) for 2.5 hours under argon. The mixture is evaporated to dryness (0.5 mm of Hg.), taken up in benzene (10 ml.), and evaporated. This procedure is repeated twice. The clear residue is taken up in dry methylene chloride (15 ml.), 1-[(S)-6-[[(phenylmethoxy)carbonyl]amino]-2-hydroxy-1-oxohexyl]-L-proline, phenylmethyl ester (1.26 g., 2.69 mmole, 1.0 eq.) is added, the mixture is cooled to 0° (ice-bath), then treated with triethylamine (0.56 ml., 4.04 mmole, 1.5 eq.) and dimethylaminopyridine (49 mg., 0.40 mmole, 0.15 eq.), stirred at 0° for 15 minutes, and then at room temperature for one hour. The mixture is partitioned between 5% potassium bisulfate and methylene chloride. The organic layer is washed with brine, dried over anhydrous sodium sulfate, and evaporated to a yellow oil. The crude oil is purified by flash chromatography (LPS-1 silica gel) eluting with hexane:acetone (7:3). Product containing fractions are pooled and evaporated to give 916 mg. of 1-[(S)-2-[[(2-phenylethyl)(phenylmethoxy)phosphinyl]oxy]-6-[[((phenylmethoxy)carbonyl]amino]-1-oxohexyl]-L-proline, phenylmethyl ester as a clear, colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([CH2:24][OH:25])[O:15][C:14]3=[O:26])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30].O.C(OCC)(=O)C>CN(C=O)C>[CH:29]([NH:32][C:33](=[O:34])[O:25][CH2:24][C@@H:16]1[O:15][C:14](=[O:26])[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=3)=[CH:12][CH:11]=2)[C@H:17]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:31])[CH3:30]
Reactant: CC(C)N=C=O
Reactant: O=C1O[C@@H](CO)[C@H](c2ccccc2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)OC[C@@H]1OC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
To (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-phenyloxazolidin-2-one (33 mg, 0.08 mmol) in 0.3 mL DMF was added isopropyl isocyanate (0.015 mL, 0.16 mmol). The reaction was stirred for 3 h at room temperature until reaction completed as judged by TLC. Water and ethyl acetate were added and the phases separated. The organic phase was washed with brine, dried (MgSO4), and concentrated. 13 mg (33%) of the title compound was obtained as a white solid after Prep-LC purification (10-90 Acetonitrile/water (0.05% ammonium acetate). 1H NMR (CDCl3) δ (ppm) 7.30-7.39 (m, 7H), 7.23-7.26 (m, 2H), 6.84-6.90 (m, 4H), 5.14 (d, 1H, J=5.6 Hz), 4.67 (d, 1H, J=7.2 Hz), 4.34-4.53 (m, 3H), 3.77-3.85 (m, 1H), 1.17 (d, 3H, J=6.5 Hz), 1.13 (d. 3H, J=6.5 Hz). HPLC-MS calculated C26H25ClN2O5 (M+H+): 481.2, found: 481.1.
Reaction SMILES: [Br:1][C:2]1[C:12]([OH:13])=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][CH2:25][CH2:26]Cl.[I-].[K+]>CN(C)C=O>[Br:1][C:2]1[C:12]([O:13][CH2:26][CH2:25][O:24][CH3:23])=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: COCCCl
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(O)c1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(OCCOC)c1Br
Temperature: 70 °C
Yield: 93.5 %

Procedure:
Using a procedure similar to that of Example 2, 0.2 moles of ethyl 2-bromo-3-hydroxy-4-nitrobenzoate and an excess of potassium carbonate (0.35 moles) and 2-chloroethyl methyl ether (0.35 moles) along with a catalytic amount of potassium iodide (7.2 g, 0.045 m) were combined with 350 mL of dimethylformamide. After heating at 70° C. for 4 hours, normal workup gave 0.187 moles of ethyl 2-bromo-3-(2-methoxyethoxy)-4-nitrobenzoate as a viscous oil. This ester can be readily hydrolyzed to its acid using the procedure of Example 8.
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][CH:13]([C:16]1[C:24]2[O:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[N:21][C:20]=2[CH:19]=[C:18]([OH:32])[CH:17]=1)[CH2:14]Br.Cl>C(#N)C>[Br:12][C:13]([C:16]1[C:24]2[O:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[N:21][C:20]=2[CH:19]=[C:18]([OH:32])[CH:17]=1)=[CH2:14]
Reactant: Oc1ccc(-c2nc3cc(O)cc(C(Br)CBr)c3o2)cc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(Br)c1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Reaction time: 24 h
Yield: 58 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.25 g, 1.65 mmol) was added into a solution of 7-(1,2-dibromoethyl)-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (0.4 g, 0.96 mmol) and acetonitrile (4 mL). The reaction mixture was stirred for 24 h, poured into cold (0° C.) HCl (1N, 10 mL) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (CH2Cl2/hexanes/isopropyl alcohol 15/5/1) gave a white solid (185 mg, 58% yield, m.p. 228–230° C.); MS m/e 332 (M+H)+.
Reaction SMILES: [I:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(O)(=O)C>ClCCl>[I:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)nc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc(I)nc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
To a solution of 6-iodopyridin-3-amine (1.077 gm, 4.90 mmole) in dichloromethane (40 ml) and pyridine (1.98 ml, 24.49 mmole) at ice bath temperature was added methanesulfonyl chloride (0.401 ml, 2.444 mmole). The mixture was allowed to warm to room temperature and stir four days. The reaction mixture was treated with 5% acetic acid and allowed to stir 20 min at room temperature. The organic phase was washed with water (2×50 ml), dried (MgSO4) and concentrated in vacuo. The residue was slowly added in portions to rapidly stirred water (100 ml) and the resulting solid collected by filtration, washed with water and dried in vacuo to give the title compound (0.7287 g, 49.9%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=3)=[O:22])=[CH:19][N:18]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:14]=2[N:15]=[CH:16][N:17]=1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[NH2:11][C:12]1[C:13]2[C:20]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][CH2:4][C:3]4[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=4[F:1])[CH:24]=3)=[O:22])=[CH:19][N:18]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ncnc2c1c(C(=O)c1cccc(NCc3cc(F)ccc3F)c1)cn2C1CCCC1
Yield: 57.7 %

Procedure:
2,5-difluorobenzaldehyde (88.1 mg, 0.62 mmol) was added to a solution of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone (100 mg, 0.31 mmol) and AcOH (18.6 mg, 0.31 mmol) in MeOH (10 mL). After 5 min NaCNBH3 was added. After 3 h the reaction was quenched with 1N NaOH. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with water, dried over MgSO4, and concentrated. Purification by flash column chromatography (CH2Cl2/MeOH 98:2) afforded the title compound as a white solid (80 mg, 58%). MS: 448.1 (MH+); HPLC Rf: 6.59 min. (HPLC method 4).
Reaction SMILES: C(=O)([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH:28]([CH3:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:30])[CH:26]=3)[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=3)(=[O:14])=[O:13])=[CH:8][CH:7]=1)OCC.[OH-].[Na+]>CO>[F:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:15]([S:12]([C:9]1[CH:8]=[CH:7][C:6]([OH:5])=[CH:11][CH:10]=1)(=[O:14])=[O:13])[CH:28]2[CH3:29]
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 75 °C

Procedure:
A solution of ethyl 4-[(8-fluoro-6-methylphenanthridin-5(6H)-yl)sulfonyl]phenyl carbonate (0.45 g, 1.02 mmol) in methanol (5.0 mL) was treated with a 1 N sodium hydroxide (5.1 mL) solution, and heated at 75° C. for 14 hours. After cooling to room temperature, the methanol was evaporated in vacuo. The resulting aqueous mixture was acidified with a 1 N hydrochloric acid solution, diluted with a saturated, aqueous, sodium chloride solution (100 mL), and extracted with dichloromethane (5×15 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a white solid. The solid was purified by filtration through a short column of silica gel, eluting with ethyl acetate, to yield the title compound as a homogeneous, white, crystalline, solid (0.34 g, 89%), m.p. 188° C.; MS [(−ESI), m/z]: 368 [M−H]−;
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]2)(C)C.C([O-])([O-])=O.[K+].[K+]>CO.C1COCC1.C(OCC)(=O)C>[C:6]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]2)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1ccc2cc(O)ccc2c1

Procedure:
Compound 110A (770 mg, 3.20 mmol) in MeOH (5 ml) and THF (10 ml) was treated with K2CO3 (885 mg, 6.41 mmol) at room temperature for 3 h. The reaction was diluted with ethyl acetate and washed with water. The organic layer was concentrated and the residue was purified by flash chromatography, eluted with DCM to provide the compound 110B.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=O.[OH-:30].[K+]>C(O)C.O>[F:29][C:28]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:20]1[CH:21]=[CH:22][C:17]([C:15]2[C:14]([CH3:13])=[C:5]([C:6]([OH:11])=[O:30])[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[N:7]=2)=[CH:18][CH:19]=1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: [OH-]
Reactant: CCC(=O)c1ccc(-c2ccccc2F)cc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1c(-c2ccc(-c3ccccc3F)cc2)nc2ccc(F)cc2c1C(=O)O
Yield: 50.9 %

Procedure:
5-Fluoroisatin (72.6 g, 0.44 mole) and 4-(2-fluorophenyl)propiophenone (100 g, 0.44 mole) were suspended in 720 ml of ethanol and stirred mechanically as a solution of KOH (147.8 g, 2.64 mole) in 300 ml of water was added dropwise over 15 minutes. The reaction mixture was heated at reflux for 12 hours, cooled and the ethanol evaporated under reduced pressure. The resulting solid was dissolved in water and washed with ethyl ether. The aqueous layer was cooled to 5° and acidified with glacial acetic acid. The resulting precipitate was filtered, washed 2 times with 300 ml of ethyl ether and dried. Recrystallization from dimethylformamide and water gave 84 g of a white 2-(2'-Fluoro-1,1'-biphenyl-4-yl)-6-fluoro-3-methyl-4-quinolinecarboxylic acid, m.p. 315°-317°.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[C:34]([O:38][C:39]([NH:41][C@H:42]([C:46]([O:48][CH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:47])[CH2:43][CH2:44]O)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[Br:1][CH2:44][CH2:43][C@H:42]([NH:41][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[C:46]([O:48][CH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:47]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](CCBr)C(=O)OC1CCCC1
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a slurry of N-bromosuccinimide (1.86 g, 10.4 mmol) in DCM (16.2 ml) was added a solution of triphenylphosphine (2.56 g, 9.74 mmol) in DCM (7.2 ml). The solution was stirred for a further 5 minutes after addition. Pyridine (338 μl, 4.18 mmol) was added, followed by a solution of Stage 4 product (Scheme 7) (1.00 g, 3.48 mmol) in DCM (8.8 ml). The solution was stirred for 18 hours, concentrated under reduced pressure and the residual solvent azeotroped with toluene (3×16 ml). The residue was triturated with diethyl ether (10 ml) and ethyl acetate:heptane (1:9, 2×10 ml). The combined ether and heptane solutions was concentrated onto silica and purified by column chromatography using ethyl acetate/heptane (1:9 to 2:8) to provide 1.02 g (84% yield) of title compound. 1H NMR (300 MHz, CDCl3), δ: 5.30-5.05 (2H, m), 4.45-4.30 (1H, m), 3.45 (2H, t, J=7.3 Hz), 2.50-2.30 (1H, m), 2.25-2.10 (1H, m), 1.95-1.60 (8H, br m), 1.47 (9H, s).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([OH:30])[CH2:28][CH3:29]>>[CH2:27]([O:30][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[CH2:28][CH3:29]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: CCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate, and 3 ml of propanol was heated to reflux while stirring for six hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 2-(3-propoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 71”).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].C(O[C:14]([C:16]1[C:25]([N:26]=[CH:27]N(C)C)=[CH:24][C:23]2[C:18](=[CH:19][C:20]([O:40][CH3:41])=[C:21]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:22]=2)[CH:17]=1)=[O:15])(C)(C)C>O1CCCC1>[CH3:41][O:40][C:20]1[C:21]([O:31][CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)=[CH:22][C:23]2[CH:24]=[C:25]3[C:16]([C:14](=[O:15])[C:7]([C:6]#[N:8])=[CH:27][NH:26]3)=[CH:17][C:18]=2[CH:19]=1
Reactant: CC#N
Reactant: COc1cc2cc(C(=O)OC(C)(C)C)c(N=CN(C)C)cc2cc1OCCN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1OCCN1CCOCC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To 15 mL of tetrahydrofuran at −78° C. is added 2.6 mL of n-butyllithium (1.6M in hexane) and the reaction mixture is stirred for 5 minutes. To this is added 0.36 mL (6.8 mmol) of acetonitrile dropwise, followed by stirring for 15 minutes. Finally, a solution of 3-(dimethylamino-methyleneamino)-7-methoxy-6-(2-morpholin-4-yl-ethoxy)naphthalene-2-carboxylic acid tert-butyl ester in 5 mL of tetrahydrofuran is added dropwise over a period of 15 minutes. The resulting mixture is stirred at −78° C. for 1 hour, then at room temperature for 1 hour. After cooling again to −78° C., the reaction is quenched with 0.5 mL of glacial acetic acid, the dry ice bath is removed and the resulting thick slurry is stirred for 1 hour. The solid is collected by filtration, washed with ethyl acetate and dried. Purification is carried out by silica gel chromatography, utilizing a gradient of 95:5 to 89:11 of methylene chloride/methanol to give 0.38 g of 7-methoxy-8-(2-morpholin-4-yl-ethoxy)-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile as a yellow solid, mp 275° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[C:12]1[CH:17]=[CH:16]C(F)=[CH:14][C:13]=1O[C@H](CC=C)C>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C@H:17]([CH2:12][CH:13]=[CH2:14])[CH3:16]
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1Br
Reactant: Cc1cc(O)c(Br)cc1C
Product: C=CC[C@H](C)Oc1cc(C)c(C)cc1Br
Yield: 59 %

Procedure:
Prepared in 59% yield from 2-bromo-4,5-dimethylphenol following the same procedure as (S)-1-bromo-4-fluoro-2-(pent-4-en-2-yloxy)benzene. 1H NMR (400 MHz, CDCl3) δ 7.30 (s, 1H), 6.73 (s, 1H), 5.92 (ddt, J=17.2, 10.1, 7.1 Hz, 1H), 5.19-5.09 (m, 2H), 4.44-4.33 (m, 1H), 2.59-2.49 (m, 1H), 2.45-2.37 (m, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 1.34 (d, J=6.0 Hz, 3H).